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  • 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

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

    Posted on May 19th, 2010 admin No comments


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

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

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

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

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

    —————————————————————————————

    John Falkenberg  New York, NY

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

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

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

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

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

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

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

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

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

    Posted on May 19th, 2010 admin No comments


    The revised USPHS guidelines for the treatment of HIV/AIDS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

  • HIV TREATMENT AS PREVENTION

    Posted on March 27th, 2009 admin 2 comments

    The proposal that testing and treating everyone who is HIV infected would end the epidemic is back in the news.

    It is not a new idea. It has been discussed at HIV/AIDS conferences. At the beginning of the year an exercise in mathematical modelling was presented in the Lancet providing some support for this notion of universal testing and treatment. Now some experts in molecular biology and virology have added their personal opinions in favour of this approach; I notice that at least on one web site addressed to HIV and Hepatitis virus infected individuals, the views of these pioneer researchers are reported with, as seems to be usual, no analysis or criticism. http://www.hivandhepatitis.com/recent/2009/032409_a.html

    It begins to look almost like an advertising campaign, with the touch of a skilled publicist; an idea is gradually brought to public attention, it is widely endorsed and the hope is that public support will ensure that funders and politicians will move the project forwards.

    The merits of the proposal, and the way it is being promoted are two different issues.

    Regarding the proposal, in principle it is certainly a worthwhile idea that deserves consideration.
    But there are several problems, not mentioned in public reports of this proposal, and barely dealt with in the professional literature, which may constitute insuperable barriers to its implementation.

    Leaving aside for the moment the question of whether such a project is even feasible, perhaps the most important problem is that infected people who do not need treatment will be asked to receive it to achieve a social benefit.

    This proposal then involves the general concept of a public health intervention on individuals who will not themselves derive any benefit from the intervention, but will only be exposed to its risks.

    We have thankfully not yet reached the point where enforced testing and treatment can be seriously proposed. (We may be getting close in the removal of written informed consent for HIV testing).

    Certainly the spectre of mandatory testing and treatment is lurking behind this proposal to test and treated everyone infected. This would do wonders for drug and testing equipment sales.

    So we would have the situation where some individuals will voluntarily take treatments that despite what we may be told can most certainly not be regarded as absolutely free of possible adverse effects, Many infected people will of course benefit from this. Others however will agree to take risks, with no benefit to themselves but for the benefit of others. Quite apart from many other issues, we can only ask these individuals to participate in the project if there is an overwhelming chance of success. At the moment we do not have this assurance.

    It is not a digression to compare this situation with that in which an individual is asked to join a clinical trial and who may be randomly assigned to receive a new treatment of as yet only conjectural benefit. We are absolutely obliged to ensure that the trial design is such that reliable information will be obtained from the study.

    Since the testing and treatment of all infected individuals to end the epidemic can in no way be regarded as an undertaking with an assured successful outcome, it really is a trial, based on an hypothesis somewhat supported perhaps by mathematical modelling. As such it will require written informed consent from the participants.

    I wonder what such a consent form would look like. It is possible, actually likely, that a consent form outlining possible risks and benefits would dissuade many from participating.
    The disincentive would be felt by those infected individuals who do not themselves require antiretroviral treatment.

    This inconvenient obstacle can be easily eliminated.

    All that is needed is for treatment guidelines to include a recommendation that antiviral treatment should be offered to all infected individuals, even those with greater than 500CD4 lymphocytes. A precedent has now been set where treatment recommendations can be made on the flimsiest of evidence. The inappropriate use of retrospective observations to justify an earlier start to antiretroviral treatment is a good example.

    So all one needs to do is to move the goal posts a little further and declare that antiretroviral treatments should be given to all HIV infected individuals, irrespective of CD4 count. There should be no difficulty in selecting retrospective observations that will support this recommendation. In the field of HIV/AIDS you can probably find retrospective data to fit whatever idea you are interested in promoting.

    There is another tool available to promote the contention that every HIV infected individual, irrespective of CD4 count will benefit from antiviral therapy. This useful tool is called “expert opinion”. (Actually, people billed as “experts” have already expressed this opinion).

    The problem with this is: what does it take to be regarded as an expert?

    We may well be in an era where we have “experts” for hire.

    Defining what was meant by “expert” was once much easier. Years of experience and significant contributions to the field might have been required attributes. But no longer.

    Experts can seemingly be created overnight, at least by commercial entities interested in marketing a product. Their credentials are easily supplied. These instant experts will give talks at conferences, they will appear on educational programs, and even put their names to ghost written articles.

    [http://healthcare-economist.com/2008/05/03/ghostwriting-by-pharmaceutical-companies/

    Revealed: how drug firms ‘hoodwink’ medical journals Pharmaceutical giants hire ghostwriters to produce articles – then put doctors’ names on them.
    http://www.guardian.co.uk/society/2003/dec/07/health.businessofresearch
    ]

    As for the practice of ghost writing , there is a great deal of evidence for this, a little shown above. I’m ashamed to admit that I once (only once many years ago) allowed an employee of a drug company to write an article which carried my name. But I had done the work without their support, and in my defense, I checked every word, changing some, – an experience the writer was evidently not used to. This was my first (and only) personal encounter with this practice

    I will hazard a prediction; before the year is out we will have arrived at the point that experts will state that every HIV infected person benefits from treatment, irrespective of CD4 count. If required we will see retrospective observational studies which show that in people who started treatment above a CD4 count of 500, mortality from all causes was reduced as compared to those starting below 500 CD4 cells. It should be just as easy to find retrospective data that shows that starting treatment immediately on diagnosis confers a benefit not seen when treatment is delayed to CD4 count of 350.

    Of course these expert views will be very widely disseminated in press reports and on numerous web sites – some will even provide the opportunity for doctors to earn CME credit. In this way conjectures are transformed into established facts.

    I don’t know how we might obtain real evidence that testing and treating all infected people is not only feasible, but would achieve its goals. The two are related.

    For example, how does one ensure that all people are tested? Or that they will agree to be treated? Or that they will adhere to their treatments?
    As imperfect as this is maybe one approach is to test these issues in a limited setting where mobility in and out of the selected areas can be controlled for.

    This could more usefully be a trial where two different strategies were compared – the present practice of starting treatment at 350 CD4 cells, and treating everyone infected, while promoting HIV tests in both groups. Despite complications introduced by the movement of people, we might get an idea if this is a feasible and effective approach.

    Sadly those bodies that instruct physicians on how to treat HIV infected people, and who tell HIV infected people what is best for them, seem to be averse to calling for prospective studies, designed to shed some light on what may in fact be best for infected people. Those who manufacture the treatments appear to prefer trials that are designed to provide them with the answer most congenial to them. Here is an account of the practice of designing trials to provide the answer most desired.
    [http://www.washingtonpost.com/wp-dyn/content/article/2008/07/14/AR2008071402145.html]

    They can also rummage in retrospective data collections selecting observations best suited to the outcome they have already decided on. Of course there is always an expert to be created to promote this outcome.

    When the mathematical modeling referred to above supporting the idea of a “test and treat everyone infected” approach appeared, I wrote a reply to the Lancet which published the article. Not my letter, which was politely rejected.
    I am adding a slightly edited copy of that letter here.

    A recent Lancet article suggests that we could end the HIV epidemic by testing and treating all who are infected, irrespective of whether or not the individual would benefit from such treatment (R. Granich et al. 2009 Lancet 373:48).

    This represents an intervention on individuals, primarily for a public health benefit. At the present time, ethical considerations make this proposal a completely indefensible approach.
    The available drugs are far from benign; for a particular individual, their use is desirable and justified when their benefits clearly outweigh their risks. Treating individuals to achieve a population benefit requires a similar risk benefit assessment. F M Hodges and colleagues have addressed this issue. (EM Hodges, JS Svoboda, RS van Howe
    Prophylactic interventions in children: balancing human rights with public health. J Med Ethics 2002; 28: 10-26)

    To protect individual liberties they propose six conditions that should be met before for such interventions are taken. All of these are reasonable. I quote a passage from their article that outlines them.

    “PROPHYLACTIC INTERVENTIONS FOR PUBLIC HEALTH BENEFIT”
    Prophylactic medical interventions are frequently performed on healthy individuals who have given informed consent. …..
    The most common example arises when the patient is at significant risk of contracting a life- and public health-threatening illness for which the proposed prophylaxis is a proven preventive. In order to safeguard individual liberties, the situations in which such procedures may be undertaken for public health benefit must meet the following requirements:
    1. The danger to public health must be substantial.
    2. The condition must have serious consequences if transmitted.
    3. The effectiveness of the intervention in safeguarding the majority of the public against the particular malady must be well established.
    4. The intervention must be the most appropriate, least invasive, and most conservative means of achieving the desired public health objective.
    5. The individual must be provided with appreciable benefit not dependent on speculation about hypothetical future behaviours of the patient.
    6. The burden to the individual’s human rights and health must be balanced against and found to be substantially outweighed by the benefit to society in helping prevent a highly contagious disease or other potentially calamitous condition from affecting the public health”.
    Clearly the proposal to treat all infected people will include some in whom the fifth consideration will not be met, but the concerns are covered in the sixth one. But here the benefit to society must be assured, or more practically, be considered to be highly probable, with credible evidence produced to support the contention (as stated in the third consideration).

    While the first two criteria are very clearly met, the present proposal to treat all who test positive fails utterly on the third point. It is far from well established that antiviral treatment of all who are infected will protect the “majority of individuals” in diverse settings. Among problems acknowledged by the authors are those related to toxicity, adherence and the development of resistance to the antiviral drugs. To this must be added the possible negative effects on behaviour deriving from a perception of being non infectious. The fourth condition is also not met. We cannot state that we have exhausted the utility of prevention education and promotion of condom use.

    Let alone the questionable wisdom of mounting an extensive and expensive public health intervention that is based only on mathematical modeling, we are very far from possessing information that would supply the slightest confidence that such a measure would effectively meet its objective.
    Regarding adherence, the optimism presented by the authors based on studies in Malawi is hardly justified. Adherence by individuals who may be ill, and certainly know they are receiving medications for their own benefit tells us nothing about adherence by people who feel healthy and know they are not taking the medications to benefit themselves.

    The general relationship between viral load and infectivity is well established. The success of the proposed strategy according to the model presented depends on achieving a significant reduction in viral load from the pre-treatment value. The solid evidence of the potent ability of antiviral drugs to very substantially reduce viral loads in a sustained fashion derives predominantly from observations in settings where untreated endemic or concurrent infections are uncommon. The ability to achieve a sustained significant drop in viral load may be more difficult where there is a high prevalence of untreated endemic or associated infections. This is the case in parts of Sub Saharan Africa. Many of these infections are able to activate and enhance HIV replication, through the action of pro inflammatory cytokines. Should these infections be associated with genital ulceration there are additional uncertainties.
    HIV disease is characterized by an enormous variability in the rates of disease progression. There is no such thing as a standard course of disease progression that is one of the assumptions used in the modeling. We know very little about the distribution of different rates of disease progression among infected individuals, or about the influence on this of associated untreated infections.
    Risking individual harm for a public benefit is a slippery slope. Will we see a proposal to administer (with consent, of course) antiretroviral medication to the whole sexually active population, HIV infected or not?

    AIDS is a preventable disease. We have far from exhausted less conjectural, as well as less speculative approaches to its prevention.

    Addendum
    Apart from this proposed strategy to treat all infected people, there definitely are situations where treatment as prevention is absolutely appropriate and desirable. One is post exposure prophylaxis (PEP), where individuals who have been exposed to HIV attempt to prevent infection by rapidly taking antiretroviral drugs – that is within 72 hours of exposure. This applies to both occupational and sexual exposure. Regarding sexual exposure – where feasible, which is certainly the case in N America Europe and in many other regions, a 3 day supply of drugs should be available 24 hours of the day, given the limited time frame for action. Measures to immediately start PEP immediately should of course be available where occupational exposure is a risk. Emergency departments should be equipped and ready to start the protocols for PEP. People at risk should even be encouraged to keep a 3 day supply of drugs at home to cover times when medical care is not available – at night or weekends. .Very importantly people at risk must be informed of the availability of PEP.

    The second is pre exposure prophylaxis. This is taking antiretroviral drugs on specific occasions when there might be a risk of exposure. This absolutely cannot replace the use of condoms, but some individuals may wish to take an additional even if unproven preventative measure. This really is a matter for individual choice. Our obligation is to make it very clear that this is not a substitute for condoms.