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  • Interferon in AIDS: Too Much of a Good Thing

    Posted on May 12th, 2011 admin No comments

    Interferon and AIDS:  Too much of a good thing

    This discovery of interferon in AIDS

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

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

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

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

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

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

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

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

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

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

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

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

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

    Finding interferon in people with AIDS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    .

    .

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    (1)

    Abstract

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

    (2)

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

    2nd International Conference on AIDS Paris 1986.  Abstract 100

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

    .

    (3)

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

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

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

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

    Posted on February 23rd, 2011 admin No comments

    Full contents of this blog:

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

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

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

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

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

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

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

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

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

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

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

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

    The second is the view of  PrEP researchers.

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

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

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

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

    .

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

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

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

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

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

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

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

    Daily Truvada as PrEP is a really bad idea.

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

    Posted on January 28th, 2011 admin No comments

    Full contents of this blog

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

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

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

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

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

    But no explanation was forthcoming.

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

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

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

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

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

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

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

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

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

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

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

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

    A note about patient management strategies:

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

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

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

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

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

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

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

    Returning to the original AZT trial:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    (1)

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

  • iPrEx trial results of preexposure prophylaxis – PrEP

    Posted on December 12th, 2010 admin No comments

    Full Contents of this blog

    Pre-Exposure prophylaxis -  PrEP -  iPrEx  trial results.

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

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

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

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

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

    “This discovery alters the HIV prevention landscape forever,”

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

    “This is a game-changing trial result,”

    Science magazine reported that..

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    This is a classic paper on sub group analysis:

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

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

    This is from that paper:

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

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

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

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

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

    This is not so fanciful.

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

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

    This is from:

    Coronary Drug Project Research Group. Influence of adherence to treatment

    and response of cholesterol on mortality in the coronary drug

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

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

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

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

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

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

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

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

    What about safety?

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

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

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

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

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

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

    Despite the disappointing results of iPrEx, PrEP is important.

    Why is PrEP important?

    There are at least two important reasons.
    1:

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

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

    2:

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

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

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

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

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

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

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

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

    .

    A few words about prevention education and condoms:

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

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

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

    .

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

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

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

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

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

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

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

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

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

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

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

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

  • HIV exposed individuals who are seronegative.

    Posted on October 18th, 2010 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

    David Imigawa and The Window Period.

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

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

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

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

    This is how the article starts:

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

    It includes this statement:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    (The following is adapted from the previous post)

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

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

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

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

    1:

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

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

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

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

    3:

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

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

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

  • HIV Treatment as Prevention. March 2010

    Posted on March 4th, 2010 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Posted on August 30th, 2009 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Posted on August 11th, 2009 admin No comments

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

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

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

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

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

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

    http://www.prepwatch.org/

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

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

    FHI has produced a set of slides listing PrEP trials.

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

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

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

    The websites of these organizations contain information about PrEP.

    AVAC :   http://www.avac.org/

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

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

    The International AIDS Society:  www.iasociety.org

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Here is an excerpt from material published by CDC:

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

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

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

    Here is another excerpt:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


    [i] [i]    http://www.cdc.gov/hiv/prep/resources/factsheets/index.htm

  • Despite the SMART study there is a role for intermittent therapy. July, 2009

    Posted on July 9th, 2009 admin No comments

    From where we are at the moment in our understanding of HIV disease, we have to accept that lifelong treatment will be required for most infected individuals..

    The drugs are not free from undesirable effects, they are costly and for many, quality of life is impaired to a greater or lesser extent by taking medications, even a single pill, day after day.

    For these reasons it is important to study ways to safely minimize exposure to these necessary drugs.

    We have potent tools to fight HIV disease but we still do not know how best to use them to achieve the most favourable antiviral effect, while minimizing toxicity and undesirable effects.

    One approach to these objectives – at the moment, perhaps the only viable approach is the study of intermittent therapy as a means to safely reduce exposure to drugs.   This approach will almost definitely not be possible for all HIV infected people needing treatment.  But it may well be possible for most. The cost savings with intermittent therapy could also be substantial.

    This important undertaking was dealt a completely unwarranted setback with the publication of the results of the SMART study, in the New England Journal of Medicine in 20061.  SMART is by far the largest study comparing continuous with intermittent therapy.  In this study more people died in the intermittent treatment arm, not only from AIDS associated events but all cause mortality was increased, including more deaths from cardiovascular disease and from some cancers not previously associated with AIDS.

    The negative effect of SMART on the study of intermittent treatment continues.   In addition, because of the association of an increased number of deaths with intermittent treatment from cardiovascular disease and other conditions not related to HIV disease, the SMART study results have been interpreted by some to indicate that HIV disease includes a much wider spectrum of clinical manifestations than previously thought.  The most favoured, and almost certainly correct explanation for how HIV infection causes heart disease and some other conditions is that they are a consequence of inflammation induced by infection with this virus.

    For a number of reasons, the conclusion that, as a generalization, intermittent therapy is associated with a worse outcome compared to continuous therapy is completely without justification.  The original SMART study report omitted information that brings this conclusion into question; this has been alluded to in a previous post.    Almost all the deaths in the study occurred at US sites, where in contrast to non-US sites multiple co-morbidities were over represented.  As seen in the table below these co morbidities included, among other conditions,  hepatitis B and C, a history of heart disease and  diabetes.  There were even significantly more smokers among those enrolled at US sites.  How can one extrapolate interpretations of observations made in such  individuals  to HIV infected  populations free from these co-morbidities?

    SMART studied just one particular strategy of CD4 guided intermittent therapy, in a population where  multiple non HIV related diseases were overrepresented in US sites, where almost all deaths occurred (79 out of a total of 85 deaths). These conditions included hepatitis B and C,  hypertension, and a previous  history of heart disease   Even setting aside interpretative difficulties concerning this particular study, one can say no more than that the particular strategy of treatment interruption used in SMART, in the population studied, indicated a worse outcome in those randomized to receive intermittent therapy.   That’s all.  The generalizations made about the danger of intermittent treatment were completely unjustified, although enthusiastically endorsed by many community commentators, and repeatedly stressed in educational  literature addressed to physicians.

    Inappropriate generalizations of course apply to other studies of treatment interruptions, which used different criteria for interrupting therapy. All the other studies were smaller than SMART and had different follow up times.  But in all of them the excess mortality observed in SMART was not seen, although in some, morbidity, particularly bacterial infections, was more frequent with intermittent treatment.

    Some examples are the Trivacan study2 which was conducted in a different population using different interruption criteria. There was an excess of bacterial infections in those receiving intermittent therapy but not the excess of deaths noted in SMART.  The Staccato study3,  using a different interruption strategy also did not show the excess mortality seen in SMART in the treatment interruption group.

    The LOTTI study4 concluded that the continuous and intermittent therapy groups could be considered equivalent.  Actually, in complete contradistinction to the SMART results, in this study, cardiovascular disease was actually worse in the continuous therapy group (controls) compared to those receiving intermittent therapy (STI group).  Although pneumonia was more frequent in the STI group.    Here is a sentence from the author’s abstract.

    A higher proportion of patients in the STI arm were diagnosed with pneumonia (P 0.037), whereas clinical events influencing the cardiovascular risk of patients were significantly (P<0.0001) more frequent among controls”.

    The finding regarding cardiovascular disease is particularly relevant.

    Much has been made of the increases in cardiovascular disease seen in the intermittent treatment group in the SMART study.  It is now considered by some that HIV infection per se constitutes a risk for heart disease and this, as noted, is attributed to HIV induced inflammation.   There are even studies now that look at arterial wall thickening as a measure of atherosclerosis and find this to be increased in untreated HIV infected people.  So this needs to be studied.  But in terms of cardiovascular clinical events, LOTTI tells us these are more frequent in people receiving continuous therapy compared to those receiving intermittent treatment.

    Despite evidence to the contrary some “experts” still tell physicians to avoid treatment interruptions in order to protect patient’s cardiovascular health!!

    There are even sponsored courses for physicians for whom CME credit can be earned where instruction is provided to not interrupt treatment precisely because this will increase the risk of heart disease, as well as other problems.

    I was shown an invitation to physicians to a free course offered by a distinguished academic institution.   Among the descriptions of what those attending the course will learn to do is the following:

    “Describe, discuss and apply the data from the SMART study on CHD  (coronary heart disease)  risk associated with ARV treatment interruption and be able to integrate these data into ARV treatment plans and algorithms for HIV-positive patients”

    What is one to make of this in the light of the LOTTI observations?

    This absurdity can only be possible because there is a selective reporting of information to HIV infected people, their advocates and to physicians who are not able to look at all the literature.   As a consequence almost none of the web sites devoted to conveying information to patients and their advocates have even mentioned the LOTTI study.

    As far as cardiovascular disease is concerned those of us who took care of HIV infected patients in the 1980s before effective treatments were available will have observed that people with AIDS characteristically had huge elevations in their serum triglycerides.  They also characteristically had low levels of HDL cholesterol (and of total cholesterol).  I helped a resident in a hospital where I once worked to prepare a report on HDL levels in HIV infected patients before HAART was available.  We used my patient records from the 1980s and were able to clearly show that as the disease progressed over time, HDL levels decreased.    There was, not surprisingly,  a correlation between falling HDL levels and falling CD4 counts – data which I never published, but probably can still find.

    So, there may indeed be something in the connection between untreated HIV disease and heart disease.  In the early days possibly our patients did not survive long enough to manifest any clinical manifestation of heart disease.   Increased triglycerides are an independent risk factor for coronary heart disease.  There even was a possible mechanism for this that was known in those days that could account for this.

    Untreated individuals with more advanced disease have high serum levels of alpha interferon (also increased levels of gamma interferon) and TNF alpha, and both of these cytokines can inhibit an enzyme called lipoprotein lipase that then results in the lipid changes noted.  Such changes have been seen in people with hepatitis C treated with recombinant interferon.

    So, why is the failure of just one form of intermittent therapy used to categorically condemn the practice in principle?   There are numerous different ways in which intermittent therapy can be structured.

    The discouragement of the study of intermittent therapy is even more peculiar in view of the different outcomes of other, albeit,  studies smaller  than SMART

    Perhaps a clue is to be found in a sentence in the LOTTI study report.

    Here it is:

    “The mean daily therapeutic cost was 20.29 euros  for controls and dropped to 9.07 euros  in the STI arm (P<0.0001)”.

    This more or less translates into a 50% reduction in drug sales to people receiving intermittent treatment according to the LOTTI protocol.

    Taking other studies of intermittent therapy into account, and considering some problems associated with SMART, I believe that one can say with a resounding affirmative that, in principle , intermittent therapy can be safe. Not for all, and maybe not for all of the time, but probably for many HIV infected individuals with over 350 CD4 lymphocytes who need treatment (who such individuals may be is also a controversial issue particularly regarding individuals with over 350 CD4 lymphocytes),   some form of intermittent therapy will probably be demonstrated to be safe.  For individuals with at least 700 CD4 lymphocytes, this is already the case.

    Many of my patients wanted to take “treatment holidays” as they were once called; some from time to time, and others on some regular basis.  I have always believed that we need to find ways where we can safely minimize drug exposure so I was supportive of their wishes, as long as some conditions were met and we had the means to monitor viral load and CD4 counts.   This desire for treatment interruptions  was obviously  true not only among my patients but it seemed quite common in New York City to hear of individuals who were receiving some form of intermittent treatment, and this must also be the case elsewhere.

    Of course for individuals with CD4 counts below 200, this was not a good idea.   Whatever we did, we knew that we needed to keep the CD4 count above this level. So, for patients with higher CD4 counts a variety of strategies were used.

    There will be many anecdotes accumulated over the years of such experiences of intermittent treatment.   I need to stress that these are just anecdotes and most definitely not formal studies.  As such they can only lead to hypotheses on which studies can be based.

    It would be foolhardy for HIV infected individuals to interrupt treatment without the advice and close supervision of an experienced physician. I have seen too many individuals who have come to harm by stopping their medications completely on their own, without supervision and not even informing their physicians that treatment was stopped.  This at least indicates that there is such a thing as “pill fatigue”, something we cannot ignore.

    Of my patients who interrupted treatment none have come to harm.  There was no established protocol to guide us and strategies used took patient preference into account.    An effective antiviral combination, one that has produced sustained suppression, at least as indicated by an undetectable viral load should work again if stopped and re started later. There may be some theoretical difficulty in abruptly stopping antivirals that are slowly eliminated without additional temporary cover.   As a result, in certain patients some form of episodic treatment was used, that is periods on treatment alternating with periods off treatment.  This approach is now generally considered to be unsafe and CD4 guided strategies are studied.   But numerous anecdotes as well as earlier studies of episodic treatment indicate that this approach can be viable in some situations, and I believe should be further studied.

    In an editorial in the journal reporting the LOTTI study Bernard Herschel and Timothy Flanagan state.

    “Many of our patients with high CD4 cell counts want to

    stop treatment. The LOTTI study does not justify a

    recommendation in that regard, but it does give clinicians

    useful information that it is probably safe to stop

    treatment within the limits of CD4 cell counts of

    LOTTI. Continued vigilance is needed so that excellent

    adherence is maintained when patients are on HAART

    to prevent the emergence of resistance.

    The LOTTI study adds important information to the

    continued question of whether there is a role for

    interrupted therapy. Further study is justified, particularly

    with newer combination therapies, which may well

    have less toxicity and therefore shift the balance towards

    continuous treatment. Clinicians will welcome the

    information from LOTTI because it can allay some of

    the concerns regarding the safety of treatment interruptions

    at high CD4 cell counts”.

    In the LOTTI trial, treatment was restarted when the CD4 count dropped  to 350 and stopped at a CD4 count of  700.  So within these limits we have some reassurance of safety.

    So, further study is absolutely warranted.

    In the LOTTI study, participants had to have a CD4 count of 700.

    What about individuals who have had  undetectable viral loads for six months (as in LOTTI) but whose CD4 count has remained stable at 500, or 450 or some number lower than 700?    Studies with different CD4 criteria should continue and not be deterred by the SMART results.

    I have written about the need to work on ways to individualize therapy to take individual rates of disease progression as well as other individual characteristics into consideration.   That is to get away from the prevailing  one size fits all approach to therapy,  mainly using a snapshot of just one or two parameters,  the CD4 count and viral load to guide one, without considering the rate of change in  CD4 numbers.

    In the same way, studies to individualize intermittent treatment interupptions in those for whom it is possible should be considered.   As noted, if an antiviral regimen is effective in fully suppressing replication – at least to the extent indicated by an undetectable viral load, there is absolutely no reason why it should not be effective again if stopped. There may be some consideration needed regarding how to stop with some drugs that are eliminated very slowly.   (Of course an individual may be super infected with a drug resistant variant).

    It is likely that some form of episodic treatment may be effective in selected individuals.   That is, periods on treatment alternating with periods off treatment.   Because of its flexibility it is probably best suited to individualization.

    As mentioned, this approach has been thought to be more dangerous than a CD4 guided strategy.  But this approach appeared to be effective in earlier studies but they have not had long periods of follow up5.   But other similar studies have shown a high rate of viral rebound6.

    However, the fact that there has been a successful study and the many anecdotes of successful episodic types of intermittent therapy provide encouragement that it is worthwhile to continue to study such an approach.

    It certainly is possible to study the characteristics of those individuals in whom such an approach has proven to be successful.

    I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals.

    The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease.

    Look at this table, which has been copied from a report on a SMART follow on study of inflammation in trial participants7.

    This table shows characteristics of individuals who died compared to those who did not.

    Kuller 2

    The 85 people who died are represented in the third column, and their characteristics have been compared to those of two individuals who did not die (controls).

    It can be seen that of the people who died, compared to those who did not, 11.8%  vs  4.7% had a history of heart disease (p=0.04);  45.9% vs 24.1%  were co infected with Hepatitis B or C  (p = 0.0008); 57.6% vs 31.8% were current smokers (p = 0.0001); 25.9% vs 14.7% were diabetic (p = 0.03); 38.8% vs 25.3% were taking medications for high blood pressure (p = 0.02).

    Thus the people who died in the SMART study tended to be sick with non HIV related conditions.  64% of them were in the treatment interruption group so this tells us that individuals who already have more traditional risk factors may increase their risk of death by interrupting treatment according to the schedule defined in SMART.

    But there is another remarkable figure in this table.  92.9 % of those who died were participants in US sites!  I have already written about this – that of the 85 deaths in SMART, 79 occurred in US sites with 55% of participants, and only 6 people died in sites outside the US where 45% of individuals were enrolled.

    Despite what some experts incessantly tell us, SMART cannot justifiably be used to conclude that intermittent treatment is dangerous, in principle,  for all HIV infected individuals, particularly with additional information that for some reason, has only been made available less than a year ago.

    The original report of the SMART study in the New England Journal of medicine in 2006 reported the baseline characteristics of participants.  All of these baseline characteristics, including co morbidities and traditional risk factors for heart disease such as hypertension and smoking were about the same in both treatment groups – that is, in those receiving continuous therapy and those on the treatment interruption arm.   However the distribution of these characteristics in those who died was not reported in this publication.  We had to wait until October 2008 to learn that those who died already had more multiple health problems unrelated to HIV infection.

    I missed seeing this 2008 publication.  It seems that most who saw it had little to say.  But the strange distribution of deaths was brought to attention again with comments in the Lancet Infectious Disease in April of this year8.   I did not miss it this time, and have already written about it.

    Because of the deleterious and unwarranted influence of SMART in discouraging the study of intermittent therapy, I thought it was absolutely important to make this information as widely known as possible.   Without further explanation, these results indicating the greater extent of co morbidities and traditional risk factors among those who died bring the often repeated conclusion  that the SMART study indicates that treatment interruptions are unsafe for all,  into question.

    To my great surprise, despite my best efforts to disseminate this information on the strange distribution of deaths during the study, there was almost no expression of interest from the many individuals I communicated with.

    This lack of interest is really puzzling.

    Despite what might be considered to be an inappropriate generalization of the results, particularly regarding the relationship of HIV infection to deaths from causes unrelated to HIV infection the SMART study was a massive undertaking and its completion should be seen as a triumph.

    Organizing such a huge endeavour that was dispersed so widely is a tremendous achievement.  There are sub studies and follow on studies that continue and will advance our understanding of HIV disease.

    We know with some security from SMART that HIV infected individuals with Hepatitis B and C,   hypertension, and a past history of heart disease and some other associated health problems would increase their risk of death by interrupting treatment for HIV according to the strategy used in SMART.

    For otherwise healthy HIV infected individuals it is likely that for some, unfortunately not for all,   a form of treatment interruption will be demonstrated to be safe.  This can already be said for those meeting the conditions of the participants in the LOTTI trial.

    The original report of the SMART study was published in the New England Journal of medicine in 2006.

    http://content.nejm.org/cgi/content/full/355/22/2283

    ———————————————————————————————————————–

    Refs

    1:    New England Journal of medicine    2006  355:2283-2296

    2:    Trivacan(ANRS 1269)    Lancet  2006  367:1981-1989

    3:    Staccato                           Lancet 2006   368: 459-465

    4:    LOTTI                                AIDS     2009   23:799-807

    5:     Proceedings National Academy of Sciences   2001   98: 15161-6

    6:      AIDS  2003    17:2257-2258

    7:      Kuller et al.   PLoS  Oct. 2008   5(10): e203

    8:      The Lancet Infectious Diseases  2009 Vol 9 Issue 5 268-9

  • The not so SMART study: a very short postscript

    Posted on June 12th, 2009 admin No comments

    I believe the SMART study team have submitted a response to Justin Stebbing and Angus Dalgleish’s comments in the Lancet Infectious Diseases, that was referred to in a previous post:

    The not so SMART study.

    The explanation that the huge discrepancy in the number of deaths in the US and non US sites was due to the fact that non US sites started to enrol participants 2-3 years later than   US sites,  was addressed in the comments in the Lancet Infectious Diseases.

    Here is the relevant part:

    “Whereas most non-US sites commenced patient recruitment 2—3 years after the US sites, it is unlikely that longer protocol exposure could account for this difference. We are told that there were 38 deaths in the first year and 47 deaths thereafter. Hence, assuming that all six non-US deaths occurred in the first year, there remain 32 deaths (38 minus six) in the USA from the first year of the study—about five-fold more than expected based on the non-US mortality rate”.

    Whatever explanation is to be offered by the SMART team, even if turns out to be consistent with their conclusions, the following questions remain.

    Why was information on the distribution of deaths withheld for so many years?

    Why was this information, when it did appear in the article by Kuller et al in PLoS last year,  ignored by community commentators  to whom HIV infected people and their advocates look to for help.?

    Did they not notice it? (I did not).

    Did they think it was of no significance?

    Hopefully the SMART team’s response will put an end to this mystery of why, with more or less the same number of participants in US and  non US sites,   79  people died  at  US sites while there were only 6 deaths at sites  outside the US.

  • Endemic Infections in Africa have everything to do with HIV/AIDS and are a long neglected therapeutic target.

    Posted on June 6th, 2009 admin 1 comment

    An article with the striking title “Africa’s 32 Cents Solution for HIV/AIDS” was just published in PLoS Neglected Tropical Diseases.  It can be seen here:

    http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000430

    This dramatic title refers to the cost of treatment of schistosomiasis with praziquantal.

    Schistosomiasis is an infection caused by parasitic worms, or helminths., of the genus  Schistosoma.    Most of the 200 million cases of schistosomiasis in the world occur in Africa.

    The species, Schistosoma haematobium is estimated to infect about 112 million people in sub Saharan Africa.  So its high prevalence puts it in the same class as that of TB, malaria and HIV.  It is responsible for a huge burden of morbidity particularly in children and young adults.

    S. haematobium  has a complicated life cycle, some of which takes place in snails.  People are infected by organisms released by snails living in fresh water. These organisms can penetrate the skin of any body part that is immersed in snail infested water.  S. haematobium affects the urinary tract.  The disease it causes is commonly called bilharzia.

    I was very conscious of its danger as a child growing up in Zimbabwe, with signs at several small lakes around Bulawayo warning one not to swim in them because of the danger of bilharzia.

    Peter Hotez and colleagues article is a welcome addition to the already substantial literature that strongly suggests that many endemic infections, not only with helminths, but also with bacteria, protozoa and viruses can increase the transmission of HIV and most probably  have a detrimental effect on the course of HIV infection.

    This paper concentrates on the local effects of S.haematobium on the female genital tract , where lesions caused by  schistosome egg deposition result in mucosal patches, that can bleed during sexual intercourse. The authors state “Presumably, the schistosome egg granulomas produce genital lesions and mucosal barrier breakdown to facilitate HIV viral entry” and go on to compare this to the process by which herpes simplex ulcers increase susceptibility to HIV.

    This does seem obvious – there is a mucosal break, so HIV has a way in.

    In fact in the case of herpes simplex, this seemingly obvious connection is probably not correct.   The large Partners in Prevention study, recently completed, found that acyclovir, a drug effective in treating herpes does not reduce the risk of HIV transmission.  The drug however was associated with a reduction in the number of recurrences of herpetic ulcerations, and significantly slowed HIV disease progression.  I have written about this in another post.

    As with herpes simplex, it is possible that systemic effects of schistosomiasis, may be much more significant, or at least as significant, as local effects in enhancing the transmission of HIV.    Of course, both local and systemic effects may play a role in enhancing HIV transmission.  The systemic effects include an impairment of virus specific immune responses; immune activation may also increase susceptibility to HIV and promote its replication.

    The influence of associated infections on the infectivity of HIV extends far beyond that of schistosomiasis.  Peter Hotez  (the lead author of the above article) has done a great service by bringing attention to a number of devastating neglected tropical diseases.  This important article can be seen in the Lancet of May 2nd, 2009, (Lancet 2009 373;1570-1575).

    The title of the article is:

    “Rescuing the bottom billion through control of neglected tropical diseases”

    By Peter J Hotez, Alan Fenwick, Lorenzo Savioli and David Molyneux

    I have copied this table from the above article:

    tropical

    These are incredibly huge numbers.

    Many of these infections occur in children and young adults and not only  have an impact on life expectancy, but significantly are the cause of chronic debility particularly in young people.

    Some also have an activating effect on HIV replication by several mechanisms, some of which  have been understood for well over ten years.  The resulting acceleration of HIV infection,  by  increasing  HIV viral loads,  as well as by other mechanisms increases the transmission of this virus.

    The health of hundreds of millions of individuals could be improved by efforts to prevent and treat these infections.  These infections are also appropriate therapeutic targets in the fight against HIV/AIDS.

    Despite a great deal of evidence for the interaction of multiple bacterial, viral, protozoal and helminthic infections and HIV,  this association has been inexplicably neglected in providing  additional approaches to controlling the epidemic..

    I had what might be described as a  misfortune to have been a member of President Mbeki’s panel on AIDS, an almost surreal experience I should write about.  The following is an excerpt from something I wrote for this panel almost 10 years ago:

    “The crucial difference in Africa, as opposed to the US, is the high prevalence of associated infections. These include STDs, TB, malaria and other protozoal infections, helminthic and bacterial  infections. Such infections would supply sustained signals, such as IL-1  IL-6 and TNF, known to activate HIV.  Some can also upregulate the expression of chemokine co receptors required for HIV entry.  Some of these infections are  somewhat immunosuppressive themselves, an effect contributed to by the secretion of IL-10.37 Sexual transmission of HIV is also known to be facilitated by a high viral burden.38 This would also be the consequence of the HIV activating effect of frequent associated infections in Africa.”

    This was almost 10 years ago, and since then literature has continued to accumulate documenting the detrimental interactions between HIV and multiple infectious agents.

    About two years ago I made a presentation at the Prevention Research Center at Berkeley, trying to understand why endemic diseases had been so neglected in our attempts to control AIDS, particularly in Africa.  I thought that part of the problem was poor interdisciplinary communication and understanding.   Specifically, there might be difficulties in   communications between public health experts and microbiologists.   Possible public health implications of the findings of microbiologists might not be perceived without additional explanation.  I illustrated this with a specific article.

    I used an excellent article to illustrate this problem.

    The article is called “Contribution of Immune Activation to the Pathogenesis and transmission of HIV type 1 infection” and the authors are Stephen Lawn, Salvatore Butera and Thomas Folks.   (Clinical Microbiology Reviews. Oct 2001 14; 753-777)

    This is part of what I said in California  in trying to illustrate the difficulty in communication:

    “Of great interest – because of its implications for disease control was the discovery that other infections, viral, bacterial, protozoal and helminthic, could influence the course of HIV disease.  Generally the effect was to enhance HIV replication, but a few seemed to ameliorate – at least temporarily, the course of infection.  Scrub typhus, measles and perhaps a form of viral hepatitis, may have a  transient beneficial effect on HIV disease, but these are exceptional cases. Most co-infections have the opposite effect.

    We now come to an example of observations made by microbiologists and work done at a molecular level with enormous implications for the control of AIDS in Africa.   This example is a review (cited above)  explaining in great technical detail how the replication of HIV can be enormously enhanced by concurrent endemic infections, and how this not only accelerates the progression of HIV disease, but also facilitates its transmission. The authors show in molecular detail how many viral, bacterial, protozoan and helminthic infections can affect HIV replication.  Included among these are common intestinal worms and water borne bacterial infections, causing severe diarrhea particularly in infants.  The discussion is largely concerned with the possible beneficial effect of drugs that might counteract this enhancement of HIV replication. There is one short sentence on public health interventions that might eliminate this problem altogether. It is of particular interest because of its brevity in a rather long article.   There is also a curious statement that where antiretroviral drugs are unavailable, measures to control endemic infections may be a useful approach.  This comment is reproduced below, and somehow ignores the significance of the implication that control of these endemic infections requires no other justification than as a measure to control AIDS.

    This paper, because of its immunological and molecular detail is not too likely to find its way to an epidemiologist or public health expert,  but for one trained in these technicalities, I would suppose the public health implications would be immediately evident.

    This particular paper also is a great illustration of the compartmentalization of information, and the difficulties of interdisciplinary communication.

    Below is an illustration from the body of the article: there is much more just like this.  A person with no training in molecular biology or virology would not be likely to spend any time with this illustration.

    lawn1

    However if one turned a few pages the following diagram may just be of some interest. But again this is unlikely.

    The part that would be of interest to a public health professional , if noted,  is contained in the large arrow at the bottom right of the illustration.  In this rather complex diagram it would be quite easy for the public health expert to be sufficiently distracted so that the bottom right hand corner would be easily missed.

    lawn21

    There is a long discussion, quite technical in nature, but at least the authors find space for the following brief comment.

    “Prevention and Treatment of Coinfections

    The widespread use of HAART in the treatment of HIV-

    infected persons in westernized countries has resulted in a

    phenomenal decrease in the incidence of opportunistic infec-

    tions and has greatly increased survival. For these individuals,

    the antiretroviral drugs are the major determinant of prognosis

    and the potential cofactor effect of opportunistic infections is

    now a more minor consideration. However, the vast majority

    (>95%) of the world’s HIV-infected people do not currently

    have access to antiretroviral drugs. Most of these people live in

    developing countries, where the quality and access to health

    care is often limited and where there is a high incidence of

    endemic infectious diseases such as malaria, TB, and infections

    by helminths and waterborne pathogens which may adversely

    affect HIV-1 disease progression. Prevention or early treat-

    ment of these diseases may therefore represent an important

    strategy in addressing the HIV-1 epidemic in developing coun-

    tries”. -

    In the above quotation, the authors are overoptimistic in their assertion that the cofactor effect of opportunistic infections is now a more minor consideration in developed countries.  Valacyclovir, a drug that inhibits the replication of  many members of the herpes virus group, but has no direct effect on HIV was reported to reduce HIV viral loads in the absence of antiretroviral therapy. In the developed world, active herpes virus infections are common in the setting of HIV infection, although most will be asymptomatic. For example, Cytomegalovirus, Epstein Barr Virus and Human herpes virus type 6 are not infrequently found to be active in HIV infected individuals. Valacyclovir will have an effect on these viruses, and may well find a place in the treatment of HIV infection in developed countries.  Indeed it may not be uncommon for experienced physicians here (in the US) to prescribe related anti herpes medications to their HIV infected patients. I certainly do.

    There is another aspect, a little more difficult to establish and perhaps altogether conjectural.  This is that we are presented with the question of why we need AIDS to justify interventions that have long been established to themselves improve the health of populations.  These include the provision of sanitation and clean water, the control of malaria and TB, and something as simple as getting rid of worms.  In the public’s assessment of the health needs of developing countries the information that is used is largely to be found in popular media, newspapers, magazines and TV.  Those who report in turn receive information from professional sources, and maybe it is here that the interdisciplinary barriers to communication I have been talking about have their effect. Thus the AIDS epidemic is perceived to be the greatest threat to the future of Africa, even though malaria kills more people, and common endemic infections contribute to an abysmal life expectancy.   (This was written 2-3 years ago and was probably incorrect even at that time;  estimates are that today there are  1.5-2 million deaths from AIDS in Africa, with close to 1 million deaths from malaria.  Malaria though  is responsible for a greater  number of deaths in children under 5 years of age).

    It continues to be remarkable that although evidence has existed for years that many of these infections can interact with HIV infection to increase its infectivity and accelerate disease progression, those who advocate for, and allocate funds to fight HIV/AIDS seem oblivious to the relevance and implications of these interactions.

    This effort of course needs absolutely no justification, but its funding is small compared to the resources that have been made available to combat HIV/AIDS –  but from all that has been described funding for these endemic infections is in fact also funding to fight HIV/AIDS “.

    Those were comments made 2-3 years ago.

    While malaria and tuberculosis are now receiving attention and are included with AIDS in some programs,   many other endemic infections  continue to be neglected.

    Going back much further in time,  interest in the activating effects of associated infections on HIV replication began within the first 10 years of the epidemic.  This started with the demonstration that proinflammatory cytokines, TNF alpha or IL 6, for example could greatly accelerate HIV replication.

    Of course these cytokines appear in the course of many different infections.  When viral load tests became available this effect was well understood by patients and physicians in N America and Europe. It became common wisdom that an HIV infected person who had a febrile illness, or had even received a flu vaccine  should delay viral load testing because the infection or vaccination was frequently associated with temporary rises in HIV viral loads.

    The implications for geographic areas where the infections were far from temporary seemed to escape notice.

    Thus endemic infections in Africa do have everything to do with HIV/AIDS.  There are numerous preventative and therapeutic measures available to control many of these infections,  and some are inexpensive.  Even something as simple as deworming may be useful.  Ascaris lumbricoides, the common intestinal round worm also is associated with immune activation and is easily got rid of.  There is a report that doing this with a drug called albendazole actually raised CD4 counts. (Walson JL et al. Albendazole treatment of HIV-1 and helminth co-infection: a randomized, double-blind, placebo-controlled trial. AIDS 22:1601-1609, 2008).

    The person who has been studying immune activation and the association of parasitic infestations and AIDS for the longest time is  Zvi Bentwich.   I can’t remember when his first  publication on this issue appeared but by the mid 1990s he was publishing on this association in Ethiopian immigrants to Israel.   Zvi Bentwich deserves the greatest credit for his early recognition of the importance of this association, its significance regarding immune activation and for his continuing contributions.   He pointed out the relevance of schistosomiasis to AIDS  (and TB) at least 10 years ago.

    The connection of so many endemic infections with AIDS  in Africa is also a connection of poverty with AIDS.  I saw an absurd and instantly forgettable paper entitled something like “Poverty does not cause AIDS” a few years ago.    Of course poverty is not the direct  cause of ascariasis,  schistosomiasis, tuberculosis, or any number of devastating infections.  Poverty is a very significant factor in  the acquisition of these infections, and as such can certainly be regarded as having a causative role.

    The lives of impoverished populations are ravaged and shortened by these infections. Many of these infections also interact with HIV to compound the devastation they cause.  Poverty, multiple endemic infections and HIV are intimately intertwined and in many instances reciprocally affect each other.  For example the debility associated with schistosomiasis has an impact on an individual’s productivity, with economic consequences not only for the individual but for the larger community.

    Controlling the AIDS epidemic in Africa must also include measures to prevent and treat the multiple endemic infections that affect hundreds of millions of individuals.

    To conclude this post I want to recommend a book published about four years ago by Eileen Stillwaggon, a professor of economics.  It is called “AIDS and the ecology of poverty” and is published by the Oxford University Press.

  • Treatment as Prevention: Protecting individual autonomy. May 2010

    Posted on May 18th, 2009 admin 2 comments

    I’m returning to this topic yet again because the French National Commission on HIV/AIDS has now published a statement on treatment as prevention.

    This document discusses treatment as prevention at the individual and the population level together.

    It  places great importance on individual autonomy, which includes the fundamental right individuals have to make decisions on their own behalf.   I have come to see the issues in a somewhat  different way after reading the French document.

    This document can be seen here:

    http://www.cns.sante.fr/spip.php?article296&lang=en

    It is worth mentioning again that the term “treatment as prevention” can be applied to two different situations.

    At an individual level  it refers to prevention of HIV transmission by sexual contact between two individuals. The Swiss statement concentrated on this aspect.

    The term is also applied at a population level, where the goal of treatment as prevention is  the control of the epidemic, even as suggested by some,  a means to end it.

    The principle underlying the proposals to use treatment as prevention in both of these situations is the same.  It is the reduction in infectivity that results from the effect of antiretroviral therapy.

    Unlike the Swiss recommendations that dealt only with transmission between two individuals, the French statement deals with both aspects.

    Treatment as prevention is not the same when applied to individuals as opposed to populations.  For example, transmission between some individuals may be interrupted by treatment without having an effect on the epidemic.

    To have an impact on the epidemic additional factors that do not apply at an individual level have to be considered.

    For example, the number of infected people who must be treated in relation to the total number of people who are infected must be taken into account, if treatment is to have an effect on the epidemic.

    For treatment as prevention to have a greater effect on the epidemic, a larger proportion of infected people must be treated.

    Canadian studies have suggested that the proportion of infected people who must be treated in order to reduce transmission would need to be increased from 50% to 75%.   Transmission would be slowed but not reversed with treatment rates below 50%.

    Thus the percentage of infected people who are treated is related to the extent of the impact treatment will have on the epidemic.

    At an extreme, if the stated objective is to end the epidemic, as has been proposed by some,  the proportion of infected people who would need to be  treated would be so large that it would have to include those who do not need treatment for their own benefit.

    [ Added October 3, 2010:     It appears that there are experts who believe that everybody who is HIV infected, no matter at what stage of their disease would benefit from treatment.  For them, there would be no ethical problem at al.   These experts believe that treatment benefits every HIV infected individual. But the practice of medicine is not a faith-based enterprise, although I imagine individuals holding this belief  probably pay lip service to evidence-based medicine.  As opposed to a belief that everyone will benefit from treatment there is no evidence of the best quality  that for  people with greater than 350 CD4 lymphocytes, the benefits of antiviral drugs will outweigh their risks.    Hopefully the START trial will provide the evidence needed to help HIV infected individuals and their health care providers make a decision as to when it's best to start treatment, that will be informed with hard evidence rather than belief based interpretations of data.   The San Francisco Department of Public Health now recommends that all HIV infected individuals receive treatment.  so they are able to  avoid having to deal with the ethical problem that arises  in recommending treatment to people not known to derive a net benefit from doing so as they too rely on their belief that all benefit.   For individuals starting treatment at higher CD4 numbers the harms caused  by the drugs may outweigh their benefits.  Such individuals may choose to receive  treatment in order to make them less infectious, but surely respect for their autonomy means that we must provide them with evidence of the best quality so that their choice is informed, and this also means that where the best evidence is not yet available on when it's best to start treatment we must tell them that this is the case.    The concern expressed last May about the threat of coercion may have been justified in the light of the San Francisco Department of Public Health's recommendations.  While it is perfectly legitimate and even expected of them, health care providers make recommendations based on their judgement, which in turn depends on the knowledge and experience they have.  This is why we turn to experts.   But their respect for individual autonomy really requires that where evidence of the best quality does not yet exist to justify their recommendation, and where there is no expert consensus  on the issue, that these facts be told to the individual.  A failure to do so in making the recommendation, can be seen as being coercive.  Consenting to the recommendation will  not be fully  informed, and in this way the individual's autonomy is not respected.]

    I have written about the multitude of problems arising from this situation in previous posts on this topic.  Lurking behind such an extreme proposal is the threat of coercion, and the possibility of an infringement of individual rights. Very disappointingly this aspect has been barely acknowledged in English language discussions of treatment as prevention.

    However if, as I believe,  an additional  goal of treating  infected people is to add a powerful tool to prevent transmission, we are then not stating an objective that would require the participation of individuals who do not themselves need treatment.

    Admittedly, treating only those who need to be treated may not have such a great impact as also treating additional infected people who do not need treatment.  Therefore we must  also intensify and improve  our efforts at targeted prevention education with the promotion of condom use.

    But we will avoid the insuperable problems and threats to personal autonomy associated with  treating individuals who do not need to be treated for their own benefit.

    The goal of treatment as prevention as applied to controlling the epidemic is perhaps better stated in a different way.

    It might be preferable to simply state that the goal is to provide treatment to every individual who needs it.  This goal must therefore be coupled with enhanced efforts to facilitate regular testing.

    If we can achieve this it is likely that not only will the individual benefit, but there will be an impact on the extent of the epidemic.

    There is evidence of a reduction in HIV transmission in areas where antiretroviral treatment has been introduced. .

    When we emphasize that our efforts are to identify infected individuals and make treatment available to all who need it, we eliminate all the problems connected with treating infected individuals who do not need treatment.

    One reason why the French document is so significant is that it stresses the importance of individual autonomy.

    It emphasizes the need to respect individual rights and adds a caution to avoid the temptation to employ  coercive measures in the name of the public good.  Testing is the key to any success of this approach to prevention, but testing must be voluntary and informed. As of course is a decision to receive treatment.

    Here is an excerpt from the French statement that shows the concern for individual autonomy and recognizes that there is a potential threat of the employment of coercive measures.

    ” if screening and massively treating infected persons enables to reduce the epidemic, it could be tempting to consider population compulsory systematic screening and to voice more or less insistent summons for the treatment of persons identified as HIV positive. Should public authorities use all convenient means to implement efficient policies that strengthen screening, they need to be careful not to yield to such fallacious reasoning. The issue of improving screening efficiency surely does not invalidate any of the reasons that have hitherto prevailed for rejecting compulsory screening. Keeping screening hinged on free and informed consent remains a matter of respecting the fundamental right of the person; it is at the same time an obligation even from the public health viewpoint,

    Pursuing a probably completely unworkable attempt to end the epidemic by yearly testing and treating everyone infected as has been suggested by some, is wrong. The problems of feasibility, adherence, resistance, and the threats to individual autonomy cannot be overcome.

    Instead we should:

    Offer treatment to all who need it.

    Facilitate testing, identifying and removing barriers that impede it.

    Intensify and improve our efforts at targeted prevention education.

    Promote condom use and make them available.

    There is a final issue.

    Who needs to be treated?  Certainly everyone with a CD4 count below 200.  Apart from this we do not know, so until we obtain some guidance from prospective randomized studies, it is prudent, in general, to not delay treatment to a CD4 count below 350 as is currently recommended.

  • Herpes Viruses and HIV: Some early History and a Bit about Safe Sex

    Posted on May 17th, 2009 admin 1 comment

    17th May, 2009

    [The relationship between herpes viruses and HIV disease is also discussed in a subsequent post:

    http://aidsperspective.net/blog/?p=520 ]

    The relationship between herpes simplex virus type 2 and HIV is in the news again.   This time the press reports are that while acyclovir failed to suppress transmission of HIV it did cause a 17% reduction in HIV disease progression.

    This reduction in disease progression was assessed by noting differences between the treated and placebo group in the numbers whose CD4 count dropped below 200, and who died.  A reduction in HIV viral load was also observed in those treated with acyclovir.

    The concept on which this study was based is absolutely solid.

    Herpes simplex virus type 2 is the most frequent cause of genital ulcers, and the presence of genital ulcers is associated with enhanced transmission of HIV.

    The failure of acyclovir to suppress HIV transmission is a disappointment, but the study should not be seen as a failure.

    There is no doubt that anti herpes drugs can suppress the recurrent herpes ulceration that some individuals experience. This was observed in the study.

    Herpes viruses – and not just herpes simplex virus,  have an impact on the course of HIV infection.  This study provides yet another demonstration that treating herpes virus infections has a beneficial effect on the course of HIV disease.

    Valtrex, a drug related to acyclovir was reported to reduce HIV viral loads in infected women in 2007.

    “Reduction of HIV-1 RNA Levels with Therapy to Suppress Herpes Simplex Virus” and it appeared in the New England Journal of medicine .

    (NEJM 2007  356:790)

    It is possible that the association of herpetic genital ulcers with HIV transmission is not as direct as generally assumed.  The reasonable suppositions included the possibility that the ulcers provided a portal of entry for HIV in the uninfected partner, that there was an accumulation of CD4 cells in the ulcer that provided a good target for HIV, or even that in the infecting partner HIV was present in greater concentrations in the ulcer.

    These assumptions about the reasons for increased HIV transmission may all be mistaken.

    We do know with some confidence that transmission of HIV is related to viral load in the infecting partner.  It may be that the assumptions outlined above derive from observing an increased frequency and duration of genital ulcers in individuals with higher viral loads who are therefore more infectious not by virtue of the ulcers.

    An individual with higher HIV viral loads  will more easily transmit the infection,  and also experience  more frequent recurrences  herpetic ulcers.  This of course only applies to HIV infected individuals.

    As far as individuals who are not HIV infected are concerned, a direct causative association between herpetic ulcers and HIV infection may also be spurious.

    Herpes simplex infections are ubiquitous but immunological mechanisms generally control the infection so that it remains latent and not manifested.

    Sometimes individuals know what provokes a recurrence.  Recurrences can be associated with febrile illnesses.  It is completely reasonable to suggest that the effects of some  intercurrent  infections may cause  both  herpetic recurrences and increase susceptibility to HIV.

    Whatever infection  causes the fever may also increase susceptibility to HIV, possibly by an association of the  infection with perturbed immunological function.    Transient immunological perturbations  can accompany many viral and tropical infections and so may not only disturb herpes simplex latency but also increase susceptibility to HIV.

    For some reason, interest in the relation of HIV to herpes viruses seems to have been almost completely confined to herpes simplex virus type 2.  At least regarding what is reported to the public.

    However the herpes virus family includes other members which have long been thought by some – including myself, to play an important role in HIV disease.

    Cytomegalovirus  (CMV) and the Epstein Barr virus (EBV) are perhaps the two that are most important.  These viruses are also sensitive to the anti herpes drugs used in these two trials.

    Since infections with CMV and EBV  are so widespread how can effects of acyclovir and Valtrex   on reducing  HIV viral loads be attributed to an effect of these drugs  on herpes simplex type2?

    I cannot recall that these two other members of the herpes virus family – or even a third, HHV6  were even mentioned in the papers demonstrating effects of acyclovir and Valtrex on HIV viral loads.

    It is entirely possible that suppression of  two viruses,  CMV and EBV, contributed, perhaps to the greatest extent,  to the anti HIV effects seen.

    One can only hope that sera from these studies were frozen and stored.  Such samples could provide information on an effect of these drugs t on EBV reactivation and on active CMV infections.

    As an historical comment, acyclovir was tried as a treatment for AIDS in 1987  around the time AZT was introduced.

    There were several studies of differing design over for some years from about 1987, some based on the hypothesis that CMV contributed to disease progression.

    AZT was tried with or without acyclovir, but the results were contradictory. Interestingly AZT also inhibits EBV replication.

    One study, ACTG 204, which compared two doses of acyclovir with Valtrex was stopped because 25% of those taking Valtrex died compared to 20% taking acyclovir.

    Some observational studies (including the MACS study) found that there was some survival benefit among those taking acyclovir.  Another retrospective observational study found no benefit.

    Nothing much can be made of these contradictory early results.

    But now, with newer techniques for measuring HIV activity by viral load assays, we   have very clear evidence that treating herpes virus infections has a beneficial effect on HIV infection.

    With the advent of the newer potent antiviral drugs, interest in anti- herpes drugs did wane, until there was a renewed interest in the past few years in connection with herpes simplex virus 2 and genital ulcer disease,  Unfortunately most of the  emphasis is on herpes simplex virus, when suppression of CMV and EBV may be as – or I believe,  of even greater importance.

    Actually there had been  interest in CMV and EBV in relation to AIDS from the time the disease was first reported in 1981.

    I have been involved in AIDS research and  treating patients with this disease from the time it started and so can  provide some historical perspective on the interest in herpes viruses,  that dates to the late 1970s, even before AIDS was described and long before HIV was discovered.   At this early time epidemiological studies on the prevalence of infection by CMV among sexually active gay men were undertaken in the US.

    As another historical interlude,  interest in herpes viruses also provided the basis for safer sex, as it is understood today.  As remarkable as this may seem, the first published and disseminated proposal to use condoms to prevent the transmission of AIDS had nothing to with HIV.   Condom use was proposed a few years before this virus was discovered, and had everything to do with herpes viruses, specifically CMV.

    From about 1978 I had the opportunity to observe and treat a very large number of men who were to be the first to succumb to this new disease.

    I knew that over 90 % of gay men attending a clinic for sexually transmitted diseases around that time had antibodies to CMV compared to 54% of heterosexual men.   By 1983  over 40% of a cohort of gay men in New York City carried CMV in their semen.   Amongst my patients, studies on EBV carried out by David Purtilo at the University of Nebraska showed an extraordinary high prevalence of reactivated EBV infections.  (Epstein Barr Virus and chronic lymphadenopathy in make homosexuals with Acquired Immunodeficiency Syndrome. H Lipscomb et al.  AIDS Research 1983 1: 59)

    At that time – 1981-1982, many of the patients I was taking care of experienced reactivated EBV infections as determined by serological methods,  and were excreting CMV in semen. Of course they were also infected with HIV , but this could not be known at that time.

    But from what was known about CMV and EBV it was reasonable to postulate that these viruses were somehow implicated in the disease.  It was thus possible to propose a way to at least prevent the sexual transmission of CMV.

    This formed the basis for the first published recommendations for condom use.

    With two of my patients, Michael Callen and Richard Berkowitz a booklet was written called “How to have sex in an epidemic: One approach”.

    The appropriate  title  was  coined by Richard.

    The twenty fifth anniversary of the publication of this booklet, that was essentially produced and widely distributed by four individuals, and funded by a single person, went almost completely unnoticed in 2007.    Although it is  in fact a landmark event in the history of the epidemic.

    Richard is only now receiving some acknowledgement for this life saving proposal  because a documentary film called Sex Positive has brought attention to  his achievement.

    An account of our collaboration in producing the safer sex guidelines can be seen by following this link.

    Safer sex recommendations.

    Michael Callen is remembered by many for his activism.   There is even a clinic in New York City named for him and Audre Lorde .

    I actually worked there as a physician for a short period, and with very few exceptions, the health care providers and others working there had no idea of who he was, let alone his contribution to safer sex.

    I just visited the Callen Lorde website, and indeed there is a photograph of Michael and of Audre Lorde with a few words about each, but no mention of Michaels contribution to safer sex.

    Thus herpes viruses, at least CMV had a role in the development of safer sex recommendations.

    As it turns out herpes viruses – CMV and EBV included, have a great deal to do with AIDS.    This is quite apart from their multiple clinical manifestations as opportunistic pathogens.  Both of these viruses almost definitely contribute to pathogenesis.

    Evidence that some herpes viruses can play a critical role in HIV disease progression has accumulated  for many years.

    In fact some evidence for this  was already apparent when AIDS was first described.

    This considerable body of evidence did not disappear with the discovery of HIV, but was relatively neglected.

    As work on HIV proceeded we gained some understanding of the ways in which herpes viruses can interact with HIV to accelerate disease progression, increase HIV infectivity and thus enhance its transmission.

    I should now describe some of the interactions that exist between herpes viruses, particularly CMV and EBV, and HIV.

    Many, perhaps most of these interactions also involve herpes simplex viruses types 1 and 2.

    The role of CMV in immune system activation, a major force in driving HIV infection.

    The systemic effects of CMV and EBV infections are most probably of great importance in this respect.

    Systemic effects resulting in immune system activation and activation of HIV replication may also  accompany reactivated herpes simplex virus infecteions.

    Among the systemic effects of active herpes virus infections are the secretion of pro inflammatory cytokines.  These circulate and attach to specific receptors on the cell surface. A consequence of this is that certain sequences on DNA will be activated resulting in the transcription of HIV DNA and ultimately the production of new HIV particles.  So, this is but one way in which an active herpes virus infections can promote the replication of HIV.  The general mechanisms are described in a previous post..

    An important and interesting  paper that also deals with   EBV and CMV in relation to HIV replication was published by V Appay and colleagues.  It can be seen  by clicking the following link.

    HIV ACTIVATION

    I am  reproducing some excerpts from Dr Appay’s paper here as the descriptions are very clear and there are references.  The references can be seen in the complete text seen by following the above link.

    “HIV-1 also causes immune activation and inflammation through indirect means. Antigenic stimulation during HIV-1 infection may be induced by other viruses, such as CMV and EBV”

    “In addition, inflammatory conditions occurring during HIV infection (eg release of proinflammatory cytokines) may also participate in

    the reactivation of latent forms of CMV and EBV. Recent studies have shown significant activation of EBV- and CMV-specific CD8+ T cells during HIV-1 acute infection [40,41] . Hence, sustained

    antigen mediated immune activation occurs in HIV-1-infected

    patients, which is due to HIV-1, but also to other viruses (and may be restricted to CMV and EBV)”.

    “CMV has been associated with strong and persistent expansions of T cell subsets that show characteristics of late differentiation and replicative exhaustion [94-96]. The anti-CMV response appears

    to monopolize a significant fraction of the whole T cell repertoire [97], so that it might compromise the response to other antigens by shrinking the remaining T cell repertoire and reducing T cell diversity. CMV infection is actually extremely common in HIV-1- infected individuals and its recurrent reactivation may put further stress on their immune resources. Interestingly, CMV-seropositive subjects generally experience more rapid HIV disease progression than CMV seronegative subjects [98]“.

    Herpes virus (including herpes simplex) infected cells express Fc receptors on their surface.  These receptors can bind certain sequences on antibody molecules. If these antibodies are attached to HIV, a portal for entry of HIV is provided on herpes infected cells that do not possess CD4 molecules on their surface. This process has in fact been demonstrated.

    Transactivation  of HIV by herpes viruses.

    In cells infected with both viruses herpes virus gene products can activate HIV and promote its replication. The transactivation is reciprocal as HIV can promote herpes virus replication.

    Acyclovir and Valtrex have no direct effect on HIV except under one unusual circumstance,  yet both have been demonstrated to reduce HIV viral loads.

    In the early 1980s when we had no effective measures against  this disease I treated my patients with high dose acyclovir.

    There then  was evidence, albeit theoretical and indirect for a role for these viruses in this new disease.

    In the absence of clear evidence from clinical studies, and given the gravity of the disease, it seemed completely appropriate to be guided by these theoretical considerations, particularly involving a drug that is so free of toxicity.

    But interestingly,  at that time,  none of these theoretical considerations placed much importance on HSV 2.

    The practice of medicine in those years, dealing with such a mysterious and deadly disorder of unknown causation , demanded responses that could only be based on one’s best judgment.

    Fortunately I also had had some experience in the transplant field and was also able to provide bactrim to my patients years before recommendations for its use were issued.

    But it was not until potent antiviral drugs became available that we were able to make significant and life saving, rather than life extending  interventions.

    What I have written of this experience with bactrim in the early years can be seen by following this LINK

    In the light of later evidence, I believe it is possible I was able to provide some small benefit in prescribing high dose acyclovir in those very early years.


    [i]   Acyclovir, when phosphate is added to it, acts like the nucleoside analogues active against HIV, drugs like AZT, D4T, 3TC etc.   But this drug has a truly remarkable quality.  The cellular enzyme that  adds phosphate to make drugs of this type active,  does not work on acyclovir as it does on AZT, 3TC and other anti HIV nucleoside analogues.   But an enzyme, thymidine kinase that is encoded by herpes viruses, and therefore only appears  in herpes virus infected cells  has the ability to add the phosphate group and turn acyclovir into an active drug.  This is the reason why acyclovir is such a safe drug.  It only disrupts DNA synthesis in herpes virus infected cells, where of course this effect is desirable; it has no effect on uninfected cells.

    However, if  the same  cell happens to be infected with HIV and a herpes virus, the herpes thymidine kinase will phosphorylate acyclovir, which now can work to  terminate  HIV DNA synthesis just as 3TC , AZT and similar drugs do when phosphorylated by the cellular enzyme.

    This effect , only observed in doubly infected cells in the laboratory is unlikely to be of much significance in the body.

  • Early concerns about confidentiality in AIDS, and what Jim Monroe had to do with this.

    Posted on April 23rd, 2009 admin No comments

    From time to time I will write about some extraordinary people I have worked with. The first of these is Jim Monroe.

    Jim worked for the Centers for Disease Control (CDC).  He worked to improve the health of all, but it is people with AIDS who probably derived the greatest benefit from his efforts.

    Those who do the most to help others often remain completely unnoticed. Maybe their commitment leaves no room for seeking personal attention; maybe they don’t care about recognition, or actively shun it.

    Jim Monroe personally helped many individuals who were in great need.  He was also the person who was probably responsible for first bringing attention to the issue of confidentiality in AIDS in the earliest years of the epidemic.

    He most certainly did not care about personal recognition.  Apart from a few friends and colleagues and those who directly benefited from his efforts, he remains largely unknown.

    I first met Jim in the late 1970s. I was at that time working for the New York City Health Department, concerned with sexually transmitted infections.  Jim worked in the same field, but for the CDC.  He was based in New York City.  Our places of work were in close proximity and we met through our common interest in the control of sexually transmitted infections.

    Jim is probably the person who was responsible for the early attention given to confidentiality in connection with AIDS

    Confidentiality in matters of health is of the greatest importance; it is also complex, with some special concerns in connection with sexually transmitted infections.

    We have an obvious obligation to respect the trust placed in us by those who seek our care. But there are different and strongly held views on the tensions that can exist between individual rights to privacy and the protection of sexual partners, as well as society at large.

    But the context in which Jim brought attention to confidentiality was the concern to protect individuals suffering from this new, untreatable, and as yet unnamed disease.   From the very start, affected individuals frequently had to contend not only with this frightening illness but with irrational and cruel discriminatory acts against them.

    Not only was the disease itself associated with stigmatization, particularly in the early years, there was yet another issue requiring attention to confidentiality.  Sexual orientation was revealed with a diagnosis when the disease was thought to be confined to gay men. As other groups of individuals were identified, perhaps only those who acquired the disease from blood products were relatively free from the threat of discriminatory practices that were all too frequently directed against gay men and IV drug users.

    Those were the days when HIV infected people in hospitals had to retrieve their meals which had been left outside their doors;  when medical personnel would refuse to care for infected people; when some children were not allowed to be in contact with those known to be infected, and infected children sometimes not allowed to attend school.  Thankfully in the US today children are protected.

    http://www.ed.gov/about/offices/list/ocr/docs/hq53e9.html

    But despite advances, AIDS is still a disease associated with stigmatization, not only in developing countries but also in the US and other developed nations.

    I will describe how Jim started a response intended to assure that those affected by this new disease would be protected by measures to maintain their confidentiality.

    A few introductory words are needed.

    I started my own research into this new disease in 1981, and received tremendous support from an old colleague in the interferon field, Dr Mathilde Krim.

    In 1983, my lawyer, Frank Hoffey with Graham Berry prepared the papers and incorporated the AIDS Medical Foundation (AMF), initially to raise funds to support my research.  Apart from Mathilde’s personal support our work was not funded.  AMF soon broadened its mission to support the work of others as well.

    Fundraising during the first year was very difficult and the foundation really owes its survival to the efforts of Dr Krim, who was the chairman of the board.

    Concern with confidentiality started with an anxious call from Jim in 1982.  The reason for his extreme agitation was that he knew that a study was to be undertaken on this new disease in the Health Department clinics for sexually transmitted infections. In particular, the clinic on 28th street was known to be the site where large numbers gay men were treated for sexually transmitted infections.   The study would be concerned with people who had “reversed T cell subset ratios”.  A reversal of the normal CD4: CD8 ratio was how we recognized AIDS before the name was coined.

    What concerned Jim was that no provision had been made to protect the confidentiality of the study participants. Their names were to be recorded.  I cannot recall if the proposed study was a CDC study or one originating with the Health Department.

    Jim told me that the study was to be submitted for review by New York  City’s Institutional Review Board (IRB) although it was not called an IRB.  I suppose he must have had little confidence that the IRB, which is a body regulated by the FDA and intended to protect human research subjects, would address the confidentiality issue. In view of what transpired he was probably correct.

    I also don’t know what he expected I could do. Maybe he just wanted to share his frustration with a person who shared his concerns.

    In the event, this call was to actually result in something that would have lasting effects.   I spoke about this to Mathilde, who I knew also shared these concerns about protecting confidentiality.

    She immediately said that she knew who could effectively deal with this problem.  Mathilde was associated with and had provided support to the Hastings Center, which was concerned with bioethics, and introduced me to Carol Levine and Ron Bayer.  I conveyed Jim’s concern about the proposed study  and the result was that I attended a meeting at the Health Department with Carol or Ron, or maybe both were there, as well as a lawyer from Lambda Legal Defense Fund, whose name I think was Chris Collins.

    As a consequence, because of a lack of provision for confidentiality protection, the study was tabled.

    Jim Monroe’s concern to protect individuals with AIDS started this train of events.

    It is hardly surprising that not much attention had been given to the issue of confidentiality in 1982. The disease was after all new, and we were just learning of the extremely hostile and irrational responses directed at those who were affected.

    Carol and Ron’s interest did not stop.  I think it was Ron Bayer who proposed that a meeting be held on the issue of confidentiality.  This meeting in fact did occur and resulted in the publication of guidelines for confidentiality in research on AIDS.

    Lloyd Schloen had worked at Memorial Sloan Kettering Cancer Center as a fund raiser.  Mathilde had introduced us and we had become friends.

    Lloyd then became an official at the Charles A. Dana Foundation, and we talked about confidentiality protection.  It is through his efforts that the meeting on confidentiality was funded.

    The meeting proceedings were published in the Hastings Center’s own publication, IRB.

    http://www.jstor.org/pss/3564421

    I believe my memory is correct in recalling that an established medical journal declined to publish the guidelines.

    I was editor of a journal devoted to AIDS called AIDS Research and had absolutely no hesitation in publishing the guidelines myself. Some pages are reproduced here.

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    Later, the CDC was to publish its own set of guidelines.

    The Hastings Center guidelines were not the only publication on confidentiality that preceded the CDC’s recommendations.

    As part of my research effort I had become associated with David Purtilo, Chairman of the Pathology and Microbiology Departments at the University of Nebraska’s medical school in Omaha. The reason for this was that David was an expert on the Epstein Barr virus, and I believed that this common herpes virus can play a significant role in the pathogenesis of HIV disease[i].

    David’s wife, Ruth Purtilo is a bioethicist. She clearly saw how important confidentiality protection was in research on AIDS. She obtained the perspective of Michael Callen, a patient of mine who was HIV infected. Together we wrote a paper on this issue in 1983.

    Confidentiality, informed consent and untoward social consequences in research on a new killer disease (AIDS).

    Clinical research, {Clin-Res}, Oct 1983, vol. 31, no. 4, p. 464-72, ISSN: 0009-9279.

    Purtilo-R, Sonnabend-J, Purtilo-D-T.[ii]

    Unfortunate developments today have made the need for respecting confidentiality as important as was the case when the epidemic began.  Differently worded legislation now exists where criminal law is applied to people who transmit HIV to others, or even who expose others to the risk of transmission. There is absolutely no evidence that such criminalization prevents the spread of this disease.  The following link will provide useful sources of information.

    http://data.unaids.org/pub/BaseDocument/2008/20080731_jc1513_policy_criminalization_en.pdf

    These laws only increase stigmatization.  The introduction of such legislation in many countries is an important additional reason why concerns about confidentiality protection remain vitally important.

    Jim Monroe returned to work at the CDC in Atlanta.  Although he was assigned to work in another field, his interest in AIDS remained. He was the kindest of individuals, personally helping people with AIDS, as well as others in difficulty.

    The very last project on which we worked was cut short by his death.

    Even then, in the late 1990s, the problem of when it is best to start antiviral therapy was of concern – indeed it had been of concern ever since the introduction of AZT.  We then believed – as many still do today, that the question is most reliably approached by a randomized prospective study.  Most certainly not by the opinions and recommendations of experts, not all of whom could properly be considered qualified to hold that rank.

    We thought that those entities that pay for the drugs might be the appropriate sponsors of prospective clinical trials.  They have a clear interest in knowing if it is beneficial or not to start treatment early rather than to defer it, or whether it makes no difference.

    It is in their interests; if early treatment provides no benefit – (at least one large retrospective study suggests that there is no benefit to starting treatment above a CD4 count of 400) then paying for an early start to treatment would be pointless. On the other hand if early treatment produced some benefit then the cost would certainly be justified.

    Among the entities covering the cost of drugs are government agencies such as Medicare and the VA.   The VA has a history of undertaking studies.  There are also the private insurance companies.

    Jim together with a Public health expert at Emory University was attempting to present a proposal to the medical directors of private insurance companies. We had the support of an eminent statistician who had also been involved with me on an earlier unsuccessful attempt to set up a study to compare early and deferred treatment with AZT.

    This attempt was brought to an end by Jim’s sudden death, as well as by the illness of another one of us working on the proposal.

    One Friday afternoon while seeing patients in a clinic in New York City,  I received a call from a friend of Jim’s in Atlanta. She told me that Jim was severely ill in Chicago. He had collapsed a few days earlier.  On Saturday I travelled to Chicago and found Jim unconscious in a hospital. He was not to recover.

    None of us knew that Jim had been ill. He kept this a secret while continuing to work  to improve the health of all people, both in his assigned work but also through his initiatives on behalf of people with AIDS.

    Jim’s final project, cut short by his death, is still absolutely relevant.

    Some recent suggestions, based on the flimsiest of evidence propose that treatment with antivirals should be started even earlier than the current recommendations.  There are well meaning physicians today who already buy into this nonsense, who state that they would treat all infected people, irrespective of CD4 count. Or they would raise the CD4 threshold above 350, which is the currently recommended level at which to initiate treatment, even in the absence of reliable evidence that their patients will benefit.

    It cannot be reliably known from any evidence we  have at present whether such prolonged exposure to  antiviral drugs will increase or decrease survival or be without effect in this respect – of course except for cost.

    We do need to really know when it is best to start treatment.  Prospective randomized studies can provide an answer to the question if, on average it is better to start treatment early or to defer it.

    Hopefully others will take on Jim’s last project and write a proposal to some of the entities who pay for the drugs, to sponsor  prospective studies,  the only reliable way to answer this question.

    Are they wasting money? Are they getting their money’s worth?

    Surely the payors, will want to know.


    [i] I still believe this to be true,  as further evidence continues to support this idea.  Our work on EBV and HIV was quite productive and will be the topic of another post.

    [ii] We were awarded a prize for this article: The Nellie Westerman  Prize for Research in Ethics awarded by the America Federation For Clinical Research.