Posted on July 1st, 2012 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.
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.
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 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:
Posted on April 12th, 2012 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.
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.
Posted on August 17th, 2011 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.
Posted on August 5th, 2011 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.
Posted on June 5th, 2011 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.
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 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/>.
(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
Posted on January 28th, 2011 No comments
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.
N Engl J Med 1987; 317:185-191July 23, 1987
Posted on December 12th, 2010 No comments
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 , 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.
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.
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.
Posted on August 31st, 2010 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.
Posted on May 19th, 2010 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
Posted on May 19th, 2010 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.
Posted on August 30th, 2009 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.
Posted on August 11th, 2009 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:
Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).
FHI has produced a set of slides listing PrEP trials.
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/
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.
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
Posted on July 9th, 2009 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.
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.
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
Posted on June 12th, 2009 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 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.