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  • Transmission of HIV from infants to women who breastfeed them.

    Posted on July 1st, 2012 admin No comments

    This title may surprise some.   In a paper (abstract, below) from a group at CDC I learned yet another HIV/AIDS related acronym.  It’s CBWT, Child-to-Breastfeeding-Woman Transmission.

    There have been several reports over many years of HIV infected infants born to mothers who were HIV uninfected.   These infections were noted as early as the late 1980s in the former Soviet Union, in Libya in 1998, in Kyrgyzstan, Kazakhstan, Romania as well as in Africa.   In every instance except in Africa, there cases were investigated with varying degrees of thoroughness.   The sources of infection were invariably associated with contaminated blood,   either from transfusions, or from procedures in unsafe healthcare settings, where for example sterilization of instruments is inadequate, or injection equipment is reused.

    The infections noted in infants that were investigated occurred as outbreaks and all were determined to be nosocomial.    Although infected infants born to uninfected mothers have been noted in Africa, remarkably, it appears that none have been investigated.

    It will probably remain for a future historian to understand why cases of HIV infection in infants, horizontally rather than vertically transmitted, have yet to be investigated in Africa.

    In those non-African outbreaks that were investigated transmission occurred through unsafe medical care, so what do we know of the safety of health care facilities in Africa ?

    Unfortunately unsafe health care remains a problem in many facilities in high prevalence areas in Africa.

    Taking Kenya as an example, Simon Colley has written in one of my blogs

    “Where does Kenya fit into this picture? As UNAIDS admit, there’s not much data. But there is a document called the Service Provision Assessment which looks at conditions in various kinds of health facility, such as hospitals, clinics and pharmacies.

    A few samples from this document may suffice to illustrate Kenya’s women capacity to prevent HIV transmission through unsafe injections and other healthcare practices: Between 10 and 15% of facilities don’t have adequate supplies of needles, syringes or latex gloves; between 55 and 70% don’t have running water or soap; many don’t have facilities for disposing of contaminated equipment or supplies of disinfectant; less than half have guidelines for infection prevention and less than 10% have guidelines for sterilization.

    Although this document dates from 2004, we don’t know if there has been any change

    There’s little doubt that unsafe health care is still a problem in Kenya and other high HIV prevalence countries. What’s not clear is how big a problem it is. Because, despite admitting that they don’t have the sort of data on unsafe health care that would allow an estimate to be made, UNAIDS and the WHO have failed to investigate or to carry out the research required”

    This is a table taken from the Service Provision Assessment  that speaks for itself.

    .

    As the title of this post indicates, infants infected either vertically or through exposure to contaminated blood are able to transmit HIV to seronegative women who breast feed them.

    Mother to child transmission is the leading cause of HIV infection in infants. Some of these infected infants will be orphans and so place seronegative women who breastfeed them at risk.  Wet-nursing is the complete nursing of another woman’s infant and still occurs as does cross-nursing which is the nursing of another infant by a woman  while still nursing her own child.  Estimates of the prevalence of these practices vary by region and the overall prevalence is not known.

    Worldwide the greatest risk for CBWT is carried by seronegative mothers whose infants become infected through exposure to contaminated blood.  Rates of CBWT were as high as 40-60% among mothers  breastfeeding infants who became infected after birth.

    This report on CBWT highlights the importance of unsafe health care facilities in the transmission of HIV.   Of course HIV is not the only pathogen that can be transmitted in such settings.

    Why so few resources have been devoted to the improvement of health care facilities in developing nations is puzzling.  Could it be that like the provision of clean water and sanitation, improving health care facilities is not something that can generate much profit?

    Perhaps it will be left to HIV activists who have successfully drawn public attention to other neglected issues, to alert funders and policy makers to the dangerous condition of many healthcare facilities in the developing world.

    The benefits of improving infection control in these facilities extend far beyond effects in HIV transmission.

    A group of individuals have been trying to bring attention to this issue for many years and I do recommend looking at the website they have created to directly alert people in Africa to dangers in health care facilities with no or poor infection control procedures.

    (1)

    A Review of Evidence for Transmission of Human Immunodeficiency Virus from Children to Breastfeeding Women and Implications for Prevention.

    Kirsten M Little, Peter Kilmarx, Allan Taylor, Charles Rose, Emilia Rivadeneira. And Steven Nesheim.

    The Pediatric Infectious Disease Journal Publish ahead of print.

    DOI:10.1097/INF.0b013e318261130f

    Abstract

    Background: Child-to-Breastfeeding-Woman Transmission (CBWT) of HIV occurs when an HIV-infected infant transmits the virus to an HIV-uninfected woman through breastfeeding. Transmission likely occurs as a result of breastfeeding contact during a period of epithelial disruption, such as maternal skin fissures and/or infant stomatitis. Despite extensive epidemiologic and phylogenetic evidence, however, CBWT of HIV continues to be overlooked.

    Objective: This paper summarizes the available evidence for CBWT from nosocomial outbreaks, during which nosocomially HIV-infected infants transmitted the virus to their mothers through breastfeeding. This paper also explores the CBWT risk associated with HIV-infected orphans and their female caretakers, and the lack of guidance regarding CBWT prevention in infant feeding recommendations.

    Methods: We searched online databases including PubMed and ScienceDirect for English language articles published from January 1975 to January 2011 using the search terms “HIV”, “perinatal”, “child-to-mother”, and “breastfeeding”. The citations from all selected articles were reviewed for additional studies.

    Results: We identified five studies documenting cases of CBWT. Two studies contained data on the number of HIV-infected women, as well as the proportion breastfeeding. Rates of CBWT ranged from 40 – 60% among women reporting breastfeeding after their infants were infected.

    Conclusions: Poor infection control practices, especially in areas of high HIV prevalence, have resulted in pediatric HIV infections and put breastfeeding women at risk for CBWT. Current infant feeding guidelines and HIV prevention messages do not address CBWT, and fail to provide strategies to help women reduce their risk of acquiring HIV during breastfeeding.

  • Have we ignored a very simple procedure that could significantly reduce the risk of heterosexual transmission of HIV to men?

    Posted on May 8th, 2012 admin No comments

    By  David Gisselquist and Joseph Sonnabend


    In 2010 there was a great deal of outraged comment about the US government’s award of $823,000 to an HIV related project in Africa. Specifically, the taxpayer dollars were to be used to teach uncircumcised African men how to wash their genitals after having sex.  The grant states; “If we find that men are able to practice consistent washing practices after sex, we will plan to test whether this might protect men from becoming HIV infected in a later study.”

    The reasoning behind the project was based on the assumption that the reported protective effect of male circumcision was due to improved genital hygiene.   This is in the project description:

    “The protective effect of male circumcision on HIV acquisition may be due to improved genital hygiene. We propose to evaluate the feasibility of a post-coital genital hygiene study among men unwilling to be circumcised in Orange Farm, South Africa. Men in high prevalence settings could potentially benefit from improved genital hygiene if this intervention proved to be efficacious in reducing HIV acquisition risk” Genital hygiene was to be improved by asking men to wash their penis after sex.

    Widespread criticism of such a use of public funds might have missed the main problem.  As it turns out, not washing immediately after sex may actually have a significant protective effective for men at risk from heterosexual intercourse – including both circumcised and uncircumcised men

    This was noted in two randomized studies of male circumcision to prevent HIV infection in the Rakai region of Uganda in 2003-2007.  Although the effect of washing on HIV acquisition received some media  attention at the time its relevance to HIV prevention remained generally unnoticed. It apparently also remained unnoticed or considered to be of no consequence to the applicants as well as the funders of the $823,000 grant noted above.

    Combining  results from these two trials, Tobian and colleagues in an article in AIDS in 2009[i] report information on risks for 105  HIV seroconversions in 6,396 initially HIV-negative men observed  during 9,604 person years (PY) of follow-up.  Half the men were circumcised for the trial and half remained uncircumcised.

    These 105 HIV seroconversions represent 1.09 infections per 100 PY.

    Among the questions that trial participants were asked in attempting to define risks for HIV infection was whether or not they washed their genitals after sex.

    Among men who did so there were 1.35 infections per 100PY compared to only 0.38 infections per 100PY among men who did not wash their genitals.  The adjusted relative risk for washing vs. not washing was 3.04 (95% confidence interval: 1.11-8.33; P = 0.031).

    The authors make the following comment in their discussion,

    “The finding that HIV incidence was increased with washing genitals after sexual intercourse is counterintuitive, but supports previous finding that washing the penis within 10 min of sexual intercourse increases the risk of HIV acquisition among uncircumcised men. The increased HIV acquisition with penile washing may be due to the removal of acidic vaginal secretions or the addition of water with a neutral pH may assist HIV survival and infectivity”.

    The “previous finding” referred to is an earlier report by Makumbi and colleagues[ii] in 2007, who interviewed 2552 uncircumcised men enrolled in the control arm of a randomized   trial of circumcision for HIV prevention in the Rakai region of Uganda (these man are included in the data reported by Tobian and colleagues in 2009).  Some of the information reported by Makumbi  and colleagues is shown in the last four slides in this presentation prepared by i-Base, UK.

    This is one of the slides showing that there were 2.32 HIV infections per 100PY among men who washed their penis within 3 minutes of intercourse, but only 0.39 infections per 100PY among men who waited for 10 minutes or longer before washing.

    If we were to express the efficacy of delayed washing in the same way that the results of PrEP trials were reported, that is as relative risk reductions, this would mean that not washing immediately, but waiting for at least 10 minutes after intercourse before washing can reduce the risk of infection by 83%. Compare this to the 44% efficacy of Truvada in the iPrEx trial, the 39 % efficacy of tenofovir gel in reducing the risk of infection in women  in the Caprisa 004 trial, and the 38-66% efficacy reported for circumcision over 24 months.

    Genital washing after sex may be quite common in parts of Africa.  A study in Nairobi in 2004 found that a majority of men washed their genitals after sex. Here is a link to a table in the report; 60% of men reported always washing their genitals after sex.

    We have had evidence that this practice may contribute to the risk of HIV infection in men since 2007.  We have to wonder if the many questions this raises have been addressed, or even considered.

    Could the practice of immediate post-coital genital washing contribute to the risk of sexual transmission of HIV to men?

    Are there regional variations in this practice, and could this be related to HIV prevalence to some extent?

    Should there be a debate on the evidence by experts, with recommendations for further research – such as adding questions to on-going or proposed studies, laboratory testing of HIV viability in semen and vaginal fluids at body temperature or conducting  a trial to nail down the risk of immediate washing, or in other words, the protective effect of delayed washing?

    If immediate washing increases the risk of infection does this not raise the question of the extent to which infection occurs after withdrawal?

    Considering how innocuous the intervention is do we have sufficient evidence now to  advise  African men at risk of HIV through heterosexual contact not to clean their penis for at least 10 minutes after sex?  Should a dry cloth without water or soap be used?

    The study teams for these trials have more information on post-coital penis cleaning that they have not reported. We know that for uncircumcised men, wiping was safer than washing, and waiting at least 10 minutes to clean significantly reduced risk for HIV (see the last several slides in this reference. But we don’t have similar details for circumcised men. What information has been collected but not reported?

    We have evidence that a common practice, at least in certain regions can substantially increase the risk of HIV infection in men through heterosexual intercourse.  Considerable attention has been given to newer prevention methods in the past few years, notably pre – exposure prophylaxis and male circumcision, but almost none to the simplest of procedures that may be even more effective in preventing the sexual transmission of HIV.

    Many other questions and concerns will no doubt arise as more people look at the evidence, and figure out what to do about it. Lives are at stake. Scientific competence and integrity are also at stake – researchers have overlooked and/or incompletely reported information that could save lives.


    [i] Tobian AAR, Ssempijja V, Kigozi G, et al. Incident HIV and herpes simplex virus type 2 infection among men in Rakai, Uganda. AIDS 2009; 23: 1589-1594.

    [ii] Makumbi FE, Gray RH, Wawer, M, et al. Male post-coital penile cleansing and the risk of HIV-acquisition in rural Rakai district, Uganda. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract WEAC1LB, Sydney, 2007. Available at:

    http://www.ias2007.org/Default.aspx?pageId=11&abstractId=200705536

  • The 2012 revised DHHS HIV treatment guidelines; Expert Opinion and conflicts of interest.

    Posted on April 12th, 2012 admin No comments

    The most recent revision of the DHHS guidelines on the use of antiretrovirals in HIV infected adults and adolescents now recommends starting therapy at a CD4 lymphocyte count greater than 500/ mm3.,

    For those with greater than 500 CD4 lymphocytes the recommendation is only supported by expert opinion – the opinions of the experts on the DHHS panel.  Almost all of the non-governmental researchers on the panel have financial arrangements with entities that stand to gain from the decisions they make.  There are plenty of other experts who are not members of the DHHS panel who are not so certain that starting treatment above 500 CD4 lymphocytes will confer a net benefit to the patient..

    This particular recommendation is unlike those made for individuals with lower CD4 numbers where more reliable evidence from clinical trials clearly demonstrates a benefit to the patient

    Evidence based medicine has brought us a long way from the days when clinical decisions were based on authority and tradition (“expert opinion”); it attempts to use the best available evidence on which to base clinical recommendations.  The term “best available evidence “means that not all types of evidence are of equal quality.  There are several systems that grade the relative strengths of evidence derived from different sources.    All agree that evidence provided by randomized controlled clinical trials is of the highest quality and therefore the most reliable.  Applied to HIV medicine, a strong recommendation that antiviral treatment be initiated at 350 or fewer CD4s can be confidently made because the evidence of substantial benefit is derived from a randomized controlled clinical trial.

    At the other end of the scale rating the quality of evidence, is evidence based on “expert opinion”.   This may not even be a marginal improvement on the bad old days when the doctor knew best; when there was no need to justify a recommendation other than by the authority of the doctor or by tradition.

    According to the system used by the DHHS,  the rating of the recommendation that people with more than 500 CD4 lymphocytes start treatment is B III.   It’s a moderate recommendation supported only by the opinion of experts.

    But when expert opinion is the basis for a recommendation, this does not even mean that the opinion represents a consensus of all experts.   It only represents the opinion of those experts chosen by the organization making the recommendation.

    Making a recommendation based solely on expert opinion is particularly troublesome when the means exist to obtain evidence of the highest quality.  The START trial that directly addresses the question of when it’s best to begin antiviral treatment is enrolling, and one must wonder why the panel did not defer making a recommendation concerning individuals with greater than 500 CD4 lymphocytes until the trial results become available.  This is even more puzzling as individuals who have waited to start at CD4 numbers between 350 to 500 have in general done very well, so waiting to make a recommendation for some years until the START trial results are available seems to be a much more reasonable and prudent option than jumping the gun and making a recommendation based on  evidence of the weakest quality.

    Bur when we come to look at the associations of the experts on the DHHS panel, a recommendation based on expert opinion is even more problematic.  We note that almost all of the non-governmental researchers have financial arrangements with entities that can benefit from the decisions they make. Some of these arrangements are quite extensive.

    Take a look at them.

    A conflict of interest becomes particularly troublesome when it’s only the opinion of the expert that supports a recommendation. Since people with greater than 500 CD4 lymphocytes represent a huge proportion of the HIV infected population, treating them will have an impact on expanding the market for antiviral drugs.  With greater efforts to encourage testing, greater numbers of individuals with higher CD4 numbers will be identified, and now recommended to receive lifelong treatment with expensive and potentially toxic drugs whose benefit has not yet been proven to outweigh their harms.

    The conflicts of interest of panel members are duly noted in the DHHS financial disclosures.

    Early AIDS activists performed a great service for all individuals who must deal with illness, in asserting their right to make informed decisions concerning their care, and that the decisions are made free from coercion.   Withholding information and supplying misinformation are forms of coercion.

    Although the guidelines ask physicians to inform patients with high CD4 numbers that evidence for benefit is  not conclusive    I   think it’s safe to conclude that individuals with greater than 500 CD4s will not always, and may only rarely informed   be informed  of this important caveat. As to informing patients of the conflicts of interest noted above, this isn’t even a consideration.   They are also unlikely to be told that the recommendation that they start treatment is based on the opinion of certain experts only, and that there are other experts with a different opinion.  In fact, the DHHS guidelines   may be the only ones in the world to make this recommendation.

    Undoubtedly the DHHS panel members believe that people with higher CD4 numbers will receive a net benefit from treatment.    But the recommendations would have greater authority if the non-governmental researchers on the panel were better balanced with respect to members who had no financial arrangements with entities that stand to benefit from their decisions;  in fact many would agree that such conflicts of interest should be a disqualification for panel membership.

    The recommendations also refer to the prevention benefit of treatment.  The greatest prevention benefit will result from the treatment of individuals with lower CD4 numbers who will have the highest viral loads.   These individuals need treatment. On this point there is no doubt or debate. For those with higher CD 4 numbers, not known at this time to benefit from treatment, the prevention benefit is likely to be much lower as their viral loads will also, on average be much lower than those with more advanced HIV disease.

    Providing treatment to everybody who needs it to stay alive should surely be our first priority.   It is here that treatment will also have its greatest prevention benefit.

    Conflicts of interest are of course common among those making treatment recommendations.  However HIV medicine seems to be unique in that these conflicts of interest, which may be among the most egregious, seem to go almost  completely unnoticed.  In every other field of clinical medicine they occasion extensive discussion.

    Two years ago in a tribute to Michael Callen  I responded to similar recommendations to treat all HIV infected individuals irrespective of CD4 numbers.

    I cannot express my reservations more clearly than with the words I used then:

    I miss Michael Callen. He was my patient when AIDS began, but soon became my collaborator and friend.

    For a time, Michael and Richard Berkowitz, another patient collaborator, were able to work out of an office adjoining my practice on W 12th street in New York City. It was in this setting that Michael and Richard learned about the medical aspects of this new disease and participated in the creation of some of the earliest organized community responses to the epidemic.

    Michael and Richard helped in the formation of the AIDS Medical Foundation; they wrote the very first publication to recommend condom use by gay men. Michael played a role in the first attempt to protect the confidentiality of people with AIDS, and he helped to create both the Community Research Initiative and the PWA Health group.

    A thread running through all of these endeavours is the notion of self empowerment. This extends beyond the belief that individuals who are fighting a disease should actively participate with their doctors in making decisions about the care they receive. Empowerment also means the inclusion of affected individuals at all levels of the response to the disease, from research to the provision of services.

    The Community Research Initiative was sponsored by the PWA Coalition of which Michael was President. This is the very embodiment of self empowerment. It is people with a disease sponsoring research into that disease themselves and not waiting for some benevolent institution to come to the rescue.

    Michael understood that his interests and priorities as a person living with AIDS might sometimes be at odds with those of some scientists conducting research into this new disease. He knew very well that he was living in a world that was still capable of cruel and discriminatory behavior towards him. Who better to protect the interests of those who had the most to lose than people living with AIDS themselves?

    Self empowerment found expression in the Denver Principles. Michael and Richard were both signatories to this historic document. Michael played a major role in crafting the words of the Denver Principles.

    Almost thirty years later these Principles remain as important as when they were first articulated.

    One of the Denver principles asserts the right to obtain full explanations of all medical procedures and risks.

    I wish Michael Callen were here today to bring attention to the violation of this right.

    This is happening with little protest in places like San Francisco where antiviral medications are now recommended for healthier HIV positive individuals for whom the benefits of treatment have not been shown to outweigh the risks.

    As always, you can’t beat the truth, and the truth is that for people with more than 350 CD4 lymphocytes, the best time to start treatment is not known. This may seem surprising as potent antiretroviral drugs have been available for fifteen years.

    We have not yet done the kind of study that would most reliably provide the information those HIV positive individuals with higher CD4 numbers and their doctors need to make the best decisions about when to start treatment.

    With information provided by a properly designed and conducted prospective randomized trial, we could know with confidence when in the course of HIV infection the benefits of treatment absolutely outweigh the risks.

    Some feel that a decision can be made with less reliable information. But surely all would agree that a decision to start treatment or to defer it must always be an informed one voluntarily made by the individual considering treatment.

    It is here that the principle asserting the right to a full explanation of the risks of medical interventions is being violated.

    The San Francisco Department of Public Health in advising all HIV infected individuals to receive treatment is in effect telling them that at all stages of HIV disease the benefits of treatment outweigh the risks. This may be so, but apart from those with 350 or fewer CD4 lymphocytes, we just do not have the most reliable evidence to support this contention.

    People with higher CD4 numbers have the right to know not only what evidence there is that immediate treatment will have a net benefit compared to deferring it, but also the quality of that evidence. They surely should also be made aware that experts hold differing opinions on whether treatment should begin immediately or be deferred.

    A physician in San Francisco who recommended that all HIV infected individuals should start treatment immediately was reported to have said:

    “If I’m wrong, we’ll start people [on treatment] a couple years earlier than we otherwise would. But if I’m right and we don’t start early, there’s no going back,”

    Others who are concerned about drug side effects might feel that more may be at stake for HIV positive individuals with higher CD4 numbers. This also includes the possibility that fewer options may be available when treatment is definitely known to be needed.

    This doctor is also reported to have said:

    “The old paradigm was that drugs are toxic so we should wait as long as possible. The new paradigm is that while today’s drugs are not totally benign, they are less toxic than the virus.”

    “The” paradigm? Is it not misleading to give an impression that his views on drug toxicities represent a consensus?

    How on earth can the longer term toxicities of the newer drugs be known?

    Just a few days ago it was reported that AZT and 3TC based therapies produced a metabolic abnormality called hyperhomocysteinemia. This is a condition associated with vascular abnormalities including a greatly higher risk of heart attacks. We have been prescribing AZT and 3TC for about twenty years, so what information does the San Francisco doctor have that gives him such confidence that the drugs in use for only a few years are less toxic?

    Empowerment means that HIV positive individuals make their own decisions to start or to defer treatment. They have the right to clear and honest information to enable them to make this decision. Those with higher CD4 counts have the right to know that there still is uncertainty about when it is best to start treatment.

    The views of the San Francisco Department of Public health and those who share them are just opinions; healthier HIV positive individuals should also know that these opinions are not held by all experts. Respect for the autonomy of healthier HIV positive individuals requires that opposing views on when it’s best to start treatment be presented together with the evidence supporting these views, so those who have most at stake can decide for themselves.

    There will continue to be opposing views on when it’s best to start antiviral therapy as long as the question has not been put to the test.

    The best way to resolve uncertainty in clinical medicine is by conducting prospective randomized trials. A properly designed and conducted trial could reliably and safely answer the question of whether, on average, immediate or deferred treatment is better or worse or makes no difference.

    HIV positive individuals deserve the most reliable information to inform them in making treatment decisions. The START trial is a randomized prospective study that directly asks the question about the best time to start antiviral medications. We could really finally know what’s best, and no longer rely on opinions based on data of inferior quality.

    Is an immediate or deferred initiation of treatment better or worse, or does it make no difference? If knowledge is power a demand to complete the START trial is the embodiment of the self empowerment of HIV positive individuals. The very antithesis of self empowerment is to allow researchers to persuade us with evidence of inferior quality, such as their personal opinions, presented as if there were a consensus, or with the results of embarrassingly uninterpretable studies such as NA-ACCORD so often used to justify earlier starts to treatment. NA-ACCORD was not a prospective randomized trial. It was a review of a large number of medical records. Such retrospective observational studies are beset with interpretative difficulties because subjects are not randomly assigned to receive one or another kind of intervention, in this case, to start treatment early or to defer it. We don’t know why a particular course of action was chosen. The reasons why decisions were made to start treatment early or to defer it may have determined the outcome rather than the time treatment was started.

    In situations where prospective randomized trials cannot be conducted for whatever reasons, then we have to do the best with data of inferior quality. But fortunately this is not the case with HIV infection.

    I miss Michael Callen. He would have reminded us that HIV positive individuals must demand that the best evidence be obtained to inform their treatment choices.

    .

  • The Cost of Pre-exposure Prophylaxis with Truvada

    Posted on August 17th, 2011 admin No comments

    In my last post I wrote about the very small reduction in the absolute risk of HIV infection in the iPrEx trial among those taking Truvada  as pre-exposure prophylaxis.

    The 44% reduction in relative risk conferred by Truvada was the only efficacy measurement explicitly presented by the investigators.  That the absolute risk reduction was only 2.3% was not mentioned in the various presentations.

    I suspect that many reading press reports of this so called breakthrough were unaware that in fact, the actual risk to people taking Truvada was 2.8%.  (36 infections in 1251 participants).  True, this is less than the 5.1% risk to those on placebo, but by very little.  Certainly not enough to justify the bewildering acclaim given to the iPrEx trial results.

    Failing to clearly state the absolute risk reduction of an intervention is something we have come to expect from salesmen to inflate the efficacy of a product, but not from clinical researchers.  Large reductions in relative risk can be associated with minute reductions in absolute risk when the events prevented are low to begin with.

    Another important reason why absolute risk reduction should be stated in a report is that this allows one to calculate the number of people who need to be treated to prevent one event, in this case, one HIV infection.

    Although the iPrEx investigators did not explicitly provide these numbers, they can be worked out from data presented, as I did in my last post and was also done in a letter published in the New England Journal of Medicine of April 7, 2011 in response to the iPrEx trial report, where the authors report that 44 people need to be treated to prevent one infection (I got 45).

    They then went on to calculate that it would cost $400,000 a year to prevent a single infection.

    This figure does not even include the cost of the necessary monitoring for infection.  In another letter, it was suggested that such monitoring be done monthly to prevent the emergence of resistant virus by detecting infection early.

    From Sean Strub’s calculations (in his comment to my post on the POZ magazine website) which included doctor’s visits and tests, the annual cost would be about $500.000.

    These figures are based on drug costs in the US.

    Truvada PreP not only does not work well enough it will cost a half million dollars a year to prevent a single infection.

    Maybe this is indeed a “game changer” but not in the sense intended by the triumphalist reports coming from the recent Rome AIDS conference.

    There definitely seems to be a perception that PrEP is a viable prevention option for everybody; there even have been calls for its general implementation.  These cost estimates alone would make it unfeasible as a public health measure but there are additional reasons, importantly its relatively low efficacy.

    PrEP is a reasonable option for only a very  small number of individuals at high risk for infection who are able to be regularly checked for infection.  I believe there is no disagreement about this; the controversy is only about its general use.

    Implementation of PrEP on a wide scale will almost certainly result in an increase in new infections.  It’s not only adherence to the drug regimen that will not be maintained by all.  Adherence to a schedule of regular testing for infection cannot be relied on.

    The way PrEP has been promoted has probably already damaged targeted prevention education programs with support for continued condom use, an activity already in great need of support.

    Drugs for prevention are paid for from a different budget than prevention education programs, and health departments already under budgetary constraints may feel that prevention needs can now be paid for by those entities that pay for drugs, private insurers or Medicaid/Medicare.

    The amount of almost uniformly uncritical publicity given to PrEP is completely out of proportion to its utility.  It’s a hugely expensive and very poorly effective prevention intervention, of use to only a very small number of individuals, and its misleading promotion has probably already damaged prevention education programs.

    Considerable resources must have been devoted to publicize and promote PrEP over many years,  in a way that has not taken care to reinforce prevention education with support for continued condom use.    One can only wonder why.

    Drs Dong Heun Lee, M.D.  and Ole Vielemeyer, M.D of Drexel University College of Medicine in Philadelphia are the authors cited.

  • Pre-exposure prophylaxis against HIV with Truvada, PrEP, just does not work nearly well enough

    Posted on August 5th, 2011 admin No comments

    Prevention of HIV infection by pre-exposure prophylaxis (PrEP) is not sufficiently effective

    PrEP is a prophylactic intervention where uninfected people take anti HIV medications before sexual intercourse to prevent becoming infected with HIV. The use of a vaginal gel containing anti HIV drugs has also been tested.

    The results of several trials of PrEP have been reported in the past year, all but one hailed as huge successes, with reported efficacies of up to 90% among those adhering to the treatment regimen.

    The efficacy of PrEP in preventing HIV infection was reported to be so great that this intervention has been trumpeted as signalling a revolution in HIV prevention.  A new era has opened up we are told; PrEP is a “game changer”.

    With such enthusiastic coverage it may come as a surprise that none of the reports explicitly told us what the actual efficacies of the interventions were in preventing HIV infection. Perhaps because they were so low, as I’ll explain.   Maybe what’s even more startling is that this omission seems to have gone completely unnoticed, at least in the universally jubilant press reports and equally enthusiastic press releases from AIDS advocacy organizations.

    How has this been possible?

    The reason is that the results have been reported as reductions in relative risk only.   This tells you nothing about actual risk reduction.  What is reported is a percentage reduction in risk from a number that was never clearly stated.  For example in the iPrEx trial of PrEP among men who have sex with men, the drug, Truvada, was reported to reduce the risk of infection by 44%.  But 44% of what?  We were not explicitly told, although it’s possible to calculate what it is.

    In fact we can calculate that the absolute risk reduction conferred by Truvada is a measly 2.3%, a number nowhere to found in the trial report.  The relative risk reduction may have been 44%, but this translates into only an actual 2.3% reduction in risk, as is shown below.

    Reporting relative risk reduction only is the oldest trick in the book to exaggerate the effects of an intervention, used by salesmen, but apparently also by clinical researchers.

    What makes the unquestioning acceptance of these reports of relative risk reductions achieved by PrEP even more remarkable is that there is a tremendous amount of material explaining the difference between relative and absolute risk reduction.   Just type the words “relative risk absolute risk” into the Google search box.

    Relative risk reduction tells you the percentage reduction in risk in the treated group compared to that in the group receiving placebo, or how much lower the risk with the intervention is relative to the risk to begin with.

    If you are not clearly told what the risk is to begin with, then you can’t tell what the actual reduction in risk is when taking the intervention; all you know is how much lower it is than a number that’s not clearly presented to you.

    Although not included in the iPrEx trial report there is information that allows one to calculate the absolute risk reduction conferred by Truvada.  To do this we need to know what the risk of infection is to begin with.

    This is the number of infections occurring in the placebo group over the time period of the study.

    64 out of 1248 people in the placebo group were infected, which is 5.1%, or 0.051 in 1.  (since then there have been additional infections reported at the Rome AIDS conference, reflecting an increase in the number of infections over a longer time period).

    In the group receiving Truvada 2.8% of 1251 people were infected.

    The absolute risk reduction conferred by Truvada is simply 5.1 minus 2.8 which is 2.3.

    A 2.3% reduction in absolute risk conferred by Truvada is the more accurate measure of its efficacy.    Hardly something to celebrate.

    A 44% reduction in relative risk sounds much better, although far from spectacular,  but unfortunately it’s a number that tells you nothing about actual risk reduction.

    Relative risk reduction is calculated as follows:

    It is the number of events in the treatment group subtracted from the number of events in the placebo group divided by the number of events in the placebo group.

    On its own, relative risk reduction is not a helpful number.

    Of much greater help to a person considering Truvada PrEP is knowledge of the actual risk while taking Truvada (over the period of the study, a median of 1.2 years).

    That number is 2.8%.

    Knowing the absolute risk reduction allows one to calculate another important measure.  This is the number of people who need to be treated to prevent one infection (NNT).   From information contained in the trial report 45 people need to be treated to prevent one infection.  I did not notice this number in the trial report nor was the absolute risk reduction of 2.3% reported.   NNT is a useful number as it allows one to estimate what it would cost to prevent a single infection with Truvada.

    The cost of the drug is the least of it.  A person taking Truvada PrEP needs to be monitored at regular intervals for toxicity and importantly, for infection, in order to avoid the inevitable emergence of resistant viruses as a result of sub optimal treatment.

    If Prep is implemented on a large scale which some AIDS advocates seem to be calling for, but is unlikely to happen, then there may well be increases in new infections with viruses resistant to the drugs in Truvada  in men who have sex with men, in IV drug users and in Africans.

    PrEP is not a success, at least not with Truvada.     However such a failure was transformed into a triumph, part of the explanation is the use of relative risk reduction numbers with care taken to remain silent on absolute risk reduction.   Despite all the literature available to help people tell the difference between absolute and relative risk reduction, this evidently was a resource not used by those cheering along  this ineffective intervention.

  • Treatment as Prevention: Protecting Individual Autonomy

    Posted on June 5th, 2011 admin No comments

    Treatment as Prevention

    Protecting patient autonomy

    Patient autonomy is just a particular instance of individual autonomy, a term that may sound pretty dry and academic but if we used the term individual freedom we would essentially be talking about the same thing.

    Respect for the autonomy of the individual may be the most important of the principles that form the foundation of medical ethics. (1)

    One attribute of personal autonomy is: “the capacity to be one’s own person, to live one’s life according to reasons and motives that are taken as one’s own and not the product of manipulative or distorting external forces.” (2)

    There is no disagreement about the importance of respect for individual autonomy but as I’ll explain, it seems that its pre-eminence is being questioned in some proposals to use antiretroviral treatment to prevent transmission of HIV.

    The recent demonstration that antiretroviral treatment can prevent transmission of HIV among serodiscordant heterosexual couples is great news. However, when the person offered treatment has not yet been shown to personally benefit from it, an ethical issue needs to be addressed. It has not yet been reliably demonstrated that for people with greater than 350 CD4 lymphocytes, starting treatment immediately rather than deferring it confers a net benefit; indeed, it may even prove to be harmful. A randomized controlled trial now enrolling will provide needed information, but we will have to wait several years for its results.

    The issue isn’t whether or not people with greater than 350 CD4 lymphocytes should receive treatment. A respect for their autonomy requires that the decision whether or not to do so is made by them and is made free from coercion.

    A recent issue of the Journal, Public Health Ethics (3) is devoted to ethical issues associated with the proposal that a program of universal testing and treatment of infected individuals could bring an end to the HIV/AIDS epidemic. Such a proposal would involve the treatment of healthier HIV infected individuals not at this time known to personally benefit from antiviral medications which could even harm them.

    In an article in the journal referred to above, public health ethics is said to require an approach where respect for individual autonomy is not paramount; a commitment to the supremacy of individual autonomy could have no place where the “primacy of collective wellbeing is the starting point”.

    In that case I wonder just how desirable a collective wellbeing would be where individual rights were subservient to whatever was defined as the collective good.

    I can only hope that this goes nowhere, as abandoning the pre-eminence of respect for individual autonomy opens the door to tyranny, paternalistic or otherwise. Individual freedoms have been hard won, and we should always be aware of harms that have been perpetrated in the name of the public good, even leaving alone the problem of who defines what constitutes the public good.

    In public health, medical research and medical practice, concern for individual autonomy remains paramount. The only commonly agreed acceptable exemption is the restriction of personal freedoms to prevent harm to others such as limiting the movement of individuals with highly communicable diseases where the harm that may be done to others is considerable. That is, outside the criminal justice system, among individuals who are free.

    People have the right to make decisions about their treatment, their participation in a research study, or in a public health intervention, free from coercion.

    Providing misleading information is a form of coercion; withholding information may also be coercive.

    Providers of health care have an obligation to provide patients with honest information to inform their decisions. This must include information about what is known about the risks and benefits of treatment, as well as what remains conjectural.

    Information and the strength of the evidence upon which it rests:

    It’s not enough to simply provide individuals with information concerning the benefits and risks of a particular treatment. In order for the information to be useful we must also indicate the strength of the evidence on which the information rests. (4)

    The most reliable evidence regarding the effects of a particular treatment is provided by results of randomized controlled clinical trials. This is because the treatment in question has been put to the test in a protocol that minimizes bias; we can therefore have a greater degree of confidence that effects observed are in fact caused by the treatment.

    Unfortunately information derived from randomized controlled trials is often unavailable. The clinical trial may not yet have been completed, or for whatever reasons the trial cannot be undertaken.

    When this is the case we have to consider evidence of inferior quality, for example, evidence derived from reviews of patient records or observational studies, and the opinion of experts.

    Observational studies are beset with interpretative difficulties because subjects are not randomly assigned to receive one or another kind of intervention. The particular reasons why participants were selected for study may influence the outcome rather than the effects of the intervention.

    Expert opinion:

    In all the systems I have seen that grade the quality of different kinds of evidence, expert opinion is at the bottom of the list. But expert opinion can be valuable to an individual in coming to a treatment decision when evidence of the highest quality is not available.

    Respect for patient autonomy means that patients make their own decisions free from coercion. As noted, supplying misleading information is a form of coercion. To state that something is known to be the case, when it is only an opinion is misleading.

    HPTN 052

    HPTN 052 is the study which demonstrated the efficacy of antiretroviral treatment in preventing transmission of HIV among serodiscordant heterosexual couples. Although the result was not unexpected it is nonetheless significant because it was obtained from a randomized controlled clinical trial.

    We now know that the uninfected partners of individuals with greater than 350 CD4 lymphocytes will benefit from treatment of the HIV positive partner. At this time we can only have an opinion about whether starting treatment immediately or deferring it will benefit or harm the infected partner with greater than 350 CD4s or be without effect – apart from cost.

    Most of the jubilant reports of the results of HPTN 052 do not mention the problem facing the healthier HIV positive partner in coming to a decision. Do the commentators just assume that it’s been established that all infected individuals receive a net benefit from treatment irrespective of CD4 numbers? Or do they not believe it to be important that patients make their own decisions regarding their treatment?

    I wish I could say I was startled to read in one newsletter that “For treatment as prevention to work….. people need to be convinced that early treatment is in their interest.”

    Convincing people to take a possibly perilous course of action based merely on opinion and evidence of inferior quality is a step on a road that ends with enforcement.

    A respect for individual autonomy means that we respect the right of individuals to make decisions on their own behalf, free from even subtle coercion. Our obligation as providers of health care information is to not only provide information, but also an indication of the quality of the evidence supporting it.

    At this time we do not know that individuals with greater than 350 CD4 lymphocytes receive a net benefit from antiviral treatment. There is evidence that they may, but until this is put to the test in a randomized controlled trial such as START, we must not mislead them by trying to convince them that “early treatment is in their interest”.

    Given adequate information, a person with greater than 500 CD4 lymphocytes may reasonably decide to take antiretroviral drugs to lessen the risk of infecting a partner even knowing that there may be no personal benefit or that there is a possibility of harm.

    At the end of the day what’s of central importance is that we respect our patient’s right to make choices about his or her treatment, and provide honest information to inform that choice, recognizing the difference between expert opinion and established fact.

    (1) Ever since Beauchamp and Childress published the first edition of their classic text, Principles of Biomedical Ethics, in 1979 it’s been commonly accepted that beneficence, nonmaleficence, justice and respect for autonomy, are four principles that should guide medical ethics.

    The Four Principles are general guides:

    Respect for autonomy: respecting the decision-making capacities of autonomous persons; enabling individuals to make reasoned informed choices.

    Beneficence: this considers the balancing of benefits of treatment against the risks and costs; the healthcare professional should act in a way that benefits the patient

    Non maleficence: avoiding the causation of harm; the healthcare professional should not harm the patient. All treatment involves some harm, even if minimal, but the harm should not be disproportionate to the benefits of treatment.

    Justice: distributing benefits, risks and costs fairly; the notion that patients in similar positions should be treated in a similar manner.

    Beauchamp and Childress; Principles Biomedical Ethics, OUP, 5th edition

    (2) Christman, J, 2001″Autonomy in Moral and Political Philosophy”, The Stanford Encyclopedia of Philosophy (Fall 2007 Edition) , Edward N. Zalta (ed.), URL = <http://plato.stanford.edu/archives/fall2007/entries/autonomy-moral/>.

    (3) http://phe.oxfordjournals.org/content/3/3.toc

    (4) Several systems have been devised to grade the quality of evidence.For example: http://www.cebm.net/index.aspx?o=1025 The GRADE working group has been working on assessing the quality of evidence since 2000. http://www.gradeworkinggroup.org/index.htm

  • Interferon in AIDS: Too Much of a Good Thing

    Posted on May 12th, 2011 admin No comments

    Interferon and AIDS:  Too much of a good thing

    This discovery of interferon in AIDS

    AIDS was first recognized in 1981.  Interferon was found in the blood streams of people with AIDS later that same year, making it one of the earliest of the significant AIDS associated immunologic abnormalities to be noted.    Large amounts of interferon were found that were present for very prolonged periods, a situation noted before only in auto-immune diseases like lupus.

    The interesting story of how interferon came to be discovered in people with AIDS so early in the epidemic illustrates at least one way in which science can progress;  it also demonstrates a way in which scientific progress can be retarded.

    The production of interferon following viral infections is part of the innate immune response that is the immediate first line of defence against viral infections.   Interferon has potent antiviral activity against a broad range of viruses.  It also has widespread effects on the immune system as well as effects on other organ systems.  Some of these effects are harmful if prolonged, so there are mechanisms for turning off the interferon response after a few days as other antiviral mechanisms come into play.

    HIV and disease causing SIV infections differ from most viral infections in that the production of interferon is not turned off; it continues to be produced, sometimes at very high levels.  The prolonged presence of interferon contributes to the disease process and is a factor in the loss of CD 4 cells.

    The sustained activation of both innate and adaptive immune responses is now understood to be at the heart of AIDS pathogenesis.

    Interferon continues to be produced, sometimes in large amounts, in HIV infected individuals.  In untreated HIV disease we have the unusual situation where increasing amounts of interferon are associated with increased HIV replication.

    Interferon can’t be exerting much of an antiviral effect in HIV infected individuals, but this did not deter investigators from injecting yet more of it into people with AIDS early in the epidemic.

    This is even more puzzling as by 1983 we had evidence that interferon was able to suppress CD4 lymphocyte proliferation.  Long before this we knew that treatment with interferon was associated with low white blood cell counts, and a low white blood count is characteristic of advance HIV disease.

    But if interferon was of no use against HIV it has been spectacularly successful against Hepatitis C, curing many people of this infection.  It also may still have a place in treating some people whose Kaposi’s sarcoma is unresponsive to antiretroviral drugs, possibly through its ability to inhibit angiogenesis, which is the process of new blood vessel growth.

    Although there were lots of reasons to consider that prolonged exposure to high levels of interferon might have something to do with this newly recognized illness even in 1981, serious work on this possibility was delayed for many years.  The zeal to administer yet more interferon to treat AIDS is surely part of the reason for this neglect.

    The inexplicable enthusiasm to treat AIDS with interferon resulted in no benefit to patients; it probably accelerated the disease process in some.

    It also had the unfortunate effect of delaying research into interferon’s role in the pathogenesis of HIV disease.

    It’s only in the past ten years that we have gained some information on how prolonged exposure to interferon can contribute to the loss of CD 4 lymphocytes.

    Finding interferon in people with AIDS

    This is how we came to find interferon in people with AIDS so early in the epidemic.

    Early in 1981 I had referred one of my patients to Dr Joyce Wallace.  A biopsy taken of lesions seen in his stomach indicated that these were Kaposi’s sarcoma.   Joyce called to tell me that she had contacted the National Cancer Institute to help identify experts in New York City who were familiar with Kaposi’s sarcoma  because this was the first time she was confronted with this diagnosis (the first time for me as well).   She had been told that over twenty gay men had been diagnosed with Kaposi’s sarcoma and that Dr Alvin Friedman Kien at NYU was treating a number of them.  I knew Alvin through my association with Jan Vilcek, a long-time colleague in the field of interferon research.  Alvin is a dermatologist but also worked in the NYU lab that Jan headed.

    I immediately called Jan who confirmed that Alvin was treating a number of gay men with Kaposi’s sarcoma. Jan very kindly allowed me to work in his lab.  I then arranged my time so that I worked in the virology lab in the mornings and saw my patients in the afternoon.

    I was one of several scientists who thought it likely that cytomegalovirus (CMV) played a role in this newly recognized disease so initially my lab work centered on this virus.

    In the early months of the epidemic Alvin had sent blood samples to Pablo Rubenstein at the New York blood center for HLA typing.   HLA refers to the human leukocyte antigen system which allows the immune system to differentiate foreign antigens from self-antigens. It’s important in organ transplantation, where a match in HLA antigens between recipient and donor can prevent organ rejection.

    HLA typing is important in investigating a newly recognized disease as there is an association of certain HLA types with some diseases, even some infectious diseases.

    A serologic method was then used for HLA typing.  It depended on the attachment of HLA specific antibodies to HLA antigens on the surface of leukocytes.

    HLA typing of our first patients with Kaposi’s sarcoma proved to be difficult because the patient’s own antibodies were already coating the   surface of their leukocytes, interfering with the test.

    At the same time I had come across a preprint of a paper reporting an important observation by Jan Vilcek.  The CD3 antigen is present on the surface of T cells.  Jan had reported that an antibody against the CD3 antigen was a powerful inducer of gamma interferon.

    As I read this report it occurred to me that Pablo Rubenstein’s observation that antibodies were attached to our patient’s leukocytes could mean that these blood cells were secreting gamma interferon, which we might be able to detect in their sera.

    I discussed this possibility with Jan and Alvin and we immediately set out to test the sera of Alvin’s patients.  This idea was to bear fruit, but not what we had expected.    Rather than gamma interferon, large amounts of alpha interferon were found.

    Jan Vilcek has also described this event, which can be seen by clicking here.

    Maybe what’s important is to have a reasonable idea that can be tested, not that the idea need be correct.  In fact much later, using more sensitive tests gamma interferon was eventually found in AIDS sera.

    Robert Friedman is a colleague from the early days of interferon research, with whom I had published work on the mechanism of interferon’s antiviral action.  He was – and still is ,chairman of the pathology department at the Uniformed Services University of the Health Sciences in Bethesda.  He, Jan and I have been colleagues since the 1960s when Alick Isaacs, a discoverer of interferon was still alive.   We joined forces to study the association of interferon with AIDS.

    Our extended findings including data obtained at both Jan Vilcek’s and Bob Friedman’s lab was published in the Journal of Infectious diseases in 1982.

    Since there were so many names, it was left to me to decide their order, and I chose that they be listed alphabetically. Thus Gene DeStefano became lead author. He was a technician in Jan’s lab and I believe he went on to become a dentist.  This is the title.

    Acid-Labile Human Leukocyte Interferon in Homosexual Men with Kaposi’s Sarcoma and Lymphadenopathy

    E. DeStefanoR. M. FriedmanA. E. Friedman-KienJ. J. GoedertD. Henriksen,O. T. PrebleJ.Sonnabend* and J.Vilček (1)

    This early discovery prompted a pretty obvious question:  could the sustained presence of interferon have anything to do with the pathogenesis of this newly recognized disease?  From what was then known about the effects of interferon it was a question that certainly needed to be explored.

    Although interferon had been discovered in 1957 through its antiviral properties, by the 1970s it was already known that it had widespread effects on the immune system.

    In the first few years of the epidemic I was in a position  to begin to begin to explore the possibility that interferon played a role in this newly recognized disease.

    I was able to obtain interferon assays on sera from my patients at Robert Friedman’s lab.   Further interferon tests were done by Mathide Krim, then head of the interferon lab at Memorial Sloan Kettering cancer center.

    I also was able to obtain quite extensive immunological tests on my patients through my collaboration with David Purtilo at the University of Nebraska in Omaha.    As a result I had (and still have) a small database of my own and so was able to produce further evidence for the association of high interferon levels with low CD4 counts, as well as some other associations with interferon. (2).

    The numbers of patients was not huge but the following graphic shows that 7 people with over 50 units of interferon/ml had under 50 CD4s, 12 people with 10-49  units had under 500 CD4s while 17 people without interferon had about 700.

    There are several other interesting correlations.  Interferon levels correlate with IgA levels and not surprisingly there is an inverse correlation between CD4 counts  and IgA levels.

    This was a CRIA presentation in the 1990s from the days when I was the medical director, but the data had first been presented in 1986.

    Being familiar with the adverse immunological effects of prolonged exposure to interferon I was puzzled by the attempts to conduct trials of alpha interferon to treat AIDS.  This is very different to the benefits of interferon in treating Hepatitis C and some cases of Kaposi’s sarcoma.

    The zeal to use interferon as a treatment for HIV disease created a strange situation concerning a molecule called beta-2 microglobulin (beta 2M).

    In the early  years of the epidemic various markers were sought that could act as prognostic indicators.   It was soon found that a raised beta 2M level in the serum of patients was an adverse prognostic indicator.   High levels were indicative of a poor prognosis.   But interferon is the major stimulus for the synthesis and release of beta 2M, something that was known in the 1970s.

    In fact the adverse prognostic significance of serum interferon had already been reported early in the epidemic.

    A 1991 paper by a noted AIDS researcher, reported studies undertaken to evaluate the hypothesis that elevated beta 2M levels were associated with the production of interferon.   But this association had been well known for about 20 years!

    Beta 2M levels can be elevated in certain conditions where interferon is not detectable. But even before the onset of the epidemic we knew that when interferon levels are elevated we expect to see increases in beta 2M.   Nonetheless this particular paper was noteworthy in that it discussed this association.   Few others papers dealing with beta-2M  during those years made any mention of it, thus avoiding the following question.   If elevated beta-2M levels indicated an adverse prognosis should we not be concerned that administering interferon will result in yet further increases in beta-2M?

    This of course doesn’t mean that beta-2M mediated any pathogenic effects, but it simply prompts a question.  Of course we now know that interferon mediates some of the pathological effects of HIV disease, and beta-2M can properly be regarded as a surrogate marker for interferon.

    How is it possible to explain why in a disease characterised by low CD 4 lymphocyte counts and the presence of large amounts of interferon, it was thought that injecting yet more interferon could possibly be of help?

    Dr Fauci and other investigators tried to explain the paradox of administering interferon to people who already had huge amounts of it in their blood stream by claiming that the endogenous interferon was different.   The difference referred to was that the AIDS associated interferon could be partially inactivated by acid, whereas the administered interferon was resistant to acid (3).

    But we knew that AIDS associated interferon was neutralized by monoclonal antibodies against administered interferon, meaning that the molecules were identical, and the interferon in patients’ blood had the antiviral activity expected of alpha interferon when tested in cell cultures.  It certainly was responsible for the beta 2M.

    In fact the sensitivity to acid is not a property of the interferon molecule but is conferred by other components.  Interferon from patients that is partially purified loses its sensitivity to acid.

    This explanation which cannot stand up to even the most cursory scrutiny was apparently good enough for community writers on AIDS treatment.

    I repeatedly tried to bring attention to the probable contribution of interferon to pathogenesis without success.  I received no response to a letter that can be seen by clicking   here.

    In 1990 I was able to organize a meeting to bring basic researchers and clinicians together to discuss the role of interferon in pathogenesis and in treatment.

    The meeting was very well attended, but I have no idea if it accelerated interest in interferon’s role in pathogenesis.

    I probably angered a number of investigators when I tried – with the help of Michael Callen and Richard Berkowitz to inform people of the risks of receiving very high doses of interferon in clinical trials. We felt that information about interferon should be included in the consent form.  We even went to the lengths of taking out a paid advertisement in the New York Native to inform people about potential problems associated with receiving high dose interferon. This can be seen here. Richard Berkowitz has posted the complete ad on his website, Richardberkowitz.com

    .

    .

    It’s now more difficult to undertake studies that can investigate correlations between endogenous interferon levels and various immunological abnormalities.  It would have to be done on material stored before AZT was introduced or on individuals not receiving antiretroviral drugs.

    The reason for this is that antiviral therapy promptly removes interferon from the circulation.  This is something that the group I worked with at Roosevelt hospital, including Elena Klein and Michael Lange found shortly after AZT was introduced.  We had access to sera from clinical trials of AZT.  In one of these trials AZT was administered for a week on alternate weeks.

    We found that interferon promptly disappeared during the week on AZT, only to reappear just as promptly when AZT was discontinued.

    Another report studying sera from the same trial looked at the effect of intermittent AZT therapy on beta 2M.  The same saw tooth response of beta 2M was unsurprisingly seen, but my recollection is that the word interferon was not mentioned.

    Undoubtedly researchers today are looking at the significance of this almost immediate turning on and off of the interferon response in pin pointing the mechanism of its induction.

    With continuous AZT therapy interferon remains suppressed for about 5 weeks and then reappears and increases steadily.  Interestingly HIV as measured by p24 antigen  reappears many weeks after interferon

    One interesting implication of the effect of AZT (and other antiretroviral drugs) on endogenous interferon levels relates to hepatitis C.  It’s been noted that in coinfected individuals starting anti HIV drugs, sometimes there is an increase in liver enzymes as well as an increase in hepatitis C RNA.  It’s possible that in some individuals, hepatitis C is controlled to some extent by endogenous interferon, and flares up when interferon is removed by the anti HIV drugs.  Some researchers have commented on this although I don’t know it this possibility has actually been studied.  There are also other reasons why liver enzymes can increase on starting anti HIV drugs.

    We presented these results at a meeting I organized in New York in 1990.

    The innate immune response is a first line of defence against infection coming into play within hours.  Secretion of interferon is an important part of this response which also includes the inflammatory response.  Innate immune responses are immediate attempts to localize and overcome infections.  These beneficial responses last for a brief period because they become harmful if prolonged.  There are mechanisms that turn them off.  But in HIV infection and in pathogenic SIV infections innate immune responses are not turned off.  Persistent immune activation involving the adaptive immune system as well is at the heart of HIV disease pathogenesis.

    Several important research questions that I’m sure are being pursued are:   Why is the interferon response not turned off in HIV disease?  Why does the innate immune response continue to be activated?   What are the mechanisms that normally turn off interferon production and why are they not working?

    The precise role of interferon in contributing to CD4 loss remains to be worked out, although several mechanisms by which this can occur have been elucidated.

    But for years there was almost no work on identifying what induced such high levels of interferon and on determining which cell produced it.   It took over twenty years since interferon was first identified in AIDS sera for work to be undertaken to identify the ways in which it contributes to pathogenesis. There is still much to be learned, and hopefully the findings can be translated into new therapeutic possibilities.

    The reasons why the role of interferon in pathogenesis has been neglected for so long are undoubtedly multiple and complex. But one reason for this neglect was surely the early enthusiasm to administer it as treatment.

    But many years have been  lost by the neglect of a critical line of research the importance of which was evident in the same year that AIDS first came to attention.

    I have chosen these three references from a growing literature to illustrate what we are beginning to learn about interferon’s role in the pathogenesis of HIV disease.

    1. Herbeuval JP, Shearer GM.  HIV-1 immunopathogenesis: How good interferon Turns Bad.Clinical Immunology (2007); 123920:121-128
    2. Boasso A,Hardy AW et al.  HIV-1 induced Type 1 interferon and Tryptophan Catabolism Drive T Cell Dysfunction Despite Phenotypic Activation. PLoS ONE  (2008); 3(8): e2961
    3. Stoddart CA, Keir ME et al.  IFN-α-induced upregulation of CCR5 leads to expanded HIV tropism in vivo, PLoS pathogens (2010); 6(2) e1000766

    (1)

    Abstract

    Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-α) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with bovine cells, a characteristic of HuIFN-α, and all of 14 representative samples tested were neutralized by antibody to HuIFN-α. In addition, the HuIFN-α in six of eight representative patients was inactivated at pH 2 and therefore appears to Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy be similar to the HuIFN-α found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.

    (2)

    Sonnabend J., Saadoun S., Griersen H., Krim M., Purtilo D.  Association of serum interferon with hematologic and immunologic parameters in homosexual men with AIDS and at risk for AIDS in New York City.

    2nd International Conference on AIDS Paris 1986.  Abstract 100

    There were several other interesting associations including a positive correlation between IgA and interferon, so needless to say, there is an inverse correlation between CD4 counts and IgA.   In the early days I used easily obtainable IgA measurements as an unproven  prognostic indicator.

    .

    (3)

    I found a transcript of a meeting in New York where Dr Fauci answered questions posed people with AIDS and their advocates, where he explains this.

    You can see this at the very end of another article I wrote about interferon and AIDS in 2009 that contains some of the same material in this blog.

    http://aidsperspective.net/blog/?p=118

  • HIV pre-exposure prophylaxis (PrEP): A misguided guidance issued on its use.

    Posted on February 23rd, 2011 admin No comments

    Full contents of this blog:

    Pre-exposure prophylaxis – called PrEP, is an HIV prevention intervention where antiviral drugs are taken by HIV uninfected individuals in the hope that sexual transmission of HIV will be prevented.   A recent trial of daily Truvada, a combination of two anti-HIV drugs demonstrated only a 44% reduction in the risk of becoming HIV infected by sexual transmission among men who have sex with men (MSM).     I have written about this trial a few months ago.

    Unbelievably, the use of this intervention has in effect been endorsed by the US Centers for Disease Control (CDC).   True, the CDC call their recommendations on the use of daily Truvada as PrEP an “interim guidance”.    But anything short of “don’t risk your life by taking an intervention that cannot even halve the chance of becoming HIV infected” is in effect an endorsement.    Simon Collery has also written about this calling the CDCs recommendations a “mixed message”.

    The CDC is not alone in regarding an intervention that is only 44% effective in preventing a potentially lethal infection to be good enough to be implemented.  Quite surprisingly some groups claiming to represent the interests of those at risk share this bizarre view.  One implication is that these groups, supposedly representing people at risk for sexually transmitted HIV, as well as the CDC have given up on persuading MSM to use a condom, as described by Michael Weinstein in a recent article .

    In reality groups calling for an implementation of an insufficiently effective intervention to prevent a life threatening infection may be a  small minority whose real influence is probably insignificant in relation to their noisy irrational advocacy.

    People on the ground, dealing with risk are often wiser than those who claim to advocate on their behalf, but do not have the means to influence the way issues are reported in the media.  They know that a 44% efficacy in reducing the chance of acquiring a life threatening infection is just not good enough.  They know that condoms are the most effective way to prevent sexual transmission of HIV.

    But when this insufficiently effective measure was first announced in November of 2010, it was hailed as a triumph.    Time magazine even called this ineffective intervention the most significant medical breakthrough of 2010!     I suspect these accolades may have resulted from the skill of publicists rather than of independent investigative reporting.

    But of course I may be part of a  minority in considering that a trial demonstrating that an intervention that is only 44% effective in preventing a potentially lethal infection is far from a triumph and  rather is an emphatic failure because a much more effective protective measure is readily available that’s cheaper and safer.

    Concerns that condoms may not be used regularly in appropriate situations to prevent the sexual transmission of HIV are better expressed by a support for extended properly targeted prevention education.

    PrEP trials began in the early 2000s and have had a troubled history.  Trials were planned and even several started in African countries and in Thailand and Cambodia.  Some never got off the ground, and several were stopped for a variety of reasons.  There were vigorous activist demonstrations in connection with some.     The varied concerns of activists included provision of care to trial participants who became infected, or the provision of sterile injection equipment to IV drug users in Thailand.

    I posted a blog on the POZ magazine website in August 2009 describing an ethical problem   with  PrEP trials,  essentially that  PrEP would have to be tested with an imperative to provide and encourage the use of effective means already available to prevent HIV transmission, namely condoms and sterile needles.  If these measures are conscientiously provided and their use encouraged it’s unlikely that any effect solely attributable to PrEP could be measured.  iPrEx  told us that self-reported adherence to medication is unreliable, so there is no reason to believe that self-reported frequency of unprotected sexual intercourse is any less so.

    In that post there are links to two significant articles published in 2005.   The first represents the view sympathetic to those who demonstrated against PrEP trials.  It can be seen by following this link:

    The Tenofovir pre-exposure prophylaxis trial in Thailand: Researchers should show more openness in their engagement with the community

    The second is the view of  PrEP researchers.

    The Abandonded Trials of PreExposure Prophylaxis for HIV: What went wrong?

    We Must Not Let Protestors Derail Trials of Pre Exposure Prophylaxis for HIV

    One of the ways suggested to forestall the problems that have beset so many PrEP trials in the past was to solicit a greater degree of community involvement early in the process with a view to obtaining their commitment.

    An effort was made to obtain community support for PrEP  trials  with the help of UNAIDS.      There have been many teleconferences and many publications about PrEP best seen by looking at this website. http://www.avac.org/

    .

    It’s evident that much effort and expense has been placed into engaging communities in the design and conduct of PrEP trials.  Apparently with some success as I believe the earlier upheavals associated with PrEP trials have not been repeated.

    As for as expenditure on PrEP trials and PrEP promotion, the following figure indicate funding amounts and sources.

    Despite this expenditure, it’s most unlikely that PrEP with Truvada will be used by more than a very small minority of individuals.

    Apart from the cost of the medication, it will be necessary to pay for regular tests for HIV infection and for monitoring for drug toxicity.  It’s likely that some of those who choose to use Truvada as PrEP will forgo these regularly needed tests, because of cost and other reasons.   Not only are these individuals risking infection with an insufficiently effective preventative measure, they also risk the development of virus resistant to the antiviral drugs in Truvada because of receiving a suboptimal dose during an unidentified infection.

    With only a 44% reduction in the risk of becoming HIV infected, unidentified infections are a very real possibility among individuals who choose to use daily Truvada as PrEP.  It’s realistic to be concerned that some of these individuals will not be tested regularly to detect infection.  Individuals with an undetected infection could then pose a risk to their uninfected sexual partners.    Who knows how suboptimal treatment will influence the course of initial HIV infection?.   Even the illness of primary infection that could be an alert,  may be less likely to occur.     Failure to be tested regularly would also mean that drug toxicity, specially to the kidneys is less likely to be detected.

    With all these hazards, not only to the individual using PrEP, and with the likelihood that   Truvada, and indeed other antiviral medications can be  obtained without a prescription,  the CDC’s  interim guidance is unwise.   It’s also unfortunate that there may be  some who will see additional significance in that the guidance  is specifically directed at “high risk” MSM.

    Properly targeted prevention education with the promotion of, and support for condom use  needs all the support it can receive.

    Daily Truvada as PrEP is a really bad idea.

  • AZT: The Clinical Trial that led to its approval.

    Posted on January 28th, 2011 admin No comments

    Full contents of this blog

    The clinical trial that led to the approval of AZT for the treatment of AIDS in 1987 is a landmark event, not only in the field of HIV medicine but I believe it had a major impact on the drug regulatory process that has had effects in all fields of clinical medicine.

    The trial reported in the New England Journal of medicine, had produced a dramatic result (1). Before the planned 24 week duration of the study, after a mean period of participation of about 120 days, nineteen participants receiving placebo had died while there was only a single death among those receiving AZT.   This appeared to be a momentous breakthrough and accordingly there was no restraint at all in reporting the result; prominent researchers triumphantly proclaimed the drug to be “a ray of hope” and “a light at the end of the tunnel”.  Because of this dramatic effect, the placebo arm of the study was discontinued and all participants offered 1500mg of AZT daily.

    I was treating many HIV infected individuals in 1987 when the drug was approved for the treatment of advanced AIDS.  I was puzzled by the results of the trial quite simply because those patients of mine who resembled trial participants would not have died in the period before the placebo arm was terminated.   Many patients enrolled in the trial had experienced an episode of pneumocystis pneumonia within four months of participation.  My patients and those of other experienced physicians were unlikely to die within four months of an episode of this type of pneumonia.

    This means that if my patients had enrolled in the trial it’s probable that there would have been no deaths at all by the time the placebo arm was discontinued and thus an apparent dramatic effect of AZT on mortality would not have been seen.

    There had to be an explanation for the discrepancy between the outcome of my patients (and those of other experienced physicians) and individuals participating in the trial; I was confident that an academic clinical researcher would sort this out.

    But no explanation was forthcoming.

    I was then able to obtain a copy of the FDA review of the  application submitted by Burroughs Wellcome, (the NDA) and tried to understand the discrepancy myself.

    I reviewed the report as a primary care provider to people with AIDS, and thus challenged very aggressively, both by my colleagues and by many patient advocates, to prescribe AZT.  I also reviewed the report as a clinical researcher who had designed and implemented clinical trial protocols.

    This is the report I wrote after reading the review of the NDA. (1)

    Essentially it makes the point that patient management strategies were the most significant factor influencing mortality, at least in the short term, and it could not be excluded that differences in the ways patients were managed in the trial, were to a greater or lesser extent, responsible for survival differences.  Patient management in this context refers to all the measures available, before the introduction of specific antiviral therapy, to care for individuals susceptible to infections and malignancies associated with impaired cell mediated immunity.   For example, the speed with which a potentially fatal opportunistic infection is suspected and diagnosed and efficiently treated can make the difference between life and death.   Much experience in the treatment of immunocompromised individuals had been gained before the AIDS epidemic, particularly in the field of renal transplantation, but also in other conditions.

    The AZT trial took place in 12 centers across the country.  There was no uniform approach to patient management during the trial; each of the 12 medical centers approached the most important determinant of life and death in the short term, independently.

    I will return to the implications of this lack of uniformity in patient management strategies.

    It may seem surprising today that so little attention was paid to developing methods for the optimal day to day care of patients with AIDS, but at the time there was a pervasive defeatist attitude concerning treatment.    All too commonly it was felt that nothing could be done to halt the inevitable progression of the disease to its fatal end.

    I’m not sure that it’s even possible to adequately describe the terror and desperation felt in the early 1980s.   At that time doctors on the front lines were trying to do what they could for their patients but had received little help from experts at academic medical centers and virtually none at all from Government scientists, although by 1981 when the first AIDS cases were reported,  diseases of the immunocompromised host had already become a distinct medical subspecialty.

    But by 1986 nothing of any use regarding treatments had come from the Public Health Service.  For example, people with AIDS had to wait until 1989 for the CDC to issue guidelines for the prevention of pneumocystis pneumonia, the most frequent cause of death among them, while this type of pneumonia had often been routinely prevented in many other individuals who were also at risk because they were recipients of kidney transplants, or were children with leukemia.  The means to prevent pneumocystis pneumonia had been published in 1977.

    Some community doctors were not waiting for recommendations from government scientists or from their colleagues in academic medical centers, and were learning how to care for their patients. I and several colleagues were preventing pneumocystis pneumonia among our patients for many years before the Public Health Service got around to making their recommendations.

    Those who had taken on the medical leadership of the epidemic were telling us in their silence that there was nothing much we could do – we just had to wait for a drug.

    Then, after six years of silence regarding treatments Government scientists at last told us that help was on the way.  Dr Samuel Broder who was head of the National Cancer Institute appeared on television shows trumpeting the benefits of a drug he called Compound S.   I well remember a TV show where he appeared with an AIDS patient who enthusiastically attested to the benefit he had received from the drug, presumably from 1.5G of AZT daily.

    A note about patient management strategies:

    There really was a lot that we were able to do for our patients before the advent of specific antiviral therapy.    After all, most deaths were caused by opportunistic infections, and we certainly could do a great deal to prevent and treat many of them.

    Without much guidance some doctors with large practices were able to develop structured programs of patient care.   These included the prevention of opportunistic infections when possible, the determination of susceptibility to some, and their early diagnosis and aggressive treatment.

    All too often symptoms, particularly diarrhea, fever, weight loss, and anemia were simply attributed to AIDS and not investigated. In fact, such symptoms could frequently be ameliorated if their causes were aggressively sought.  More often than not they were caused by treatable conditions.   So, patient management strategies included aggressively trying to establish the causes of such symptoms and treating them.

    It was the experts who in fact were more likely to attribute them to AIDS and therefore consider them to be untreatable

    The provision of general support, including attention to nutrition and mental health issues are parts of patient management.

    All of this is pretty labour intensive doctoring, but these measures were able to prolong the lives of our patients.

    Needless to say, it was community doctors who had to develop such strategies without much help from the experts. I suppose one has to conclude that the government medical leadership of the response to the epidemic, unlike community doctors dealing with it, must have felt that nothing could be done for people with AIDS, that the only hope to be found was in a new drug.

    Returning to the original AZT trial:

    If in the short term patient management strategies can make the difference between life and death is there any reason to consider that such strategies may have differed in those receiving placebo or AZT?

    The reason why randomized placebo controlled clinical trials are blinded, (so that neither investigator nor participant knows who is receiving placebo or active drug) is to minimize bias.  Bias can influence the outcome that might incorrectly be attributed to a drug effect.   But it’s impossible to blind a trial using AZT.  The drug causes changes in routine blood counts that investigators need to see.   Therefore we must conclude that investigators could know who was receiving AZT or placebo.   The FDA reviewer was aware of this.

    If patient management is the most important determinant of mortality in the short term, could bias have influenced the ways patients were managed?

    Unfortunately, because this was essentially an unblinded trial, the answer is yes.

    Patients known to be taking AZT or placebo might have unintentionally been treated differently, with either greater or lesser care, when the investigator was also the treating physician.  AZT may therefore have been even more effective than claimed or may have been worse.

    In some centers were there  instances where the participant also had a personal physician?   There was no analysis of trial outcomes based on this difference.  There was also no analysis of outcomes by study center.   New York City was a study site.  Were patients referred to the study site at St Lukes Roosevelt Hospital Center by personal physicians who continued to care for their patients?

    Information must still be available regarding mortality at different study centers, and in relation to whether the participant was treated by the study doctor or had a personal physician.

    Dr Fischl was the principal investigator of the trial but I don’t know if she and her team at the University of Miami were the treating physicians as well as the trial investigators.

    Incidentally this also brings up the important question of   the propriety of an individual serving as both investigator and treating physician. I believe these two roles are often incompatible; that there can be an insuperable conflict of interest that should preclude an individual from functioning in these two roles concurrently.  I have served in both capacities but in most instances, not simultaneously.

    The survival benefit in the trial attributed to AZT   may therefore, to a greater or lesser extent have been due to differences in how placebo or AZT recipients were managed.  All we can say is that the question remains, not that this was in fact the case.

    The problems resulting from unblinding were clearly acknowledged by the FDA reviewer but not by the study investigators.   Around the time of the trial report I took part in a Canadian Broadcasting Corporation telephone interview.  When I tried to bring up the issue of bias I was cut short by a NIH official who said this was too technical a detail for the audience!

    Very unfortunately, the most vocal of the critics of the AZT trial included some individuals who believed that HIV could not cause AIDS.   Their strident criticisms were unhelpful; it was evident that none of these critics had any experience in clinical trial methodology.

    It was immensely disappointing to find that many of the problems in the trial were identified by Ellen Cooper, the FDA reviewer, yet the drug was still approved at a dosage that proved to be so toxic that another trial compared a similar dose with half that dose. This exercise resulted in excess deaths among those taking the higher dose. (A randomized controlled trial of a reduced daily dose of zidovudine in patients with the Acquired Immunodeficiency Syndrome. Margaret A Fischl et al. NEJM 1990: 323:1009-14).

    Among the many bizarre aspects surrounding the introduction of AZT was the claim that the excess deaths in those receiving the higher dose were due to AIDS – that in the case of AZT, less is better – the explanation given for the superiority of the low dose compared to the high dose was that the lower dose allowed people to remain on the drug for longer – not even a hint that the higher dose contributed to the increased mortality.  Here is the representation of the mortality differences between the two dosages:

    It’s worth reproducing the disingenuous words in which this is stated.

    “The findings in this study indicate that a lower daily dose of zidovudine is at least as effective ………as the initially tested dose of 1500mg per day and is less toxic”  “Moreover low dose therapy was associated with a better survival rate” “The reason for this better interim survival is not certain, but is most likely related to the greater likelihood that continuous antiviral therapy can be maintained with lower doses of zidovudine”

    If ever evidence was needed that AZT – at the initial recommended dose of 1500mg daily probably caused an excess mortality – the figure above provides it, despite the disingenuous claims of the authors that the deaths were due to AIDS.  A rational response would have been to work out the minimum effective dose. Why stop at 600mg a day? 300mg a day is probably just as good.  It is the dose I prescribed with no evidence that 300mg AZT daily was associated with a worse outcome.  As described in another article it is likely that endogenous interferon plays a role in pathogenesis, and AZT promptly removes it from the circulation

    That the possibility that more people on the higher dose died from AZT toxicity  is not even mentioned in the above report is a sad indication of what has become of the discussion of results section in a scientific paper, at least in the field of AIDS. Traditionally all reasonable possibilities are discussed, even to be dismissed, but not in this paper.

    The publicity following the approval of AZT was huge. Doctors received a video where AZT was billed as “A ray of hope”. I recall white coated doctors speaking about the “light at the end of the tunnel”.

    The dosage schedule was absurd.  There was no scientific basis at all for four hourly dosing.  AZT was to be taken even at night, and patients were given beepers to remind them to take their medicine exactly at the appointed time.   AZT is not the compound that blocks HIV replication. It is changed into the active compound within the cell by the addition of phosphate, and so blood levels tell you nothing about the levels of the active form in the cell. It is also a little gruesome – because as it turned out adherence to this difficult ritual was associated with great toxicity, and I can imagine that sometimes the manifestations of this toxicity would be attributed to AIDS and patients encouraged to still keep their beeper going and continue to take AZT.  At first the drug was only available if patients met certain criteria, and I know colleagues, devoted to their patients, who forged the papers to enable their patients to get the huge dose of AZT.   All on the basis of an approval based on a terribly flawed trial.

    Of course the need for some therapy was quite desperate and one must wonder if this desperation lowered the threshold of what was deemed to be acceptable, so that there was perhaps less scrutiny of the trial and the failures of AZT at the dose used – until of course toxicity forced a reconsideration of the dosage.

    The approval of AZT also set an important precedent that seemed to go unnoticed at the time, and indeed has escaped comment subsequently.

    AZT was the first drug of its kind to be approved for lifelong human use.

    The drug  is an analogue of thymidine which is a normal building block of DNA.  It is incorporated, instead of thymidine, into DNA during its synthesis, and then immediately stops further DNA chain elongation because nothing can be added to it.

    The use of such analogues able to disrupt DNA synthesis was considered to be perilous when I first dealt with them in the 1960s.  I had used them in the virology laboratory in experiments conducted in vitro, and they were handled with caution, as potentially hazardous substances.

    In clinical practice, apart from acyclovir which is a similar drug, but in a special category,   such analogues were used systemically in malignancies and some viral infections – such as herpes encephalitis or neonatal herpes, but only for short periods.  Acyclovir is in a different category as it can only be used by the herpes virus enzymes, and has no effect in cells not infected with herpes viruses.    The idea of a possibly lifelong exposure to a DNA chain terminating compound – or even an analogue that is incorporated into DNA that continues to be synthesized, was I believe a novel concept at that time. To emphasize, what was novel was not the use of such compounds, but a life time exposure to them. .    So, I was somewhat concerned at the very idea of this approach, and also found it strange that colleagues were mostly silent on this issue.  These analogues need to undergo changes in the cell, and are added to the growing DNA chain by enzymes, either those that belong to the cell, or enzymes that are specific to the virus, such as the reverse transcriptase of HIV.  It was hoped that AZT, which is turned into its active form by cellular enzymes, would be preferentially used by the viral rather than the cell enzymes that synthesize DNA, and therefore not terminate cellular DNA synthesis; there was some evidence to support this. HIV’s reverse transcriptase adds AZT to the viral DNA chain, while cellular enzymes add it to cellular DNA. Cell DNA is found in two different sites. In the nucleus it is the DNA that constitutes our genome – that is all the information that determines our inherited characteristics. DNA is also found in cellular structures called mitochondria which are the source of the energy needed by the cell. Two different enzymes are needed to make DNA in each situation. While there was comforting evidence that AZT much preferred the viral reverse transcriptase to the enzyme that makes our genomic DNA, this preference was less evident in the case of the enzyme that makes mitochondrial DNA. In fact much of the toxicity of AZT is a result of its effect on mitochondrial DNA synthesis.

    I never prescribed AZT when it was first approved, and when I did it was at a dose of 300mg a day.  Because I was one of the few physicians around 1987 who did not prescribe AZT I attracted patients who were reluctant to take it and whose physicians were nor supportive of this choice.  I also received severe criticism for my position

    This original AZT trial did however clearly demonstrate to me how important patient management strategies were in the treatment of AIDS, particularly in the days before the more potent antiviral drugs became available.

    The New England Journal of medicine, which reported the original trial, rejected my review of the FDA report.    I sent copies to all the clinicians who were prominent in the field – as well as to several patient advocates. There was not a single response – not even to reject the points I made.  Just total silence.  Realizing the difficulty in publishing independent material we – myself and mostly Michael Callen , decided to publish an independent journal.  We called it AIDS Forum. Michael was the editor, and it lasted for three issues.

    One last comment on the baneful effects of this trial:  While it was not responsible for the undue influence industry has on medical practice, this trial probably provided the greatest impetus towards the sad situation we are in today. It is possible that in the field of HIV medicine, industry had its greatest opportunity to establish a firm hold on many different ways to influence practice. These include not only marketing strategies, but influence on guidelines committees, support of continuing medical education, the support of medical conferences and influence on reports of their proceedings, as well as the invention of the Key Opinion leader or KOL, to provide information to physicians.    “Key Opinion Leader” is not the only absurd designation in this field.  We also have “Thought Leader”.  Needless to say these distinctions are not conferred by any academic institution; I would assume that the marketing departments of pharmaceutical companies are responsible for choosing who deserve these titles.

    (1)

    N Engl J Med 1987; 317:185-191July 23, 1987

  • iPrEx trial results of preexposure prophylaxis – PrEP

    Posted on December 12th, 2010 admin No comments

    Full Contents of this blog

    Pre-Exposure prophylaxis –  PrEP –  iPrEx  trial results.

    Pre-exposure prophylaxis, or PrEP, is an HIV prevention intervention in which anti-HIV drugs are taken to prevent infection.    A safe, effective and affordable drug that could achieve this would be a powerful prevention intervention even possibly capable of halting the spread of the epidemic.

    Last week we were told the results of the iPrEx trial that tested the efficacy of PrEP with Truvada, a combination of two anti-HIV drugs, in reducing new HIV infections among a group of men who have sex with men considered to be at high risk for HIV infection.

    The announcement of the results was greeted with almost universal jubilation.

    “That’s huge,”  said a prominent AIDS researcher,  “That says it all for me.”

    “Today marks a major step forward in our quest to combat HIV among MSM

    “This discovery alters the HIV prevention landscape forever,”

    “….. the new data “represents the most promising development in HIV/AIDS since the introduction of triple combination drug therapy in 1996.”

    “This is a game-changing trial result,”

    Science magazine reported that..

    “The researchers applauded and some even cried when they heard the bottom line”; “I have not cried this hard in years” – said one researcher.

    These exultant cheers are usually reserved for the most momentous of breakthroughs.

    Demonstrating that a drug could be safe and effective in preventing infection would indeed be a momentous breakthrough as already noted.

    But the iPrEx results, far from representing such a breakthrough, indicated that PrEP,  at least with Truvada, together with counselling and provision of condoms, reduced new HIV infections among men who have sex with men only modestly.   It’s unlikely that the 44% reduction in new infections that was seen is of sufficient magnitude to make PrEP with Truvada viable as a public health prevention intervention. Moreover, as will be described there are significant safety concerns, a demonstrated danger of the emergence of drug resistant HIV, and the drug is far from affordable.

    A 44% reduction in new infections is not huge; even those extolling the trial results would agree (at least I think they would, but who knows considering the over-the-top responses).

    But what is most troubling is that the researchers have squeezed an efficacy of Truvada  of over 90%  by a questionable statistical sleight of hand,  an improper use of sub-group analysis, a technique of data dredging has been soundly discredited.  I’ll return to this.

    This has resulted in  headlines such as “PrEP works – if you take your pills”, I don’t know if this will persuade some people to abandon condoms and religiously take their pills.  Unfortunately the type of analysis that provides confidence to do so is not reliable.  Maybe consistent use of Truvada will reduce new infections by over 90%. Maybe not.

    For the moment staying with the ability to reduce new infections by 44%, as a public health intervention to be used on a wide scale, this degree of efficacy is just not good enough to justify using Truvada to prevent a life threatening infection.   Even if the risk of infection is low this must be balanced against the gravity of the infection. About 3% of participants in the Truvada arm of the trial became infected as opposed to about 5% among those receiving placebo.

    Perhaps it’s on this issue that I’m at odds with the huge acclaim given to the trial results.  Maybe the prevailing view is that a 44% reduction in new infections is indeed good enough; some commentators are even discussing implementation.

    PreP proponents like to compare it to malaria prophylaxis.  If the efficacy of malaria prophylaxis were of the same order as that of Truvada in relation to HIV, I suspect many people might think twice before visiting an area where there was a risk of malaria.

    Let’s take a closer look at the trial results, particularly the claimed greater degree of efficacy in compliant participants   reported in the New England Journal of medicine.

    I have commented briefly on this in my blog on the POZ magazine website.

    The medication used in the trial,   Truvada,  is a combination of two HIV anti-HIV drugs, FTC and tenofovir.  It was compared with placebo in over 2000 men who have sex with men, considered to be at high risk for HIV infection.

    The 44% reduction in new infections was achieved in conjunction with counselling, provision of condoms and monthly tests to monitor for infection.

    This is not a good enough performance to justify widespread use of Truvada to protect against infection.  The investigators then looked at blood and tissue levels of the drugs in people who became infected and those who did not.  They found that those who remained uninfected had detectable drug levels while those who became infected did not.

    They incautiously trumpeted this result as proving that Truvada works well if the pills are taken consistently – stating that in those who took their pills more consistently the relative risk reduction was well over 90%.

    On the surface this sounds good. Almost all the commentators thought so.

    However looking at the results in a sub-group of participants can be misleading.  Most particularly in a sub-group that is defined after randomization; who would or would  not comply with treatment could not have been known.    The problems with subgroup analyses will be clearer after a short account of intention to treat analysis.

    Intention to treat analysis is the most reliable way to analyse clinical trial data.   In such an analysis participants are analysed in the group to which they were randomized, irrespective of whether they dropped out, or didn’t adhere to the treatment or strayed from the protocol in other ways. This seems counter-intuitive, but there are sound reasons why intention to treat is regarded as the best way to analyse trial data, among them  that it more reliably reflects what happens in real life, rather than in a clinical trial.  For example, one reason why pills may not work is because they are not taken. If they are not taken in a trial we have to be concerned that they may not be taken in real life.  Take a look at this excellent explanation of intention to treat:  Making sense of intention to treat.

    As noted, the trial investigators made a lot of the sub-group analysis showing greater efficacy in those who took  Truvada pills as measured by finding the drugs in blood and tissue samples.

    This is surprising  as the pitfalls inherent in such post-hoc sub-group analyses have been recognized for years.  Commentators, some of whom are clinical researchers, in their over-the-top exultation at the results of the analysis in those compliant with Truvada  may have forgotten about the treachery inherent in sub group analysis.  A few commentators give the problem only passing acknowledgement.

    This is a classic paper on sub group analysis:

    Yusuf S, Wittes J, Probstfield J, Tyroler HA: Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials.

    Journal of the American Medical Association 1991 , 266:93-98

    This is from that paper:

    “Analysis of improper subgroups, though seductive, can be extremely misleading, because a particular treatment effect may influence classification to the subgroup. Thus, an apparent subgroup effect may not be a true effect of treatment but rather the result of inherent characteristics of patients that led to a particular response or to the development of side effects”.

    In iPrEx  the subgroups were categorized by events that happened after randomization, so the adherent group is an “improper” subgroup.  “Subgroups of clinical trial subjects identified by baseline characteristics … is a proper subgroup while a subgroup determined by post randomization events or measures is an improper subgroup”.

    In actuality the attention given to the subgroup that had blood and tissue drug levels is an example of the treachery of such sub-group analyses.

    As an illustration, the reduction in new infections seen in this group may well have resulted from the following possibility.

    People who take their pills consistently are more likely to use condoms consistently and in general are more attentive to risk.   So if it were possible to do a subgroup analysis of people who adhered to placebo we might conclude that the placebo also works – (and it’s cheaper).

    This is not so fanciful.

    “In one study [3], those who adhered to the trial drug (clofibrate) had reduced

    mortality; but those who adhered to the placebo pill had the same reduction in mortality”.

    This is from:

    Coronary Drug Project Research Group. Influence of adherence to treatment

    and response of cholesterol on mortality in the coronary drug

    project. Engl J Med 1980;303:1038-1041

    A classic example of the pitfalls of subgroup analysis is  what it demonstrated in the ISIS-2, a trial examining the effects of aspirin after myocardial infarction.  A subgroup analysis showed it was of benefit to all except in people who were either Libras or Geminis.

    Maybe Truvada taken consistently can reduce new infections by over 90%; maybe not.  There was no basis for the investigators and commentators to present the first possibility with such overwhelming confidence.

    We must accept that a 44% reduction in new infections is at this time the most reliable estimate of Truvada’s efficacy as PrEP.   Although, the confidence interval , a measure of reliability, was wide.

    We have an intervention that can reduce new infections by 44%, if taken in conjunction with a program of counselling, condom use, and monthly tests for HIV infection.  That is the benefit.   What about the down side?

    The two most important are the development of resistance of HIV to the component drugs of Truvada and the toxicity of the drugs.

    The utility in treating HIV infection of FTC and tenofovir – Truvada’s component drugs is lost if the virus becomes resistant to the drugs.  Moreover, some mutations conferring resistance to these drugs can also affect sensitivity to some other drugs.  The danger of resistance, and even cross resistance to other drugs developing when Truvada is used as PrEP is not a trivial concern.    Truvada used as PrEP provides a suboptimal dose in treating established HIV infections.  This is precisely the situation in which resistance is likely to develop.   There were in fact two instances of developed resistance in the iPrEx trial in individuals who became infected, but undetected before the trial began.

    Resistant viruses in the community are a danger to all, so the risk of generating resistance is not confined to the individual taking Truvada as PrEP.

    What about safety?

    The claim in many reports that Truvada is without significant toxicity is also misleading.

    Maybe poor adherence has some bearing on the lack of significant toxicity.

    A median of 1.2 years exposure to Truvada can tell us little about cumulative and long term effects. Experience with long term use of Truvada in HIV infected people makes concern about toxicity realistic. Renal toxicity, sometimes severe occurs not uncommonly. It’s mostly but not always reversible on stopping the drug.   Thinning of bones, osteopenia and osteoporosis is also seen. There are additional adverse effects associated with the drugs.

    There were small abnormalities in some paramaters measuring kidney function among those treated with Truvada.  Although these changes were reversible on stopping the drug, the fact that they were seen at all is a reason for great concern about the effects of longer term treatment.

    With the experience we have gained from longer term treatment with Truvada, it is disingenuous to stress its overall safety from just 1.2 years of very inconsistent use.

    It’s important to point out that for HIV infected individuals, the benefits of treatment with Truvada far outweigh the risks.  For uninfected individuals, an entirely different risk benefit analysis must be made.

    Despite the disappointing results of iPrEx, PrEP is important.

    Why is PrEP important?

    There are at least two important reasons.
    1:

    PrEP could protect receptive partners in sexual intercourse, both men and women, who are unable to ensure that a condom is used by their partner and for a variety of reasons are unable to refuse sex .   The best and most respectful way of addressing this would be to find ways to empower these individuals; in some way providing them with the means to protect themselves could be seen to also have the effect of perpetuating their subjugation and abuse.

    But there are women and men who need protection now and providing them with a means to prevent infection that they can control is vital.  This can go hand in hand with working to empower them and helping them to try to ameliorate or leave abusive relationships.

    2:

    Sex is one of life’s joys.  It is vitally important to the human experience.

    Condoms can be a barrier to intimacy which for many is the most essential aspect of sexual intercourse, for both receptive and insertive partners.  So recommending the use of condoms without acknowledging the significant obstacle they may present to a fulfilling sexual experience is a real problem.   Pleasure is part of that fulfilment and for some insertive partners condoms are a significant impediment to experiencing it.

    A fully effective  and safe means of pre-exposure prophylaxis may also allow the removal of a barrier to conception.

    But people are different; for example some individuals have found that condoms can increase intimacy in the reassurance they provide concerning their and their partners safety.

    We should never minimize or trivialize the difficulties condoms can present.  We should also keep in mind that their use is the most effective means of preventing sexual transmission of HIV.

    Their use will remain necessary in order to remain uninfected until we are free from HIV or a safe an effective PrEP method can be found.

    These  considerations, a prevention method that the receptive partner can control,allow conception  and  remove an impediment to full sexual expression are reasons to work towards finding a safe and effective form of PrEP.   If this can be achieved safely and affordably it could even help to bring the epidemic to an end.

    Truvada unfortunately has not proved to be sufficiently effective or safe to be of utility as a general recommendation.  The use of condoms still  remains the most efficient way to prevent the sexual transmission of HIV.

    .

    A few words about prevention education and condoms:

    The  consistent use of condoms is the most effective means to  prevent sexual transmission of HIV.

    PrEP proponents agree but many go on to say that people just don’t use condoms consistently.  This is an attitude that has apparently concluded that prevention education does not and  cannot work.

    But how can one conclude that it does not work when there has been so little of it?   This has some analogy with the claims made for the efficacy of Truvada.   It works, if you take the pills

    .

    If prevention education has been a failure, it’s not because it doesn’t work, but because we have not provided it well enough.  There has been too little and most has not been properly targeted.

    Proper targeting to those most at risk is critical. I have written about this.  We need more and better prevention education.

    The CDC now tells us that the group at greatest risk by far in the US is men who have sex with men.  Nothing has changed except the ethnic distribution, so why are they only telling this to us now?     For over twenty years we were told that AIDS was an equal opportunity infection making prevention education targeted to those at greatest risk even more difficult.

    It’s only now, 25 years too late, that the CDC appears to recognize the urgency of providing prevention education to gay men.

    Neglect of properly targeted prevention education, with encouragement for condom use and continuing support to sustain their use helped to allow the spread of HIV into African American communities in plain view while millions were spent on “America Responds to AIDS” a vacuous prevention message.

    Similarly we have known for years that in the US younger men who have sex with men are at particular risk.  We know where to target prevention messages, but we don’t do it well enough.

    We know that highly targeted prevention education, when crafted by the communities at greatest risk can work.  This was demonstrated in the earliest years of the epidemic in San Francisco and New York City.

    In  1982 when Michael Callen, Richard Berkowitz and I first recommended condom use to gay men in New York City, we stressed that in doing so it was important to celebrate sex, recognizing that  for some individuals condom use, or perhaps more precisely, HIV,  could present a barrier to its full expression.      We have come far in freeing ourselves from long standing societal constraints that for too many have stood in the way of a fulfilling sexual experience burdening it instead with guilt.   It’s important to take care in providing continuing support for condom use and recognize that for many they do get in the way. But it’s really HIV that’s getting in the way, and consistent condom use can help to bring it to an end.

    Finding conditions where sex without condoms is safe is important.   On the showing of iPrEx – despite its ecstatic reception, PrEP unfortunately is not yet ready.

    At the moment consistent condom use is the best protection there is.

    The often uncritical response to iPrEx should not persuade anyone that Truvada  is a safe and effective alternative.

    iPrEx is a large and complicated study.  The investigators deserve the highest praise for completing this difficult phase and for havine provided a result.  It may not be the result that many had hoped for.  But providing clear information is a great achievement and a major advance . iPrEx results clearly show that continued condom use is still necessary to prevent the sexual transmission of HIV.

  • HIV infection in HIV antibody negative individuals

    Posted on November 6th, 2010 admin No comments

    HIV infection in HIV antibody negative individuals

    There is another post on this topic:   HIV exposed individuals who are seronegative.

    The possibility that there are individuals who are infected with HIV but who are negative on the test for HIV antibodies has always been theoretically possible. Considerable evidence has accumulated for many years that there are indeed such individuals. Despite the importance of this phenomenon, it receives relatively little comment.

    It sometimes seemed to me ever since I first tried to discuss this possibility in the mid 1980s that there was a wilful discouragement of any discussion of this topic.

    In 1989 David Imagawa reported that that 31 of 133 HIV antibody negative men showed the presence of HIV.

    In 27 of them this persisted for 36 months despite remaining seronegative (1). This resulted in a vigorous response culminating in what almost looked like a retraction by the authors. At that time many unsuccessful attempts to replicate these results were reported, and the findings of David Imagawa were generally presented as due to technical errors, such as incorrect specimen labelling. In view of many subsequent findings, the likelihood is that David Imagawa and his colleagues were correct. The furious response to Imagawa’s paper is an indication of how non rational considerations can influence the progress of science. This is of course nothing new.
    Curiously in a recent book, Imagawa’s findings are included in a list of what are stated to be errors and controversies in the HIV/AIDS epidemic that impeded scientific progress (2).
    What in fact impeded progress was a rigid adherence to what was only a hypothetical, not an empirical model of the course of HIV infection.
    David Imagawa died shortly after this controversy, and sadly did not live to see that his initial conclusions were absolutely consistent with what has been learned of the complexity and diversity of individual responses to HIV infection.

    I certainly experienced considerable resistance and disbelief when I raised the possibility of silent HIV infections. In the late 1980s I took part in a NPR program, and was quite abruptly dismissed by another scientist (I have forgotten who) when I raised the absolutely reasonable theoretical possibility of persistent latent infections in antibody negative individuals.

    Apart from very few exceptions there was an almost complete lack of interest in HIV seronegative, but infected individuals, by science writers; there was no shortage of community commentators who also seemed to be oblivious or uncaring of this phenomenon.
    To be sure there were occasional reports of seronegative but infected individuals. Gus Cairns, a UK journalist wrote about this in the UK magazine, Positive nation. I wrote something about this as a result of an interview with him in 2000, which he published. I have scanned the article. I was unable to make a perfect copy, but a legible version can be seen by clicking HERE.

    In the US reports confirming the existence of seronegative infected people continued to receive very little comment; what little there being generally quite hostile..
    Today this issue was again brought to my attention by an article I saw reporting the presence of HIV proteins and HIV RNA in cervical biopsies from women who were persistently HIV seronegative negative, at least for the duration of the study which was one year. They did not have antibodies to HIV despite being infected ; of course it is possible that they are in an unusually long “window” period and will eventually seroconvert.
    I expect that, as is usual this report will provoke little or absolutely no interest.
    But it is enormously interesting; (just one of many questions: can these women infect their male partners?) Seeing this article is the reason why I decided to make this issue the subject of this post.

    It was no great surprise when evidence appeared that there were some individuals who were HIV infected but remained negative on the HIV antibody test. It must be said that there were probably more papers in the early years in which silent HIV infections in HIV antibody negative individuals was not observed. In another approach, reports started to appear that HIV antibody negative individuals had T lymphocyte responses to HIV which means that they were exposed to the virus, not necessarily that they were infected – although that is quite a real possibility. Some early papers, before 2000, including those showing T cell responses can be seen by clicking HERE. There was quite an extensive literature at that time, but most, as mentioned reported that there was no such thing as a silent antibody negative infection, apart from the short window period following infection.

    Why has the possibility of prolonged latency always been theoretically possible?
    As part of its life cycle HIV is turned into DNA and is then incorporated into the host genome. In infected cells it effectively becomes part of our genetic material. Once inserted into human DNA, it must be activated to start the process of making new virus particles. Cellular signals that start the process of activating HIV DNA include cytokines, which are messenger molecules produced and released by cells, which can then act on other cells to evoke a variety of responses. Amongst these HIV activating cytokines are those that are produced during inflammation. Once HIV DNA is activated, and at least some of its proteins made, these then mediate further activation.
    There are some other factors that can activate HIV DNA.
    Alloantigens are antigens expressed on foreign cells. When these antigens are in contact with a cell containing integrated HIV DNA, activation occurs; HIV DNA is transcribed and new viral particles made. In earlier days HIV was isolated from infected lymphocytes in this way. Latently Infected lymphocytes were induced to produce HIV by culturing them together with lymphocytes from an uninfected donor.
    It is the nature of HIV infection that it is frequently acquired in situations which involve exposure to foreign cells (to alloantigens). This may be exposure to semen in sexual transmission, or blood cells in the case of infection by shared needles, or by blood transfusion.
    Herpes viruses have the ability to activate HIV if a cell is infected with both viruses. I suppose this must happen but I imagine doubly infected cells may not be too frequent. Of course active herpetic infections in non HIV infected cells may be associated with the production of pro inflammatory cytokines, which circulate and can activate HIV DNA at a distance.

    There is absolutely no reason not to expect that in some circumstances incorporation of HIV DNA into human DNA will result in a state of stable integration. This means that HIV DNA remains in the genome, it is not activated, and no virus is produced. Since antibodies are made as a response to viral proteins, and as none are made, the HIV antibody test will be negative.

    So it was no surprise when such individuals were again reported in 1999 . These individuals remained in good health and were reported to be antibody negative as long as they were observed.

    We cannot know if these individuals may seroconvert (or maybe already have), but what is established is that stable integration of HIV DNA without seroconversion can occur. In such individuals limited expression of HIV can occur, at least sufficient to induce, if not antibodies, a cellular immune response.

    The presence of such cellular immune responses in HIV antibody negative individuals is further evidence consistent with HIV DNA persistence, but in itself does not indicate this.
    Demonstration of cell mediated immunity to HIV:
    Apart from the identification of antibodies, specific immunity to HIV can also be detected by a much more elaborate test that measures cellular immunity rather than immunity determined by detecting specific anti HIV antibodies. In this case what is measured is the ability of lymphocytes to recognize HIV. They will do so only if they have been exposed to the virus, which would obviously be the case if they were taken from an infected individual.
    The detection of such lymphocyte responses in the mid 1990s was one of the first indications that there may be infected people who don’t make antibodies. Other interpretations are that the infection was overcome, or that that the individual was infected with defective virus.

    Gene Shearer was i believe the first to report this phenomenon. HIV antibody negative sexual partners of HIV positive people, as well as individuals who had occupational contact with HIV were among those showing these responses.
    It is unknown how widespread this phenomenon of silent HIV infection is. It may be exceedingly rare. It is also unknown if this condition of stable integration is really just a prolonged “window” period that always follows all HIV infections.
    But It is entirely possible that there are individuals in whom the ability to control HIV is such that they will remain healthy and HIV negative.

    A number of different possible outcomes of HIV infection are possible:
    Some of the factors that influence this:
    Host genetic factors.
    Size of the inoculum – the amount of infecting virus.
    Route of infection.
    The particular virus strain.
    The presence of associated systemic infections.
    these provide signals activating HIV proviral DNA. In the case of some tropical infections there may be cytokines (IL 10) that blunt immune responses.
    Sexually transmitted infections with genital ulcers.
    Double infection of a cell with HIV and herpes viruses – probably an unusual occurrence.
    Exposure to alloantigens; a theoretical possibility.
    These are some of the known influences.

    Maybe the most common outcome is a productive infection where viral DNA is activated within a few weeks.
    But this scenario is also possible:
    Infection is followed by insertion of HIV DNA into cellular nuclear DNA. Possibly with small inoculums, and in the absence of strong or sustained activation signals, the proviral DNA remains silent. This has been observed.
    Or this one:
    There is a limited burst of viral production, not sufficient to elicit an antibody response but enough to induce a cell mediated response with the generation of lymphocytes that recognize HIV antigens and can kill HIV infected cells. HIV seronegative individuals with such specific lymphocyte responses have certainly been observed. In this case if there is an incipient burst of HIV production, the producing cells are promptly killed. Each time this happens the cellular immune response is primed and strengthened. Such a mechanism has been well studied in EBV infections. This common virus is totally unlike HIV, but it does similar things. It remains present in B lymphocytes rather than T lymphocytes for life. The mechanism of persistence is quite different – EBV is not a retrovirus. But the majority of individuals carry this virus – which in rare situations can have lethal effects, in their B lymphocytes for life. We have evolved many mechanisms to keep this virus in check. The ability of some types of lymphocytes to kill EBV infected cells which start to make virus is well understood. Similar mechanisms must exist for HIV – but obviously for most are insufficiently effective. But in those with very limited HIV production these killer lymphocytes may actually be what allows such rare fortunate individuals to remain HIV seronegative.
    With this outcome, one can view the infection as actually having an immunizing effect.
    If there were not yet enough reason to study the phenomenon of persistently seronegative HIV infection, here is an important one. What are the circumstances that produce this outcome? Individuals who are seronegative but have lymphocyte responses to HIV are of great interest.

    Yet another scenario is one of stable integration, but where some HIV proteins, but not complete virus, are produced. Maybe the women referred to whose cervical biopsies contained HIV antigens might be in this category. This is a strange situation as antigens were detected but these women apparently did not develop antibodies.

    Shortly after HIV was discovered a description of the course of HIV infection was produced. Everyone interested in this disease will have seen this picture: Here it is again:

    The life span after untreated infection was said to be 10 -11 years. But this period had not even passed since the start of the epidemic. This picture is a total construct, but presented as something that had empirical foundations.

    Within 5-6 years of the start of the epidemic scientists confidently presented this conjectural picture as fact. It does not allow for the immense variation in the course of HIV disease and has I believe adversely affected research progress as well as had implications for treatment, where a one size fits all approach seems to be standard.

    The uncritical acceptance of the above depiction of the course of HIV infection is particularly odd as not only was the disease new – we have no precedents of human retroviral diseases (apart from HTLV-1 associated disease, but the techniques used to study the disease were themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea then of the variation in T subset numbers in health and disease. Other immunological and virological techniques were being introduced as the epidemic was proceeding.
    The validity of the very concept of a “standard” course of HIV infection is in question. HIV infection can progress in different ways. If we were more open to this there may greater interest and funding into research that investigates the various factors that influence how the disease progresses. HIV disease is in this sense like almost every other infectious disease. I could probably leave out the almost.

    I have often wondered why there has been such resistance to not only the reasonable idea, but also to actual evidence that HIV disease may take a different course to that shown above.
    It may be that most untreated infections follow such a course; we may never know now that we have treatments.
    But we do know that there are other responses to HIV infection.

    In conclusion, the study of prolonged HIV seronegativity in infected people is important. Some reasons are:
    1. There are obvious implications for vaccine development.
    2. Seroprevalence may significantly underestimate the prevalence of HIV infection.
    3. Understanding the phenomenon will advance our understanding of the pathogenesis of this disease, which in turn will open new therapeutic approaches.

    1. Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al.. Human immunod-eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. New EnglandJournal ofMedicine 1989 320:1458-1462.
    2. Scientific Errors and Controversies in the U.S. HIV/AIDS Epidemic: How They Slowed Advances and Were Resolved
    By Scott D. Holmberg
    Published by Greenwood Publishing Group, 2008

  • HIV exposed individuals who are seronegative.

    Posted on October 18th, 2010 admin No comments

    A current supplement to the Journal of Infectious Diseases is devoted to natural immunity to HIV infection.

    It contains several articles dealing with individuals who have been repeatedly exposed to HIV and remain seronegative. They are apparently able to resist infection and do not develop antibodies against HIV.   Several different genetic and immunological mechanisms have already been discovered that can account for this phenomenon.   The best known may be the inherited absence of a particular cell surface molecule that HIV needs in order to infect a cell, as a result of a genetic mutation (CCR5delta32).   But this is far from the only basis for the apparent resistance of some individuals to HIV infection.

    Gene Shearer is a pioneer in the study of HIV exposed seronegative individuals who published some of the earliest reports on this phenomenon.  In this journal supplement he with Mario Clerici estimate that about 10 – 15 % of individuals repeatedly exposed to HIV remain uninfected.       They note that in the first years of the epidemic “little attention was given to the chance observation that mucosal [or] parenteral exposure to human immunodeficiency virus type 1 (HIV) would not consistently induce infection, and none to the possibility that such putative non-infectious exposures might induce protective immunity “.

    I can’t recall that there ever was an assumption that mucosal or parenteral exposure to HIV would  consistently induce infection.   This would have accorded HIV the probably unique ability among infectious agents to infect 100% of those exposed to it.      However I certainly recall that in the earliest years after HIV was discovered it was assumed that infection would invariably lead to disease.  HIV infection it was claimed was like a Mack truck with nothing but time standing in the way of its inevitable progression to disease.  This too would have made HIV infection almost unique among infectious diseases.  Rabies may be the only infectious disease where 100% of infected (and unvaccinated) individuals become ill, although I believe some exceptions have been described.

    The rapid acceptance of the assumption that HIV infection always leads to disease was quite remarkable at that time, as there could not yet have been sufficient observations to justify ascribing such an unusual property to HIV infection.    Yet this view was so firmly held by the HIV research leadership that it was left to AIDS activists to alert them in the 1990s(1)  to the fact that there were indeed individuals who appeared not to have progressive disease, or whose disease progressed very slowly.

    We had come to understand that infection and disease are not synonymous terms, but remarkably it seemed that this important lesson learned at least a century ago had somehow been ignored by some of those producing a detailed picture of the course of HIV infection at a time when so little was known about it.

    These words were written by Rene Dubos, a great microbiologist, in Man Adapting published in 1966.

    “…….This approach requires that the determinants of infection be separated conceptually from the determinants of disease; its objective will be to understand and control the processes responsible for converting infection into overt disease”

    That there is a distinction between infection and disease is something I learned as a medical student in Johannesburg in the 1950s which I in turn tried to pass on when I taught medical students in New York in the late 1960s until 1977.    Even in the first years of the epidemic I sent copies of Man Adapting to several individuals involved in the early response as I was discovering with surprise that some concepts that I thought were firmly established in our understanding of infectious diseases seemed all too frequently  to have been forgotten.

    Rene Dubos, was associated with the Rockefeller University in New York for 50 years.  He was a truly towering figure; his writings helped move us beyond the oversimplification that is the germ theory of disease.  While recognizing that the doctrine of specific etiology – as represented by the germ theory of disease was “the most powerful single force in the development of medicine”, he also wrote that “there is now increasing awareness that it fails to provide a complete account of most disease problems as they naturally occur”.

    Rene Dubos died in 1982, one year after AIDS was first recognized.  The “now” in the above quotation refers to a period before 1966, when “Man Adapting” was published.  The increasing awareness of the limitations of the doctrine of specific etiology had apparently dissipated by 1981, at least in the medical response to AIDS.   At that time, genetic factors, socio- economic factors, behavioral factors, the effect of concurrent infections, or anything else were not going to slow the Mack truck.  By 1990, only six years after HIV had been discovered we were also told that, except for a period of 3 to 6 months after infection, called the window period, tests for HIV antibodies could not fail to detect infection.

    But reality cannot be held at bay indefinitely, and to the surprise of some there did indeed appear to be individuals who were HIV infected but were able to control the infection to varying degrees, as well as those who were infected for prolonged periods but had no detectable antibodies.    However when the first reports of these phenomena appeared, the authors were subjected to a torrent of outraged criticism, much of it abusive.

    David Imigawa and The Window Period.

    In 1989 David Imagawa, reported that in 31 of 133 HIV antibody negative individuals it was possible to detect the presence of the virus for periods longer than 6 months.  In 27 of these individuals, HIV continued to be detected for up to 36 months despite remaining HIV antibody negative (2).   This publication in the New England Journal of Medicine resulted in a furious response culminating in a letter to the New England Journal of medicine from David Imagawa and Roger Detels that almost appeared to be a retraction but certainly was not.

    David Imagawa and his colleagues were subjected to hostile and  baseless criticism, not only from leading researchers but also from science writers.

    This is the headline of a story in the New York Times in 1991 which will give an indication of the kind of response the report received.

    THE DOCTOR’S WORLD; Researchers in Furor Over AIDS Say They Can’t Reproduce Results.

    This is how the article starts:

    “THE scientists who came up with one of the most shocking scientific findings about AIDS — one that set off alarms concerning the safety of the blood supply and about the state of mind of people at risk — now cannot reproduce their own results. But they still have not said clearly that their finding was incorrect”.

    It includes this statement:

    “Even this confusing letter would not have appeared without constant pressure behind the scenes from officials of the National Institutes of Health who paid for the original research and who were determined to try to straighten the record”.

    But how secure was the record from which David Imagawa and Roger Detels had strayed?

    In 1989, only 5 years after the discovery of HIV, with relatively little experience accumulated by that time, we could only be at a stage of establishing a record.   Activists had yet to alert officials that long term non progressors really existed.

    Whatever attributes science possesses that distinguishes it from more metaphysical pursuits surely one is a requirement to as best as we can describe phenomena as they are, rather than as we might wish to see them,  so the constant behind the scenes pressure exerted on David Imagawa sounds more like demands made on an apostate to recant.

    David Imagawa’s observations were in fact correct. Similar observations have been made by others.

    Sadly he did not live to experience the vindication of his pioneering studies.  He died of a heart attack shortly after the New york Times article appeared.

    A fairly detailed account of the course of HIV infection had been constructed only 5 to 6 years after the discovery of HIV, essentially that illustrated in this very familiar diagram.

    The rapid acceptance in those early years  that there  even was  a typical course of HIV infection is particularly odd as not only was the disease newly recognized, we then had no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease were themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea at that time of the variation in T subset numbers in health and disease. Other immunological and virological techniques were, and continue to be introduced.

    At that time, only 5 to 6 years after the discovery of HIV there could not have been a solid enough empirical basis to justify the confident assertion, in the case of sexually transmitted HIV that there could not be situations where integrated HIV DNA is carried for prolonged periods without seroconversion.  Unlike infections acquired by blood or blood products, the time of initial infection can rarely be known.  The infecting dose of virus in the case of sexual transmission could be even orders of magnitude less than that when infection is acquired by blood transfusion.

    How then to account for the persistence of recoverable virus for up to 36 months in the absence of seroconversion?

    In the original New England Journal of Medicine publication David Imagawa and his colleagues raised the possibility of a “silent” HIV infection, suggesting that HIV in the form of proviral DNA integrated into the genome could persist without production of HIV virions.   This is a perfectly reasonable suggestion.  But in their subsequent letter, they changed their minds and ascribed their finding to the ability of the men to overcome the infection. Because of continued high risk activity virus was repeatedly detectable.   In a more recent article Roger Detels expands on this explanation, noting:  “The fact that we isolated HIV ONLY from those men who continued their high-risk exposure suggested that transient infection and clearance of HIV was the more likely explanation”.

    Of course this may be the explanation.  If so, HIV sequences should have been consistent on repeated isolations, whereas if infections were transient, variations would likely  have been seen with repeated isolates.

    But it was not the explanation in another report of HIV DNA in two antibody negative individuals (3).   In the abstract of this paper the authors note:  (ES refers to exposed seronegative individuals)

    “Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specificcytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.05 + /- 0.01 copies per million cells) at multiple visits spanning 69 to 130 weeks in two ES individuals at levels that were on average 10(4)-to 10(6)-fold lower than those of other HIV-1-infected populations reported. Sequences of HIV-1 envelope and gag genes remained markedly homogeneous, indicating little to undetectable virus replication. These results provide the evidence ……… suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1strains despite continued high-risk sexual exposures to multiple HIV-infected partners. Understanding the mechanisms that confer diminished replicative capacity of HIV-1 in these hosts is paramount to developing strategies for protection against and control of HIV-1 infection”.

    At the heart of the furious response to David Imagawa’s observation is the fear it raises about the safety of the blood supply and the peace of mind of those testing HIV negative.  Roger Detels in the article linked to above makes these comments:

    “We were presented with an ethical dilemma — should we publish knowing that there was a possibility that the publication would create panic, or should we not publish to prevent the panic? “

    As far as the blood supply is concerned, the most reliable data on the window period were derived from observations on transfusion related infections, and antibody tests have been  hugely effective in ensuring the safety of the blood supply  (even without additional tests reducing the risk to less than 1 in 1,000,000).   So the New York Times article and others like it were quite unjustified in raising fears for the safety of transfused blood based on observations made on sexual transmission.

    As far as the peace of mind of individuals testing negative is concerned, if there should be those who are able to maintain HIV in latency in the form of proviral DNA, that is never fully expressed, it’s entirely possible that in some of these individuals, HIV has had an immunizing effect rather than causing productive infection.

    It appears that to this day the reluctance to even consider HIV seronegative infection persists.

    Returning to the supplement of the Journal of Infectious Diseases dealing with natural immunity to HIV, the possibility of stable HIV infections that remain unexpressed is not considered at all as at least one explanation for persistent seronega   tivity  of some individuals exposed to HIV.   It seems to be just taken for granted that these individuals are resistant to infection.  But how can it be known that all of these seronegative individuals exposed to HIV have resisted infection?   Some may carry HIV in the form of unexpressed proviral DNA.   Even if this is not detected in cells circulating in the blood stream this does not mean a great deal as only a tiny minority of CD4 + cells circulate, and the DNA containing HIV may be in cells without the CD4 receptor.

    Over a year ago I wrote about HIV infection in seronegative individuals.     There I outlined one possible consequence of HIV infection.  Retroviral replication requires prior integration of the viral genome into that of the host cell in the form of proviral DNA which must be activated before new virions can be made.  Under certain conditions it’s possible that the process may stop at integration or be aborted after a very limited expression of viral gene products.  No virus is produced so there will be no antibodies as these are made in response to viral proteins. If there had been very limited expression of viral gene products this might induce cell mediated immune responses, as has often been reported in HIV seronegative individuals.  This may be sufficient to kill HIV infected cells that start to express HIV antigens on their surface, and with each incipient burst of replication the immune response might be further primed.

    EBV is a virus that remains latent in B lymphocytes rather than T lymphocytes. Virtually all adults carry this virus and remain in good health although EBV can be lethal under certain circumstances.   Much is understood of the elaborate mechanisms that maintain this virus in latency.   EBV is very different to HIV, it’s a double stranded DNA virus, huge in comparison with HIV – with a genome of 172 Kbp compared to HIV’s of less than 10.  Unlike HIV its replication does not require integration into the host genome.   Despite these differences, if HIV can be maintained in latency we might expect that analogous mechanisms operate, and provide a helpful model.

    If HIV can be carried in a stable integrated form as proviral DNA, that is not expressed at all or only partially and intermittently expressed, then this may be the basis for the apparent resistance of some ESNs.  Such individuals are not resistant to infection, but for probably a variety of reasons connected both with the virus, as well as host factors, the infection is aborted at the stage of integration.

    We know some of the signals that can activate HIV DNA to start the process of making new viral particles.  Some cytokines are potent activators of HIV and can also appear during the course of other.    In the absence of sustained activating signals and with a small infecting dose of virus abortive but persistent infection might occur.  If there is very limited viral replication this may be sufficient to induce a cell mediated immune respons

    It would be extremely difficult to identify such individuals as cells carrying HIV DNA may not be in the circulation.

    Since it’s not too practical to study biopsy specimens, HIV genome detection techniques applied to tissues from a large number of unselected autopsies may just surprise us.

    (The following is adapted from the previous post)

    A model representing the course of HIV infection shown in the above illustration was constructed before sufficient evidence was available to justify it.  It really had a very limited empirical basis at that time; moreover it seemed to utterly ignore what we knew of other chronic viral diseases.  For example, hepatitis B and hepatitis C can both have very variable courses.  These can range from clearing the infection, running a fulminant course ending fatally,  to the establishment of a chronic active state which may progress at varying rates.  If we were to construct a model of the course of HIV disease less than 10 years  after the virus was discovered, why  did we not consider the precedents of other chronic viral diseases?   Thus we might have then included the real possibility that some exposures may result in infections that are cleared, as well as a situation where disease does not progress.    The picture shown above – and presented in every text on HIV disease may indeed represent the most common course of HIV infection. But even this is not known.

    HIV infection, like other chronic viral infections can progress in different ways. If we were more open to this there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses. This has obvious therapeutic implications  –  for example as proinflammatory cytokines promote HIV replication, the control of endemic infections in some areas where they are highly prevalent is absolutely relevant to the control of HIV infection.  Steps as simple as the provision of sanitation and clean water may well have an impact on the control of HIV infection in some geographical areas.  Had we not been so tied to the notion of  a fixed course of HIV infection, we might have placed importance on the individualization of therapy, not only considering a fixed CD4 count as a signal to start therapy, but also considering each individuals rate of disease progression.

    HIV disease is in this sense like every other infectious disease, the course of which to a greater or lesser extent can be influenced by many different factors, including host factors, factors related to the pathogen, the particular variant , the size of the infecting dose, the route of infection amongst many others.

    I have often wondered why there has been such resistance to not only the reasonable idea, but also to actual evidence that HIV disease does not necessarily take the course shown above.

    1:

    http://www.poz.com/articles/hiv_macs_anniversary_401_16589.shtml

    “Gonsalves recalls a meeting with Anthony Fauci, MD, head of the National Institute of Allergy and Infectious Diseases, in the early 1990s. He and fellow activist Mark Harrington, along with a New York City physician named Joseph Sonnabend, explained to Fauci that Sonnabend had a small group of patients with HIV who didn’t seem to have disease progression. They wanted Fauci to explore this phenomenon—and it was the MACS that took up the question.

    Phair says he and other MACS researchers confirmed the existence of these nonprogressors ….”
    2:

    Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al.  Human immunod eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. New England Journal of Medicine 1989 320:1458-1462.

    3:

    Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals.

    Journal of virology, {J-Virol}, Jun 2003, vol. 77, no. 11, p. 6108-16,

    Zhu-TuofuCorey-LawrenceHwangbo-YonLee-Jean-MLearn-Gerald-HMullins-James-IMcElrath-M-Juliana.

  • AIDS Origins.

    Posted on September 30th, 2010 admin No comments

    Unsafe medical practices in equatorial Africa fifty to eighty years ago probably helped to set in motion an epidemic of hepatitis C infection.

    Two articles in the current issue of Clinical Infectious Diseases show that injections for the treatment and prevention of endemic diseases highly prevalent in parts of the Central African Republic and Cameroon were probably responsible for the spread of the hepatitis C virus and of human T lymphotropic virus 1 (HTLV-1).

    Human African Trypanosomiasis more familiarly known as sleeping sickness is spread by the bite of the tsetse fly and is almost invariably fatal if untreated.  It is a horrible disease.  This video will give some idea of its impact1.

    Sleeping sickness was highly prevalent in south-eastern regions of the Central African Republic.

    It was treated with intramuscular injections of pentamidine after about 1946 until 1950.  Before 1946, subcutaneous or intravenous injections of another drug, orsanine, had been used.  If there was central nervous system involvement treatment consisted of 12 weekly intravenous injections of yet another drug,  tryparsamide.   Injections of pentamidine were also used at a population level to prevent infection.   Intramuscular injections were given twice a year between 1947 and 1953.

    In Cameroon, the risk of acquiring hepatitis C was associated with the intravenous administration of quinine to treat malaria.   Other possibilities for transmission 50-80 years ago include intravenous injections to treat syphilis or yaws, and   blood transfusions.

    Re-usable equipment was all that was available at that time.  Disposable needles and syringes had not yet been introduced.   Much less information would have then been available about how easily infectious agents can be transferred by contaminated injection equipment.

    The relevance to HIV is that the rural areas in the south east of the Central African Republic and the southern Cameroon are close to the sites where SIVcpx has been isolated from chimpanzees.   This virus is believed to be the precursor of HIV-1.

    The HIV-1 and HIV-2 epidemics originated from cross species jumps from two different non-human primates.  Attempts have been made, in the case of HIV-1, to pinpoint in time when the fateful transfer occurred, as if it were a unique event, rather than something that has probably happened countless times.  Cross species transmission of some viruses may in fact be quite efficient.  Simian foamy virus (SFV) causes absolutely  no ill effects in humans, but about 25% of people reporting a monkey bite or scratch in Cameroon  have evidence of SFV infection.

    Man and other primates have been living in proximity in Africa for millennia, so cross species transfer of viruses will have been frequent.

    The “why now” question about the HIV epidemic is not about when the species jump occurred, but about when conditions were such that widespread human to human infection became likely enough to start an epidemic.    It’s just not plausible that two unique events, the jump of HIV-1 and HIV-2, each from two different primate species occurred in the same time frame.

    Conditions that enabled the widespread transmission of HIV between humans probably resulted from a multiplicity of factors coming together at the same time.  But part of the puzzle may be explained by unsafe medical practices 50 to 80 years ago in regions of Africa where SIVcpz has been found.   What may have been fateful was not a unique monkey to human transmission but that something that happens repeatedly    was occurring at a particular time and place where further spread between humans was facilitated to a greater or lesser extent by unsafe medical practices.

    In previous posts about the pathogenesis of HIV disease I have frequently pointed out the relevance of some endemic infections in Africa to HIV disease.   Some of these infections, by contributing to immune activation will enhance HIV replication, and it seems reasonable that infectivity will increase because of greater viral loads.   So this is yet an additional factor favouring the spread of HIV.  The regions of the Central African Republic and Cameroon mentioned above carry a particularly heavy burden of endemic infections associated with immune activation.

    Are unsafe medical practices a thing of the past?

    Do we no longer need to be concerned that they may contribute to the spread of HIV infection?

    Simon Collery works in development in Kenya.  He is in a position to address the issue of the safety of medical practices from the field.

    The following was written by Simon Collery:

    I have been studying the spread and decline of HIV through Kenya for seven years, using any relevant material I can find, whether it be medical, scientific, economic, geographical or administrative. Part of the picture I have of the epidemic in Kenya is drawn from this research.

    Another part of the picture derives from living and working in Kenya, and also some time in Tanzania and Uganda, for three years, talking with people, observing, writing, discussing and reasoning.

    My tentative conclusions are that, despite being extremely poor, having a very high disease burden, low levels of education, terrible healthcare, crumbling infrastructure, long periods of food insecurity and many other adverse conditions, Kenyans are much like people from other countries.  That may not sound like a very profound conclusion until you compare it to assumptions that are frequently made that Africans have a great deal of sex much of it being unsafe.

    On the other hand when it comes to health care facilities Kenyans are exposed to conditions that are vastly different to those experienced by people living in the developed world.

    Let’s look at Kenya in more detail. Overall prevalence of HIV infection is about 7%, but in North Eastern Province it’s less than 1%, about a third of the level found in Washington DC. But in the poorest province, the one with the highest rates of poverty, the lowest levels of education, the least access to health services and some of the highest rates of ‘unsafe’ sexual behaviour, you also find the lowest prevalence of HIV.

    In contrast, the highest rates of HIV are found among one tribe, the Luo, many of whom depend on the fast declining fishing industry around Lake Victoria. Prevalence there is 20% or higher, closer to rates found in the highest prevalence countries in the world, such as Swaziland or Lesotho.

    Many aspects of sexual behaviour in the Luo area are similar to what you’d find in other areas, in Kenya and elsewhere.

    HIV is not just about sex. Therefore, reducing HIV transmission should consist of more than education to reduce sexual transmission.

    When it comes to non-sexual transmission of HIV, such as transmission through unsafe injections, UNAIDS does not say very much, merely referring to their statement that 70 -90% of transmissions result from heterosexual sex.

    How did they work out that HIV transmission from unsafe injections in Kenya probably only contribute between 0.6 and 2% of infections? The question is pertinent considering the same report that includes this table, admits that there is very little information available on injection safety and that it is difficult to get baselines.

    The World Health Organization gives a slightly different story . They estimate that, worldwide, up to 40% of injections are unsafe, because needles and syringes are reused without sterilization. In some countries this figure can be as high as 70%. They also estimate that about 70% of injections are unnecessary or the drug could be administered orally. These phenomena give rise to over one third of hepatitis B and C infections and between 2% and 9% of HIV infections.

    Where does Kenya fit into this picture? As UNAIDS admit, there’s not much data. But there is a document called the Service Provision Assessment which looks at conditions in various kinds of health facility, such as hospitals, clinics and pharmacies.

    A few samples from this document may suffice to illustrate Kenya’s capacity to prevent HIV transmission through unsafe injections and other healthcare practices: Between 10 and 15% of facilities don’t have adequate supplies of needles, syringes or latex gloves; between 55 and 70% don’t have running water or soap; many don’t have facilities for disposing of contaminated equipment or supplies of disinfectant; less than half have guidelines for infection prevention and less than 10% have guidelines for sterilization.

    Although this document dates from 2004, we don’t know if there has been any change.

    Here is part of a table from the report:

    There’s little doubt that unsafe health care is still a problem in Kenya and other high HIV prevalence countries. What’s not clear is how big a problem it is. Because, despite admitting that they don’t have the sort of data on unsafe health care that would allow an estimate to be made, UNAIDS and the WHO have failed to investigate or to carry out the research required.

    While sexual transmission may be the predominant mode of HIV transmission, non-sexual transmission is significant and neglected.  What is inescapable is that, if we truly care about the health of populations, the conditions of health care facilities in many parts of the world are completely unacceptable, as shown in the WHO report above.  These conditions pose a danger of acquiring not only HIV, but of many other infectious diseases.

    ————————————————————————————————————————————

    1:  This video was made in the Democratic Republic of Congo where in some regions the prevalence of trypanosomiasis exceeds that of HIV.  Although HIV replication can be enhanced by many endemic infections In Africa, trypanosomiasis may be one that could exert an inhibitory effect.

    This was also posted to my POZ blog site.

  • Posted on September 28th, 2010 admin No comments

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  • HIV disease and Positive feedback: An additional comment.

    Posted on August 31st, 2010 admin No comments

    HIV Disease and Positive Feedback.  An additional comment.

    A previous post focussed on the positive feedback interaction between HIV replication and immune activation.   HIV replication and immune activation reciprocally enhance each other.

    While HIV infection is an essential cause of the immune activation that’s characteristic of HIV disease, there are other factors that also contribute to it.   In that post as well as in the blog I write on the POZ magazine website, I described some of these additional factors that can add to immune activation.   As noted, viruses of the herpesvirus family, cytomegalovirus (CMV) in particular are the most important of these worldwide, while in parts of Africa certain endemic infections may be of great significance in contributing to immune activation.

    Since sustained immune activation, involving both innate and adaptive immunity is at the heart of the pathogenesis of HIV disease an understanding of how it is perpetuated is critical.

    Evidence for activation of innate immunity was noted in 1981, the year that AIDS was first reported, in the detection of large amounts of alpha interferon in the circulation of patients.  We even knew then that interferon alpha and gamma could  induce an enzyme, indole 2,3-dioxygenase  (IDO),  (IDO was known to be responsible for the inhibition of toxoplasma gondii by depletion of  tryptophan  in cells treated with gamma interferon) but we did not know then that this enzyme could contribute to the loss of T lymphocytes.   Another observation of historical interest is that even before AIDS was first reported in 1981, interferon was known to preferentially inhibit CD4 lymphocyte proliferation in mixed lymphocyte culture.

    Since immune activation and its effects, including  inflammation, are harmful if sustained,   there are mechanisms that can  dampen it.

    But in HIV disease, immune activation persists with continued deleterious consequences.

    The reason I’m revisiting this now is that there is a question that continues to be bothersome.

    HIV disease is not the only infection associated with long standing immune activation.

    Several endemic infections in Africa are also associated with sustained immune activation, certainly not all – some even have a dampening effect on immune responses. TB is another example of an infection associated with chronic immune activation.   In none of these conditions is there such a profound loss of CD4 lymphocytes as in HIV disease.  While individuals with active pulmonary  TB have been reported to have lower CD4 counts than healthy individuals, the numbers were well above 500.

    Is the difference between sustained immune activation associated with HIV and that associated with other chronic infections in HIV negative individuals a matter of degree – is it a quantitative difference?

    Could the  mechanisms that dampen and check  immune activation be impaired in HIV disease?   These mechanisms include the secretion of cytokines that have anti-inflammatory properties, such as IL-10, IL-13, and  TGF-beta, among others.  Specialized immune system cells can also dampen immune activation.  Tregs, a subset of T lymphocytes, have such a dampening effect.   Although there are conflicting reports on the relationship of Tregs to HIV disease, it is known that HIV targets some of  these particular T lymphocytes.

    This graphic comes from a previous post.

    In the diagram,  disease progression is represented by a circular  clockwise movement propelled by a positive feedback interaction between HIV replication and immune activation.   It can be accelerated by infections that contribute to immune activation, CMV in particular, but probably also  some endemic infections in parts of Africa.   CMV probably also has a positive feedback association with HIV in that it is more likely to be driven out of latency in the setting of HIV infection, and active CMV infections can enhance HIV replication by several mechanisms including their contribution to immune activation.   Some endemic infections probably also have analogous reciprocal interactions with HIV.    The influences that can slow the cycle are those mechanisms that dampen immune activation.   They include the effects of  Tregs, a subset of T cells with regulatory functions that  dampen immune responses, and the effects of cytokines with anti-inflammatory properties.

    In graphic terms, the speed of the clockwise circular movement will be the balance of forces that speed it up and those that slow it down.

    HIV disease progression is represented as moving clockwise in a circle, reinforced by sources of immune activation other than HIV and retarded by Tregs and other mechanisms that dampen immune responses.  Tregs  act as brakes, but HIV can directly make the brakes less effective.

    Could critical differences between HIV disease and other infectious causes of long standing immune activation where CD4 numbers are relatively preserved, be  the preferential targeting of Tregs by HIV and a different pattern of cytokine secretion?

    I wonder if this revised representation of HIV disease lends itself to a more formal modelling process.

    In this particular model a disease process is represented by a circular motion in a clockwise direction, with forces that both propel and retard it.  Some predictions can be made.

    The degree of immune activation at the time of HIV seroconversion would favour more rapid HIV disease progression.  The set point – the level from which CD4 lymphocytes decline following an acute HIV infection, would be lower, and the subsequent  rate of CD4 decline higher when HIV infection occurs in a person where there already is a higher degree of immune activation, compared to an individual where this is not the case.  There already is  some evidence in support of this possibility.

    It’s well established that HIV disease progresses more rapidly with increasing age.  Could an explanation for this be that immune activation increases with age – indeed, it’s been suggested that immune activation  contributes to the aging process.

    HIV disease progresses more rapidly in individuals with active TB.  CMV viremia was noted to carry an adverse prognostic significance in HIV disease very early in the epidemic.  There are but two  examples, but there are many more of  of a more rapid course of HIV disease in the setting of other  infections caused by bacteria, protozoa, viruses and helminthes.  Some are referred to in a previous post.

    Are Treg numbers at seroconversion and for a period immediately afterwards  related to subsequent disease progression?

    Could treatment with anti CMV agents during acute HIV infection retard subsequent disease progression?

    There already  is some evidence that treatment of HIV during acute infection might slow the subsequent course of HIV disease.

    The utility of any model of a disease process lies in its ability to provide a common explanation for disparate observations as well as to make predictions that can be tested by an analysis of available data or by experimentation.

    Viewing HIV disease as a process with a positive feedback interaction between HIV replication and immune activation with forces that both enhance and retard this interconnection,  provides a useful descriptive framework as well as testable predictions.

  • We need reliable evidence to justify an earlier start of anti-retroviral therapy. May, 2009

    Posted on May 19th, 2010 admin No comments


    The most recent revision of the US Department of Health and Human Services (DHHS) guidelines for the treatment of HIV/AIDS recommended initiation of anti-retroviral treatment at a CD4 count of 500.

    This recommendation was made in the absence of evidence from a prospective randomized clinical trial.   Instead, evidence of inferior quality was relied on.

    Much is at stake for HIV infected individuals.  The point in the course of HIV infection when treatment is initiated can affect the duration and quality of life.

    Rather than issuing interim guidelines pending the completion of a prospective randomized trial the guidelines committee has jumped the gun, relying on evidence of inferior quality.

    In the following article, John Falkenberg reminds us of the harm that has resulted from basing recommendations on observational cohort studies.

    —————————————————————————————

    John Falkenberg  New York, NY

    Doctors and patients always have the right to choose treatment that is not based on data generated from well-designed clinical trials.  However, I worry when treatment guidelines are based on cohort studies or anecdote, and it’s alarming when the city of San Francisco and Project Inform endorse that practice.

    No study is cited more often than NA-ACCORD, an observational cohort study, to support early antiretroviral therapy.  Besides the many historical examples of harm caused by treatment guidelines based on observational studies (see the Nurses’ Health Study, below), NA-ACCORD suffers from more than the self selection bias of observational studies:  a large percentage of the deferred treatment group, approximately 45%, did not initiate therapy and/or did not have a decline in CD4 counts.  How can those findings be extrapolated to clinical practice?  In addition, the early treatment group may have had incomparable medical care.  For example, were lipids more carefully monitored in that group resulting in more aggressive use of statins, a class of drug with pleiotropic effects that include improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response.  These drugs have demonstrated morbidity and mortality benefits in clinical settings where lipid levels are normal.

    The history of HIV treatment guidelines is an excellent reminder of the risk of formulating guidelines based on observational studies and anecdotal evidence.  However, HIV is not the best example.  There are clinical settings where “more compelling” cohort data using medications considered relatively safe served as the basis for treatment guidelines that ultimately were proven wrong at a significant cost.

    I think the best example pertains to the use of hormone replacement therapy (HRT) in postmenopausal women.  There were many anecdotal, observational and retrospective reports of the many benefits of HRT, but the Nurses’ Health Study was the flagship.  The Nurses Heath Study was a case control, observational study of over 120,000 nurses, including over 20,000 who were post menopausal.  As the follow up continued for years, an increasing number of women reached menopause, and various health variables were monitored and reported.  The most striking “conclusion” of this study was that the relative risk of death was 0.63 in HRT users vs. non users.  The risk of major coronary artery disease among HRT users was 0.60 when compared to those who never used HRT.  Both of these findings were statistically significant.  These data were broadly reported in medical journals, and professional meetings.  The data were added to the HRT prescribing information and aggressively promoted by the pharmaceutical industry, particularly the manufacturer of Premarin (American Home Products, renamed Wyeth, recently acquired by Pfizer), the most widely prescribed HRT.

    There was huge resistance to conducting a prospective randomized controlled trial in this population.  “It denies the placebo-controlled group the protective heart benefits of HRT.”  “It is unethical to randomize people who would clearly benefit from HRT to placebo.”  “No one would enroll in this trial considering what we already know about the benefits of HRT in this population.”  Despite the criticism, the Women’s Health Initiative, a prospective randomized controlled study of HRT in postmenopausal women was conducted.  In July 2002 the study was halted early due to a statistically significant excess risk of heart attack, stroke and breast cancer in those receiving HRT versus those on placebo; a finding that literally rocked the world of HRT.

    More recently, long-term treatment recommendations in diabetes were debunked by results from the first well designed, randomized controlled study (coincidently named ACCORD), with cardiovascular clinical endpoints.  Using multiple medications for intensive glucose lowering and intensive blood pressure reduction did not reduce cardiovascular events but only increased adverse events.  Once again, guidelines formulated without data derived from controlled clinical trials did more harm than good.

    There is a lot at stake here and I fear that this is déjà vu all over again.  The NA-ACCORD results are compelling and generate a hypothesis that needs to be tested, but the clinical trial has yet to be performed and the evidence is absent.  I find it difficult to understand why those of us who have lived during decades of this epidemic, who have seen those living with HIV experience a wide range in the rate of disease progression, and who have seen the rise and fall of early antiretroviral therapy, do not demand more.  I’m shocked by both the city of San Francisco and Project Inform.

    I cannot claim to know the motivation behind the current push for early treatment without evidence.  However, I do know the pressure felt by the pharmaceutical industry as they approach a patent cliff with little in the advanced research pipeline and significant overcapacity.  It is not coincidental that lobbying efforts have been stepped up in an economic climate where value driven medicine is a new priority.  That lobbying includes an aggressive push to eliminate informed consent for HIV testing and a push for early treatment.  And, here we are with major public health agencies and CBO’s jumping on the bandwagon without the evidence

  • Treatment of HIV/AIDS. The revised USPHS guidelines. May, 2010

    Posted on May 19th, 2010 admin No comments


    The revised USPHS guidelines for the treatment of HIV/AIDS

    Guidelines for the treatment of HIV/AIDS were first issued by the US Department of Health and Human Services (DHHS) in 1998. They have undergone numerous revisions since then; the most recent was in December 2009.

    The first guidelines were issued shortly after potent antiviral medications became available.  We knew very little about how best to use these drugs at that time, and with only a few years experience our knowledge of their adverse effects was understandably limited.

    Perhaps the only reliable information we then had was that individuals with fewer than 200 CD4 lymphocytes received a life saving benefit from their use.

    Despite such limited information the panel that had been convened to write the guidelines made firm recommendations for the use of antiviral drugs in groups of patients for whom evidence of a net benefit was lacking.

    Even in the absence of experience with the newer antiviral agents, at least two probable problems associated with their use could have been anticipated in 1997.   The propensity of just about any microorganism to develop resistance to antimicrobial agents was no mystery.  Nor was it a surprise  that adverse reactions to new drugs appeared as they were used for longer periods.

    As might have been anticipated  healthier HIV infected individuals  have not infrequently had to deal with  both of these problems.

    Why then did the first HIV/AIDS treatment guidelines panel not propose and encourage the conduct of a randomized prospective clinical trial to answer the question of whether immediate or deferred treatment with antiviral drugs could or could not prolong life and improve its quality or made no difference apart from cost?

    Since the problems that were to arise  could have been anticipated, if not their extent,  the guidelines committee must have accepted that whatever evidence existed was sufficient to reassure them that there would be a net benefit to starting treatment at 500 CD4 lymphocytes.

    The most recent revision of the DHHS guidelines now propose, as the first guidelines did, that treatment be initiated at a CD4 count of 500.   A prospective randomized trial that directly addresses the question of when treatment is best initiated has yet to be completed.  In the absence of information from such a trial the committee has relied on evidence from some large retrospective observational studies.

    In the next post John Falkenberg writes about some previous experiences where advice based on results of retrospective analyses of observational data had to be reversed when the results of randomized controlled studies became available.

    I believe the biggest mistake made in 1997 by the guidelines committee was in not responding to the very real  possibilities of dangers associated with early treatment initiation  by encouraging the completion of a prospective randomized trial, such as START, that could by now have reliably provided an answer to the question of whether immediate or deferred treatment is better or worse or makes no difference that is, apart from cost.

    It’s not the benefits of early treatment that are in question. Of course there are benefits, but the question we need an answer to is when in the course of HIV disease the benefits of treatment outweigh the risks.

    Long term exposure to antiretroviral drugs can  have harmful effects.  It can take many years to recognize some of these adverse effects. For example we learned only in the last few months that under certain circumstances neurocognitive function improved in some people who stopped antiviral drugs (ACTG 5170).

    So the challenge is to find out how best to use the drugs.  Put another way, we must find ways to safely minimize exposure to the drugs, which until we have drugs without significant adverse effects, is what determining the optimal time to start treatment is all about.  We don’t know if a person deferring treatment until a CD4 count of 350 will or will not live longer with an overall better or worse quality of life than someone starting at 800 or even 500 CD4s.

    We do know that at 350 CD4s, benefits of treatment far outweigh risks.   But no matter what NIH guidelines committee members may feel, we do not yet have the most reliable evidence that benefits of treatment will outweigh risks when starting at higher numbers.

    The wording of the USPHS guidelines is such that depending on whose vote one goes with, I suppose  might even be interpreted  to mean a recommendation for every HIV positive individual to receive treatment irrespective of CD4 count.

    A letter written to the DHHS panel in 1997 suggesting that a randomized prospective trial be encouraged to provide guidance for individuals with greater than 200 CD4 lymphocytes remained unanswered although received.

    Sadly the repeated changes to the guidelines since their first appearance in 1998 appear to indicate a retreat from evidence-based recommendations.  Maybe this should be stated as a retreat from attempting to find the most reliable evidence on which to base recommendations.  The guidelines panel go to great lengths to reassure us that their recommendations are indeed evidence based.

    But as they recognize, the quality of evidence can vary. They also recognize that evidence of the highest quality is derived from the results of prospective randomized trials.   Yet not only do they not vigorously encourage the completion of such trials, their recommendations actually inhibit enrolment into START which is such a trial.

    Unfortunately the DHHS recommendations while not binding have a huge influence.  Remarkably they are even regarded by some  as setting an ethical standard, so that fears have been expressed that enrolment into START  might be considered unethical as the current guidelines revision recommend starting treatment at 500 CD 4 lymphocytes.

    Thirteen years after the first guidelines were issued, the DHHS panel has now made revisions that continues to threaten enrolment into a randomized controlled trial that will provide clear guidance to HIV positive individuals and their doctors about when to initiate antiviral therapy.

    Surely, when we recognize that reliable evidence is lacking to inform a  very important clinical decision, is it not our obligation to seek the evidence, rather than settle for the  uncertainties  associated with evidence of inferior quality?  This is not only for the benefit of our patients but also to affirm that our stated respect for evidence-based recommendations is more than lip service.

    At this time the DHHS guidelines are the only ones that recommend a start to treatment at 500 CD4 lymphocytes.

    The DHHS guidelines have been of benefit to people with HIV/AIDS.  But on the issue of when to start antiviral therapy they have not best served the interests of HIV positive individuals.

    We need a randomized controlled trial to answer this question, not the votes of a committee.

    I believe that many health care providers would welcome the opportunity to be   able to present an option to their patients with greater than 350 CD4s, to enrol in a study such as START.

    At the end of the day, determining when it’s best to start is not something you vote on. It’s something so important that you nail it down with a trial such as START.

  • AIDS Pathogenesis: HIV disease has characteristics of positive feedback systems

    Posted on April 2nd, 2010 admin No comments

    There is a similar and slightly extended version of this post on the blog I have on the POZ website. It’s in two parts:

    Part 1

    Part 2

    HIV infection and many other infections caused by a wide variety of microorganisms have a mutually enhancing relationship that is characteristic of positive feedback systems.

    Although the reciprocal enhancing effects of HIV and other infections have been frequently described since the late 1980s, it is useful to explicitly recognize these as positive feedback systems as this highlights the implications they have for treatment of individuals and for control of the epidemic.  Explicitly recognizing the positive feedback characteristic of HIV disease also provides a way of looking at pathogenesis that can suggest further studies, both clinical and laboratory, that might advance our understanding of mechanisms of disease acquisition.

    This is an illustration of positive feedback.    A stimulates B which in turn stimulates A. In this way the effects of A and B are increased.

    The infections associated with the immunological disorders of HIV disease are generally, but not solely, caused by microorganisms that replicate within cells.     Many of the organisms that cause these infections survive in healthy people without causing disease, prevented from doing so by a competent immune system.   When the immune system fails these infectious agents start to divide.   They may then cause disease.  An additional effect of some of these active infections is to accelerate the replication of HIV.  Several mechanisms are responsible for this effect, which can then result in further immunological deterioration.

    In addition, co-infection with many of the pathogens that also affect individuals with intact immune systems can also promote HIV replication.

    Not all co- infections result in a more rapid progression of HIV disease.  Many have no effect and a few have even been reported to cause a temporary improvement of HIV disease.    This may be the case with measles, scrub typhus and a form of transfusion associated hepatitis.   But more often, when an effect of a co-infection has been noted, it has been to promote HIV disease progression.

    Different co-infections can therefore affect the course of HIV disease in different ways.  Some may have no impact on the course of HIV disease; a few may possibly cause a temporary amelioration.   Those that are able to accelerate it are highly prevalent in HIV infected individuals.

    Worldwide, viruses of the herpes family are probably the most important of the co-infections that interact with HIV in a mutually enhancing fashion. .    Virtually all adults are infected with some of these viruses that usually exist in a latent or dormant state.  They are readily activated in the setting of HIV infection and then promote further HIV replication by a number of different mechanisms.

    In developing nations a range of different endemic infections, depending on geography, may be just as important; many can also accelerate HIV disease progression.  Conversely, HIV infection can promote progression of some  endemic infections.

    Several different mechanisms have been uncovered that can explain the effects of co-infections on promoting HIV replication.    With such a wide range of infections, the precise ways in which each do this will vary in detail.

    However there is one characteristic possessed by all HIV potentiating infections.  This is their ability to add to the immune activation that is a feature of progressive HIV disease.

    By now I think it is generally accepted that chronic immune activation not only results from HIV infection but is a major contributor to the pathogenesis of HIV disease.   A state of sustained high level immune activation is the basis of the chronic inflammation and immunologic deterioration characteristic of progressive   HIV disease.

    But what exactly is immune activation?

    Immune activation refers to those changes that take place in the immune system when exposed to an infectious agent that allow it to eliminate or control the infection.  Essentially, the immune system is activated from a resting state to fight an infection.   Generally this process will last for days until the infection is overcome, and usually but not always, is followed by a lifelong immunity to the infectious agent.

    However in progressive HIV disease the immune system continues to be activated at a high level and it is this sustained immune activation that eventually results in disease.   An activated state of the immune system is characterized by differentiation of precursor immune system cells.  Differentiation is the process by which these cells develop specialized functions.   Examples of cells that have acquired specialized functions are those that produce specific antibodies, or those with the ability to kill other cells infected with specific microorganisms.   Proliferation of immune system cells is an important characteristic of an activated state.  This is usually a short-term response subsiding with control of the infection that stimulated it.  But in progressive HIV disease, proliferation is sustained, probably with episodic cycles of further accelerations, and this continued proliferation contributes to the loss of immune system cells.

    These cellular changes, differentiation and proliferation, are associated with the secretion of a variety of cytokines.  Cytokines are molecules that can change the behaviour of cells by binding to specific receptors on their surfaces, for example, causing them to divide.  Once released, cytokines not only attach to receptors on other cells but can also come back and attach to the receptors on the cell that produced it.

    The cytokines that are released   have widespread effects.  Importantly, they include those that are associated with inflammatory changes, – the pro-inflammatory cytokines.    With respect to positive feedback, pro-inflammatory cytokines including IL-6 and TNF alpha are able to accelerate HIV replication.

    A part of the immune system, the innate immune system, responds immediately to infection by recognizing molecular patterns common to different organisms.  The more familiar adaptive immune system responds to specific characteristics unique to each organism.

    The innate immune system is also activated in untreated HIV infection.   Interestingly effects of activation of innate immunity were recognized very early in the epidemic, even before HIV was discovered, and so are among the earliest recognized AIDS related immunological abnormalities.  Activated innate immunity is responsible for the large amounts of alpha interferon in the circulation of people with untreated HIV/AIDS, first noted in 1981, the year this disease first came to our attention[i].   At that time the origin of this endogenous interferon was not known.   For a period, elevated levels of beta 2- microglobulin were regarded as an adverse prognostic marker.  This molecule can be regarded as a surrogate marker for interferon.   The association of interferon with abnormalities characteristic of this disease – including low CD4 numbers was also reported in the first 2-3 years of the epidemic[ii].   Over twenty years later mechanisms have been discovered that can explain the participation of interferon in the disease process[iii].

    Interferon appearing in the circulation in untreated HIV disease may even be the first marker of immune activation noted, although not recognized as such when first observed

    The changes that occur on activation of the immune system are associated with many other markers that can be measured.    Different molecules appear on the surface of activated cells.  These can be detected and measured, as can the cytokines associated with immune activation.

    These measurements can tell us the extent of immune activation.   Importantly, the degree of immune activation parallels the rate of HIV disease progression.

    Although it is now accepted that the consequences of continued activation and proliferation of immune system cells contribute to the loss of CD4 cells and the development of disease, the precise way it does so is not yet known, although there  are a number of different mechanisms  that could account for it.  The   associated inflammation also has adverse effects beyond the immune system.   For more detailed information on these mechanisms there are references to two reviews at the end of this article[iv].

    Sustained immune activation is therefore at the heart of HIV/AIDS pathogenesis.   It is the sustained nature of the activated state that is critical.  Short lived states of immune activation are of course beneficial allowing us to recover from infections.  But in progressive HIV disease the process continues at variable rates.   Understanding what causes continued immune activation is central to an understanding of the pathogenesis of HIV disease.

    What causes Immune activation?

    While infection with HIV may start the process, other causes of immune activation are almost certainly also necessary to keep it going.

    The following all contribute:

    1:            The immune response to HIV itself.   This includes both innate and adaptive immune responses.  As noted above, adaptive responses are the familiar specific antibody and cell mediated responses that provide generally lifelong immunity to specific infectious agents.  Innate responses depend on recognition of molecular patterns common to several organisms.

    Some suggest that HIV contributes directly to immune activation through binding of some of its proteins to immune system cells.

    2:            Microbial products that can penetrate into the intestinal wall as a result of damage caused by HIV.  These microbial products then activate immune system cells.

    3:            Other infections.

    Some like active herpesvirus infections or the more traditional opportunistic infections can be seen as indirect effects of HIV infection.

    Others are infections that can cause disease in people with intact immune systems like the endemic infections in developing nations. Some of these can be more severe in the setting of HIV infection.

    Infections that can accelerate HIV replication include those caused by bacteria, viruses, protozoa and helminths.

    Those that promote HIV disease progression can  usefully be  described in three categories.

    A:            Herpes virus infections.   These are probably the most important worldwide.  Virtually 100% of adults are infected with some of them.     They represent infections that are more often latent, but are  readily activated  in HIV infected individuals.

    B:            Endemic infections caused by a variety of different microorganisms than promote HIV disease progression and HIV replication.   These are important in developing nations.

    C:            Other infections.  These include the opportunistic infections, as well as those that can affect people with intact immune systems.  TB may be the most important.  HIV infected individuals are much more susceptible to active TB infections than those who are HIV uninfected.  HIV transcriptional activity and viral loads have been noted to be higher in people with active TB.

    Here is a little more detail about these three classes of infection:

    A:  Herpesviruses.

    There are eight members of the herpesvirus family that can infect humans.   Herpes simplex virus types 1 and 2 (HSV-1, HSV-2) are perhaps the most familiar.  Cytomegalovirus (CMV) and the Epstein-Barr virus (EBV) infect close to 100% of adults.   Varicella-Zoster virus (VZV) causes chicken pox on initial infection and shingles when reactivated. Of the three remaining human herpes viruses HHV-6, HHV-7, and HHV-8, the last is associated with Kaposi’s sarcoma.

    With all of the herpes viruses, once infected, individuals carry them for the rest of their lives, usually in a dormant or inactive state.  All can be periodically reactivated with or without symptoms.

    Humans and herpes viruses have co-existed for evolutionary periods and are well adapted to each other.   The immune system generally maintains these viruses in a latent sate so that they cause no harm.  Reactivation does occur periodically but is generally limited.  Virtually 100% of adults will carry some viruses of the herpesvirus family, usually in a dormant or latent state.

    The impaired immunity characteristic of HIV disease however results in reactivation of herpes virus infections. In progressive HIV disease these viruses become active and through a variety of mechanisms, including their contribution to immune activation, promote the replication of HIV.    Cytomegalovirus (CMV) may be the most important of the herpesviruses that promote HIV disease progression.  It can be part of a positive feedback system in its interactions with HIV.

    HIV → latent herpes infections  →active herpes infections → HIV

    It is not only through their contributions to immune activation that herpes viruses promote HIV replication.   In addition to the pro-inflammatory cytokines that have this effect, herpes virus gene products can directly activate HIV if a cell is infected with both viruses.  This process, called transactivation works both ways; HIV can also activate herpes viruses.

    In addition herpes infections cause a receptor (Fc) to appear on cell surfaces that allows HIV to enter it.  In this way cells that do not possess CD4 molecules can become infected with HIV.   Active CMV infections can also exert a mildly immunosuppressive effect.

    Herpesviruses, particularly CMV are singled out because they probably play a significant role in the pathogenesis of HIV disease.  CMV infections are so common that it is hard to find HIV infected individuals who are free from it so that they can be compared to those who are not.   But as early as 1991 this was done with HIV infected haemophiliac patients, when it was noted that those also infected with CMV had a much more rapid progression of their HIV disease[v].

    That CMV may play a role was suggested by many very early in the epidemic.  A multifactorial model for the development of this disease published in 1983 before HIV was discovered suggested a major role for CMV and EBV[vi].    The considerable evidence for a role for herpesviruses, particularly for CMV, did not disappear with the discovery of HIV.   The interactions of CMV and other herpes viruses with HIV that have been discovered may now explain their role.

    Large studies on the effects of acyclovir on the course of HIV infection have provided compelling evidence that active infection with these viruses can be regarded as part of the disease process for most HIV infected individuals.    Investigators focussed on HSV-2 undoubtedly because it is the most common cause of genital ulcers.   The dose of acyclovir used would also have suppressed  HSV-1, which is even more prevalent than HSV-2 and may be more sensitive to acyclovir.  HIV viral loads and the rate of HIV disease progression were reduced in individuals receiving acyclovir compared to those receiving placebo.  Although genital ulcer recurrences were suppressed by acyclovir, the drug had no effect on the transmission of HIV.

    The effects of acyclovir on HIV probably resulted from suppression of active herpes infection.  This is entirely consistent with a model that places HIV and herpesviruses in a positive feedback relationship.

    EBV and CMV are much more resistant to acyclovir than HSV-1 and 2.   But it cannot be excluded that this drug did not have some effect in also diminishing reactivations of CMV and EBV.   If samples from the trial have been stored appropriately, this can be looked at.  EBV reactivation patterns are easily recognized, CMV virus isolation is possible and even detection and quantification of activated T lymphocytes would tell us something.

    B:  Endemic infections:

    These are singled out because of their high prevalence in some parts of the developing world.

    These infections affect significant proportions of the population, they tend to be chronic and persist in the absence of treatment.    The specific infections will depend on geography and many are transmitted by insects.   Many of these can also accelerate   HIV disease progression, and some also progress more rapidly in the setting of HIV infection[vii].

    C:   Other infections:

    On an individual level, some episodic infections can promote HIV replication.   An acute febrile illness may increase HIV viral loads, but this is a transient effect lasting for the duration of the infection.

    Most of the serious opportunistic infections occur late in the course of HIV disease, and may promote even further disease progression.

    TB deserves special consideration because of its high prevalence in HIV infection.  Susceptibility to TB is increased even at higher CD4 levels. Active TB can then promote further HIV replication thus becoming a partner with HIV in a positive feedback interaction[viii].

    A role for immune activation in a positive feedback system:

    One way to look at the process of disease acquisition in HIV infection assigns a central role to immune activation.

    Immune activation not only results from HIV infection, it can also promote further replication of HIV.

    HIV replicates more efficiently in activated immune system cells.  Secondly, the pro-inflammatory cytokines that are associated with an activated immune system   can directly stimulate HIV replication.   Progressive HIV disease and immune activation are therefore components of a positive feedback system in this way.

    HIV disease → Immune activation → HIV disease → Immune activation

    The process starts with HIV infection, and is promoted by other infections , some of which are activated by HIV infection.

    Whatever is driving immune activation is driving HIV disease.

    The following diagram illustrates this.

    Looking at the course of HIV infection in this way has a number of implications.

    Pathogenesis.

    In the above diagram the course of HIV disease is represented by a self perpetuating cycle proceeding in a clockwise direction.

    In addition to the elements that have positive effects in driving the process, there will also be those that retard the cycle.  Two influences that will slow the cycle are the residual immunological control of HIV  infection, and those mechanisms that dampen immune activation.  Amongst the latter are the effects of a  subset of Tregs,  T cells with regulatory function, and the secretion of anti-inflammatory cytokines.    Since sustained immune activation is harmful, there are mechanisms that can dampen it.     This is illustrated in the next diagram (edited from an earlier version ) which focuses for simplicity on those infections that add to immune activation and on processes that dampen it.    Of course there are other mitigating factors, for example, genetic factors conferring varying degrees of resistance resulting from receptor polymorphism.

    In the diagram, the connection of HIV with CMV and other herpes viruses is probably constant and indicated by a red arrow.   The connection of HIV with endemic and associated infections is indicated by a blue dotted line, because HIV infection does not increase susceptibility to all of them, nor does it accelerate the progression of all.

    [October 5,2010:  This illustration is one  redrawn  for a later post.  The added text is HERE.

    The positive feedback cycle starts with HIV infection.  At least some of the determinants of the rate of disease progression may be found in the conditions that exist at the time of initial infection that promote or retard the cycle.

    There is evidence that the degree of immune activation at the time of seroconversion predicts future disease progression.[ix] [x] It may also be an important determinant of what is called the set point.  This is the point following initial infection with HIV, from which CD4 numbers decline.

    The degree of immune activation at seroconversion thus influences the starting CD4 level; the rate of subsequent decline is influenced by the degree of immune activation  in a system where once started, conditions can exist where  immune activation increases with falling CD4 numbers, in a self perpetuating and accelerating fashion.   Whatever the outcome, it will be the balance of positive and negative influences.

    In the earliest years there were reports of EBV reactivation preceding HIV seroconversion[xi].

    I have not seen any follow up of this interesting report.   It at least suggests that there might even be   situations in which active herpes infections could sometimes promote seroconversion.  They certainly produce signals that can activate HIV transcription from proviral DNA.

    Treatment and prevention.

    The role of immune activation in driving HIV disease is generally accepted now.   There are sources of immune activation other than HIV and some of these can be controlled.

    Attempts to identify and control additional sources of immune activation may be critical in the fight against HIV/AIDS.

    Perhaps the most significant benefit in this respect concerns the developing world, where there are so many additional sources of immune activation. Even ascariasis, infestation with the common intestinal round worm is associated with significant immune activation.   Worldwide prevalence is estimated to be about one billion, with 173 million in sub-Saharan Africa.

    Many highly prevalent endemic infections can promote HIV replication.  Controlling these are perfectly appropriate targets in the fight against HIV/AIDS, and of course this would independently improve the lives of millions of individuals.

    Measures to control endemic infections include traditional public health interventions, such as the provision of sanitation and clean water and the control of insect vectors. Effective drugs are sometimes inexpensive.  Peter Hotez has written an article entitled “Africa’s 32 cent solution to AIDS”.[xii] This refers to the price of Praziquantel , effective in treating  schistosomiasis as a single dose.

    The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause.  Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.

    Recent and ongoing studies will probably lead to the routine use of drugs that are effective against herpes virus infections.       Trials of valacyclovir to reduce HIV viral loads are in progress. Given the ubiquitous nature of herpes infections, the use of acyclovir as adjunctive therapy might be warranted even in the absence of recurrent herpetic ulcers.  Valacyclovir unfortunately is not yet available as a generic medication.

    Unfortunately EBV and CMV are much more resistant to these drugs.   The development of agents less toxic than valgancyclovir is important.   Valgancyclovir has already been shown to reduce immune activation in HIV infected individuals as measured by a reduction in activated CD8 lymphocytes.

    In summary it is useful to explicitly recognize the positive feedback interactions between HIV and other infections that can promote its replication, some of which are in turn promoted by HIV.    Control of the AIDS epidemic in Africa must include measures to prevent and treat multiple endemic infections that affect hundreds of millions of individuals.


    [i] This is of particular interest to me as I was involved in the discovery of large amounts of interferon in the circulation of people with HIV/AIDS in 1981, the year the disease was a first described.

    http://aidsperspective.net/articles/Interferon_Vilcek.pdf

    http://aidsperspective.net/blog/?p=118

    [ii] http://aidsperspective.net/articles/Interferon-AZT-1991.pdf Fig 1 shows CD4 counts in relation to serum interferon  . Presented 1986 at the 2nd international aids conference in Paris.

    [iii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491901/

    [iv] Immune activation and inflammation in HIV-1 infection:  causes and consequences.

    V.Appay and D. Sauce

    J.Pathol. 2008; 214: 231-241

    (This is an important  review)

    HIV immunopathogenesis and strategies for intervention.

    M. Cadogan and A Dalgleish

    Lancet Infectious diseases. 2008: 8: 675-84

    [v] http://www3.interscience.wiley.com/journal/119316871/abstract?CRETRY=1&SRETRY=0

    [vi] http://aidsperspective.net/articles/NYAS.pdf

    [vii] Endemic infections in Africa have everything to do with HIV/AIDS:

    http://aidsperspective.net/blog/?p=403

    [viii]

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905977/

    http://www.ncbi.nlm.nih.gov/pubmed/14551885?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=4

    http://www.ncbi.nlm.nih.gov/pubmed/12416451?ordinalpos=1&itool=PPMCLayout.PPMCAppController.PPMCArticlePage.PPMCPubmedRA&linkpos=5

    [ix] http://jvi.asm.org/cgi/content/full/81/16/8838?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=fig&searchid=1&FIRSTINDEX=1440&resourcetype=HWFIG

    [x]

    http://bloodjournal.hematologylibrary.org/cgi/content/full/104/4/942

    [xi]

    http://www3.interscience.wiley.com/journal/119342256/abstract?CRETRY=1&SRETRY=0

    [xii] http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0000430

  • HIV Treatment as Prevention. March 2010

    Posted on March 4th, 2010 admin No comments

    “Treatment as prevention” is in the news again as part of the media coverage of two conferences in California this month where claims were again made that treatment of virtually all HIV infected individuals could bring an end to the AIDS epidemic.

    “Research shows that treatment could end the epidemic in thirty years” is typical of the headlines that enthusiastically announced this proposal to test and treat everybody found to be infected. Sadly, most of the reports I saw failed to comment on the huge practical difficulties that will need to be overcome to make such a project feasible. All ignored a probably insuperable ethical obstacle that will have to be confronted, which may well make the project completely unworkable. Added to these difficulties is the lack of agreement on the soundness of the mathematical model on which the proposal is based.

    This initiative is also described as “treatment as prevention” although I also saw the term “seek, test and treat” used.

    The prevention in “treatment as prevention” results from the reduced ability to transmit HIV that results from treatment with antiviral drugs.

    It’s important to note that “treatment as prevention” can refer to two very different situations where infectivity is reduced by treatment. It describes the mathematical model, noted above that was published about a year ago in the Lancet, an influential weekly medical journal, which claims that the AIDS epidemic could be eliminated with regular tests for HIV and the immediate commencement of antiviral treatment of all who are infected. This is the title of the article: “Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model “ (Reuben Granich and colleagues. Lancet 2009 373: 7).

    Antiviral therapy according to this model would be given to all infected individuals whether or not the individual needs treatment. It would include lifelong treatment of healthier HIV infected people who have not been shown to benefit from it, such as those with more intact immune systems as well as those fortunate individuals whose disease does not progress. This is the root of the ethical problem; people who themselves are not known to benefit from treatment will be asked to receive it for a societal benefit. The benefits of treatment to such individuals are conjectural but as the drugs are not free from adverse effects, the risks are real. Unlike individuals with more advanced disease where the benefits of treatment vastly outweigh the risks, this cannot be known in the case of healthier HIV infected individuals.

    This is very different to the analysis of the reduction in transmission of HIV that results from treating only those HIV infected individuals known to benefit from antiviral drugs. This is also referred to as “treatment as prevention” but unfortunately in none of the reports I saw was the distinction made between treatment only of those who benefit from it and treatment of all infected individuals. These two very different meanings of “treatment as prevention” were almost always conflated by commentators which could quite easily convey a mistaken impression that all HIV infected individuals are known to benefit from treatment.

    Treatment must always be voluntary. But a voluntary decision to receive treatment does not mean a great deal if it is uninformed. The decision can most certainly seen to be coerced if misinformation is supplied. HIV infected individuals must be clearly informed about the risks and benefits of the intervention. As already noted, for individuals with more advanced disease, treatment without question provides a net benefit, but this is not known to be the case for HIV infected individuals with more intact immune systems.   There are suggestions that HIV infection may be associated with morbidity resulting from inflammatory reactions.   It is far from firmly established  if this is indeed the case and if it is, whether  it is an inevitable or even common  consequence of HIV infection, or if it can be prevented or treated with antiviral drugs.   It may also prove to be true that, as claimed by some investigators,  the newer antiviral drugs are less toxic than the older ones.  But the full range of their effects, particularly their longer term effects cannot be yet known. HIV disease can manifest in so many different ways that sorting out what is a drug effect from what is an effect of the infection itself may take a long time.

    For healthier HIV infected individuals, the benefits of treatment remain conjectural as long as clinical trials have not been completed that are designed to provide a reliable answer to the question of when in the course of HIV disease it is best to start treatment. Quite remarkably, about fifteen years after potent antiviral drugs became available no such trial has been completed.

    If a decision about whether or not to receive treatment is fully informed, healthier HIV infected individuals faced with an intervention that is accompanied with very real risks but only conjectural benefits may well choose to remain untreated, at least at that particular time in the course of their disease. The purpose of treatment is to reduce infectivity to others, but many might feel that this can be achieved with greater safety, and even possibly with greater reliability, by the use of condoms.  It should be said though that those researchers who point out the prevention benefits of treatment do not suggest that treatment is an alternative to condoms. On the contrary they recommend that treated individuals continue to use condoms.

    Since the objective of treating all infected people is to end the epidemic, this can only be achieved if a large percentage of infected people receive treatment. But faced with a consent form clearly stating what is known about risks and benefits, it is most unlikely that enough healthier HIV infected people will agree to receive treatment. This is but one reason that if a decision to start treatment is properly informed the project is unlikely to enrol enough individuals to achieve its objective. A danger is that treatment of healthier HIV infected people may be claimed to have a net benefit with greater confidence than is warranted with information we presently have.   To succeed, the project also requires a lifetime of adherence to the treatment regimen.  When drugs are taken without confidence that they are of personal benefit, we cannot know how adherence to the regimen will play out.   Failures in this respect will not only diminish the chances that the project will succeed,  they can also result in the emergence of drug resistant strains of HIV which then could limit treatment options when treatment is needed.

    There evidently is a belief that all HIV infected individuals, no matter the stage of disease will benefit from treatment. But this remains just that, a belief, as long as there is no firm evidence to support it. The evidence there is that healthier HIV infected individuals would receive a net benefit from treatment is of inferior quality, and therefore remains insecure. It comes from some retrospective observational studies. In such studies medical records are analyzed to compare outcomes in individuals who started treatment earlier with those who started later. Such studies however are beset with interpretative difficulties. Because individuals were not randomly assigned to start treatment early or later, a particular outcome, say improved survival of those starting treatment early, may result from whatever the reasons were that treatment was started at a particular time.

    The great benefit of randomly assigning individuals to receive one treatment or another when two are compared is the elimination of interpretative  problems that arise when one or the other course of action is chosen.

    The problem of such confounding factors was also discussed in a previous post: http://aidsperspective.net/blog/?p=75

    The retrospective analysis most frequently cited in support of an earlier start to antiviral therapy, the NA-ACCORD study is also discussed in that post.

    HIV infected individuals and those who advise them surely deserve more reliable evidence to support a decision whether to start or defer treatment than that provided by retrospective observational studies or worse, by mere belief.

    Prospective randomized trials remain the best way to achieve this. They minimize bias, and thus misinterpretation, and remain the most reliable way to resolve uncertainty. There is no getting over this. Such trials may be expensive, and last a long time, but in the end, probably more time and money is lost by repeating inconclusive and conflicting retrospective studies. Surely we need to know, and not guess when it is best to start treatment.

    START is a large clinical trial designed to provide an answer to the question of whether it is best to start treatment early or to defer it.     Another casualty of the pursuit of treatment as prevention that aims to treat all infected individuals is enrolment in START which may become more difficult. Those promoting treatment of all infected individuals as prevention must evidently feel that they already know the answer to be that an early start is best. How can this belief be reconciled with a respect for evidence based medicine that many of same experts claim to have?

    We should rather concentrate our efforts on providing treatment to all HIV positive individuals who are at a stage in their disease where treatment is of unquestionable benefit. The fact that treatment reduces their infectivity to others is an added powerful argument to encourage widespread testing. An additional benefit is that people who know their HIV status are more likely to take steps to prevent infection of others.

    The proposal to treat every infected person as a prevention strategy can be criticized on many levels. I have focussed here on the difficulty that arises from including the treatment of individuals not known to benefit from it. This can usefully be linked to support for and encouragement of enrolment in START.

    The lack of concern for the ethical problem that arises from treating people not known to benefit from it is puzzling. A headline on the front page of the UK Independent newspaper reporting on the proposal to treat all infected people states: “AIDS: is the end in sight?”  The report quotes the opinion of one scientist that “the problem is that we are using the drugs to save lives, but we are not using them to stop transmission”   This statement  is quite remarkable.   The real problem arises when we administer drugs that can have adverse effects to people for any reason other than for their benefit.   We can only ask individuals to agree to take risks for a societal benefit if we have good reasons to believe that the endeavour has a good chance of success – in this case the grandiose one of ending the epidemic.  For reasons outlined above we cannot provide any confidence that this will be so.  At any rate many may feel that their societal concerns can be more safely met by using condoms, a proven way to reduce transmission of HIV.

    I also wrote about this issue for the magazine POZ about a month ago. It can be seen by following this link. http://blogs.poz.com/joseph /archives/2010/02/treatment_of_hiv_dis.html

    I also commented on this issue about a year ago. http://aidsperspective.net/blog/?p=152 This post repeats several points that were made then.

  • HIV Prevention Education and Pre-Exposure Prophylaxis Against HIV. August 2009

    Posted on August 30th, 2009 admin No comments

    Since my last post on this subject I have heard a variety of different views as well as discussed the issue with several  interested individuals.

    As a result I have come to see the issue somewhat differently; I suppose I could just amend my last post, but it’s better to leave it as it is and  describe the differences in how I now view PrEP efficacy trials after having heard several different descriptions of  ways in which these are seen.

    I listened to presentations at two conferences during the  last few weeks.  A teleconference organized by CHAMP, a community group, and one organized by the Centers for Disease Control (CDC).  These conferences attempted to engage and inform individuals about PrEP.       As a consequence I realize that I was mistaken in stating so categorically that efficacy trials of PrEP,  unlike safety trials, could not be undertaken in human research subjects.   However I do not think that if all the ethical requirements are met, that is to provide condoms, consistent counseling and sterile injecting equipment, a generalizable result will be obtained indicating that it is an effective prevention strategy.  Of course I don’t know this, and was wrong in my view that trials of PrEP efficacy should not proceed.

    The most important concern with the way the promotion of PrEP, at least as a concept, is being pursued is the neglect of encouraging  prevention education.

    Prevention education remains the most important tool we actually have, as opposed to theoretical and unproven approaches.  The latter include PrEP, and the test and treat every infected person proposal.   We absolutely know that in principle prevention education, including the use of condoms can work.   It worked in curbing the increase in the epidemic among gay men in the late 1980s .

    The principle is thus established, admittedly without application to those who have no control over the use of condoms by the male partner.  This group is therefore in need of prevention strategies they can control themselves, and PrEP may be the only realistic possibility.

    For everyone else, the sexual transmission of HIV can be controlled by the use of condoms, even if not with 100% efficacy.  We have a powerful tool in our hands, and if there are new infections, this is certainly not an indication that it does not work well enough.   It indicates that it is an activity that receives insufficient support, or  it may well be that some of those doing it are just not very good at it.  Maybe there is little societal support for HIV prevention education, even little support from individuals at risk who could use condoms but would like not to.

    Unfortunately, from what I have experienced, the several groups supporting and promoting PrEP seemed to have given little thought to prevention education in presenting this intervention to stakeholders. .  They may be diligent in the context of efficacy trials, in ensuring the availability of condoms and counselling to participants.

    But what seems to be missed is this:  Unless the promotion of PrEP is accompanied by very clear advocacy of prevention education with condom use,  PrEP can be seen as an alternative to safer sex practices as now recommended.

    This cannot be the intention, but from comments I have heard after the CHAMP and CDC conferences this seems to be a dangerous conclusion that some have drawn.

    The explanation of the utility of PrEP must be accompanied by a strengthening of prevention education to avoid this unfortunate misinterpretation. The very promotion of the concept of PrEP in the way it has so far been done can actually be seen as an undermining of condom use.  A possible alternative to condoms is presented. One can only hope that in the absence of accompanying prevention education there will not be instances sex with available antiretroviral drugs rather than with condoms.

    Prevention education is in a dismal state as it is, and we should be aware of any activity that can undermine it further, unless care is taken in how it is presented.

    I have commented in other posts that in HIV medicine a one-size-fits-all approach seems to be the norm.  Admittedly it’s cheaper to deal with populations rather than individuals. A single size that fits everybody is even cheaper  than providing  small, medium or large varieties, let alone customizing the size to fit individual needs.

    So in HIV medicine, treatment recommendations have been made for all infected individuals, without considering the rate of disease progression, and many other characteristics applicable to any given person.

    So it is with PrEP.  Its relevance is different to different constituencies.

    At one extreme, for those who have no power to control the use of a condom by their male partner, PrEP may be the only realistic possibility of avoiding infection with HIV.  PrEP to these individuals is obviously of vital importance.

    In fact it is so important that it would be useful even if its efficacy, if this can be demonstrated, proves to be inferior to the consistent use of condoms.   Such individuals have no alternative.

    The situation of people who are perfectly capable of consistent condom use is different.

    The power of the receptive partner in this case is the power to say no. No condom, no sex.   Both partners have an effective means of preventing the sexual transmission of HIV.  There is no need for PrEP to prevent infection, except that some may welcome an additional layer of protection.

    There are others whose hopes for PrEP are different.  The desire to conceive is one.

    Yet others hope that PrEP will make sex without condoms safe with respect to HIV transmission.   In this case the efficacy of PrEP would have to be known to be at least equal to the consistent use of condoms (and free from toxicity and affordable).   Of course  individuals decide to take risks that involve danger to  themselves only, but full information should be available, and certainly we should take care not to disseminate material that can  mislead, even if only by implication.   We do not have full information on the efficacy of PrEP, and I can see no way of testing its efficacy without the use of condoms.   But it is here that we need to take great care not to mislead, even by implication, that PrEP is as safe as using condoms unless in the unlikely event, it is actually  proven to be so.

    Even a modest degree of efficacy is better than nothing for those who are unable to avoid sex with a partner who cannot be relied on to use a condom. There actually is nothing else to protect them.

    A modest degree of efficacy is insufficient for those who are well able to refuse to have sex if a condom is not used.   That’s my opinion, and I would believe that of many others, but as  always risking  harm to oneself only,  is an individual choice;  our obligation is not to mislead, and ensure  that full and accurate information is available.

    So, PrEP is of undoubted importance to individuals who have no control over the use of a condom by their male partner.  Apart from the female condom, it is the insertive partner who has to use a condom.  All the receptive partner has as protection now,  is the ability to just say no.  We recognize that there are situations when this is not possible, and no practical remedy is available to change this.

    Of course there are other situations when it is possible to attempt a change.  If an individual just cannot say no to a partner who cannot be relied on to use a condom because he or she is ignorant of safer sex practices this is something we must try to remedy with intensive prevention education.  This will include imparting the knowledge of the lapses in judgement that can accompany the use of drugs or alcohol.

    Getting away from the one-size-fits-all approach, there probably will be some individual situations in which PrEP, even if less effective than consistent condom use may be considered.  An example noted by one commentator is when condom use may be associated with sexual dysfunction.

    Prevention education with consistent condom use is the best available means we have to prevent the transmission of HIV.   Prevention education should be strengthened and care taken not to undermine it.

    Where individuals have no control over the use of a condom by their male partners  we should do what we can to provide them with the means to protect themselves, and PrEP may be all we have to work on at present.

    Others may look to PrEP as a means to avoid the use of condoms.  The price of failure seems to be an extraordinary high one, considering that condom use is known to be highly effective in preventing HIV transmission.

    There are people who need PrEP. There are also people perfectly able to use condoms but who want PrEP.

    In promoting PrEP studies we must take great care not to undermine efforts at prevention education, even by implication.  Promotion of PrEP must go hand in hand with promotion of HIV prevention education.

  • PrEP: Pre exposure prophylaxis to prevent HIV infection. August 2009

    Posted on August 11th, 2009 admin No comments

    Pre exposure prophylaxis in relation to HIV infection refers to the administration of anti HIV medications to uninfected people as a means of protecting them from becoming infected with HIV.     It is not known if this intervention will succeed in achieving its goal.   Several trials have been underway to test it for safety and efficacy, and many more are planned worldwide.

    I have paid little attention to these initiatives but was prompted to do so by notices of a meeting to discuss pre exposure prophylaxis – now known as PrEP – in the coming weeks.   The wording of this notice is quite vague, but the notice suggests that it is urgent to start planning for the implementation of PrEP as the analysis of initial safety and efficacy trials are expected within the next year.

    This is quite startling in its implication that PrEP actually works and presumably is safe.  The actual words of the notice are:

    “Results and analyses of initial safety and efficacy trials are expected within the next year, which highlights the urgency to beginning to plan now for how PrEP might be used to maximize its public health impact”.

    This is a convoluted statement, to the point of being quite unintelligible. It can be misleading in the implication that can easily be drawn from it that PrEP works. Why else begin to plan for how to use it?

    I had not been aware of just how extensive the PrEP initiative has been.   To get some idea of the many trials that are underway or planned, take a look at this website:

    http://www.prepwatch.org/

    Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).

    http://www.fhi.org/en/Topics/preexposure_prophylaxis.htm

    FHI has produced a set of slides listing PrEP trials.

    http://www.prepwatch.org/pdf/Meetings/Cates_TDF_slides_May.2006.pdf

    Among the “research consortia” listed as involved in PrEP research are the Bill and Melinda Gates Foundation, Gilead Sciences, the Centers for Disease Control (CDC), The National Institutes of Health (NIH),  and UCSF. These trials are conducted  in many countries, including Peru, Botswana, Thailand, the US and Malawi.

    Organizations listed under “community consortia” are GMHC,  AVAC, Global Campaign for Microbicides, CHAMP, and the IAS.

    The websites of these organizations contain information about PrEP.

    AVAC :   http://www.avac.org/

    Global Campaign for Microbicides:  http://www.global-campaign.org/

    CHAMP:  http://www.champnetwork.org/about

    The International AIDS Society:  www.iasociety.org

    All the trials use a once daily drug, tenofovir, with or without emtricitabine (FTC). Tenofovir is manufactured by Gilead in the US although I believe a generic version is produced in India.

    The trials vary in design.   Some require daily tenofovir, some are used intermittently or specifically before sexual intercourse. Some use a gel formulation.

    Previous trials had run into difficulties; several were stopped for different reasons.  For example a trial in Cameroon was stopped amid allegations that those who seroconverted did not receive adequate treatment.  A trial in Nigeria was stopped because of inadequate standards in laboratory testing.

    A trial of PrEP among Cambodian sex workers was stopped in 2004 by the Cambodian government.  This was perhaps the most publicized of the several PrEP trials that were stopped, because several activist groups brought attention to it at the XV International AIDS Conference in Bakgkok.   Among the many reasons stated for pressure by activist groups to stop the trial were poor HIV prevention counselling, and a lack of medical services to those who seroconverted.    Act Up-Paris was active in stopping PrEP trials both in Cambodia and Cameroon, although it is reported that this organization is supportive of tenofovir trials in general.

    These events are described in an article entitled “The Abandoned Trials of Pre-Exposure Prophylaxis for HIV: What Went Wrong?”  The authors are Jerome Singh and Edward Mills.  It can be seen here.

    http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0020234

    For reasons I will describe I do believe that there is no way to design a trial of the efficacy of PrEP that can meet acceptable ethical standards.   On the other hand, it is perfectly possible to conduct trials to determine the safety of tenofovir for pre exposure prophylaxis.

    So maybe an answer to Drs Singh and Mills as to what went wrong with the abandoned trials of pre exposure prophylaxis is that the question of efficacy, unlike that of safety, cannot and should not be tested on human research subjects.

    Here are the reasons why this cannot be done, at least regarding the use of tenofovir to prevent sexual transmission of HIV.

    No ethically designed and conducted trial can definitely prove that PrEP works.  Definite proof of course may be an unattainable goal, but even credible evidence regarding efficacy  would not be found if the trial were to be conducted in an ethical manner, simply because with the availability of condoms, and the imperative to provide counselling  that they be consistently  used,  such  a trial could not answer the question asked of it. This is essentially because the consistent use of condoms will ensure that insufficient seroconversions occur in participants receiving  placebo.

    In any trial that studies the ability of a new intervention to prevent sexual  transmission of HIV, participants must receive persistent counselling about the need to use condoms.  These must be provided, with ongoing support for their continued use.  This is the ethical requirement.

    Quite clearly if great care is taken to meet this requirement there will be few infections in people receiving placebo.  The investigators are presented with a conflict of interest that no amount of verbal assurance can resolve.  The conflict is that on the one hand the investigator must always be cognisant of the importance of doing all that’s possible to encourage condom use to prevent the sexual transmission of HIV infection, and on the other hand the investigator has an interest in demonstrating an effect of PrEP in preventing it.

    It is only when condom use falls below a certain level that the effect of another preventative measure can be assessed.  We are obliged to do all we can to ensure that this does not happen.

    The Centers for Disease Control (CDC) are sponsoring several trials of PrEP[i].  They are very sensitive to the need to provide risk reduction counselling to participants.

    Here is an excerpt from material published by CDC:

    “One of the greatest risks, as efforts progress to identify new biomedical prevention approaches, is that individuals at risk will reduce their use of existing HIV prevention strategies. It will therefore be crucial to reinforce proven behavioral prevention strategies, both within and beyond these trials. All three trials are taking multiple steps to address this issue during the education and enrolment of trial participants and through ongoing participant counselling.

    First, it is critical to ensure that participants understand that trial participation may not protect them from HIV infection—either because they may receive a placebo or because they may receive a study drug, the efficacy of which remains unproven. This and other key aspects of the trial, including the potential risks and benefits of participation, are explained to potential volunteers in the language of their choice, prior to their enrolment. To ensure participants fully understand all aspects of their participation, all volunteers are required to pass a comprehension test prior to providing written informed consent. Study participants are also free to withdraw from the trial at any time and for any reason”.

    So there is clear recognition that there may be a falling off in the use of proven prevention approaches, importantly, the use of condoms.

    Here is another excerpt:

    “To assist participants in eliminating or reducing HIV risk behaviours, extensive counselling is provided at each study visit, and more often if needed. This interactive counselling has proven effective in reducing the risk of HIV and other STDs in multiple populations, including past participants of similar HIV prevention trials. Participants are also offered free condoms and STD testing and treatment to reduce their risk for HIV infection”.

    If such counselling is effective, the prevention of sexual transmission of HIV particularly through the consistent use of condoms will make it impossible to detect an effect of PrEP.   As mentioned the investigators are presented with a conflict that it is not possible to resolve.

    PrEP is an experimental approach to prevention, while consistent condom use is an established method to substantially reduce the sexual transmission of HIV.

    The argument that may be presented by those who are proponents of PrEP is that condom use is not consistent, and that we need an alternative

    The implication of such an argument supporting PrEP is that prevention education, essentially the use of condoms, has not been sufficiently effective.  This cannot be known to be true of prevention education in principle.

    What is definitely true is that those responsible for prevention education have not been sufficiently effective.

    Our efforts  should be focussed on improving prevention education and support for the consistent use of condoms,

    There is so much more that can be done with persistent, culturally sensitive, highly targeted prevention education.  In order to improve our efforts at prevention education we have to first confront the fact that we may have not been too successful in this endeavour, understand why,  and absolutely not take the position that the undertaking is an impossible one.

    Every new infection today represents a failure, not of prevention education as an undertaking, but a failure to provide it effectively.  The introduction of condom use among gay men in the US in the 1980s originated in this community, it was promoted and effectively advocated for by this community and proved to be effective..   In those early years there was certainly no help from the Government which was to spend enormous sums on a vacuous and ineffective untargeted campaign “ America responds to AIDS” which did absolutely  nothing to stop the advance of this disease into African American communities , although this was happening in plain sight.

    What we can learn from this is that different affected communities are best able to understand the  issues specific to their communities that must be emphasized  and  promote prevention education that is most effective for each of them. Their input is therefore  absolutely vital.

    The design and implementation of well funded and highly targeted prevention education has been neglected.   These initiatives need to be specifically targeted to different groups, the needs of which must be assessed,  barriers identified, continuing support provided, as well as some instrument developed to evaluate the success of the programs. .   It is an enormous challenge.

    We know that gay men were able to make it work for them before the concept of risk reduction had even been articulated. It can work and this is where our efforts must be concentrated.  Not on trials of the efficacy of PrEP that are impossible to conduct in an ethical fashion.

    However It is entirely possible  that PrEP may add an additional layer of safety to condom use during sexual intercourse.  This may be of  particular importance in certain circumstances such as among sex workers.  This is also the case among some women who are unable to rely on the use of a condom by their male partners.   Trials of the safety of once daily tenofovir are absolutely possible and even desirable.  Such trials would be unburdened with the ethical problems that make efficacy trials impossible to conduct.  It will be clear that the trials are to determine the safety of tenofovir when used with condoms to provide an additional level of safety.   It is true that we may never be able to firmly establish its efficacy, but if it proves to be safe, there is sufficient – if far from conclusive evidence to justify its use.

    It is clear that all that has been written about concerns the sexual transmission of HIV.    For those in whom the risk of infection  is through intravenous drug use there is an entirely different set of considerations.  The only known prophylactic measure, the reliable provision of sterile injecting equipment is probably just unavailable for most, and efficacy trials are therefore not burdened with the same ethical constraints.

    One cannot help but note that at least  in two initiatives, pharmacological rather than behavioural approaches to prevention are now being emphasized.  Of course PrEP to prevent  transmission of HIV is one. The other is the attempt to end the HIV epidemic by testing and treating all HIV infected people, whether or not a particular infected individual needs treatment for his or her benefit.  Both are beset with ethical problems.

    The use of condoms can significantly reduce the sexual transmission of HIV.  We know this.   Therefore  our greatest efforts should be placed in improving prevention education.  It is a tremendous challenge given the cultural diversity of the populations involved, and the special difficulties experienced by some. This is particularly true where women are disempowered.

    We know that untargeted efforts such as “America Responds to AIDS” do not work.  We need to understand the barriers to effective prevention education.

    A denial of  the importance of sexual expression to the human experience, stigmatization of those infected, homophobia, racism, bigotry in general and the fact that unlike the use of drugs, prevention education provides no financial return,  are surely amongst them.


    [i] [i]    http://www.cdc.gov/hiv/prep/resources/factsheets/index.htm

  • Despite the SMART study there is a role for intermittent therapy. July, 2009

    Posted on July 9th, 2009 admin No comments

    From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..

    The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.

    For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.

    We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.

    One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs.   This approach will almost definitely not be possible for all HIV infected people needing treatment.  But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.

    This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061.  SMART is by far the largest study comparing continuous with intermittent therapy.  In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.

    The negative effect of SMART on the study of intermittent treatment continues.   In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought.  The most favoured, and almost certainly correct explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.

    For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification.  The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post.    Almost all the deaths in the study occurred at US sites, where in contrast to non-US sites multiple co-morbidities were over represented.  As seen in the table below these co morbidities included, among other conditions,  hepatitis B and C, a history of heart disease and  diabetes.  There were even significantly more smokers among those enrolled at US sites.  How can one extrapolate interpretations of observations made in such  individuals  to HIV infected  populations free from these co-morbidities?

    SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where  multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C,  hypertension, and a previous  history of heart disease   Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy.   That’s all.  The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational  literature addressed to physicians.

    Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times.  But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.

    Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART.  The Staccato study3,  using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.

    The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent.  Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group).  Although pneumonia was more frequent in the STI group.    Here is a sentence from the author’s abstract.

    A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.

    The finding regarding cardiovascular disease is particularly relevant.

    Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study.  It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation.   There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people.  So this needs to be studied.  But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.

    Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!

    There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.

    I was shown an invitation to physicians to a free course offered by a distinguished academic institution.   Among the descriptions of what those attending the course will learn to do is the following:

    “Describe, discuss and apply the data from the SMART study on CHD  (coronary heart disease)  risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”

    What is one to make of this in the light of the LOTTI observations?

    This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature.   As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.

    As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides.  They also characteristically had low levels of HDL cholesterol (and of total cholesterol).  I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available.  We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased.    There was, not surprisingly,  a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.

    So, there may indeed be something in the connection between untreated HIV disease and heart disease.  In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease.   Increased triglycerides are an independent risk factor for coronary heart disease.  There even was a possible mechanism for this that was known in those days that could account for this.

    Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted.  Such changes have been seen in people with hepatitis C treated with recombinant interferon.

    So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle?   There are numerous different ways in which intermittent therapy can be structured.

    The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit,  studies smaller  than SMART

    Perhaps a clue is to be found in a sentence in the LOTTI study report.

    Here it is:

    “The mean daily therapeutic cost was 20.29 euros  for controls and dropped to 9.07 euros  in the STI arm (P<0.0001)”.

    This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.

    Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes),   some form of intermittent therapy will probably be demonstrated to be safe.  For individuals with at least 700 CD4 lymphocytes, this is already the case.

    Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis.  I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts.   This desire for treatment interruptions  was obviously  true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.

    Of course for individuals with CD4 counts below 200, this was not a good idea.   Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.

    There will be many anecdotes accumulated over the years of such experiences of intermittent treatment.   I need to stress that these are just anecdotes and most definitely not formal studies.  As such they can only lead to hypotheses on which studies can be based.

    It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped.  This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.

    Of my patients who interrupted treatment none have come to harm.  There was no established protocol to guide us and strategies used took patient preference into account.    An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover.   As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment.  This approach is now generally considered to be unsafe and CD4 guided strategies are studied.   But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.

    In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.

    “Many of our patients with high CD4 cell counts want to

    stop treatment. The LOTTI study does not justify a

    recommendation in that regard, but it does give clinicians

    useful information that it is probably safe to stop

    treatment within the limits of CD4 cell counts of

    LOTTI. Continued vigilance is needed so that excellent

    adherence is maintained when patients are on HAART

    to prevent the emergence of resistance.

    The LOTTI study adds important information to the

    continued question of whether there is a role for

    interrupted therapy. Further study is justified, particularly

    with newer combination therapies, which may well

    have less toxicity and therefore shift the balance towards

    continuous treatment. Clinicians will welcome the

    information from LOTTI because it can allay some of

    the concerns regarding the safety of treatment interruptions

    at high CD4 cell counts”.

    In the LOTTI trial, treatment was restarted when the CD4 count dropped  to 350 and stopped at a CD4 count of  700.  So within these limits we have some reassurance of safety.

    So, further study is absolutely warranted.

    In the LOTTI study, participants had to have a CD4 count of 700.

    What about individuals who have had  undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700?    Studies with different CD4 criteria should continue and not be deterred by the SMART results.

    I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration.   That is to get away from the prevailing  one size fits all approach to therapy,  mainly using a snapshot of just one or two parameters,  the CD4 count and viral load to guide one, without considering the rate of change in  CD4 numbers.

    In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered.   As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly.   (Of course an individual may be super infected with a drug resistant variant).

    It is likely that some form of episodic treatment may be effective in selected individuals.   That is, periods on treatment alternating with periods off treatment.   Because of its flexibility it is probably best suited to individualization.

    As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy.  But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5.   But other similar studies have shown a high rate of viral rebound6.

    However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.

    It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.

    I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.

    The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.

    Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.

    This table shows characteristics of individuals who died compared to those who did not.

    Kuller 2

    The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).

    It can be seen that of the people who died, compared to those who did not, 11.8%  vs  4.7% had a history of heart disease (p=0.04);  45.9% vs 24.1%  were co infected with Hepatitis B or C  (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).

    Thus the people who died in the SMART study tended to be sick with non HIV related conditions.  64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.

    But there is another remarkable figure in this table.  92.9 % of those who died were participants in US sites!  I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.

    Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle,  for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.

    The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants.  All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm.   However the distribution of these characteristics in those who died was not reported in this publication.  We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.

    I missed seeing this 2008 publication.  It seems that most who saw it had little to say.  But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8.   I did not miss it this time, and have already written about it.

    Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible.   Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion  that the SMART study indicates that treatment interruptions are unsafe for all,  into question.

    To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.

    This lack of interest is really puzzling.

    Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.

    Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement.  There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.

    We know with some security from SMART that HIV infected individuals with Hepatitis B and C,   hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.

    For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all,   a form of treatment interruption will be demonstrated to be safe.  This can already be said for those meeting the conditions of the participants in the LOTTI trial.

    The original report of the SMART study was published in the New England Journal of medicine in 2006.

    http://content.nejm.org/cgi/content/full/355/22/2283

    ———————————————————————————————————————–

    Refs

    1:    New England Journal of medicine    2006  355:2283-2296

    2:    Trivacan(ANRS 1269)    Lancet  2006  367:1981-1989

    3:    Staccato                           Lancet 2006   368: 459-465

    4:    LOTTI                                AIDS     2009   23:799-807

    5:     Proceedings National Academy of Sciences   2001   98: 15161-6

    6:      AIDS  2003    17:2257-2258

    7:      Kuller et al.   PLoS  Oct. 2008   5(10): e203

    8:      The Lancet Infectious Diseases  2009 Vol 9 Issue 5 268-9

  • The not so SMART study: a very short postscript

    Posted on June 12th, 2009 admin No comments

    I believe the SMART study team have submitted a response to Justin Stebbing and Angus Dalgleish’s comments in the Lancet Infectious Diseases, that was referred to in a previous post:

    The not so SMART study.

    The explanation that the huge discrepancy in the number of deaths in the US and non US sites was due to the fact that non US sites started to enrol participants 2-3 years later than   US sites,  was addressed in the comments in the Lancet Infectious Diseases.

    Here is the relevant part:

    “Whereas most non-US sites commenced patient recruitment 2—3 years after the US sites, it is unlikely that longer protocol exposure could account for this difference. We are told that there were 38 deaths in the first year and 47 deaths thereafter. Hence, assuming that all six non-US deaths occurred in the first year, there remain 32 deaths (38 minus six) in the USA from the first year of the study—about five-fold more than expected based on the non-US mortality rate”.

    Whatever explanation is to be offered by the SMART team, even if turns out to be consistent with their conclusions, the following questions remain.

    Why was information on the distribution of deaths withheld for so many years?

    Why was this information, when it did appear in the article by Kuller et al in PLoS last year,  ignored by community commentators  to whom HIV infected people and their advocates look to for help.?

    Did they not notice it? (I did not).

    Did they think it was of no significance?

    Hopefully the SMART team’s response will put an end to this mystery of why, with more or less the same number of participants in US and  non US sites,   79  people died  at  US sites while there were only 6 deaths at sites  outside the US.

  • Endemic Infections in Africa have everything to do with HIV/AIDS and are a long neglected therapeutic target.

    Posted on June 6th, 2009 admin 1 comment

    An article with the striking title “Africa’s 32 Cents Solution for HIV/AIDS” was just published in PLoS Neglected Tropical Diseases.  It can be seen here:

    http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000430

    This dramatic title refers to the cost of treatment of schistosomiasis with praziquantal.

    Schistosomiasis is an infection caused by parasitic worms, or helminths., of the genus  Schistosoma.    Most of the 200 million cases of schistosomiasis in the world occur in Africa.

    The species, Schistosoma haematobium is estimated to infect about 112 million people in sub Saharan Africa.  So its high prevalence puts it in the same class as that of TB, malaria and HIV.  It is responsible for a huge burden of morbidity particularly in children and young adults.

    S. haematobium  has a complicated life cycle, some of which takes place in snails.  People are infected by organisms released by snails living in fresh water. These organisms can penetrate the skin of any body part that is immersed in snail infested water.  S. haematobium affects the urinary tract.  The disease it causes is commonly called bilharzia.

    I was very conscious of its danger as a child growing up in Zimbabwe, with signs at several small lakes around Bulawayo warning one not to swim in them because of the danger of bilharzia.

    Peter Hotez and colleagues article is a welcome addition to the already substantial literature that strongly suggests that many endemic infections, not only with helminths, but also with bacteria, protozoa and viruses can increase the transmission of HIV and most probably  have a detrimental effect on the course of HIV infection.

    This paper concentrates on the local effects of S.haematobium on the female genital tract , where lesions caused by  schistosome egg deposition result in mucosal patches, that can bleed during sexual intercourse. The authors state “Presumably, the schistosome egg granulomas produce genital lesions and mucosal barrier breakdown to facilitate HIV viral entry” and go on to compare this to the process by which herpes simplex ulcers increase susceptibility to HIV.

    This does seem obvious – there is a mucosal break, so HIV has a way in.

    In fact in the case of herpes simplex, this seemingly obvious connection is probably not correct.   The large Partners in Prevention study, recently completed, found that acyclovir, a drug effective in treating herpes does not reduce the risk of HIV transmission.  The drug however was associated with a reduction in the number of recurrences of herpetic ulcerations, and significantly slowed HIV disease progression.  I have written about this in another post.

    As with herpes simplex, it is possible that systemic effects of schistosomiasis, may be much more significant, or at least as significant, as local effects in enhancing the transmission of HIV.    Of course, both local and systemic effects may play a role in enhancing HIV transmission.  The systemic effects include an impairment of virus specific immune responses; immune activation may also increase susceptibility to HIV and promote its replication.

    The influence of associated infections on the infectivity of HIV extends far beyond that of schistosomiasis.  Peter Hotez  (the lead author of the above article) has done a great service by bringing attention to a number of devastating neglected tropical diseases.  This important article can be seen in the Lancet of May 2nd, 2009, (Lancet 2009 373;1570-1575).

    The title of the article is:

    “Rescuing the bottom billion through control of neglected tropical diseases”

    By Peter J Hotez, Alan Fenwick, Lorenzo Savioli and David Molyneux

    I have copied this table from the above article:

    tropical

    These are incredibly huge numbers.

    Many of these infections occur in children and young adults and not only  have an impact on life expectancy, but significantly are the cause of chronic debility particularly in young people.

    Some also have an activating effect on HIV replication by several mechanisms, some of which  have been understood for well over ten years.  The resulting acceleration of HIV infection,  by  increasing  HIV viral loads,  as well as by other mechanisms increases the transmission of this virus.

    The health of hundreds of millions of individuals could be improved by efforts to prevent and treat these infections.  These infections are also appropriate therapeutic targets in the fight against HIV/AIDS.

    Despite a great deal of evidence for the interaction of multiple bacterial, viral, protozoal and helminthic infections and HIV,  this association has been inexplicably neglected in providing  additional approaches to controlling the epidemic..

    I had what might be described as a  misfortune to have been a member of President Mbeki’s panel on AIDS, an almost surreal experience I should write about.  The following is an excerpt from something I wrote for this panel almost 10 years ago:

    “The crucial difference in Africa, as opposed to the US, is the high prevalence of associated infections. These include STDs, TB, malaria and other protozoal infections, helminthic and bacterial  infections. Such infections would supply sustained signals, such as IL-1  IL-6 and TNF, known to activate HIV.  Some can also upregulate the expression of chemokine co receptors required for HIV entry.  Some of these infections are  somewhat immunosuppressive themselves, an effect contributed to by the secretion of IL-10.37 Sexual transmission of HIV is also known to be facilitated by a high viral burden.38 This would also be the consequence of the HIV activating effect of frequent associated infections in Africa.”

    This was almost 10 years ago, and since then literature has continued to accumulate documenting the detrimental interactions between HIV and multiple infectious agents.

    About two years ago I made a presentation at the Prevention Research Center at Berkeley, trying to understand why endemic diseases had been so neglected in our attempts to control AIDS, particularly in Africa.  I thought that part of the problem was poor interdisciplinary communication and understanding.   Specifically, there might be difficulties in   communications between public health experts and microbiologists.   Possible public health implications of the findings of microbiologists might not be perceived without additional explanation.  I illustrated this with a specific article.

    I used an excellent article to illustrate this problem.

    The article is called “Contribution of Immune Activation to the Pathogenesis and transmission of HIV type 1 infection” and the authors are Stephen Lawn, Salvatore Butera and Thomas Folks.   (Clinical Microbiology Reviews. Oct 2001 14; 753-777)

    This is part of what I said in California  in trying to illustrate the difficulty in communication:

    “Of great interest – because of its implications for disease control was the discovery that other infections, viral, bacterial, protozoal and helminthic, could influence the course of HIV disease.  Generally the effect was to enhance HIV replication, but a few seemed to ameliorate – at least temporarily, the course of infection.  Scrub typhus, measles and perhaps a form of viral hepatitis, may have a  transient beneficial effect on HIV disease, but these are exceptional cases. Most co-infections have the opposite effect.

    We now come to an example of observations made by microbiologists and work done at a molecular level with enormous implications for the control of AIDS in Africa.   This example is a review (cited above)  explaining in great technical detail how the replication of HIV can be enormously enhanced by concurrent endemic infections, and how this not only accelerates the progression of HIV disease, but also facilitates its transmission. The authors show in molecular detail how many viral, bacterial, protozoan and helminthic infections can affect HIV replication.  Included among these are common intestinal worms and water borne bacterial infections, causing severe diarrhea particularly in infants.  The discussion is largely concerned with the possible beneficial effect of drugs that might counteract this enhancement of HIV replication. There is one short sentence on public health interventions that might eliminate this problem altogether. It is of particular interest because of its brevity in a rather long article.   There is also a curious statement that where antiretroviral drugs are unavailable, measures to control endemic infections may be a useful approach.  This comment is reproduced below, and somehow ignores the significance of the implication that control of these endemic infections requires no other justification than as a measure to control AIDS.

    This paper, because of its immunological and molecular detail is not too likely to find its way to an epidemiologist or public health expert,  but for one trained in these technicalities, I would suppose the public health implications would be immediately evident.

    This particular paper also is a great illustration of the compartmentalization of information, and the difficulties of interdisciplinary communication.

    Below is an illustration from the body of the article: there is much more just like this.  A person with no training in molecular biology or virology would not be likely to spend any time with this illustration.

    lawn1

    However if one turned a few pages the following diagram may just be of some interest. But again this is unlikely.

    The part that would be of interest to a public health professional , if noted,  is contained in the large arrow at the bottom right of the illustration.  In this rather complex diagram it would be quite easy for the public health expert to be sufficiently distracted so that the bottom right hand corner would be easily missed.

    lawn21

    There is a long discussion, quite technical in nature, but at least the authors find space for the following brief comment.

    “Prevention and Treatment of Coinfections

    The widespread use of HAART in the treatment of HIV-

    infected persons in westernized countries has resulted in a

    phenomenal decrease in the incidence of opportunistic infec-

    tions and has greatly increased survival. For these individuals,

    the antiretroviral drugs are the major determinant of prognosis

    and the potential cofactor effect of opportunistic infections is

    now a more minor consideration. However, the vast majority

    (>95%) of the world’s HIV-infected people do not currently

    have access to antiretroviral drugs. Most of these people live in

    developing countries, where the quality and access to health

    care is often limited and where there is a high incidence of

    endemic infectious diseases such as malaria, TB, and infections

    by helminths and waterborne pathogens which may adversely

    affect HIV-1 disease progression. Prevention or early treat-

    ment of these diseases may therefore represent an important

    strategy in addressing the HIV-1 epidemic in developing coun-

    tries”. –

    In the above quotation, the authors are overoptimistic in their assertion that the cofactor effect of opportunistic infections is now a more minor consideration in developed countries.  Valacyclovir, a drug that inhibits the replication of  many members of the herpes virus group, but has no direct effect on HIV was reported to reduce HIV viral loads in the absence of antiretroviral therapy. In the developed world, active herpes virus infections are common in the setting of HIV infection, although most will be asymptomatic. For example, Cytomegalovirus, Epstein Barr Virus and Human herpes virus type 6 are not infrequently found to be active in HIV infected individuals. Valacyclovir will have an effect on these viruses, and may well find a place in the treatment of HIV infection in developed countries.  Indeed it may not be uncommon for experienced physicians here (in the US) to prescribe related anti herpes medications to their HIV infected patients. I certainly do.

    There is another aspect, a little more difficult to establish and perhaps altogether conjectural.  This is that we are presented with the question of why we need AIDS to justify interventions that have long been established to themselves improve the health of populations.  These include the provision of sanitation and clean water, the control of malaria and TB, and something as simple as getting rid of worms.  In the public’s assessment of the health needs of developing countries the information that is used is largely to be found in popular media, newspapers, magazines and TV.  Those who report in turn receive information from professional sources, and maybe it is here that the interdisciplinary barriers to communication I have been talking about have their effect. Thus the AIDS epidemic is perceived to be the greatest threat to the future of Africa, even though malaria kills more people, and common endemic infections contribute to an abysmal life expectancy.   (This was written 2-3 years ago and was probably incorrect even at that time;  estimates are that today there are  1.5-2 million deaths from AIDS in Africa, with close to 1 million deaths from malaria.  Malaria though  is responsible for a greater  number of deaths in children under 5 years of age).

    It continues to be remarkable that although evidence has existed for years that many of these infections can interact with HIV infection to increase its infectivity and accelerate disease progression, those who advocate for, and allocate funds to fight HIV/AIDS seem oblivious to the relevance and implications of these interactions.

    This effort of course needs absolutely no justification, but its funding is small compared to the resources that have been made available to combat HIV/AIDS –  but from all that has been described funding for these endemic infections is in fact also funding to fight HIV/AIDS “.

    Those were comments made 2-3 years ago.

    While malaria and tuberculosis are now receiving attention and are included with AIDS in some programs,   many other endemic infections  continue to be neglected.

    Going back much further in time,  interest in the activating effects of associated infections on HIV replication began within the first 10 years of the epidemic.  This started with the demonstration that proinflammatory cytokines, TNF alpha or IL 6, for example could greatly accelerate HIV replication.

    Of course these cytokines appear in the course of many different infections.  When viral load tests became available this effect was well understood by patients and physicians in N America and Europe. It became common wisdom that an HIV infected person who had a febrile illness, or had even received a flu vaccine  should delay viral load testing because the infection or vaccination was frequently associated with temporary rises in HIV viral loads.

    The implications for geographic areas where the infections were far from temporary seemed to escape notice.

    Thus endemic infections in Africa do have everything to do with HIV/AIDS.  There are numerous preventative and therapeutic measures available to control many of these infections,  and some are inexpensive.  Even something as simple as deworming may be useful.  Ascaris lumbricoides, the common intestinal round worm also is associated with immune activation and is easily got rid of.  There is a report that doing this with a drug called albendazole actually raised CD4 counts. (Walson JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 22:1601-1609, 2008).

    The person who has been studying immune activation and the association of parasitic infestations and AIDS for the longest time is  Zvi Bentwich.   I can’t remember when his first  publication on this issue appeared but by the mid 1990s he was publishing on this association in Ethiopian immigrants to Israel.   Zvi Bentwich deserves the greatest credit for his early recognition of the importance of this association, its significance regarding immune activation and for his continuing contributions.   He pointed out the relevance of schistosomiasis to AIDS  (and TB) at least 10 years ago.

    The connection of so many endemic infections with AIDS  in Africa is also a connection of poverty with AIDS.  I saw an absurd and instantly forgettable paper entitled something like “Poverty does not cause AIDS” a few years ago.    Of course poverty is not the direct  cause of ascariasis,  schistosomiasis, tuberculosis, or any number of devastating infections.  Poverty is a very significant factor in  the acquisition of these infections, and as such can certainly be regarded as having a causative role.

    The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause.  Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.  For example the debility associated with schistosomiasis has an impact on an individual’s productivity, with economic consequences not only for the individual but for the larger community.

    Controlling the AIDS epidemic in Africa must also include measures to prevent and treat the multiple endemic infections that affect hundreds of millions of individuals.

    To conclude this post I want to recommend a book published about four years ago by Eileen Stillwaggon, a professor of economics.  It is called “AIDS and the ecology of poverty” and is published by the Oxford University Press.

  • Treatment as Prevention: Protecting individual autonomy. May 2010

    Posted on May 18th, 2009 admin 2 comments

    I’m returning to this topic yet again because the French National Commission on HIV/AIDS has now published a statement on treatment as prevention.

    This document discusses treatment as prevention at the individual and the population level together.

    It  places great importance on individual autonomy, which includes the fundamental right individuals have to make decisions on their own behalf.   I have come to see the issues in a somewhat  different way after reading the French document.

    This document can be seen here:

    http://www.cns.sante.fr/spip.php?article296&lang=en

    It is worth mentioning again that the term “treatment as prevention” can be applied to two different situations.

    At an individual level  it refers to prevention of HIV transmission by sexual contact between two individuals. The Swiss statement concentrated on this aspect.

    The term is also applied at a population level, where the goal of treatment as prevention is  the control of the epidemic, even as suggested by some,  a means to end it.

    The principle underlying the proposals to use treatment as prevention in both of these situations is the same.  It is the reduction in infectivity that results from the effect of antiretroviral therapy.

    Unlike the Swiss recommendations that dealt only with transmission between two individuals, the French statement deals with both aspects.

    Treatment as prevention is not the same when applied to individuals as opposed to populations.  For example, transmission between some individuals may be interrupted by treatment without having an effect on the epidemic.

    To have an impact on the epidemic additional factors that do not apply at an individual level have to be considered.

    For example, the number of infected people who must be treated in relation to the total number of people who are infected must be taken into account, if treatment is to have an effect on the epidemic.

    For treatment as prevention to have a greater effect on the epidemic, a larger proportion of infected people must be treated.

    Canadian studies have suggested that the proportion of infected people who must be treated in order to reduce transmission would need to be increased from 50% to 75%.   Transmission would be slowed but not reversed with treatment rates below 50%.

    Thus the percentage of infected people who are treated is related to the extent of the impact treatment will have on the epidemic.

    At an extreme, if the stated objective is to end the epidemic, as has been proposed by some,  the proportion of infected people who would need to be  treated would be so large that it would have to include those who do not need treatment for their own benefit.

    [ Added October 3, 2010:     It appears that there are experts who believe that everybody who is HIV infected, no matter at what stage of their disease would benefit from treatment.  For them, there would be no ethical problem at al.   These experts believe that treatment benefits every HIV infected individual. But the practice of medicine is not a faith-based enterprise, although I imagine individuals holding this belief  probably pay lip service to evidence-based medicine.  As opposed to a belief that everyone will benefit from treatment there is no evidence of the best quality  that for  people with greater than 350 CD4 lymphocytes, the benefits of antiviral drugs will outweigh their risks.    Hopefully the START trial will provide the evidence needed to help HIV infected individuals and their health care providers make a decision as to when it’s best to start treatment, that will be informed with hard evidence rather than belief based interpretations of data.   The San Francisco Department of Public Health now recommends that all HIV infected individuals receive treatment.  so they are able to  avoid having to deal with the ethical problem that arises  in recommending treatment to people not known to derive a net benefit from doing so as they too rely on their belief that all benefit.   For individuals starting treatment at higher CD4 numbers the harms caused  by the drugs may outweigh their benefits.  Such individuals may choose to receive  treatment in order to make them less infectious, but surely respect for their autonomy means that we must provide them with evidence of the best quality so that their choice is informed, and this also means that where the best evidence is not yet available on when it’s best to start treatment we must tell them that this is the case.    The concern expressed last May about the threat of coercion may have been justified in the light of the San Francisco Department of Public Health’s recommendations.  While it is perfectly legitimate and even expected of them, health care providers make recommendations based on their judgement, which in turn depends on the knowledge and experience they have.  This is why we turn to experts.   But their respect for individual autonomy really requires that where evidence of the best quality does not yet exist to justify their recommendation, and where there is no expert consensus  on the issue, that these facts be told to the individual.  A failure to do so in making the recommendation, can be seen as being coercive.  Consenting to the recommendation will  not be fully  informed, and in this way the individual’s autonomy is not respected.]

    I have written about the multitude of problems arising from this situation in previous posts on this topic.  Lurking behind such an extreme proposal is the threat of coercion, and the possibility of an infringement of individual rights. Very disappointingly this aspect has been barely acknowledged in English language discussions of treatment as prevention.

    However if, as I believe,  an additional  goal of treating  infected people is to add a powerful tool to prevent transmission, we are then not stating an objective that would require the participation of individuals who do not themselves need treatment.

    Admittedly, treating only those who need to be treated may not have such a great impact as also treating additional infected people who do not need treatment.  Therefore we must  also intensify and improve  our efforts at targeted prevention education with the promotion of condom use.

    But we will avoid the insuperable problems and threats to personal autonomy associated with  treating individuals who do not need to be treated for their own benefit.

    The goal of treatment as prevention as applied to controlling the epidemic is perhaps better stated in a different way.

    It might be preferable to simply state that the goal is to provide treatment to every individual who needs it.  This goal must therefore be coupled with enhanced efforts to facilitate regular testing.

    If we can achieve this it is likely that not only will the individual benefit, but there will be an impact on the extent of the epidemic.

    There is evidence of a reduction in HIV transmission in areas where antiretroviral treatment has been introduced. .

    When we emphasize that our efforts are to identify infected individuals and make treatment available to all who need it, we eliminate all the problems connected with treating infected individuals who do not need treatment.

    One reason why the French document is so significant is that it stresses the importance of individual autonomy.

    It emphasizes the need to respect individual rights and adds a caution to avoid the temptation to employ  coercive measures in the name of the public good.  Testing is the key to any success of this approach to prevention, but testing must be voluntary and informed. As of course is a decision to receive treatment.

    Here is an excerpt from the French statement that shows the concern for individual autonomy and recognizes that there is a potential threat of the employment of coercive measures.

    ” if screening and massively treating infected persons enables to reduce the epidemic, it could be tempting to consider population compulsory systematic screening and to voice more or less insistent summons for the treatment of persons identified as HIV positive. Should public authorities use all convenient means to implement efficient policies that strengthen screening, they need to be careful not to yield to such fallacious reasoning. The issue of improving screening efficiency surely does not invalidate any of the reasons that have hitherto prevailed for rejecting compulsory screening. Keeping screening hinged on free and informed consent remains a matter of respecting the fundamental right of the person; it is at the same time an obligation even from the public health viewpoint,

    Pursuing a probably completely unworkable attempt to end the epidemic by yearly testing and treating everyone infected as has been suggested by some, is wrong. The problems of feasibility, adherence, resistance, and the threats to individual autonomy cannot be overcome.

    Instead we should:

    Offer treatment to all who need it.

    Facilitate testing, identifying and removing barriers that impede it.

    Intensify and improve our efforts at targeted prevention education.

    Promote condom use and make them available.

    There is a final issue.

    Who needs to be treated?  Certainly everyone with a CD4 count below 200.  Apart from this we do not know, so until we obtain some guidance from prospective randomized studies, it is prudent, in general, to not delay treatment to a CD4 count below 350 as is currently recommended.

  • Herpes Viruses and HIV: Some early History and a Bit about Safe Sex

    Posted on May 17th, 2009 admin 1 comment

    17th May, 2009

    [The relationship between herpes viruses and HIV disease is also discussed in a subsequent post:

    http://aidsperspective.net/blog/?p=520 ]

    The relationship between herpes simplex virus type 2 and HIV is in the news again.   This time the press reports are that while acyclovir failed to suppress transmission of HIV it did cause a 17% reduction in HIV disease progression.

    This reduction in disease progression was assessed by noting differences between the treated and placebo group in the numbers whose CD4 count dropped below 200, and who died.  A reduction in HIV viral load was also observed in those treated with acyclovir.

    The concept on which this study was based is absolutely solid.

    Herpes simplex virus type 2 is the most frequent cause of genital ulcers, and the presence of genital ulcers is associated with enhanced transmission of HIV.

    The failure of acyclovir to suppress HIV transmission is a disappointment, but the study should not be seen as a failure.

    There is no doubt that anti herpes drugs can suppress the recurrent herpes ulceration that some individuals experience. This was observed in the study.

    Herpes viruses – and not just herpes simplex virus,  have an impact on the course of HIV infection.  This study provides yet another demonstration that treating herpes virus infections has a beneficial effect on the course of HIV disease.

    Valtrex, a drug related to acyclovir was reported to reduce HIV viral loads in infected women in 2007.

    “Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus” and it appeared in the New England Journal of medicine .

    (NEJM 2007  356:790)

    It is possible that the association of herpetic genital ulcers with HIV transmission is not as direct as generally assumed.  The reasonable suppositions included the possibility that the ulcers provided a portal of entry for HIV in the uninfected partner, that there was an accumulation of CD4 cells in the ulcer that provided a good target for HIV, or even that in the infecting partner HIV was present in greater concentrations in the ulcer.

    These assumptions about the reasons for increased HIV transmission may all be mistaken.

    We do know with some confidence that transmission of HIV is related to viral load in the infecting partner.  It may be that the assumptions outlined above derive from observing an increased frequency and duration of genital ulcers in individuals with higher viral loads who are therefore more infectious not by virtue of the ulcers.

    An individual with higher HIV viral loads  will more easily transmit the infection,  and also experience  more frequent recurrences  herpetic ulcers.  This of course only applies to HIV infected individuals.

    As far as individuals who are not HIV infected are concerned, a direct causative association between herpetic ulcers and HIV infection may also be spurious.

    Herpes simplex infections are ubiquitous but immunological mechanisms generally control the infection so that it remains latent and not manifested.

    Sometimes individuals know what provokes a recurrence.  Recurrences can be associated with febrile illnesses.  It is completely reasonable to suggest that the effects of some  intercurrent  infections may cause  both  herpetic recurrences and increase susceptibility to HIV.

    Whatever infection  causes the fever may also increase susceptibility to HIV, possibly by an association of the  infection with perturbed immunological function.    Transient immunological perturbations  can accompany many viral and tropical infections and so may not only disturb herpes simplex latency but also increase susceptibility to HIV.

    For some reason, interest in the relation of HIV to herpes viruses seems to have been almost completely confined to herpes simplex virus type 2.  At least regarding what is reported to the public.

    However the herpes virus family includes other members which have long been thought by some – including myself, to play an important role in HIV disease.

    Cytomegalovirus  (CMV) and the Epstein Barr virus (EBV) are perhaps the two that are most important.  These viruses are also sensitive to the anti herpes drugs used in these two trials.

    Since infections with CMV and EBV  are so widespread how can effects of acyclovir and Valtrex   on reducing  HIV viral loads be attributed to an effect of these drugs  on herpes simplex type2?

    I cannot recall that these two other members of the herpes virus family – or even a third, HHV6  were even mentioned in the papers demonstrating effects of acyclovir and Valtrex on HIV viral loads.

    It is entirely possible that suppression of  two viruses,  CMV and EBV, contributed, perhaps to the greatest extent,  to the anti HIV effects seen.

    One can only hope that sera from these studies were frozen and stored.  Such samples could provide information on an effect of these drugs t on EBV reactivation and on active CMV infections.

    As an historical comment, acyclovir was tried as a treatment for AIDS in 1987  around the time AZT was introduced.

    There were several studies of differing design over for some years from about 1987, some based on the hypothesis that CMV contributed to disease progression.

    AZT was tried with or without acyclovir, but the results were contradictory. Interestingly AZT also inhibits EBV replication.

    One study, ACTG 204, which compared two doses of acyclovir with Valtrex was stopped because 25% of those taking Valtrex died compared to 20% taking acyclovir.

    Some observational studies (including the MACS study) found that there was some survival benefit among those taking acyclovir.  Another retrospective observational study found no benefit.

    Nothing much can be made of these contradictory early results.

    But now, with newer techniques for measuring HIV activity by viral load assays, we   have very clear evidence that treating herpes virus infections has a beneficial effect on HIV infection.

    With the advent of the newer potent antiviral drugs, interest in anti- herpes drugs did wane, until there was a renewed interest in the past few years in connection with herpes simplex virus 2 and genital ulcer disease,  Unfortunately most of the  emphasis is on herpes simplex virus, when suppression of CMV and EBV may be as – or I believe,  of even greater importance.

    Actually there had been  interest in CMV and EBV in relation to AIDS from the time the disease was first reported in 1981.

    I have been involved in AIDS research and  treating patients with this disease from the time it started and so can  provide some historical perspective on the interest in herpes viruses,  that dates to the late 1970s, even before AIDS was described and long before HIV was discovered.   At this early time epidemiological studies on the prevalence of infection by CMV among sexually active gay men were undertaken in the US.

    As another historical interlude,  interest in herpes viruses also provided the basis for safer sex, as it is understood today.  As remarkable as this may seem, the first published and disseminated proposal to use condoms to prevent the transmission of AIDS had nothing to with HIV.   Condom use was proposed a few years before this virus was discovered, and had everything to do with herpes viruses, specifically CMV.

    From about 1978 I had the opportunity to observe and treat a very large number of men who were to be the first to succumb to this new disease.

    I knew that over 90 % of gay men attending a clinic for sexually transmitted diseases around that time had antibodies to CMV compared to 54% of heterosexual men.   By 1983  over 40% of a cohort of gay men in New York City carried CMV in their semen.   Amongst my patients, studies on EBV carried out by David Purtilo at the University of Nebraska showed an extraordinary high prevalence of reactivated EBV infections.  (Epstein Barr Virus and chronic lymphadenopathy in make homosexuals with Acquired Immunodeficiency Syndrome. H Lipscomb et al.  AIDS Research 1983 1: 59)

    At that time – 1981-1982, many of the patients I was taking care of experienced reactivated EBV infections as determined by serological methods,  and were excreting CMV in semen. Of course they were also infected with HIV , but this could not be known at that time.

    But from what was known about CMV and EBV it was reasonable to postulate that these viruses were somehow implicated in the disease.  It was thus possible to propose a way to at least prevent the sexual transmission of CMV.

    This formed the basis for the first published recommendations for condom use.

    With two of my patients, Michael Callen and Richard Berkowitz a booklet was written called “How to have sex in an epidemic: One approach”.

    The appropriate  title  was  coined by Richard.

    The twenty fifth anniversary of the publication of this booklet, that was essentially produced and widely distributed by four individuals, and funded by a single person, went almost completely unnoticed in 2007.    Although it is  in fact a landmark event in the history of the epidemic.

    Richard is only now receiving some acknowledgement for this life saving proposal  because a documentary film called Sex Positive has brought attention to  his achievement.

    An account of our collaboration in producing the safer sex guidelines can be seen by following this link.

    Safer sex recommendations.

    Michael Callen is remembered by many for his activism.   There is even a clinic in New York City named for him and Audre Lorde .

    I actually worked there as a physician for a short period, and with very few exceptions, the health care providers and others working there had no idea of who he was, let alone his contribution to safer sex.

    I just visited the Callen Lorde website, and indeed there is a photograph of Michael and of Audre Lorde with a few words about each, but no mention of Michaels contribution to safer sex.

    Thus herpes viruses, at least CMV had a role in the development of safer sex recommendations.

    As it turns out herpes viruses – CMV and EBV included, have a great deal to do with AIDS.    This is quite apart from their multiple clinical manifestations as opportunistic pathogens.  Both of these viruses almost definitely contribute to pathogenesis.

    Evidence that some herpes viruses can play a critical role in HIV disease progression has accumulated  for many years.

    In fact some evidence for this  was already apparent when AIDS was first described.

    This considerable body of evidence did not disappear with the discovery of HIV, but was relatively neglected.

    As work on HIV proceeded we gained some understanding of the ways in which herpes viruses can interact with HIV to accelerate disease progression, increase HIV infectivity and thus enhance its transmission.

    I should now describe some of the interactions that exist between herpes viruses, particularly CMV and EBV, and HIV.

    Many, perhaps most of these interactions also involve herpes simplex viruses types 1 and 2.

    The role of CMV in immune system activation, a major force in driving HIV infection.

    The systemic effects of CMV and EBV infections are most probably of great importance in this respect.

    Systemic effects resulting in immune system activation and activation of HIV replication may also  accompany reactivated herpes simplex virus infecteions.

    Among the systemic effects of active herpes virus infections are the secretion of pro inflammatory cytokines.  These circulate and attach to specific receptors on the cell surface. A consequence of this is that certain sequences on DNA will be activated resulting in the transcription of HIV DNA and ultimately the production of new HIV particles.  So, this is but one way in which an active herpes virus infections can promote the replication of HIV.  The general mechanisms are described in a previous post..

    An important and interesting  paper that also deals with   EBV and CMV in relation to HIV replication was published by V Appay and colleagues.  It can be seen  by clicking the following link.

    HIV ACTIVATION

    I am  reproducing some excerpts from Dr Appay’s paper here as the descriptions are very clear and there are references.  The references can be seen in the complete text seen by following the above link.

    “HIV-1 also causes immune activation and inflammation through indirect means. Antigenic stimulation during HIV-1 infection may be induced by other viruses, such as CMV and EBV”

    “In addition, inflammatory conditions occurring during HIV infection (eg release of proinflammatory cytokines) may also participate in

    the reactivation of latent forms of CMV and EBV. Recent studies have shown significant activation of EBV- and CMV-specific CD8+ T cells during HIV-1 acute infection [40,41] . Hence, sustained

    antigen mediated immune activation occurs in HIV-1-infected

    patients, which is due to HIV-1, but also to other viruses (and may be restricted to CMV and EBV)”.

    “CMV has been associated with strong and persistent expansions of T cell subsets that show characteristics of late differentiation and replicative exhaustion [94-96]. The anti-CMV response appears

    to monopolize a significant fraction of the whole T cell repertoire [97], so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity. CMV infection is actually extremely common in HIV-1- infected individuals and its recurrent reactivation may put further stress on their immune resources. Interestingly, CMV-seropositive subjects generally experience more rapid HIV disease progression than CMV seronegative subjects [98]”.

    Herpes virus (including herpes simplex) infected cells express Fc receptors on their surface.  These receptors can bind certain sequences on antibody molecules. If these antibodies are attached to HIV, a portal for entry of HIV is provided on herpes infected cells that do not possess CD4 molecules on their surface. This process has in fact been demonstrated.

    Transactivation  of HIV by herpes viruses.

    In cells infected with both viruses herpes virus gene products can activate HIV and promote its replication. The transactivation is reciprocal as HIV can promote herpes virus replication.

    Acyclovir and Valtrex have no direct effect on HIV except under one unusual circumstance,  yet both have been demonstrated to reduce HIV viral loads.

    In the early 1980s when we had no effective measures against  this disease I treated my patients with high dose acyclovir.

    There then  was evidence, albeit theoretical and indirect for a role for these viruses in this new disease.

    In the absence of clear evidence from clinical studies, and given the gravity of the disease, it seemed completely appropriate to be guided by these theoretical considerations, particularly involving a drug that is so free of toxicity.

    But interestingly,  at that time,  none of these theoretical considerations placed much importance on HSV 2.

    The practice of medicine in those years, dealing with such a mysterious and deadly disorder of unknown causation , demanded responses that could only be based on one’s best judgment.

    Fortunately I also had had some experience in the transplant field and was also able to provide bactrim to my patients years before recommendations for its use were issued.

    But it was not until potent antiviral drugs became available that we were able to make significant and life saving, rather than life extending  interventions.

    What I have written of this experience with bactrim in the early years can be seen by following this LINK

    In the light of later evidence, I believe it is possible I was able to provide some small benefit in prescribing high dose acyclovir in those very early years.


    [i]   Acyclovir, when phosphate is added to it, acts like the nucleoside analogues active against HIV, drugs like AZT, D4T, 3TC etc.   But this drug has a truly remarkable quality.  The cellular enzyme that  adds phosphate to make drugs of this type active,  does not work on acyclovir as it does on AZT, 3TC and other anti HIV nucleoside analogues.   But an enzyme, thymidine kinase that is encoded by herpes viruses, and therefore only appears  in herpes virus infected cells  has the ability to add the phosphate group and turn acyclovir into an active drug.  This is the reason why acyclovir is such a safe drug.  It only disrupts DNA synthesis in herpes virus infected cells, where of course this effect is desirable; it has no effect on uninfected cells.

    However, if  the same  cell happens to be infected with HIV and a herpes virus, the herpes thymidine kinase will phosphorylate acyclovir, which now can work to  terminate  HIV DNA synthesis just as 3TC , AZT and similar drugs do when phosphorylated by the cellular enzyme.

    This effect , only observed in doubly infected cells in the laboratory is unlikely to be of much significance in the body.

  • Interferon: Another Historical Digression

    Posted on May 10th, 2009 admin No comments

    This is about something I wrote in 1964, which was recently reproduced and is now available on line.

    It can be seen by clicking on this link:

    1964 interferon article.

    Seeing this 45 year old document prompted me to write this post.

    It is about interferon and has nothing to do with AIDS, at least not in any immediately obvious fashion.

    It is an interesting story, about at least one of the ways in which science progresses.  It is a story of how an apparently insignificant change in an experiment can sometimes lead to very significant advances.  In this instance, about how cytokines exert their effects.

    Cytokines are protein or peptide molecules released by cells which then attach to the surfaces of other cells.  As a consequence, the behaviour of the cells to which they attach is altered.  In this respect cytokines are similar to hormones.

    Generally, each cytokine will only attach to a specific receptor on the surface of the cell.

    When a cytokine attaches to its matching receptor, a cascade of events is set in motion resulting in the activation of specific sequences in nuclear DNA.

    Messenger RNA molecules are then transcribed from specific DNA sequences and these direct the synthesis of specific proteins that ultimately are the molecules that cause the particular effects produced by the cytokine.

    Therefore, as the picture below demonstrates, cytokines are not themselves the molecules that directly mediate the effects they cause.  Through a complex series of signalling events in the cell, set in motion by the binding of the cytokine to its receptor, specific proteins are made by the cell.  These proteins are the actual mediators of the cytokine’s effects. [1]

    In the illustration, the right angled arrow in the nucleus represents the messenger RNAs which will direct the synthesis of these proteins.

    HIV DNA is integrated into host DNA.   Should certain cytokines,  IL-6 or TNF alpha for example,  attach to their receptors on the cell membrane,  a series of events follow, ultimately resulting in sequences in nuclear DNA being activated which in turn causes HIV DNA to make RNA which directs the synthesis of HIV proteins and ultimately of new HIV particles.

    cytokine

    Since many of those cytokines that can activate HIV in this way are produced during the course of many different infections, this then is but one of the several ways in which HIV replication can be enhanced by many different concurrent infections.  TB and malaria are among them, as are the bacterial diarrheal infections associated with a lack of sanitation and clean water.   Controlling these many  HIV enhancing infections,  is  with the exception of TB,  a neglected target in the fight against the epidemic.

    Interestingly,   discoveries about the ways in which cytokines exert their actions have largely been made since AIDS was first recognized in 1981.

    Thus HIV research has progressed in tandem with research on molecular cell biology.  There have been reciprocal benefits.  HIV research has both contributed to our understanding of molecular cell biology, as well as itself being advanced by discoveries in this field.

    Interferon was the very first cytokine to be discovered.  It was discovered by Alick Isaacs and Jean Lindenmann .   Actually it was not really discovered as a specific molecule; the term interferon was coined by Alick  Isaacs in 1957, to describe an activity – an antiviral activity released by virus infected cells. It was perhaps a bit premature to assume that this activity resided in a single molecule. But that was what we all thought at the time; it was nonetheless a concept that facilitated research as probably did the coining of the word “interferon” to describe this antiviral substance.

    We now know that there are many types of interferon, and we therefore should properly speak of the interferons.  Also, as is the case with cytokines generally, the interferons have multiple effects, but the antiviral effect is how it was first recognized and also measured.

    Alick Isaacs  was my mentor in the laboratory study of viruses; I shared a lab with him and  worked on the mechanism of the antiviral action of interferon.

    In 1963, we had no idea about how interferon exerted its antiviral effect. We at least knew that it did not directly inactivate viruses.  Molecular biology – at least as far as eukaryotic cells were concerned, had hardly developed.

    The 1964 article that can be seen by following the link at the beginning of this post resulted from the work of Joyce Taylor.1964 interferon article.

    Joyce Taylor is a biochemist.  She also worked in Alick’s lab in 1963.  It was rather unusual,  in those days for a biochemist to be working in a lab concerned with animal viruses. Animal virology was just beginning to employ biochemical methods.

    Joyce was attempting to show that interferon blocked the synthesis of viral RNA.   This of course required the use of biochemical techniques to identify and measure viral RNA.

    She was able to demonstrate that viral RNA was not made in cells treated with interferon. This was accomplished by using a compound that blocked DNA directed cell RNA synthesis, actinomycin D.  It was necessary to use actinimycin D because there is so much background  cellular  DNA directed  RNA synthesis that unless this can be stopped it would be impossible to observer viral RNA synthesis. She used an RNA virus (SFV) that was unaffected by actinomycin D.

    Joyce very clearly showed that the synthesis of SFV RNA was blocked in cells treated with interferon.  as with the availability of actinomycin D,  she was able to detect and measure viral RNA.

    We are now coming to the happy, but at the time seemingly  insignificant change in the sequence of steps in an experiment,  that had such far reaching consequences.

    This is how Joyce did her experiments.  Cells were exposed to interferon for some hours, and then the SFV virus added with actinomycin D, to allow the measurement of viral RNA synthesis by removing the background of cellular RNA synthesis.  As mentioned,  in this way, Joyce was able to show very clearly that pre-treatment of the cells with interferon blocked the synthesis of SFV RNA.

    One day, because Joyce had to leave early and she did not want her technician to handle actinomycin D, she added this drug with the interferon, at the beginning of the period of interferon treatment  .  Nobody at that time would have thought that this would make the slightest difference.   It is this change in the time when the actinomycin was added that was critical, but it was not at all expected to have any effect.

    But it did have an extraordinary effect.  When cells were treated with interferon in the presence of actinomycin D it had no antiviral effect.  At first it was thought that an inactive preparation of interferon was used, but the same result was obtained when the experiment was repeated.

    The significance of the change in the order in which actinomycin was added was that now, while the cells were exposed to interferon, DNA directed RNA synthesis was also blocked.

    The implications of this were quite extraordinary.  At that time, 1963 and 1964, the foundations of our understanding of basic molecular cell biology were being worked out mostly in bacterial systems.  The structure of DNA had been worked out, messenger RNA discovered (although there is some dispute as to who discovered it) and there was some understanding of derepression – that is the ability of certain molecules to cause the synthesis of specific proteins by bacteria.

    The result of the changed order of Joyce’s experiment suggested that something similar might be happening in animal cells- that interferon was inducing the synthesis of a specific messenger RNA which in turn directed the synthesis of a  protein  responsible for its antiviral effect.  This is what prompted me to write the short article that can be seen by clicking the link at the beginning of this post.

    What was described in 1964 was  in fact the first demonstration that cytokines exert their effect by attaching to a receptor on the cell surface,  and  as a result of this,    specific regions on cellular  DNA are activated,and  RNA synthesized.  Work showing that this RNA is responsible for the synthesis of proteins followed immediately.

    Robert Friedman, was visiting the laboratory from the National Cancer Institute, and we worked together to show that not only RNA synthesis, but also protein synthesis was required for interferon action – and as was to be found, for the action of all cytokines.

    Joyce Taylor remembers this story somewhat differently, but I trust that my version is correct.  I have repeated it so frequently since the events in question, as an illustration of how science sometimes progresses.

    Joyce changed the order of adding reagents. As a result we knew that interferon action needed cell the participation of cell DNA and the synthesis of RNA.  Bob Friedman and I then showed that interferon action also required cell protein synthesis. Ian Kerr who was also in the lab around that time, and others then showed a part of what changes interferon induced in cells.

    Interferon was the tool by which a signalling pathway was demonstrated that could account for the effects exerted on nuclear DNA by a molecule interacting with its receptor at the cell surface.   Ian Kerr was a key contributor to this work.

    This post was not directly connected with HIV/AIDS.  But cytokines are most certainly  connected with HIV/AIDS.  This will be the subject of future posts.

    [1]  The genetic code is defined by the sequence of the four bases that make up genomic DNA. A particular sequence of three nucleotides can be regarded as a code component  which ultimately defines a particular  amino acid; amino acids are the building blocks of proteins.  The DNA code is conveyed from the nucleus to the protein synthesizing apparatus in the cell cytoplasm in the form of messenger RNA. This RNA molecule is made from a DNA template and exactly reflects the nucleotide sequence of the section of DNA from which it is transcribed.

    genetic-code

  • Treatment as Prevention. A last short postscript

    Posted on May 1st, 2009 admin No comments

    I have written several posts dealing with “Treatment as Prevention”  referring to proposals that the epidemic could be controlled by testing and treating all infected people.   However, as this phrase is also used in a different, although related context, I am adding this last postscript.

    Thus,  “treatment as prevention” has a context that concerns populations and considers a strategy to  control and even end the epidemic.    The same phrase  also has a context that deals with prevention of infection at an individual level, and focuses on transmission risks  between two people.

    The latter context was brought to attention in 2008 by the Swiss Federal Commission on HIV/AIDS.  Their publication essentially states that, under certain conditions,  with effective antiviral treatment achieving an undetectable viral load, the risk of sexual transmission without condom use is not greater than that with the use of condoms.

    Among the conditions stipulated is that there is no sexually transmitted infection, and that the viral load has been undetectable for at least six months.

    http://www.aids.ch/e/fragen/pdf/swissguidelinesART.pdf

    Now a German voluntary organization, Deutsche AIDS-Hilfe, has added support – with some modifications to the Swiss statement.

    http://www.aidshilfe.de/media/de/0904_DAH-Papier_HIV-Therapie_und_Praevention_Englisch.pdf

    There was a huge controversy when the Swiss recommendations were first made public in 2008.  Their conclusions were rejected  by groups  in the US,  even by those who promoted the application of the same principle – the reduction in infectivity conferred by treatment – as a means of controlling the epidemic.

    I was – and am – absolutely supportive of the Swiss recommendations as applied to individuals.  Here is an excerpt from a letter I wrote when the Swiss document was published:

    “The report is absolutely reasonable. There are caveats and cautions in it, and since I can see no reasonable objection to them, we have to look elsewhere to try and understand why the report has provoked such a furious response. I know it is a bit pedantic and pretentious but I’m going to add a quotation that is over 100 years old that recognizes that scientists can be as irrational as anyone else (especially about sex), here it is:

    In Man Adapting, Rene Dubos notes that:

    “The presuppositions on which medicine operates are thus conditioned by the general philosophy of the social group as a whole” and adds the words of Oliver Wendell Holmes in 1860:

    “The truth is that medicine, professedly founded on observation, is as sensitive to outside influences, political, religious, philosophical, imaginative, as is the barometer to the changes in atmospheric density”10
    I would bet that some who have commented have not even read the cautious Swiss text, and have allowed their prejudices and squeamishness about sex in general to surface at the very mention of sex without condoms.

    The Swiss authors do deserve some recognition for their courage. There are circumstances in which it is not irresponsible to have sex without condoms. And even for those for whom these circumstances do not apply, the knowledge of the possibility of sex without condoms will be an encouragement, in at least two ways.

    Firstly, to continue using condoms when this is necessary, and then as a support with treatment adherence and monitoring.

    I say these things as someone who had something to do with the original introduction of condom use for AIDS prevention in 1983, – briefly described here:

    http://aidsperspective.net/articles/Callen-Berk_collaboration4.pdf

    and until now thought – as probably most did, that condom use  would be forever.

    Knowing that this is not necessarily so is a tremendous encouragement and I believe this thought alone will help our prevention efforts”.

    I have continued to encourage the use of condoms, but I do welcome the Swiss document for pointing out, with appropriate documentation and caution, that there are circumstances when it is not irresponsible to dispense with them.

    This also means that there are circumstances when conception is possible. There are also implications in situations where there are laws that criminalize sexual contact with HIV infected people under certain circumstances.

    A large part of the irrational responses to the proposal are I believe based on a disparaging attitude towards sex.

    For many, the use of condoms is a barrier to intimacy.  The knowledge that if certain circumstances can be met, an infected person is not endangering their sexual partner by dispensing with condoms is in fact a life affirming celebration of sex, one of life’s joys.

    Admittedly, dispensing with condoms will not be possible for most individuals.  It is probably most relevant to serodiscordant couples in a stable relationship – that is where only one of the partners is HIV infected.

    But knowing that this might be achieved could be a great support to most HIV infected people  who must continue to use condoms   It will also be a greater incentive to remain adherent to one’s treatment regimen.

    Of course the diminished infectivity of effectively treated individuals is the basis for the proposals to use treatment of all infected people as a means of controlling the epidemic.

    This is a very different situation, most importantly because it will involve treating people who do not need to be treated for their own personal benefit. These healthier people will derive no benefit from the medications and only be exposed to their side effects.  I have written about this in previous posts on treatment as prevention.

    Except for the relatively uncommon situations outlined in the Swiss document, and more cautiously and explicitly, in the German document, the consistent use of condoms remains one of the most important measures we have to prevent infection.

  • The Not So SMART Study

    Posted on April 27th, 2009 admin 2 comments

    I have borrowed this title from a comment in the journal, Lancet Infectious Diseases, entitled “Not so Smart?” by Justin Stebbing and Angus Dalgleish.

    The SMART study as many will recall was a randomized comparison of two antiretroviral treatment strategies.

    HIV infected individuals were randomized to receive either  continuous antiviral treatment or to receive it intermittently while the CD4 count had fallen below 250. This trial received a tremendous amount of publicity.  Deaths from all causes – including those that were not obviously related to HIV infection, were significantly increased in the group that were treated intermittently.  This seemed to dampen enthusiasm for treatment interruptions and brought attention to a possible relationship between HIV infection and deaths from causes previously not associated with it.

    5,472 patients participated in this study at 318 sites in 33 countries.

    There were a total of 85 deaths in the study.

    79 of these 85 deaths occurred in the US where 55% of the patients were randomized.

    There were only 6 deaths among the 45% of patients randomized in countries outside the US.

    .

    It would seem that treatment interruptions are quite safe, as long as they occur in countries outside the US.

    Did I miss this information in the original report of the study published in 2006?

    There were numerous discussions of the SMART study on websites and newsletters addressed to HIV infected people and their health care providers.  Did I miss those that reported on the fact that only 6 of the 85 deaths occurred in countries outside the US?

    Of course I looked at the original report again but could not find this information – perhaps it was buried in a supplementary appendix?

    For some reason, it seems that the authors of the report on the SMART study did not feel it necessary to draw attention to this information – at least not with the prominence that it deserved, if it was mentioned at all.

    Most of the deaths on the study were not from AIDS associated opportunistic infections or malignancies.

    With a presumption (maybe this  suggestion is too harsh) that despite this, the deaths were indeed related to HIV,  a possible relationship with this virus was sought. One obvious possibility of connecting these deaths with HIV was by linking them with the inflammation that is associated with HIV disease.

    Thus, as a follow up to the SMART study, various markers of inflammation were looked at in both groups, and not surprisingly these were increased in the group with the most deaths, those receiving intermittent treatment rather than continuous treatment. As mentioned almost all of these deaths were confined to the US.

    So, what we have is the observation that people who were to die within a relatively short period had increases in markers of inflammation. Of these, D-dimer, CRP and IL 6 had already been associated with all cause mortality, even in people not infected with HIV.

    With respect to the cardiovascular deaths in the study, here is a quotation from PM Ridker:  “In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis”.

    IL-6 is a pro inflammatory cytokine and levels were increased in those receiving intermittent therapy.  IL-6 promotes HIV replication,  and can be produced by HIV infected cells but also by many other stimuli.

    So IL 6, which is associated with atherogenesis,  also directly increases the replication of HIV.  IL 6 secretion is increased by numerous and diverse factors. For example bacterial toxins induce IL 1 which in turn stimulates IL 6 release and  hepatitis C virus core proteins induce IL 6.  HIV infected cells can also release IL 6.

    But with so many different agents able to do this it is difficult to attribute IL 6 production to HIV.  This is of course muddied by the fact that whatever stimulates IL 6 secretion, IL 6 itself will accelerate the replication of HIV.

    But possibly the most intriguing feature of the report of this follow up study  is the first sentence of the Results section:

    “Most of the deaths (79 of 85) occurred in the US”.

    Having made this rather startling statement, the authors never return to it.  It remains undiscussed,  as if it is of no consequence!

    Are we to believe that intermittent therapy with antiviral agents  promotes inflammation with its lethal consequences only in the US?

    The outcome measurement of the SMART study included death from all causes. Only 8% were the result of opportunistic disease.

    There were 16 deaths from cancer ( 11 in the intermittent therapy(IT) group and 5 in the continuous therapy group(CT)), 11 deaths from cardiovascular   disease  (7, IT, 4,  CT);

    8 people died from substance abuse, 7 from violence.

    18 deaths were from causes that could not be determined. Of these 18, 15 occurred in those on intermittent treatment and only 3 in those receiving continuous treatment.  This last rather large difference leads one to ask if it is possible that the two groups were treated differently. At least, in the US, where almost all the deaths occurred.

    This may seem like an outrageous question. But unintentional bias in unblinded studies cannot be ignored and I will return to this.

    Many of the deaths reported –  certainly far from all, were caused by  conditions that might have been ameliorated by appropriate medical care ( this does not only mean from the point of view of the physician. The patient is also involved – for example, were medical visits made? Did the patient pay attention to symptoms? Was there compliance with prescribed treatment?)

    With almost all of the mortality confined to the US,  it looks like something else must be at play here, something other than the antiretroviral treatment strategies, and the first place to look is the overall quality of medical care – which,as mentioned, includes issues that may entirely be related to the patient – such as poor compliance with recommendations, despite adequate support.

    There are two distinct  questions to be asked.

    Firstly,  why was there such  a difference  in  the trial outcomes between US and non US sites?

    Secondly, in the US can we reliably attribute the differences in outcomes in the two treatment arms to the differences in the antiviral treatment strategies?

    The first two questions one would ask in trying to explain the difference between 6 deaths and 79 deaths is related to the quality of general medical care in the US as compared to the non US countries, and then to possible differences in the patient populations.   The patient populations may have differed for example in the extent of co- morbidities,  and in the degree of compliance with recommended treatments.

    But  I don’t know that one can come up with an answer about the quality of medical care.   We must assume that there were probably no great differences.  However there was some information on co- morbidities such as Hepatitis b and C,  but not enough to attribute the differences in the number of deaths to this factor.  [Note`added on April 4 2010. The difference in co-morbidities is in fact probably  the reason for the striking difference in mortality between US and non US sites. Here is a link to a later post where a table is reproduced  from the paper describing the mortality difference referenced below. The population enrolled in US sites, where most of  the deaths occurred,  were much more likely to suffer from non HIV related health problems than those enrolled in non US sites.  Here are two sentences from the later post:  ”The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease:

    I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals”. This current entry on the SMART study, which I’m leaving unchanged,  should be looked at in conjunction with my subsequent post. LINK TO LATER POST ]

    The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.

    I doubt if information on compliance is available.

    Even if one could show differences between the US and non US sites ,  how would  this  affect the study outcome?  More people died in the intermittent treatment arm compared to those receiving continuous treatment. So this is the second question.

    Could there be an explanation for the differences noted between the study arms (albeit only in the US) other than the antiviral treatment strategies?

    There could be a connection with general patient care.

    In order to minimize bias in a study, where possible when treatments are compared, participants and those conducting the trial do not know what treatment is being received by particular participants.

    The study is blinded, so that as far as it is possible, we can attribute any effects observed to the treatment, not to any anything else.  For example, if patients knew what they were or were not receiving in a treatment trial, they may behave differently, and  in ways that may affect the outcome, which then could not be attributed to the particular treatment being studied.

    For example if a patient knew they were receiving a placebo, they may then take other medications that might affect the outcome of the trial, or if doctors knew patients were taking a medicine they believed worked they might treat their patients with greater care or with less care.  We do recognize that some behaviors that may alter the outcome of a study are  certainly not intentional.

    It was impossible to blind the SMART study.  So, both participants and physicians knew which arm of the study patients were randomized to.

    If the study doctor was also the person who provided  general  care than the specter of bias unfortunately is lurking and may confound interpretations.

    This is not to say that differences in general care between both study arms, if indeed there were differences, were intentional.

    To put the questions in another way:

    1: Can general patient management strategies ( not the strategy of antiviral treatment being studied) have an impact on all cause mortality?  In other words, can the way health care providers manage the general  health of their patients make a difference to survival?

    2: Can bias influence the ways physicians take care of their patients?

    The answer is of course yes., although we may not like to admit this.    So bias might be a factor in an unblinded study and affect the outcome.

    So we are still in the dark regarding regarding the value or danger  of treatment interruptions.

    As a postscript, a similar problem hangs over the original AZT study – the study that led to the approval of this drug by the FDA.  Of course the dramatic life saving effect of zidovudine seen in this trial  has never been observed again.

    This placebo controlled study was also in effect unblinded. Patients and doctors knew who was receiving placebo or active drug.

    Deaths were mostly due to opportunistic infections. Patient management strategies can make the difference between life and death with regard to these infections. Rapid diagnosis, effective treatments obviously make a difference. Can bias influence patient management strategies?

    I wrote about this in – I think 1989, and the article can be seen by clicking here.

    I suppose that one must conclude that the fact that almost all the deaths in the SMART study occurred in the US was not known to journalists and those who specialize in informing us about issues related to AIDS.  I also missed it when it was  published in 2008 [iii].

    The report of Dr Kuller may be the first public mention of this odd result. But it is just mentioned and not discussed at all.

    Here is what Justin Stebbing and Angus Dalgleish wrote in the Lancet Infectious diseases about this report:

    ” The follow-on case-control study by Kuller and colleagues showed that it is apparently safer to be off  HAART outside the USA rather than on HAART within the USA”

    As a clinician I don’t know what to make of the SMART results. In the lamentable absence of firm evidence one has to use one’s best judgment in caring for patients.  Numbers of my patients have – at their request and at my recommendation, temporarily interrupted their treatments, using a variety of strategies, with no harm, and with a better quality of life.

    I imagine that some will have been persuaded to stop this practice  by their new physicians. But I am still in touch with one, who had a CD4 count of 0 when first seen, who still regularly interrupts his treatment.  He is extremely well, leading an active and productive life.


    The Lancet Infectious Diseases, Volume 9, Issue 5, Pages 268 – 269, May 2009

    The New England Journal of Medicine [NEJM 355(22): 2283-96 (2006)

    PLoS Medicine 5 (10); e203.doi:10.1371/journal.pmed.0050203

    Kuller LH, et al. (2008) Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV infection.

    HarrisTB et al 1999  Association of elevated IL6 and CRP levels with mortality in the elderly, Am J Med 106: 506

    Ridker PM et al 2000 Plasma concentrations of IL 6 and the risk of future myocardial infarction among apparently healthy men.  Circulation  101 1767

    Shorr AF et al 2002 D-dimer corerelates with proinflammatory cytokine levels and oycomes in critically ill patients, CHEST 121: 1262

    HIV disease is in fact characterized by multiple examples of positive feedback systems – a subject for another post.




  • Early concerns about confidentiality in AIDS, and what Jim Monroe had to do with this.

    Posted on April 23rd, 2009 admin No comments

    From time to time I will write about some extraordinary people I have worked with. The first of these is Jim Monroe.

    Jim worked for the Centers for Disease Control (CDC).  He worked to improve the health of all, but it is people with AIDS who probably derived the greatest benefit from his efforts.

    Those who do the most to help others often remain completely unnoticed. Maybe their commitment leaves no room for seeking personal attention; maybe they don’t care about recognition, or actively shun it.

    Jim Monroe personally helped many individuals who were in great need.  He was also the person who was probably responsible for first bringing attention to the issue of confidentiality in AIDS in the earliest years of the epidemic.

    He most certainly did not care about personal recognition.  Apart from a few friends and colleagues and those who directly benefited from his efforts, he remains largely unknown.

    I first met Jim in the late 1970s. I was at that time working for the New York City Health Department, concerned with sexually transmitted infections.  Jim worked in the same field, but for the CDC.  He was based in New York City.  Our places of work were in close proximity and we met through our common interest in the control of sexually transmitted infections.

    Jim is probably the person who was responsible for the early attention given to confidentiality in connection with AIDS

    Confidentiality in matters of health is of the greatest importance; it is also complex, with some special concerns in connection with sexually transmitted infections.

    We have an obvious obligation to respect the trust placed in us by those who seek our care. But there are different and strongly held views on the tensions that can exist between individual rights to privacy and the protection of sexual partners, as well as society at large.

    But the context in which Jim brought attention to confidentiality was the concern to protect individuals suffering from this new, untreatable, and as yet unnamed disease.   From the very start, affected individuals frequently had to contend not only with this frightening illness but with irrational and cruel discriminatory acts against them.

    Not only was the disease itself associated with stigmatization, particularly in the early years, there was yet another issue requiring attention to confidentiality.  Sexual orientation was revealed with a diagnosis when the disease was thought to be confined to gay men. As other groups of individuals were identified, perhaps only those who acquired the disease from blood products were relatively free from the threat of discriminatory practices that were all too frequently directed against gay men and IV drug users.

    Those were the days when HIV infected people in hospitals had to retrieve their meals which had been left outside their doors;  when medical personnel would refuse to care for infected people; when some children were not allowed to be in contact with those known to be infected, and infected children sometimes not allowed to attend school.  Thankfully in the US today children are protected.

    http://www.ed.gov/about/offices/list/ocr/docs/hq53e9.html

    But despite advances, AIDS is still a disease associated with stigmatization, not only in developing countries but also in the US and other developed nations.

    I will describe how Jim started a response intended to assure that those affected by this new disease would be protected by measures to maintain their confidentiality.

    A few introductory words are needed.

    I started my own research into this new disease in 1981, and received tremendous support from an old colleague in the interferon field, Dr Mathilde Krim.

    In 1983, my lawyer, Frank Hoffey with Graham Berry prepared the papers and incorporated the AIDS Medical Foundation (AMF), initially to raise funds to support my research.  Apart from Mathilde’s personal support our work was not funded.  AMF soon broadened its mission to support the work of others as well.

    Fundraising during the first year was very difficult and the foundation really owes its survival to the efforts of Dr Krim, who was the chairman of the board.

    Concern with confidentiality started with an anxious call from Jim in 1982.  The reason for his extreme agitation was that he knew that a study was to be undertaken on this new disease in the Health Department clinics for sexually transmitted infections. In particular, the clinic on 28th street was known to be the site where large numbers gay men were treated for sexually transmitted infections.   The study would be concerned with people who had “reversed T cell subset ratios”.  A reversal of the normal CD4: CD8 ratio was how we recognized AIDS before the name was coined.

    What concerned Jim was that no provision had been made to protect the confidentiality of the study participants. Their names were to be recorded.  I cannot recall if the proposed study was a CDC study or one originating with the Health Department.

    Jim told me that the study was to be submitted for review by New York  City’s Institutional Review Board (IRB) although it was not called an IRB.  I suppose he must have had little confidence that the IRB, which is a body regulated by the FDA and intended to protect human research subjects, would address the confidentiality issue. In view of what transpired he was probably correct.

    I also don’t know what he expected I could do. Maybe he just wanted to share his frustration with a person who shared his concerns.

    In the event, this call was to actually result in something that would have lasting effects.   I spoke about this to Mathilde, who I knew also shared these concerns about protecting confidentiality.

    She immediately said that she knew who could effectively deal with this problem.  Mathilde was associated with and had provided support to the Hastings Center, which was concerned with bioethics, and introduced me to Carol Levine and Ron Bayer.  I conveyed Jim’s concern about the proposed study  and the result was that I attended a meeting at the Health Department with Carol or Ron, or maybe both were there, as well as a lawyer from Lambda Legal Defense Fund, whose name I think was Chris Collins.

    As a consequence, because of a lack of provision for confidentiality protection, the study was tabled.

    Jim Monroe’s concern to protect individuals with AIDS started this train of events.

    It is hardly surprising that not much attention had been given to the issue of confidentiality in 1982. The disease was after all new, and we were just learning of the extremely hostile and irrational responses directed at those who were affected.

    Carol and Ron’s interest did not stop.  I think it was Ron Bayer who proposed that a meeting be held on the issue of confidentiality.  This meeting in fact did occur and resulted in the publication of guidelines for confidentiality in research on AIDS.

    Lloyd Schloen had worked at Memorial Sloan Kettering Cancer Center as a fund raiser.  Mathilde had introduced us and we had become friends.

    Lloyd then became an official at the Charles A. Dana Foundation, and we talked about confidentiality protection.  It is through his efforts that the meeting on confidentiality was funded.

    The meeting proceedings were published in the Hastings Center’s own publication, IRB.

    http://www.jstor.org/pss/3564421

    I believe my memory is correct in recalling that an established medical journal declined to publish the guidelines.

    I was editor of a journal devoted to AIDS called AIDS Research and had absolutely no hesitation in publishing the guidelines myself. Some pages are reproduced here.

    img0822

    img083

    img084

    Later, the CDC was to publish its own set of guidelines.

    The Hastings Center guidelines were not the only publication on confidentiality that preceded the CDC’s recommendations.

    As part of my research effort I had become associated with David Purtilo, Chairman of the Pathology and Microbiology Departments at the University of Nebraska’s medical school in Omaha. The reason for this was that David was an expert on the Epstein Barr virus, and I believed that this common herpes virus can play a significant role in the pathogenesis of HIV disease[i].

    David’s wife, Ruth Purtilo is a bioethicist. She clearly saw how important confidentiality protection was in research on AIDS. She obtained the perspective of Michael Callen, a patient of mine who was HIV infected. Together we wrote a paper on this issue in 1983.

    Confidentiality, informed consent and untoward social consequences in research on a new killer disease (AIDS).

    Clinical research, {Clin-Res}, Oct 1983, vol. 31, no. 4, p. 464-72, ISSN: 0009-9279.

    Purtilo-R, Sonnabend-J, Purtilo-D-T.[ii]

    Unfortunate developments today have made the need for respecting confidentiality as important as was the case when the epidemic began.  Differently worded legislation now exists where criminal law is applied to people who transmit HIV to others, or even who expose others to the risk of transmission. There is absolutely no evidence that such criminalization prevents the spread of this disease.  The following link will provide useful sources of information.

    http://data.unaids.org/pub/BaseDocument/2008/20080731_jc1513_policy_criminalization_en.pdf

    These laws only increase stigmatization.  The introduction of such legislation in many countries is an important additional reason why concerns about confidentiality protection remain vitally important.

    Jim Monroe returned to work at the CDC in Atlanta.  Although he was assigned to work in another field, his interest in AIDS remained. He was the kindest of individuals, personally helping people with AIDS, as well as others in difficulty.

    The very last project on which we worked was cut short by his death.

    Even then, in the late 1990s, the problem of when it is best to start antiviral therapy was of concern – indeed it had been of concern ever since the introduction of AZT.  We then believed – as many still do today, that the question is most reliably approached by a randomized prospective study.  Most certainly not by the opinions and recommendations of experts, not all of whom could properly be considered qualified to hold that rank.

    We thought that those entities that pay for the drugs might be the appropriate sponsors of prospective clinical trials.  They have a clear interest in knowing if it is beneficial or not to start treatment early rather than to defer it, or whether it makes no difference.

    It is in their interests; if early treatment provides no benefit – (at least one large retrospective study suggests that there is no benefit to starting treatment above a CD4 count of 400) then paying for an early start to treatment would be pointless. On the other hand if early treatment produced some benefit then the cost would certainly be justified.

    Among the entities covering the cost of drugs are government agencies such as Medicare and the VA.   The VA has a history of undertaking studies.  There are also the private insurance companies.

    Jim together with a Public health expert at Emory University was attempting to present a proposal to the medical directors of private insurance companies. We had the support of an eminent statistician who had also been involved with me on an earlier unsuccessful attempt to set up a study to compare early and deferred treatment with AZT.

    This attempt was brought to an end by Jim’s sudden death, as well as by the illness of another one of us working on the proposal.

    One Friday afternoon while seeing patients in a clinic in New York City,  I received a call from a friend of Jim’s in Atlanta. She told me that Jim was severely ill in Chicago. He had collapsed a few days earlier.  On Saturday I travelled to Chicago and found Jim unconscious in a hospital. He was not to recover.

    None of us knew that Jim had been ill. He kept this a secret while continuing to work  to improve the health of all people, both in his assigned work but also through his initiatives on behalf of people with AIDS.

    Jim’s final project, cut short by his death, is still absolutely relevant.

    Some recent suggestions, based on the flimsiest of evidence propose that treatment with antivirals should be started even earlier than the current recommendations.  There are well meaning physicians today who already buy into this nonsense, who state that they would treat all infected people, irrespective of CD4 count. Or they would raise the CD4 threshold above 350, which is the currently recommended level at which to initiate treatment, even in the absence of reliable evidence that their patients will benefit.

    It cannot be reliably known from any evidence we  have at present whether such prolonged exposure to  antiviral drugs will increase or decrease survival or be without effect in this respect – of course except for cost.

    We do need to really know when it is best to start treatment.  Prospective randomized studies can provide an answer to the question if, on average it is better to start treatment early or to defer it.

    Hopefully others will take on Jim’s last project and write a proposal to some of the entities who pay for the drugs, to sponsor  prospective studies,  the only reliable way to answer this question.

    Are they wasting money? Are they getting their money’s worth?

    Surely the payors, will want to know.


    [i] I still believe this to be true,  as further evidence continues to support this idea.  Our work on EBV and HIV was quite productive and will be the topic of another post.

    [ii] We were awarded a prize for this article: The Nellie Westerman  Prize for Research in Ethics awarded by the America Federation For Clinical Research.

  • Treatment as prevention. Another postscript.

    Posted on April 19th, 2009 admin 1 comment

    This additional postscript was prompted by an article that appeared a few days ago in the Washington Post. It was written by Dr Anthony Fauci, who adds his voice to support a policy of universal HIV testing and treatment of all those infected, adding also the treatment of uninfected people at high risk.

    He points to the dire situation in DC, and states that our prevention efforts have been insufficient. That is perfectly true. But he, with all of us, have watched  this terrible situation developing over the past 20 years;  as my first post, AIDS and Minorities  indicates, we did little to prevent it.

    We get Dr Fauci’s point that probably more than 56,000 Americans have been infected with HIV every year for the past decade. But if we look at the graph in my first post we can see that over the years, the proportion of infections in African Americans rose, while it fell in white Americans, although the numbers have levelled in the past 6-7 years.

    So, when we are told that our prevention efforts have been insufficient, are we not really being told that we just neglected or were unable to develop adequate prevention education programs for some populations? Or are we being told that this is inherently an impossible task?

    It is not. Gay men were able to make a significant impact of the spread of AIDS in the early years of the epidemic. Safer sex with the use of condoms did make a difference.

    Safer sex originated in this community without the slightest outside help.  I would also guess that the armies of behavioral psychologists who entered the field found that within this community, essential behavioral modifications had been already learned without much need for their interventions or recommendations.

    We might learn something from this experience.  Empowered communities can respond to threat, and maybe we should be providing  the support communities need to achieve this.

    Dr Fauci’s “three pronged” approach is fraught with danger. Firstly it implies that prevention education cannot work.  This is very unfortunate as it provides an excuse to diminish, rather than intensify our efforts. We absolutely have not exhausted all the potential there is to create persistent and effective highly targeted prevention education programs. It is possible that with adequate support communities can best do this themselves.

    Then there is the problem discussed in an earlier post  “Treatment as Prevention”  that deals with the many implications of providing treatment to individuals for a social good, but where the treated individuals will derive no benefit themselves.

    Infected individuals who do not need treatment will therefore be asked to receive it and thus be exposed to the risks of the drugs but derive no personal benefit from them.

    The first of the three bold approaches suggested is the treatment of uninfected people at high risk; this is called pre-exposure prophylaxis (PrEp).

    This of course includes sexually active gay men, IV drug users, and heterosexual female and male partners to an infected person. If this means intermittent use of PrEp I would agree that this may well be a useful, if as yet unproven approach.  The persistent use of PrEp is another matter as drug toxicity is an issue.

    Here it can certainly be argued that the uninfected  individual taking  antiviral drugs may certainly  benefit from their use, unlike the treatment of healthy HIV infected people with higher CD4 counts who may be slow or even non progressors.

    For the uninfected individual at risk the persistent use of PrEp  is something that individuals should decide on themselves,  given adequate information.  I doubt whether this will make the slightest difference to the state of the epidemic, but may provide individual benefit.

    The multitude of problems associated with the second and third approaches were simply ignored.  I will not repeat the problems that exist in treating people, not for their benefit, but for a social benefit; these are discussed in my previous post.

    It is far from clear – as the article categorically states that benefit will be derived from starting treatment as soon as possible after infection. There is no direct evidence to support this contention. We simply do not know if very prolonged exposure to antiviral drugs will prolong, shorten or have no effect on an individual’s life span.

    As far as toxicity is concerned, it is often stated that the newer drugs are less toxic.  How on earth do we know this with only a few years use? We have enough experience of severe toxic effects only being recognized after years of use.  The drugs that block the HIV co-receptor are particularly worrisome.   CCR5 does not exist on the cell surface for the convenience of HIV. It serves a physiological function and time will tell if blocking its natural function has deleterious effects, and if these outweigh the benefits the drugs confer in inhibiting HIV replication.

    As far as eradication is concerned – which appears to be the third new bold approach, this possibility is so far in the future, if it ever can be achieved, that it is absolutely unrealistic to base any practical policy on its success.  The difficulties in killing all cells that harbour stable integrated HIV DNA, or of excising it from the human genome are enormous.

    Before undertaking such a “three pronged” project we would need some assurance of success; we would need to know, for example what degree of compliance would be necessary for it to work. But these issues are discussed in my previous post.

    At the moment the only winners in this approach will be the drug and testing equipment manufacturers.

    We should renew and redouble our efforts towards producing and persistently disseminating prevention education messages, appropriately targeted to specific populations. We should provide communities with adequate support so that they can craft their own prevention education materials, and disseminate them.

    We should remove all barriers to testing. This includes the most difficult of undertakings which is to fight the stigmatization still associated with this disease.

    This will entail an avoidance of policies and legislation that have the effect of increasing stigmatization.  Among other disincentives to testing is the lack of assurance of a link to medical care.  The cavalier approach to informed consent recently demonstrated by some providers and community groups is misguided:

    http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=58009

    It is likely that the consequences of “streamlining” the consent process for testing will actually have the effect of dissuading individuals from being tested.

    Those proposing “streamlining” the consent process may think HIV testing is routine.  Those testing positive may soon come to a different conclusion when they learn that HIV disease is serious, can be associated with stigmatization, treatments may not be affordable or available, may have adverse effects, jobs may be lost, and  families may abandon infected individuals.

    Can a test that  opens the door to such difficulties be regarded as routine?

    As long as these consequences of testing remain possible, we absolutely must obtain informed consent for testing so that our patients will know  of the implications of both a negative and positive test.  We all gain from  doing  everything possible to be supportive and retain the trust of our patients.   This will not be achieved by misleading them.

    In conclusion: Providing antiviral drugs to people who do not need them is no substitute for developing a variety of highly targeted prevention education strategies.

  • When is it best to start antiretroviral treatment: an update April 2009

    Posted on April 13th, 2009 admin 2 comments

    “Starting HIV Therapy Earlier Saves Lives”

    “Study: Treatment for HIV Should Start Earlier”

    “Starting Therapy Earlier Found to Improve Survival”

    “Earlier HIV Treatment Boosts Survival”

    With headlines like these you would think that there is a clear answer to the question of when is it best for HIV infected people  to start antiretroviral treatment.  There can be no doubt at all that starting antiviral therapy early – in this case at a CD4 count above 500 improves survival.  These headlines, addressed to HIV infected individuals their physicians and the public are a unanimous response to a study that just appeared in the New England Journal of medicine (NEJM).  http://content.nejm.org/cgi/content/full/NEJMoa0807252

    But is this confidence justified?

    Unfortunately, despite these headlines, the study which occasioned them was absolutely unable to justify the conclusion ; we still do not know when it’s best to start treatment.

    The study examined data that had been previously collected.  It was a retrospective observational study with all the problems inherent in such studies. These have been outlined in a previous post.

    About a week after this study appeared in the NEJM, another large retrospective observational study was published in the Lancet (April 9th 2009

    doi:10.1016/S0140-6736(09)60612-7http://www.thelancet.com/images/clear.gif ).

    While both studies support the desirability of not delaying a start to antiviral therapy to a CD4 count below 350, they do differ with respect to the reported benefits of starting above that number.  The Lancet study, whose lead author is Jonathan Sterne, finds a decreasing benefit at start times increasing above a CD4 count of 350, with nothing   at starting around 400.

    The authors of both reports  agree that prospective randomized studies are the best way to approach a resolution of the “when to start” question – a question that might have already  received a reliable general answer had we begun these studies in 1997, as some of us suggested we do at that time.

    Obviously we cannot just wait for the results of randomized prospective studies.  We do need guidelines now, but any recommendation based on available information must be regarded as provisional, until the results of prospective randomized studies are in.  It is important that this be clearly stated. If we are ever going to be able to enrol a prospective randomized study then we cannot afford to delude ourselves that the answer to the when to start question is already known.

    While the lead author of the New England Journal of Medicine did pay homage to prospective randomized trials – and a kind of ritualized homage is exactly what it sounded like, this gesture most certainly did not inhibit her from unreservedly recommending an earlier start to treatment, a start even at a CD4 count above 500, without conducting such a prospective study.  Her conclusion:

    “The early initiation of antiretroviral therapy before the CD4+ count fell below two

    prespecified thresholds significantly improved survival, as compared with deferred

    therapy

    One of these prespecified thresholds was a count 500 CD4 lymphocytes.

    This categorical statement, arrived at by the kind of study that cannot possibly justify such confidence, will have a negative  effect on  enrolment in proposed randomized trials, which are in fact the kind of study that can provide conclusions in which we can have justified confidence.

    This study may well be the last coffin nail in any hopes there may have been for the completion of prospective randomized trials designed to address the “when to start” issue.  It may now be impossible to enrol, and will never get off the ground. This difficulty is made so much worse by the kind of uncritical headlines shown above

    I wonder how the commentators who rushed so uncritically to announce Dr Kitahata’s conclusion on the benefits of starting treatment at CD4 counts even greater than 500 will respond to the Lancet report, which did not find a benefit with starting at such high CD4 numbers?   I hope I’m wrong in suspecting that this study will be largely ignored; the headlines trumpeting the survival benefit of starting treatment early – even above a CD4 count of 500 will not be marred by any doubt introduced by the study reported in the Lancet.

    Among the problems with the New England Journal of Medicine study is that a significant number of people were left out of the analysis, because their HIV disease failed to cooperate with preconceived notions about the course of this disease.

    This is a significant criticism and I will try to explain why.  The study examined two groups of people, one with over 500 CD4 lymphocytes, and one with CD4 counts between 351 and 500.

    Let’s just take the 351 to 500 group.    Here, deaths in those starting at counts between 351 and 500 were compared with deaths in those starting below 350. Sounds reasonable?   Maybe, until we learn that significant numbers of people with 351 – 500 CD4 cells who did not start treatment  also did not progress to below 350 CD4 cells.   So the authors just left these people out of their calculations. They in effect did not exist for the investigators.

    The recommendations the authors make are meant for all people, including those who did not progress and were left out of the analysis.  These people are also going to be treated with drugs they don’t need, as they cannot be identified.

    I suppose this will do wonders for drug sales, but there will be individuals taking drugs for no reason and some may only suffer their ill effects as well as cost while deriving no benefit.

    Here is another serious problem with this study.

    Among those people with CD4 counts between 351 and 500, it is important to know just how long treatment was delayed in those who waited until their counts fell below 350.   This information was provided; the median count at the time of starting treatment among all who waited was 286.   But what was the CD4 count at starting treatment among those in this group who died?

    This information was not given – at least I was unable to find it.

    Could there have been those starting treatment with counts below 100, below 50 – maybe even below 20.   In an extreme example, if a person waited to start treatment to a point close to death, there would not be much surprise that delaying treatment   initiation is associated with a worse outcome.

    Many physicians are proud that the field has abandoned uncritical authority as a guide to practice and has now embraced evidence based medicine. David Sackett, one of its originators, has stated that one pillar of evidence based medicine is the use of the best external evidence in making clinical decisions.

    All too frequently physicians, while priding themselves on practising evidence based medicine,  somehow are still able to make decisions based solely on their unproven beliefs, as if they have a private source to the truth, some special access to an oracle.  I have  heard one physician state that anyone with a viral load should be treated, another saying essentially the same thing in stating that he would treat every HIV infected patient no matter what the CD4 count. How on earth have they arrived at these conclusions?  Patients might just as well seek advice from a palm reader.

    As always you can’t beat the truth. No matter what the private sources of information to which  some physicians and patients apparently have access, the truth remains  that apart from people with under 200 CD4 cells the best time to initiate antiviral therapy is unknown.

    I have once before faced this kind of opposition to conducting a randomized prospective study to address the question of when is it best to start treatment.  In the early 1990s I participated in an effort to conduct a trial of early versus deferred treatment with AZT.  A pilot study was initiated, and I participated with some statisticians in describing the study to numbers of physicians in New York City, with the hope of encouraging them to enrol patients.  Despite expressions of enthusiasm, the response was so dismal that the trial could never take place.  However there was one physician – just a single physician in San Jose who was able to recruit many more patients than all the others combined.  He was so successful that we asked him to come to New York City to explain how he was able to enrol so many patients.  His answer was simple.  He told patients the truth. He did not know when it was best to start treatment, so he and his patients let the toss of a coin determine this, as a means of finding out what was best by participating in a study.

    This means that the other doctors were unable to say they did not know.  Maybe, as is the case today some actually felt that they did know, as they had complete faith in their intuition, or perhaps had some private access to the truth. For these physicians the practice of medicine is more akin to a faith based activity.  Maybe other physicians  did not know when it was best to start treatment, but might have felt unable to admit this; maybe some patients felt they knew and physicians acceded to their wishes.

    The rational response to uncertainty – having first overcome the hurdle of being able to admit that there is uncertainty – is to try to resolve this by the best means available.

    I fear we are not even close to recognizing that there is uncertainty about when to start treatment in people with over 200 CD4 cells.  The NEJM article exacerbates the problem with its assumption of certainty, an assumption very sadly shared by some health care providers, some journalists and community commentators to whom HIV infected people turn to for advice.

    In conclusion I cannot lose an opportunity to yet again bring attention to the need to individualize therapy.   The rate of HIV disease progression is so widely variable that there are limitations in setting a fixed CD4 count as a guide to start therapy.  A prospective appropriately designed trial can tell us if on average it is better to start above rather than below a certain CD4 count, or on average it is better to start treatment immediately or to defer it.

    It is the “on average” limitation that needs fine tuning for each individual patient.

    Not only will the rate of disease progression vary widely between patients, but there are other individual considerations that impact the decision to start treatment. For example, adequate housing, mental health issues, co morbidities and many other factors need to be considered.

    These two aspects, the general and the particular, fit so very neatly into David Sackett’s description of evidence based medicine that I will quote a passage:

    The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice“.

    BMJ 1996;312:71-72 (13 January) : Evidence based medicine: what it is and what it isn’t.  David L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson

    The best available external evidence will be the  results of a prospective randomized trial; these  will provide general guidance.  Individual clinical expertise will apply this to particular patients,  taking into account many factors, not least of which is the patient’s rate of disease progression.

    A previous post discusses the  issue of individualization of treatment.


    If we took individualization of treatment seriously, we could in fact come some way to identifying rapid and slow/non progressors.  See previous post on individualization of treatment.

    Often forgotten, the second pillar is individual clinical judgement.

  • HIV Infection in HIV Antibody Negative Individuals

    Posted on April 1st, 2009 admin 2 comments
    • HIV infection in HIV antibody negative individuals

    There is another post on this topic: HIV infection in individuals who are HIV antibody negative:

    The possibility that there are individuals who are infected with HIV but who are negative on the test for HIV antibodies has always been theoretically possible. Considerable evidence has accumulated for many years that there are indeed such individuals. Despite the importance of this phenomenon, it receives relatively little comment.

    It sometimes seemed to me ever since I first tried to discuss this possibility in the mid 1980s that there was a wilful discouragement of any discussion of this topic.

    In 1989 David Imagawa reported that that 31 of 133 HIV antibody negative men showed the presence of HIV.

    In 27 of them this persisted for 36 months despite remaining seronegative  [1]. This resulted in a vigorous response culminating in what almost looked like a retraction by the authors. At that time many unsuccessful attempts to replicate these results were reported, and the findings of David Imagawa were generally presented as due to technical errors, such as incorrect specimen labelling. In view of many subsequent findings, the likelihood is that David Imagawa and his colleagues were correct. The furious response to Imagawa’s paper is an indication of how non rational considerations can influence the progress of science. This is of course nothing new.

    Curiously in a recent book, Imagawa’s findings are included in a list of what are stated to be errors and controversies in the HIV/AIDS epidemic that impeded scientific progress [2]

    What in fact impeded progress was a rigid adherence to what was only a hypothetical, not an empirical model of the course of HIV infection.

    David Imagawa died shortly after this controversy, and sadly did not live to see that his initial conclusions were absolutely consistent with what has been learned of the complexity and diversity of individual responses to HIV infection.

    I certainly experienced considerable resistance and disbelief when I raised the possibility of silent HIV infections. In the late 1980s I took part in a NPR program, and was quite abruptly dismissed by another scientist (I have forgotten who) when I raised the absolutely reasonable theoretical possibility of persistent latent infections in antibody negative individuals.

    Apart from very few exceptions there was an almost complete lack of interest in HIV seronegative, but infected individuals, by science writers; there was no shortage of community commentators who also seemed to be oblivious or uncaring of this phenomenon.

    To be sure there were occasional reports of seronegative but infected individuals. Gus Cairns, a UK journalist wrote about this in the UK magazine, Positive nation. I wrote something about this as a result of an interview with him in 2000, which he published. I have scanned the article. I was unable to make a perfect copy, but a legible version can be seen by clicking HERE.

    In the US reports confirming the existence of seronegative infected people continued to receive very little comment; what little there was was generally quite hostile..

    Today this issue was again brought to my attention by an article I saw reporting the presence of HIV proteins and HIV RNA in cervical biopsies from women who were persistently HIV seronegative , at least for the duration of the study which was one year [3]. They did not have antibodies to HIV despite being infected; of course it is possible that they are in an unusually long “window period” and will eventually seroconvert.  If we use “window period” in this sense then we  can speak of a distribution of window periods of different lengths, including an indefinite one.

    I expect that, as is usual this report will provoke little or absolutely no interest.

    But it is enormously interesting; (just one of many questions: can these women infect their male partners?)

    Seeing this article is the reason why I decided to make this issue the subject of this post.

    It was no great surprise when evidence appeared that there were some individuals who were HIV infected but remained negative on the HIV antibody test. It must be said that there were probably more papers in the early years in which silent HIV infections in HIV antibody negative individuals was not observed.

    In another approach, reports started to appear that HIV antibody negative individuals had T lymphocyte responses to HIV which means that they were exposed to the virus, not necessarily that they were infected – although that is quite a real possibility. Some early papers, before 2000, including those showing T cell responses can be seen by clicking HERE . There was quite an extensive literature at that time, but most, as mentioned reported that there was no such thing as a silent antibody negative infection, apart from the short window period following infection.

    Why has the possibility of prolonged latency always been theoretically possible?

    As part of its life cycle HIV is turned into DNA and is then incorporated into the host genome. In infected cells it effectively becomes part of our genetic material. Once inserted into human DNA, it must be activated to start the process of making new virus particles. Cellular signals that start the process of activating HIV DNA include cytokines, which are messenger molecules produced and released by cells, which can then act on other cells to evoke a variety of responses. Amongst these HIV activating cytokines are those that are called proinflammatory cytokines.  These appear during the course of many different infections.  Once HIV DNA is activated, and at least some of its proteins made, these then mediate further activation.

    There are some other factors that can activate HIV DNA.

    Alloantigens are antigens expressed on foreign cells. When these antigens are in contact with a cell containing integrated HIV DNA, activation occurs; HIV DNA is transcribed and new viral particles made. In earlier days HIV was isolated from infected lymphocytes in this way. Latently infected lymphocytes were induced to produce HIV by culturing them together with lymphocytes from an uninfected donor.

    It is the nature of HIV infection that it is frequently acquired in situations which involve exposure to foreign cells (to alloantigens). This may be exposure to semen in sexual transmission, or blood cells in the case of infection by shared needles, or by blood transfusion.

    Herpes viruses have the ability to activate HIV if a cell is infected with both viruses. I suppose this must happen but I imagine doubly infected cells may not be found  too frequently. Of course active herpetic infections in non HIV infected cells may be associated with the production of pro inflammatory cytokines, which circulate and can activate HIV DNA in a cell at a distance.

    There is absolutely no reason not to expect that in some circumstances incorporation of HIV DNA into human DNA will result in a state of stable integration. This means that HIV DNA remains in the genome, it is not activated, and no virus is produced. Since antibodies are made as a response to viral proteins, and as none are made, the HIV antibody test will be negative.

    So it was no surprise when such individuals were again reported in 1999 [4]. These individuals remained in good health and were reported to be antibody negative as long as they were observed [5].

    We cannot know if these individuals may seroconvert (or maybe already have), but what is established is that stable integration of HIV DNA without seroconversion can occur. In such individuals limited expression of HIV can occur, at least sufficient to induce, if not antibodies, a cellular immune response.

    The presence of such cellular immune responses in HIV antibody negative individuals is further evidence consistent with HIV DNA persistence, but in itself does not indicate this.

    Demonstration of cell mediated immunity to HIV:

    Apart from the identification of antibodies, specific immunity to HIV can also be detected by a much more elaborate test that measures cellular immunity rather than immunity determined by detecting specific anti HIV antibodies. In this case what is measured is the ability of lymphocytes to recognize HIV. They will do so only if they have been exposed to the virus, which would obviously be the case if they were taken from an infected individual.

    The detection of such lymphocyte responses in the mid 1990s was one of the first indications that there may be infected people who don’t make antibodies. Other interpretations are that the infection was overcome, or that that the individual was infected with defective virus.

    Gene Shearer was I believe the first to report this phenomenon. HIV antibody negative sexual partners of HIV positive people, as well as individuals who had occupational contact with HIV were among those showing these responses.

    It is unknown how widespread this phenomenon of silent HIV infection is. It may be exceedingly rare. It is also unknown if this condition of stable integration is really just a prolonged “window” period that always follows all HIV infections.

    But it is entirely possible that there are individuals in whom the ability to control HIV is such that they will remain healthy and HIV negative.

    A number of different  outcomes of HIV infection are possible:

    Some of the factors that influence this:


    Host genetic factors.

    Size of the inoculum – the amount of infecting virus.

    Route of infection

    The particular virus strain.

    The presence of associated systemic infections.

    these provide signals activating HIV proviral DNA. In the case of some tropical infections there may be cytokines (IL 10) that blunt immune responses.

    Sexually transmitted infections with genital ulcers.

    Double infection of a cell with HIV and herpes viruses – probably an unusual occurrence.

    Exposure to alloantigens; a theoretical possibility.

    These are some of the known influences.

    Maybe the most common outcome is a productive infection where viral DNA is activated within a few weeks.

    But this scenario is also possible:

    Infection is followed by insertion of HIV DNA into cellular nuclear DNA. Possibly with small inoculums, and in the absence of strong or sustained activation signals, the proviral DNA remains silent. This has been observed.

    Or this one:

    There is a limited burst of viral production, not sufficient to elicit an antibody response but enough to induce a cell mediated response with the generation of lymphocytes that recognize HIV antigens and can kill HIV infected cells. HIV seronegative individuals with such specific lymphocyte responses have certainly been observed. In this case if there is an incipient burst of HIV production, the producing cells are promptly killed. Each time this happens the cellular immune response is primed and strengthened. Such a mechanism has been well studied in EBV infections. This common virus is totally unlike HIV, but it does similar things. It remains present in B lymphocytes rather than T lymphocytes for life. The mechanism of persistence is quite different – EBV is not a retrovirus. But the majority of individuals carry this virus – which in rare situations can have lethal effects, in their B lymphocytes for life. We have evolved many mechanisms to keep this virus in check. The ability of some types of lymphocytes to kill EBV infected cells which start to make virus is well understood. Similar mechanisms must exist for HIV – but obviously for most, are insufficiently effective. But in those with very limited HIV production these killer lymphocytes may actually be what allows such rare fortunate individuals to remain HIV seronegative.

    With this outcome, one can view the infection as actually having an immunizing effect.

    If there were not yet enough reason to study the phenomenon of persistently seronegative HIV infection, this is an important one. What are the circumstances that produce this outcome?

    So, for many reasons individuals who are seronegative but have lymphocyte responses to HIV are of great interest.

    Yet another scenario is one of stable integration, but where some HIV proteins, but not complete virus, are produced. Maybe the women referred to whose cervical biopsies contained HIV antigens might be in this category. This is a strange situation as antigens were detected but these women apparently did not develop antibodies.

    Another very early observation that can be explained by the prior presence of integrated HIV  DNA that is only activated by a subsequent non HIV  infection is the finding that  episodes  of EBV reactivation may precede HIV seroconversion. [6].  This raises the possibility that at least some illnesses associated with primary HIV infection are nothing of the sort. They instead may represent rather non specific viral infections that activate already present integrated HIV DNA, and thus  followed by HIV seroconversion. This is a completely plausible scenario. Of course self reported sexual histories may sometimes  not be too reliable, but nontheless, I well recall an older gay male patient of mine who told me that he had had no sexual contact for years, he had several negative HIV tests over a period of a few years, and then tested positive.  I wondered  then if he may possibly have been infected years before, that he carried latent HIV DNA and this was subsequently activated by some febrile illness. I know this is only an anecdote, and that individuals can be guarded about their sexual histories.  I wonder if others have had similar experiences?

    I think around 1996  a description of the course of infection was produced. Everyone interested in this disease will have seen this picture: Here it is again:

    hivaids_9_fig-53

    This may represent a typical course of infection.  But HIV disease is probably so variable in the course it can take that there may well not be such a thing as a typical infection.

    This depiction does however give the impression that there is,  and discourages an appreciation of the probably  immense variations in the course of  HIV disease.  The notion of a “standard” course of HIV disease has  had implications for treatment.  Recommendations are made that take no account of  individual  rates of disease progression;  a one size fits all approach has been adopted.

    The  rapid acceptance that there is a typical – or an  average  course of HIV infection is particularly odd as not only is the disease new – we have no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease are themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea then of the variation in T subset numbers in health and disease. Other immunological and virological techniques were, and continue to be introduced as the epidemic is proceeding.

    A model was constructed before sufficient evidence was available to justify it.  It really had no empirical basis; moreover it seemed to utterly ignore what we knew of other chronic viral diseases.  For example, hepatitis B and Hepatitis C can both have very variable courses.  These can range from clearing the infection, running a fulminant course ending fatally  to the establishment of a chronic active state which may progress at varying rates.  If we were to construct a model of the course of HIV disease only about  12 to 15 years after the disease was first seen, why on earth did we not consider the precedents of other chronic viral diseases?   Thus we might have  included the real possibility that some exposures may result in infections that may be cleared , as well as the now demonstrated situation where silent antibody negative infections occur.    The picture shown above – and presented in every text on HIV disease may indeed represent the most common course of HIV infection. But even this is not  known.

    HIV infection, like other chronic viral infections  can progress in different ways. If we were more open to this there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses. This has obvious therapeutic implications  –  for example as proinflammatory cytokines promote HIV replication, the control of endemic infections in some areas where they are highly prevalent is absolutely relevant to the control of HIV infection.  Steps as simple as the provision of sanitation and clean water may well have an impact on the control of HIV infection in some geographical areas.  Had we not been so tied to the notion of  a fixed course of HIV infection, we might have placed importance on the individualization of therapy, not only considering a fixed CD4 count as a signal to start therapy, but also considering each individuals rate of disease progression.

    HIV disease is in this sense like  every other infectious disease, the course of which  to a greater or lesser extent can be influenced by many different factors , including host factors, factors related to the pathogen, the particular variant , the size of the infecting dose, the route of infection amongst many others.

    I have often wondered why there has been such resistance to not only the reasonable idea, but also to actual evidence that HIV disease  does not necessarily  take the course  shown above.

    In conclusion, the study of prolonged HIV seronegativity in infected people is important. Some reasons are:

    1. There are obvious implications for vaccine development.

    2. Seroprevalence may significantly underestimate the prevalence of HIV infection.

    3. Understanding the phenomenon will advance our understanding of the pathogenesis of this disease, which in turn will open new therapeutic approaches.

    4. There are instances of infected people remaining seronegative and in good health.

    [1]

    Imagawa, D.T., M.H. Lee. S.M Wolinsky. et al..

    Human immunod­eficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods.

    New England Journal of Medicine 1989 320:1458-1462.

    [2]

    Scientific Errors and Controversies in the U.S. HIV/AIDS Epidemic: How They Slowed Advances and Were Resolved

    By Scott D. Holmberg

    Published by Greenwood Publishing Group, 2008

    [3]

    Human Immunodeficiency Virus (HIV) Antigens and RNA in HIV-Seronegative Women with Cervical Intraepithelial Neoplasia
    Jayasri Basu, Seymour L. Romney, Ruth H. Angeletti, Sten H. Vermund, Edward Nieves, Anna S. Kadish, Magdy S. Mikhail, and George A. Orr

    The publisher of this journal kindly sends me the contents of each issue as I started this journal around 1983 and was its first editor, seeing it through its first two volumes. It was then simply called AIDS Research.

    [4]

    Zhu T, Corey L, Akridge R, Change Y, Feng F, Kim J, Alef C, Mcelroy J, Mullins J, Mcelrath J.

    Evidence for HIV-1 latent infection in exposed seronegative individuals.

    Abstract No.8, 6th Conference on Retroviruses and Opportunistic Infections. Chicago. 1999.

    [5]

    Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals.

    Journal of virology, {J-Virol}, Jun 2003, vol. 77, no. 11, p. 6108-16,

    Zhu-Tuofu, Corey-Lawrence, Hwangbo-Yon, Lee-Jean-M, Learn-Gerald-H, Mullins-James-I, McElrath-M-Juliana.

    Abstract

    Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specific cytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.05 + /- 0.01 copies per million cells) at multiple visits spanning 69 to 130 weeks in two ES individuals at levels that were on average 10(4)-to 10(6)-fold lower than those of other HIV-1-infected populations reported. Sequences of HIV-1 envelope and gag genes remained markedly homogeneous, indicating little to undetectable virus replication. These results provide the evidence for HIV-1 infection in ES individuals below the detection limit of standard assays, suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1 strains despite continued high-risk sexual exposures to multiple HIV-infected partners. Understanding the mechanisms that confer diminished replicative capacity of HIV-1 in these hosts is paramount to developing strategies for protection against and control of HIV-1 infection.

    [6]
    Schattner, A, Hanuka N, Sarov B, Sarov I, Handzel Z, Bentwich Z.

    Sequential serological studies of homosexual men with and without HIV infection. Epstein-Barr virus activation preceding and following HIV seroconversion.

    Clin Exp Immunol 1991; 85: 209-13.

  • HIV treatment as prevention – a short postscript

    Posted on March 27th, 2009 admin 1 comment

    My last post was published about 30 minutes ago. Within minutes I received my copy of the Lancet. There were about eight letters in response to the article I had referred to which presented the mathematical model of the outcome of an initiative to test and treat every infected individual as a means of ending the epidemic. It is reassuring that most expressed reservations regarding the assumptions on which the model was based, and in general about its feasibility. The Lancet issue containing these letters is: The Lancet Vol 373, March 28, 2009.

    Only one letter emphasized the ethical problem concerned with treating people who do not need to be treated themselves, for the good of the public.
    This was the point I concentrated on in my recent post, and in my own letter in response to the article. The potential hazards of treating individuals with higher CD4 cell numbers, where there were no proven benefits to be had were referred to by others.

    Despite these welcome responses, I believe it is likely that attempts to advance this idea of universal testing and treatment of all infected persons will proceed.

    As a project it will get nowhere. But there is another consideration that is propelling it. There is a political constituency that has been advocating mandatory universal HIV testing almost since the test became possible.

    We should be doing all we can to encourage individuals to be tested. But absolutely not to the extent of enforcing tests. The views of the AIDS pioneers referred to in the previous post unfortunately can provide some spurious ammunition to those who would like to see mandatory HIV testing in place.

    Our efforts should be concentrated on finding ways to encourage individuals to be tested. What obstacles are there in different communities that discourage testing? How can we remove them? Some are quite obvious and probably apply to all communities, such as stigmatization and problems with access to care.

    The following may seem counter intuitive, but the removal of written informed consent which ostensibly should facilitate testing, may actually be less effective in this respect than encouraging testing with written informed consent. Removing written informed consent can be seen as implying that HIV disease is not serious, a view that might well make anyone suspicious of an authority that presents this opinion, no matter how indirectly.

  • HIV TREATMENT AS PREVENTION

    Posted on March 27th, 2009 admin 2 comments

    The proposal that testing and treating everyone who is HIV infected would end the epidemic is back in the news.

    It is not a new idea. It has been discussed at HIV/AIDS conferences. At the beginning of the year an exercise in mathematical modelling was presented in the Lancet providing some support for this notion of universal testing and treatment. Now some experts in molecular biology and virology have added their personal opinions in favour of this approach; I notice that at least on one web site addressed to HIV and Hepatitis virus infected individuals, the views of these pioneer researchers are reported with, as seems to be usual, no analysis or criticism. http://www.hivandhepatitis.com/recent/2009/032409_a.html

    It begins to look almost like an advertising campaign, with the touch of a skilled publicist; an idea is gradually brought to public attention, it is widely endorsed and the hope is that public support will ensure that funders and politicians will move the project forwards.

    The merits of the proposal, and the way it is being promoted are two different issues.

    Regarding the proposal, in principle it is certainly a worthwhile idea that deserves consideration.
    But there are several problems, not mentioned in public reports of this proposal, and barely dealt with in the professional literature, which may constitute insuperable barriers to its implementation.

    Leaving aside for the moment the question of whether such a project is even feasible, perhaps the most important problem is that infected people who do not need treatment will be asked to receive it to achieve a social benefit.

    This proposal then involves the general concept of a public health intervention on individuals who will not themselves derive any benefit from the intervention, but will only be exposed to its risks.

    We have thankfully not yet reached the point where enforced testing and treatment can be seriously proposed. (We may be getting close in the removal of written informed consent for HIV testing).

    Certainly the spectre of mandatory testing and treatment is lurking behind this proposal to test and treated everyone infected. This would do wonders for drug and testing equipment sales.

    So we would have the situation where some individuals will voluntarily take treatments that despite what we may be told can most certainly not be regarded as absolutely free of possible adverse effects, Many infected people will of course benefit from this. Others however will agree to take risks, with no benefit to themselves but for the benefit of others. Quite apart from many other issues, we can only ask these individuals to participate in the project if there is an overwhelming chance of success. At the moment we do not have this assurance.

    It is not a digression to compare this situation with that in which an individual is asked to join a clinical trial and who may be randomly assigned to receive a new treatment of as yet only conjectural benefit. We are absolutely obliged to ensure that the trial design is such that reliable information will be obtained from the study.

    Since the testing and treatment of all infected individuals to end the epidemic can in no way be regarded as an undertaking with an assured successful outcome, it really is a trial, based on an hypothesis somewhat supported perhaps by mathematical modelling. As such it will require written informed consent from the participants.

    I wonder what such a consent form would look like. It is possible, actually likely, that a consent form outlining possible risks and benefits would dissuade many from participating.
    The disincentive would be felt by those infected individuals who do not themselves require antiretroviral treatment.

    This inconvenient obstacle can be easily eliminated.

    All that is needed is for treatment guidelines to include a recommendation that antiviral treatment should be offered to all infected individuals, even those with greater than 500CD4 lymphocytes. A precedent has now been set where treatment recommendations can be made on the flimsiest of evidence. The inappropriate use of retrospective observations to justify an earlier start to antiretroviral treatment is a good example.

    So all one needs to do is to move the goal posts a little further and declare that antiretroviral treatments should be given to all HIV infected individuals, irrespective of CD4 count. There should be no difficulty in selecting retrospective observations that will support this recommendation. In the field of HIV/AIDS you can probably find retrospective data to fit whatever idea you are interested in promoting.

    There is another tool available to promote the contention that every HIV infected individual, irrespective of CD4 count will benefit from antiviral therapy. This useful tool is called “expert opinion”. (Actually, people billed as “experts” have already expressed this opinion).

    The problem with this is: what does it take to be regarded as an expert?

    We may well be in an era where we have “experts” for hire.

    Defining what was meant by “expert” was once much easier. Years of experience and significant contributions to the field might have been required attributes. But no longer.

    Experts can seemingly be created overnight, at least by commercial entities interested in marketing a product. Their credentials are easily supplied. These instant experts will give talks at conferences, they will appear on educational programs, and even put their names to ghost written articles.

    [http://healthcare-economist.com/2008/05/03/ghostwriting-by-pharmaceutical-companies/

    Revealed: how drug firms ‘hoodwink’ medical journals Pharmaceutical giants hire ghostwriters to produce articles – then put doctors’ names on them.
    http://www.guardian.co.uk/society/2003/dec/07/health.businessofresearch
    ]

    As for the practice of ghost writing , there is a great deal of evidence for this, a little shown above. I’m ashamed to admit that I once (only once many years ago) allowed an employee of a drug company to write an article which carried my name. But I had done the work without their support, and in my defense, I checked every word, changing some, – an experience the writer was evidently not used to. This was my first (and only) personal encounter with this practice

    I will hazard a prediction; before the year is out we will have arrived at the point that experts will state that every HIV infected person benefits from treatment, irrespective of CD4 count. If required we will see retrospective observational studies which show that in people who started treatment above a CD4 count of 500, mortality from all causes was reduced as compared to those starting below 500 CD4 cells. It should be just as easy to find retrospective data that shows that starting treatment immediately on diagnosis confers a benefit not seen when treatment is delayed to CD4 count of 350.

    Of course these expert views will be very widely disseminated in press reports and on numerous web sites – some will even provide the opportunity for doctors to earn CME credit. In this way conjectures are transformed into established facts.

    I don’t know how we might obtain real evidence that testing and treating all infected people is not only feasible, but would achieve its goals. The two are related.

    For example, how does one ensure that all people are tested? Or that they will agree to be treated? Or that they will adhere to their treatments?
    As imperfect as this is maybe one approach is to test these issues in a limited setting where mobility in and out of the selected areas can be controlled for.

    This could more usefully be a trial where two different strategies were compared – the present practice of starting treatment at 350 CD4 cells, and treating everyone infected, while promoting HIV tests in both groups. Despite complications introduced by the movement of people, we might get an idea if this is a feasible and effective approach.

    Sadly those bodies that instruct physicians on how to treat HIV infected people, and who tell HIV infected people what is best for them, seem to be averse to calling for prospective studies, designed to shed some light on what may in fact be best for infected people. Those who manufacture the treatments appear to prefer trials that are designed to provide them with the answer most congenial to them. Here is an account of the practice of designing trials to provide the answer most desired.
    [http://www.washingtonpost.com/wp-dyn/content/article/2008/07/14/AR2008071402145.html]

    They can also rummage in retrospective data collections selecting observations best suited to the outcome they have already decided on. Of course there is always an expert to be created to promote this outcome.

    When the mathematical modeling referred to above supporting the idea of a “test and treat everyone infected” approach appeared, I wrote a reply to the Lancet which published the article. Not my letter, which was politely rejected.
    I am adding a slightly edited copy of that letter here.

    A recent Lancet article suggests that we could end the HIV epidemic by testing and treating all who are infected, irrespective of whether or not the individual would benefit from such treatment (R. Granich et al. 2009 Lancet 373:48).

    This represents an intervention on individuals, primarily for a public health benefit. At the present time, ethical considerations make this proposal a completely indefensible approach.
    The available drugs are far from benign; for a particular individual, their use is desirable and justified when their benefits clearly outweigh their risks. Treating individuals to achieve a population benefit requires a similar risk benefit assessment. F M Hodges and colleagues have addressed this issue. (EM Hodges, JS Svoboda, RS van Howe
    Prophylactic interventions in children: balancing human rights with public health. J Med Ethics 2002; 28: 10-26)

    To protect individual liberties they propose six conditions that should be met before for such interventions are taken. All of these are reasonable. I quote a passage from their article that outlines them.

    “PROPHYLACTIC INTERVENTIONS FOR PUBLIC HEALTH BENEFIT”
    Prophylactic medical interventions are frequently performed on healthy individuals who have given informed consent. …..
    The most common example arises when the patient is at significant risk of contracting a life- and public health-threatening illness for which the proposed prophylaxis is a proven preventive. In order to safeguard individual liberties, the situations in which such procedures may be undertaken for public health benefit must meet the following requirements:
    1. The danger to public health must be substantial.
    2. The condition must have serious consequences if transmitted.
    3. The effectiveness of the intervention in safeguarding the majority of the public against the particular malady must be well established.
    4. The intervention must be the most appropriate, least invasive, and most conservative means of achieving the desired public health objective.
    5. The individual must be provided with appreciable benefit not dependent on speculation about hypothetical future behaviours of the patient.
    6. The burden to the individual’s human rights and health must be balanced against and found to be substantially outweighed by the benefit to society in helping prevent a highly contagious disease or other potentially calamitous condition from affecting the public health”.
    Clearly the proposal to treat all infected people will include some in whom the fifth consideration will not be met, but the concerns are covered in the sixth one. But here the benefit to society must be assured, or more practically, be considered to be highly probable, with credible evidence produced to support the contention (as stated in the third consideration).

    While the first two criteria are very clearly met, the present proposal to treat all who test positive fails utterly on the third point. It is far from well established that antiviral treatment of all who are infected will protect the “majority of individuals” in diverse settings. Among problems acknowledged by the authors are those related to toxicity, adherence and the development of resistance to the antiviral drugs. To this must be added the possible negative effects on behaviour deriving from a perception of being non infectious. The fourth condition is also not met. We cannot state that we have exhausted the utility of prevention education and promotion of condom use.

    Let alone the questionable wisdom of mounting an extensive and expensive public health intervention that is based only on mathematical modeling, we are very far from possessing information that would supply the slightest confidence that such a measure would effectively meet its objective.
    Regarding adherence, the optimism presented by the authors based on studies in Malawi is hardly justified. Adherence by individuals who may be ill, and certainly know they are receiving medications for their own benefit tells us nothing about adherence by people who feel healthy and know they are not taking the medications to benefit themselves.

    The general relationship between viral load and infectivity is well established. The success of the proposed strategy according to the model presented depends on achieving a significant reduction in viral load from the pre-treatment value. The solid evidence of the potent ability of antiviral drugs to very substantially reduce viral loads in a sustained fashion derives predominantly from observations in settings where untreated endemic or concurrent infections are uncommon. The ability to achieve a sustained significant drop in viral load may be more difficult where there is a high prevalence of untreated endemic or associated infections. This is the case in parts of Sub Saharan Africa. Many of these infections are able to activate and enhance HIV replication, through the action of pro inflammatory cytokines. Should these infections be associated with genital ulceration there are additional uncertainties.
    HIV disease is characterized by an enormous variability in the rates of disease progression. There is no such thing as a standard course of disease progression that is one of the assumptions used in the modeling. We know very little about the distribution of different rates of disease progression among infected individuals, or about the influence on this of associated untreated infections.
    Risking individual harm for a public benefit is a slippery slope. Will we see a proposal to administer (with consent, of course) antiretroviral medication to the whole sexually active population, HIV infected or not?

    AIDS is a preventable disease. We have far from exhausted less conjectural, as well as less speculative approaches to its prevention.

    Addendum
    Apart from this proposed strategy to treat all infected people, there definitely are situations where treatment as prevention is absolutely appropriate and desirable. One is post exposure prophylaxis (PEP), where individuals who have been exposed to HIV attempt to prevent infection by rapidly taking antiretroviral drugs – that is within 72 hours of exposure. This applies to both occupational and sexual exposure. Regarding sexual exposure – where feasible, which is certainly the case in N America Europe and in many other regions, a 3 day supply of drugs should be available 24 hours of the day, given the limited time frame for action. Measures to immediately start PEP immediately should of course be available where occupational exposure is a risk. Emergency departments should be equipped and ready to start the protocols for PEP. People at risk should even be encouraged to keep a 3 day supply of drugs at home to cover times when medical care is not available – at night or weekends. .Very importantly people at risk must be informed of the availability of PEP.

    The second is pre exposure prophylaxis. This is taking antiretroviral drugs on specific occasions when there might be a risk of exposure. This absolutely cannot replace the use of condoms, but some individuals may wish to take an additional even if unproven preventative measure. This really is a matter for individual choice. Our obligation is to make it very clear that this is not a substitute for condoms.

  • HIV disease and alpha interferon

    Posted on March 21st, 2009 admin No comments

    I had intended to continue writing about individualization of treatment for HIV infection with an emphasis on the variability of the natural history of HIV disease. Instead, I will make an historical digression. I’ll do this from time to time. An account of the diverse AIDS related issues with which I have been involved since 1981 (and even before the epidemic was first recognized) is on my web site aidsperspective.net. I’m slowly adding content. This should speed up; a lucky circumstance has provided me with access to professional web advice. I have until now had to rely on “how to” articles to get the site going. Surprised that at 76 I have got this far. At the outset I had said that one purpose of this blog was to bring attention to the web site, and that is one reason for this short introduction.

    This post is concerned with the connection between alpha interferon and AIDS. I should say connections; there are many.

    Today, most people will probably only be aware of interferon in connection with the treatment of hepatitis C in HIV infected and uninfected individuals. The benefit conferred by interferon treatment to many people with Hepatitis C, even those co infected with HIV is tremendous. The FDA first approved interferon alpha for the treatment of hepatitis C in 1991.

    There are many connections between interferon and AIDS; the first of these became evident in 1981, the year the epidemic was recognized.

    People with AIDS produce large amounts of interferon themselves. The sustained production of large amounts of interferon by untreated HIV infected people with more advanced disease is not only a part of the disease, but the most compelling evidence suggests that its various actions contribute to producing some of the abnormalities associated with it. But, paradoxically, in the early years of the epidemic more was injected into patients in attempts to treat the underlying disease. (There is an important difference between this and treating Kaposi’s sarcoma or Hepatitis C in coinfected people with interferon).

    That interferon can be seen as both contributing to the disease and also as a means of treating it makes for a confusing but interesting story [1]

    It will be helpful to start with a very brief description of the interferon system.

    The interferons – there are several types, are a family of proteins produced by vertebrates. They are cytokines, the name given to polypeptide or protein molecules produced by cells which act as signals that can influence their behavior, and that of other cells distant from the producing cell. In acting at sites distant from where they are produced, cytokines are akin to hormones.

    All the interferons share some common properties, and it is easier to write about interferon in the singular. Interferon is best known for its broad antiviral effect. It is produced by cells in response to viral infections, and circulates to render other cells resistant to infection, thereby playing a central role in recovery.

    Most viruses are sensitive to interferon and it was once hoped that interferon might prove to be a broad spectrum antiviral agent, similar to broad spectrum antibiotics that act against bacteria. There was great difficulty in purifying interferon for human use but in 1980 recombinant DNA technology permitted the manufacture of large amounts of pure interferon by inserting the gene for interferon into bacteria or yeast. Apart from its antiviral effect, interferon has numerous other effects, particularly on the function of the immune system. It can inhibit the growth of certain cancers, and has an inhibitory effect on new blood vessel formation. It therefore has been effective in the treatment of AIDS related Kaposi’s sarcoma. Unfortunately its clinical utility is more limited than originally hoped. Its greatest success is in the treatment of hepatitis C. Here are some brief reviews:

    http://pathmicro.med.sc.edu/mhunt/interferon.htm

    http://www.isicr.org/pdf/IFNprimer_ISICRApril_2006.pdf

    To return to interferon and its connections with HIV:

    This paradoxical situation – in which interferon is seen at the same time to be harmful and helpful, has given rise to some peculiar interpretations. Research directions have been influenced; on balance the desire to treat HIV disease itself with interferon (as opposed to treating Kaposi’s sarcoma and Hepatitis C in coinfected individuals) has probably inhibited research into its role in pathogenesis. It is notable that the overproduction of alpha interferon, a striking abnormality in people with AIDS, known since 1981, was barely studied, let alone discussed, in the first years of the epidemic.

    This strange story of a substance seen by some to be harmful, and by others to be beneficial in the same circumstances, is best told in the light of my own experiences in both fields; in AIDS and in interferon.

    The two areas that have occupied my professional life have been the laboratory study of the mechanism of interferon’s antiviral action, and clinical work in HIV disease, providing direct medical care to a very large number of HIV infected people as well as conducting clinical and laboratory research on this disease.

    In the strangest of circumstances these two fields came together as early as 1981. In that year, AIDS was first recognized, although I and others had already noted early manifestations of what was to be called AIDS among our patients.

    The first information I received concerning the occurrence of Kaposi’s sarcoma in several gay men in New York City came from Dr Joyce Wallace. She had received a biopsy report of a diagnosis of Kaposi’s sarcoma in one of our patients. Joyce had called the National Cancer Institute to ask if there was a physician in New York who was familiar with what was then a very rare condition. She had been told that there were – I think at that time, about 20 men with this condition in New York who were under the care of Dr Alvin Friedman-Kien.

    This was quite astounding. Unsurprisingly, I did not immediately connect this with what I had been seeing in my own practice, – enlarged lymph nodes, enlarged spleens, low white blood cell counts, low blood platelets among other abnormalities.

    Jan Vilcek, who was head of the virology lab at NYU is an old friend and interferon colleague, and I knew Alvin, because he also worked in Jan’s laboratory. So I immediately called to obtain more information about this remarkable news.

    Given my training and experience as a microbiologist and the nature of my practice, there was no question that I needed to contribute to the response.

    So, in 1981, I also started to work in the virology laboratory at NYU.

    I divided my time. Mornings were spent in the lab, and patients seen in the afternoons.

    My work in the lab was initially focussed on cytomegalovirus (CMV) as there was evidence that many gay men at risk for this new disease were actively infected with this ubiquitous virus and excreting it at rates higher than noted in others. There also was literature at that time suggesting that CMV was involved in the development of non AIDS related Kaposi’s sarcoma (an idea that was not to hold up).

    Once in the lab a strange circumstance brought interferon back into my life in connection with this new disease.

    I read a preprint of a paper of Jan Vilcek’s where he described the ability of an antibody to lymphocytes – specifically anti CD3, to induce the synthesis of gamma interferon. Because of other observations that were made on our first patients, I had the idea that we would find gamma interferon in the circulation of patients with AIDS. This incident has been recorded and published by Jan Vilcek and an extract of the article can be seen by clicking here.

    This is just the relevant part from a longer article, appearing in the annual “Interferon” series published by Academic Press and edited by Ion Gresser.

    It explains how we came to look for interferon in the blood of people with AIDS. Alvin Friedman-Kien provided sera from his patients, and Jan Vilcek provided just about everything else. Gene De Stefano, who is the lead author on the paper we finally published,[2] was a student working in Jan’s lab. The author’s names are in alphabetical order, as this seemed the best way to deal with the matter of precedence, as so many collaborators had become involved. I had sent sera to Robert Friedman in Bethesda, another old friend and interferon colleague, and we joined forces in pursuing this work.

    As Jan Vilcek’s account describes, my idea proved to be wrong, the interferon we found was not gamma interferon, but alpha interferon.

    Many years later gamma interferon was detected in the circulation of people with AIDS.

    This was the first of many connections between interferon and AIDS, a connection made in the first year of the epidemic.

    It immediately suggested that the sustained presence of large amounts of interferon in the circulation might be contributing to pathogenesis, and that there was an autoimmune component to AIDS. Apart from AIDS, at that time the only other situation in which there was the sustained presence of large amounts of interferon was in auto immune diseases such as lupus. Also, as individuals with various diseases, including Hepatitis C were treated with interferon, auto immune complications were noted among them.

    Since I will be critical of some aspects of AIDS research in relationship to interferon it is very important that, before I get into this, I make the following point very clearly.

    Interferon has been of inestimable value to people infected with Hepatitis C, including those coinfected with HIV. Interferon in combination with ribavirin has been able to cure many individuals of Hepatitis C infection. It has thus been life saving, as the consequences of Hepatitis C infections can include liver cirrhosis and liver cancer. It is probably the case that interferon’s greatest clinical triumph has been in the treatment of hepatitis C. At one time it was also the only available treatment for Hepatitis B.

    So, to emphasize the point, interferon for the treatment of hepatitis C in HIV infected individuals can be life saving. It may be useful in some instances of Kaposi’s sarcoma unresponsive to antiretroviral drugs.

    But I believe it has absolutely no place in the treatment of HIV disease itself. There are early reports of benefits conferred by interferon treatment [3] but there is also a great deal of persuasive evidence that long term treatment is hazardous[4]. (This article contains numerous references supporting a role in pathogenesis for interferon).

    So this is an illustration of the Jekyll and Hyde view of interferon. Does it mediate some of the pathological features of HIV disease, or should we use it to ameliorate these features?

    On balance, I believe the evidence supports the view that overproduction of alpha interferon contributes to the manifestations of HIV disease. In specific instances, particularly in Hepatitis C in coinfected individuals and in some cases of AIDS related Kaposi’s sarcoma, the benefits of interferon most definitely outweigh the risks. This is particularly true in people with higher CD4 counts.

    Nonetheless overproduction of interferon is a feature of AIDS. But It took many years for work to be done to identify the interferon producing cell. This was achieved by Frederick Siegal in 1999.

    Quite early in the epidemic, AIDS was described as a disease characterized by a dysregulation of cytokine production. Interferon is a cytokine, in fact the very first to have been described, but it rarely appeared in the list of cytokine abnormalities associated with AIDS.

    Here are some of the biological effects of interferon that resemble features characteristic of HIV disease:

    Interferon inhibits the development of white blood cells and platelet and red blood cell precursors. It causes fevers. It stimulates the production of a molecule called beta2microglobulin, which was used as an adverse prognostic marker in AIDS. It affects lipid metabolism and can cause an increase in serum triglycerides, observed in AIDS patients before the era of HAART. It modulates the activity of B cells, which make antibodies, and B cells are overactive in AIDS.

    But perhaps of greatest interest is the ability of Interferon α to selectively inhibit the proliferation of the CD4 lymphocyte subset, a finding that was published as early as 1983.[5]It also has a slight stimulatory effect on CD8 lymphocytes.

    This is the “dark and sinister” side to interferon.

    Given these effects of interferon it is hard to understand what the researchers hoped to achieve by injecting yet more of into people who were already full of it.

    Two reasons were given for administering interferon. Firstly interferon has antiviral properties. This rationale was resistant to the obvious problem that despite large amounts of interferon in the circulation, HIV continued to replicate. Indeed, as the disease progressed and viral production increased, so did the levels of interferon.

    The second reason given was that cells taken from people with AIDS could not be stimulated to produce interferon in the test tube. This was an early finding of Dr Siegal.

    The inability of cells from people with advanced HIV disease to make interferon in the test tube is actually exactly what is to be expected. It has been known for many years that when cells are exposed to large amounts of interferon for long periods, they cannot be stimulated to make interferon. They are in what is called a refractory state. The authors describing the inability of patient’s cells to make interferon seemed to not consider this, and so the strange idea that the inability to make interferon was an intrinsic abnormality in AIDS was advanced as a reason to administer interferon.

    The inability to induce interferon production in cells derived from people with AIDS is indeed strange as the circulation from which they are removed is full of it. The interferon must come from somewhere. It is possible that it comes from cells in solid tissue. The reason for suggesting this is that membrane fragments from HIV infected cells are excellent inducers of interferon. This suggests that in the body, interferon may be made by cells that are in apposition to HIV infected cells in solid tissue.

    This may be more difficult to study now. AZT promptly removes interferon from the circulation, and this is probably true for all effective antiretroviral drugs.

    The prompt removal of interferon by antiretroviral treatment must make one wonder if this is at least part of the reason for the benefits of treatment. Inhibition of HIV replication, associated with the loss of circulating interferon definitely suggests that HIV is responsible for the high levels of interferon.

    In this connection here are some results that we observed:

    aidsinf-12

    The solid line represents HIV levels, and the dotted line interferon levels. These two individuals, A and B were treated with AZT for one week at weekly intervals. Both interferon and HIV levels promptly decline when on AZT and just as quickly go up when AZT is removed.


    aids-inf-2

    These three people started AZT at time 0. Both HIV (p24) and interferon rapidly decline.


    aids-inf-3

    These are individuals on continuous AZT therapy. Interferon rapidly declines in all, but returns at varying times despite continued treatment with AZT. Is it possible that the transient and variable duration of benefit experienced, coincides with the period when interferon is absent?


    aids-inf4


    This is one person on continuous AZT treatment. Interferon starts to return and rise before 18 weeks. P24 only returns after 33 weeks. However this does not necessarily mean that interferon returns to the circulation before HIV. P24 measurements are not that sensitive and if PCR had been used HIV may have been detectable much earlier.

    This is turning out to be a long post, and I will just make a few more points and end it.

    When cells are exposed to interferon for prolonged periods several changes are noted in addition to their diminished capacity to make interferon when stimulated to do so. The antiviral action of interferon depends on the attachment of interferon to a specific cell receptor. The number of interferon receptors is reduced in cells taken from patients with AIDS, most probably as a result of exposure to endogenous interferon, and this may partly explain the diminished antiviral effect of interferon in advanced disease. This finding also has implications about possibly diminished effects of added interferon

    From the point of view of interferon’s antiviral action only, it might seem advantageous for interferon to always be present. But there are active mechanisms to turn off its production, usually after a matter of days, which supports the view that prolonged exposure to interferon can be detrimental. Its many actions – other than its antiviral action are in fact deleterious. Apart from untreated HIV disease, lupus, an autoimmune disease is also associated with the sustained production of interferon α. There are studies in this disease on the mechanisms that sustain interferon production that may also have relevance to HIV disease. In HIV disease, it may of course be the persistence of HIV, but the opportunity to do study this has probably been lost as antiretroviral treatments remove interferon from the circulation.

    When the question was asked, why add more interferon to people who already had lots of it, the answer was that the interferon already in the patient, (the endogenous interferon), was different to that to be injected. The basis for this claim of difference was that endogenous alpha interferon was unstable in acid, unlike conventional interferon.

    But endogenous alpha interferon did everything that conventional interferon did – most importantly it had the same antiviral properties. Further, there was evidence that the acid instability was not an intrinsic property of the interferon molecule[6].

    The neglect in pursuing a possible role in pathogenesis of high levels of circulating interferon was connected with a desire to use it to treat people with AIDS. This was a strange initiative. Apart from Kaposi’s sarcoma and hepatitis C it helped nobody in the long term and subjected people to extremely unpleasant side effects. Considering what interferon can do, one must wonder what effect it might have had on disease progression in the longer term.

    Here is an extract from a transcript of a meeting in New York City that Dr Fauci attended to answer questions. This is the response to a question about administering interferon to people who already had more than enough of it in their circulation:

    Fauci:

    No. I think that acid-labile alpha interferon is an abnormal form of alpha interferon that really doesn’t have the same effects as the kind of interferon we’ve been infusing. It’s almost as though it’s two different drugs. It’s very confusing, because that’s been in the literature and in the paper a lot. It really is different. It’s different. It isn’t the same. There are some similarities, obviously, because it’s the same type of species of an agent, but there are some differences. Whether or not it’s doing harm or good, we don’t know, because there’s so many other things going on ………………………

    Fouratt:…….

    You said there are differences, and then you went on. But I didn’t hear what the differences were between the two.

    Fauci:

    Yeah. In vitro effects. Joe, you look like you had a question about that.

    Sonnabend:

    I’m not aware that there are any biological differences between acid-labile interferon and conventional interferon. Acid-labile interferon is neutralized by antibodies to conventional interferon. There’s been a recent report that, as you know, in lupus, a similar interferon appears, and there’s quite some conjecture that indeed it may play a role in pathogenesis. More recently, from Jan Vilcek’s lab, there’s been a demonstration that the acid lability may be due to another protein that sticks to it. If that’s so in lupus, my guess is that there’s no reason to think it’s different in AIDS. As far as I know the biological properties of acid- labile interferon are identical to those of –

    Fauci:

    Yeah, well –

    The other argument for using treatment with interferon was that cells from AIDS patients could not make interferon. As noted, the problem with this justification is that the people from whom these cells were taken were full of interferon, which had to come from somewhere. So if the cells taken from the patients were unable to be stimulated to make interferon, other cells are actually overproducing it.

    There are still some attempts to treat HIV infection (as opposed to hepatitis C and Kaposi’s sarcoma) with interferon. It is possible that a place may eventually be found for its use, but this would almost surely be on temporary basis and in those who do not already have interferon in their circulation.

    The presentation made in 1991 from which the figures in this post were taken can be seen by clicking HERE; there are a few contemporary annotations.


    [1] “For, like the character of Dr Jekyll and Mr Hyde, interferon , while possessing great virtues, has a dark and sinister side” Susan Krown, in “Interferon 7” 1986 Academic press p 185-211

    [2] DeStefano-E, Friedman-R-M, Friedman-Kien-A-E, Goedert-J-J, Henriksen-D, Preble-O-T, Sonnabend-J-A, Vilcek-J

    Acid-labile human leukocyte interferon in homosexual men with Kaposi’s sarcoma and lymphadenopathy. The Journal of infectious diseases, {J-Infect-Dis}, Oct 1982, vol. 146, no. 4, p. 451-9, ISSN: 0022-1899.

    Abstract

    Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-alpha) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of Hu IFN had antiviral activity on bovine cells, a characteristic of HuIFN-alpha, and all of 14 representative samples tested were neutralized by antibody to HuIFN-alpha. In addition, the HuIFN-alpha in six of eight representative patients was inactivated at pH 2 and therefore appears to be similar to the HuIFN-alpha found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.

    [3] Marroni M., Gresele P., Landonio A. et al. Interferon-alpha is effective in the treatment of HIV-1-related, severe, zidovudine resistant thrombocytopenia. A prospective, placebo-controlled, double-blind trial. Ann Intern Med 1994; 121(6): 423–429.

    Skillman D. R., Malone J. L., Decker C. F. et al. Phase I trial of interferon alfa-n3 in early-stage human immunodeficiency virus type 1 disease: evidence for drug safety, tolerance, and antiviral activity. J Infect Dis 1996; 173(5): 1107–1114.

    Rivero J., Fraga M., Cancio I., Cuervo J., Lopez-Saura P. Long term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals. Biotherapy 1997; 10(2): 107–113.

    Mauss S., Klinker H., Ulmer A., et al. Response to treatment of chronic hepatitis C with interferon alpha in patients with HIV-1 is associated with higher CD4+ cell count. Infection 1998; 26(1):16–19.

    [4] Yabrov,A. It is hazardous to treat HIV patients with interferon-a

    Medical Hypotheses (2000) 54(1), 131–136

    [5] Selective effects of alpha interferon on human T-lymphocyte subsets during mixed lymphocyte cultures.

    Scandinavian journal of immunology, {Scand-J-Immunol}, Jun 1983, vol. 17, no. 6, p. 559-67, ISSN: 0300-9475.

    Hokland-M, Hokland-P, Heron-I, Schlossman-S-F.

    Abstract

    Mixed lymphocyte reaction (MLR) cultures of human lymphocyte subsets with or without the addition of physiological doses of human alpha interferon (IFN-alpha) were compared with respect to surface marker phenotypes and proliferative capacities of the responder cells. A selective depression on the T4 (inducer) T-cell subset could be demonstrated as a sequence of events: decreased fluorescence intensity of the T4 inducer cells (day 2 of culture), decreased percentages of T4 cells as demonstrated by cell cytofluorometry (days 3-6 of culture) , and decreased 3H-thymidine incorporation of purified T4 cells and decreased numbers of T4 cells harvested from IFN MLRs (days 5-6 of culture). In contrast, it was shown that the T8 (cytotoxic/suppressor) subset in MLRs was either not affected or slightly stimulated by the addition of IFN. The depression of the T4 cells by IFN was accompanied by a decrease in the number of activated T cells expressing Ia antigens. On the other hand, IFN MLRs contained greater numbers of cells expressing the T10 differentiation antigen. In experiments with purified T-cell subsets the IFN effect was exerted directly on the T4 cells and not mediated by either T8 suppressor cells or monocytes. These findings are discussed in relation to other immunoregulatory effects of IFN-alpha.

    [6] Endogenous “acid labile” interferon is neutralized by monoclonal antibodies against conventional “acid stable” interferon. The amount of interferon in a preparation was measured by observing how much the interferon containing sample could be diluted before it lost antiviral activity. Samples from patients contained antiviral molecules other than alpha interferon, and those that synergized with alpha interferon to increase its effects. Gamma interferon and TNF would be examples. These are destroyed by acid – not the interferon.

  • Individualization of HIV therapy

    Posted on March 8th, 2009 admin 1 comment

    Why treatment of HIV infection must be individualized.

    HIV disease is usually a progressive disease. That is, it has a starting point; the time of infection. The disease then progresses, and without treatment will generally end fatally. There are some very fortunate HIV infected individuals who are able to control viral replication and remain disease free. But for most, HIV disease does progress. But, for each individual, the rate at which it progresses varies widely. Disease progression is reflected in the fall in the numbers of CD4 lymphocytes.

    So any single CD4 count measurement is really a point on a descending curve, one that does not necessarily proceed in a straight line, and falls at widely differing rates in different individuals.

    Recommendations for the treatment of HIV infected individuals are issued periodically by DHHS and bodies such as the International AIDS Society. These recommendations, particularly those concerning when to start antiviral treatment, have always included a particular CD4 count as a signal to start or to consider starting antiviral treatment.

    All individuals with a CD4 count of less than 200 should be on therapy. They are in great danger of acquiring a possibly fatal opportunistic infection and evidence derived from clinical studies makes it absolutely clear that antiretroviral treatment is life saving.

    But what about people with higher CD4 counts? Here there is uncertainty about when in the course of HIV infection it is best to start treatment. Of course, if the drugs were completely harmless (including cost) it might be less important to have an answer to this question. However the drugs can have significant adverse effects, some of which only become evident after years of use. For people with fewer than 200 CD4 lymphocytes, the benefit of antiviral treatment overwhelmingly outweighs the risks.

    For others, a very mixed group, with CD4 cells anywhere from 200 to over 1000, and each with a different rate of disease progression, we cannot, with any security, make a “one size fits all” recommendation as to when it is best to start treatment.

    The best way to resolve clinical uncertainty remains randomized prospective clinical trials. By now we might already have obtained reliable evidence as to whether, on average, it is best for infected individuals with more than 200 CD4 lymphocytes, and who have no symptoms, to start antiviral treatment immediately, or to defer it. (A suggestion made in 1997 when the first guidelines were issued: http://aidsperspective.net/articles/guidelines1.pdf )

    The current recommendations, regarding people with greater than 200 CD4 lymphocytes, and who are without symptoms, propose a CD4 count of 350 as a point to start treatment ( many believe this number should be 500). This recommendation is made for all individuals – it is a one size fits all approach[1]. This kind of approach is appropriate for some aspects of treatment; for others it is very wrong[2].

    Perhaps the most important  example of a  recommendation, where its application across the board  is problematic,  is that which deals  with the time when antiretroviral treatment should be started in individuals with greater than 200 CD4 lymphocytes.  This recommendation specifies a specific CD4 count at which to start. As noted, for individuals with a CD4 count below 200, there is no doubt that they will benefit from therapy. For others who have no symptoms, specifying a CD4 count for all is mistaken. It is here that individualization is necessary.

    The reason is that no two HIV infected people are the same with respect to the rate of disease progression. During the early years of the epidemic, before antiretroviral treatment was introduced, we soon noted that the CD4 count declined at different rates in different people, and not necessarily in a straight line. As noted, at one extreme, there were the few fortunate individuals in whom there seemed to be no disease progression, at the other there were the few people whose CD4 cells fell very rapidly after infection, and who did not survive for more than 2-3 years, but most fitted somewhere between these extremes .

    To illustrate this I have considered four possible situations. This is a picture of the possible rates of CD4 decline in four different individuals. . It is true that these pictures are constructs, but they do accurately reflect the observed variability in disease progression; real examples showing this variability would be easily found in my medical records, and of course in those of other physicians during the period between 1981 and about 1993.

    The dip in CD4 cells following infection is usually seen when there is an opportunity to observe this. CD4 cells then rebound to a level called the set point, which will be different in relation to the pre infection level in different people. From then on it declines, but at a very variable rate, and can remain steady for varying periods before declining, again at varying rates.

    img049

    Look at where three of them (A ,B and C) reach a count of 450 CD4 lymphocytes; A (an unusual rapid progressor) gets there in about one year, B in about 3 years, C in 7 years, and D, who is a fortunate non progressor is nowhere close after 18 years.

    The arguments for starting early are not only to forestall reaching the dangerous level of 200 CD4 lymphocytes. The continuous deterioration of the immune system and diminished chances of recovery at lower counts are also arguments for an earlier start. There is also the possibility that there is a greater incidence of cancer, – other than lymphoma and Kaposi’s sarcoma, at higher CD4 counts in HIV infected people. If this is so then it remains to be shown how frequently these events occur and whether antiviral therapy can avert them.

    Treatment itself, particularly if extended over many years, is not without risks, some of which cannot even be completely known yet, particularly with the newer antiviral agents. We have to do the best we can in making a risk benefit assessment. In order to do this we should attempt to obtain information on the rate of disease progress in any one individual. This may not be entirely possible, as the rate of disease progression in any one individual may not be steady; it may accelerate or slow down. But it is possible to obtain a good, if not perfect, picture of the course of HIV disease in any one person.

    How might we obtain some information about a given individual’s rate of disease progression? Apart from obvious exceptions, and in people below 200 CD4 cells, there are no emergencies in HIV medicine. For each person we generally will have time to observe the CD4 count and viral load over a period of 6 to 12 months and obtain some idea of the rate of progress. A rapid fall in CD4 count might result in a decision to start in less than six months of observation. Or a consistent fall in CD4 count might lead to a decision to start treatment at CD4 numbers higher than even 500. This is far from perfect, as changes in CD4 cell numbers do not necessarily follow a straight line. But it is far better than basing a decision on a snapshot – which is what the experts are telling us to do.

    Individualization involves more than considering the rate of disease progression. There are other factors, such as associated diseases, domestic and social circumstances such as a lack of housing, as well as mental health issues, and many other considerations that are involved in individualization. Observing people also provides the time to establish a doctor patient relationship and for the physician to become familiar with the patients particular circumstances.

    The natural history of untreated HIV disease is relevant to the “when to start treatment” issue and will be the topic of the next post.


    [1] Evidence supporting the recommendation is derived in part from retrospective observations. The reasons why these are unreliable guides are outlined in the previous post. It is critical to as far as possible, eliminate bias in study designs because this increases the probability that a particular outcome can be interpreted as indeed resulting from a particular intervention. In this case it would be that improved survival is due to an earlier start of antiviral therapy and that the medications mediate the effect – and not for example, from simply being under the supervision of a physician. Retrospective observations, that is, looking back at information already gathered cannot be free of confounding factors as described in the previous post. In a prospective study people would be randomly assigned to receive immediate treatment or to defer it. This will give us the most reliable answer to the question of which approach is better on average.

    [2]Examples of measures that should be taken in the treatment of every HIV infected person, irrespective of the rate of disease progression are the types of tests that are performed on the initial assessment of an infected person. For example, the initial assessment of an HIV infected person should always include not only CD4 counts and HIV viral load measurements, but also tests for hepatitis, toxoplasmosis, and many other investigations. Another example of an intervention that is appropriate for categories of infected people is treatment to prevent Pneumocystis pneumonia in people with less than 200 CD4 cells. And of course, people in this category must always be offered antiretroviral therapy.

  • When is it best to start antiretroviral treatment. February, 2009

    Posted on February 26th, 2009 admin 1 comment

    When is it best to start antiretroviral treatment?

    The issue of when it is best for asymptomatic HIV infected people with more than 350 CD4 cells to start treatment with antiretroviral drugs has received renewed attention lately. Reports at recent conferences and discussions of these reports on several websites all seem to favour an earlier start than at a CD4 count of 350. There is absolutely no reliable evidence to support this recommendation. The evidence that is presented derives mostly from retrospective observations. Such retrospective studies cannot provide reliable evidence that improved clinical outcomes in those starting treatment earlier are actually caused by the antiretroviral drugs. That this is so can only be an hypothesis, a theory to be tested by prospective studies. Such a prospective study would essentially follow people who are randomly assigned to start treatment immediately or to defer it.

    Some of the problems associated with interpreting retrospective observations are outlined at the end of this post1.

    The “when to start” issue of course only applies to infected persons who are not symptomatic and have a CD4 count above 200. For those with fewer CD4 cells there is no doubt at all that such individuals should be on therapy.

    If the antiviral drugs were completely harmless, with no toxicity, we would have no problem at all, apart, of course from the financial toxicity. However the drugs are not without problems, particularly if we are dealing with taking the medicines for a life time. The newer drugs are touted as being less toxic. However it takes years for some toxicities to become manifest. How many years were people taking Zerit, (D4T,stavudine) before we knew about its effects on fat distribution? Another example of toxic effects only becoming apparent after years of use is thinning of bones caused by some antiviral drugs.

    When potent antiretroviral agents were introduced in the 1990s their impact on reducing mortality was unequivocally demonstrated in persons with more advanced disease. This immediately left us with a question regarding the effect of starting these drugs in individuals with less advanced disease.

    Rather than admitting that the answer to this question was unknown, and required to be studied in a prospective fashion, the Department of Health and Human Services issued a set of guidelines. It is understandable that issuing guidelines, in the face of uncertainty is reasonable, but they must be regarded as interim, pending the outcome of studies.

    In 1997 I wrote a letter in response to the publication of these guidelines; it was received by the Guidelines Committee, but I was sent absolutely no response. The letter can be seen here: http://aidsperspective.net/articles/guidelines1.pdf

    Despite attempts to rely on retrospective observations to resolve clinical uncertainty, – such as uncertainty about when to start antiviral treatment, prospective randomized trials remain the best way to achieve this. They minimize bias, and thus misinterpretation, and are therefore the most reliable way to resolve uncertainty. There is no getting over this. Such trials may be expensive, and last a long time, but in the end, probably more time and money is lost by repeating inconclusive and conflicting retrospective studies.

    As always, you can’t beat the truth. Regarding the “when to start” question, the truth was and still is that the answer to the question is unknown. Again, if the drugs were harmless there would be no problem. But it is quite possible that a person starting treatment at say 700 CD4 cells, even 500 CD4 cells, who may be a slow progressor may well have his or her life shortened by long exposure to the medications.

    If, for whatever reason one presumes to favour a particular answer one can always select snippets of data to support one’s bias. Many would like to believe that it is better to start early. I have even read on one web site, that a New York physician stated that he would start any infected person on treatment no matter what the CD4 count was. I suppose this physician, and those who share this view are happy to practice with only their unsupported beliefs as a guide. This is as reliable as using a crystal ball and sick people deserve more from their health care advisers. In this respect the writers reporting such nonsense generally make no comment on the danger of views based only on belief, thereby adding credibility to these statements of faith. The practice of medicine is not a faith based activity.

    The scientists who attach unwarranted importance to retrospective studies are also doing a disservice to clinical research. Some at the recent CROI meeting did admit that a prospective randomized trial was the best way to obtain reliable evidence on the issue of when to start. But as reported on one web site:

    “Professor Doug Richman of the University of California San Diego questioned whether a ‘when to start’ trial was worth the expense. “Rather than spend millions on a trial, given that most people aren’t diagnosed until much later, why not use all that money to identify people who have the higher risk?” he asked”.

    Similarly:

    “He [Bartlett] also believes that the field is not willing to wait the 5 to 10 years necessary to generate an answer on when to start therapy.”

    Discovering what is in the best interests of the infected person is not worth the expense? Waiting 5 to 10 years to find out is unacceptable?

    So if we dispense with the truth to inform our actions, what could it be that guides us? Whatever it is, it is certainly no more reliable than consulting a palm reader.

    Interpretations of associations found in retrospective studies presented as reliable indicators of a cause and effect relationship, rather than possibly suggestive of such a relationship, have as much meaning as the interpretations of an astrologer. Of course such data may be useful in suggesting hypotheses.

    At a recent ICAAC meeting Dr Kitahata presented an analysis of a large retrospective study comparing outcomes among people starting at a higher as compared to a lower CD4 count. There was little meaningful criticism of the interpretation that the improved outcome in those starting treatment earlier was actually due to medications taken. Dr Kitahata felt that it was possible by some statistical magic for retrospective observations to mimic a randomized prospective study.

    Here is an illustration of the interpretive pitfalls in such studies; it is a comment I sent to the web site reporting the results and conclusions of retrospective studies. I used the name James Mello, and pointed out that, as an example people who started treatment earlier were more likely to be under medical care than those who started later, and this might have contributed to their better survival. Another possibility is that most of the mortality might have occurred in those with the lowest CD4 counts; the examples I gave in my comment were a CD4 count of 1 compared to 349, when in fact the study concentrated on individuals with counts above 350. There are other possible explanations. There was one comment that suggested the possibility that people who choose to start treatment early are more likely to be concerned with their health in general and thus more prudent, and presumably more cautious in risk taking.

    This is the comment of James Mello:

    http://aidsperspective.net/articles/mello.pdf

    Another retrospective study actually showed no survival benefit in people with CD4 counts above 450. Here is a report of this study and that of Dr Kitahata:

    http://www.medpagetoday.com/MeetingCoverage/CROI/12819

    Surely we need to know, and not guess when it is best to start treatment.

    There are those who favour an earlier start and may have reasonable ideas to support these views. But they remain views – not proven ways to proceed that are in the patient’s best interests.

    Let us find out if it is a fact that there is a benefit to starting earlier. All of us – HIV infected people and their advocates should be calling for appropriate prospective studies to guide us. We need to know the truth about when it is best to start.

    Even if we were to conduct an appropriate large randomized prospective study we would only know if in asymptomatic HIV infected people with greater than 350 CD4 cells, it is on average better or worse to start treatment early or to defer it or if it makes no difference, of course apart from the expense.

    This brings up an associated extremely important but neglected issue. This is the need to individualize therapy, which will be the subject of the next post.

    1.

    The causative interpretations of retrospective observations are made difficult by what are called confounding factors and some are impossible to overcome. For example we don’t know why people choose or agree to start treatment early or defer it. The different decisions may reflect the possibilities that those choosing an earlier start may have better access to medical care, and receive better care in general, or may be more likely to be people concerned with their overall health.

    Here is another example of something that might make interpretation of retrospective observations difficult.  A retrospective study  comparing mortality in people starting treatment above and below 500 CD4 cells finds that  those who start treatment at  higher CD4 numbers have a lower risk of risk of death.  If, in those who delayed treatment and died, we are not told what the median CD4 count was at the time treatment was started the overall conclusion that antiretroviral drugs improve survival if started above 500 CD4 cells, would be unwarranted. It might well be that those most who died delayed treatment until a CD4 count of 100 or less.  Had`they started at 450, 350, or 300 – numbers of course`all below 500, the outcome might have been very different.

    ****************************************************************

    The importance of individualized treatment.

  • AIDS and MINORITIES

    Posted on February 25th, 2009 admin 1 comment

     

    February 24th 2009

    AIDS and Minorities

    In the US, African Americans constitute 12% of the population, yet almost half of the total number of AIDS cases in the country occurs among them. This disaster is only now being generally recognized, with the leadership of the Federal AIDS response finally turning their attention to this tragedy, at least publicly.

    This is a tragedy that has been developing in full view for more than twenty years. One only has to look at statistics provided by the Centers for Disease Control (CDC) since the epidemic started to know, as early as 1987 that without intervention a preventable disease was inexorably moving into African American communities.

    Firstly, take a look at the situation in 2006 (data from the Kaiser family Foundation).

    2006c3

     

    Now take a look at this picture that clearly tells a horrible story that words cannot match.

    usepidemic3

     

    In the light of this devastating evidence how is one to understand the comments of Dr Fauci, who can be regarded as the head of the Federal scientific and medical response to AIDS?

    He noted that these “shocking statistics would be tragic anywhere but are particularly inexcusable in a wealthy country such as the United States.”

    His complete statement can be seen here: http://www3.niaid.nih.gov/about/directors/news/BAAID_09.htm

    Look at the above picture again. Cases in African Americans started to exceed those in white Americans in 1994, but the trends were quite evident long before this. We knew in 1988-1989 what was coming. So, one must wonder why it took all of twenty years to announce only in 2009, that these statistics are shocking.

    A preventable tragedy was taking shape in full view of the Federal AIDS leadership, who rather than fund a vigorous prevention education campaign directed towards those most in danger, instead chose to support a wasteful, vacuous untargeted prevention education program in the form of “America Responds to AIDS”.

    It is not only the federal AIDS leadership that failed to respond to warning signals flashing brightly right in front of them. In the early days of the epidemic there was a vigorous and exemplary community activist response. This was a terrific example of people dealing with a deadly disease taking action on their own behalf, fighting for the best medical and scientific response and against the all too frequent shameful stigmatization of HIV infected individuals.

    The flowering of AIDS activism in the late 1980s and early 1990s achieved a great deal. All people dealing with serious illness have benefitted from the precedent that was set. Yet, in recognizing this achievement, we must also wonder why many of these experienced advocates, who no doubt were aware of the demographic trends shown above, seemed generally less willing to at least try to avert the disaster threatening their fellow citizens? Of course some tried, and maybe were overwhelmed by massive indifference.

    Whatever the reasons, the advocacy of US activists abroad, particularly in Southern Africa, proved to be more effective than anything they were able to achieve in their own country for their fellow African American citizens. There are also other groups where AIDS has been, and continues to be a growing problem, but have been relatively neglected.

    Not for profit organizations, that raise funds to help and advocate for people with AIDS were also aware of what was developing, but if there were any efforts devoted to preventing a calamity visibly descending on the largest community at greatest risk, these clearly were of little benefit.

    What is almost, but not quite, as shocking as the neglect of a disaster developing in front of our eyes, is the complete absence of any sense of contrition, let alone a simple acknowledgment of failure, on the part of those who might have helped to prevent it.

    If justice includes the notion of equity then prevention resources should be distributed in proportion to the needs of different communities. This clearly has not happened and it might be helpful to give some thought as to why this has been the case.

    We need to know and admit what it is that we did unsuccessfully, or failed to do, to stop a preventable disaster, so that we can get it right in the future.

     

    Instead we have a wringing of hands by those who could have done something, but did nothing, to stop this.

    A similar article was posted on a health related web site in December of last year. There was no response to the issue I raised.

    This post can be seen here.

    http://Aidsperspective.net/articles/AIDS_AND_MINORITIES.pdf

     

     

    Take yet another look at the picture showing the changes in the proportion of AIDS cases according to racial/ethnic group over the past 20 years. It tells the whole story; no comment is really needed.

     

     

     

  • AIDSPERSPECTIVE

    Posted on February 4th, 2009 admin 1 comment

    Why another AIDS blog?

    In order to just get started on this blog, the various reasons for creating it will be described on my web site: aidsperspective.net One of these reasons, which I suppose is self evident, is to bring some attention to the web site, where I am attempting to create a record of various AIDS related activities I have been involved with since the epidemic was first recognized in 1981. I have more or less learned how to construct a web site – at least to the extent that I am able to post legible material, and I am gradually adding to its content.

    Another reason for creating this blog is to provide an opportunity for comment on contemporary HIV/AIDS related events.

    With that I can start with the first post on this blog.

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