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

    Posted on April 12th, 2012 admin No comments

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

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

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

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

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

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

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

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

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

    Take a look at them.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    This doctor is also reported to have said:

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

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

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

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

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

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

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

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

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

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

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

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

    .

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

    Posted on August 5th, 2011 admin No comments

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

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

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

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

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

    How has this been possible?

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

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

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

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

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

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

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

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

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

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

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

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

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

    Relative risk reduction is calculated as follows:

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

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

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

    That number is 2.8%.

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

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

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

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

  • 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.

  • 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.

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    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

  • When is it best to start antiretroviral treatment. February, 2009

    Posted on February 26th, 2009 admin 1 comment

    When is it best to start antiretroviral treatment?

    The issue of when it is best for asymptomatic HIV infected people with more than 350 CD4 cells to start treatment with antiretroviral drugs has received renewed attention lately. Reports at recent conferences and discussions of these reports on several websites all seem to favour an earlier start than at a CD4 count of 350. There is absolutely no reliable evidence to support this recommendation. The evidence that is presented derives mostly from retrospective observations. Such retrospective studies cannot provide reliable evidence that improved clinical outcomes in those starting treatment earlier are actually caused by the antiretroviral drugs. That this is so can only be an hypothesis, a theory to be tested by prospective studies. Such a prospective study would essentially follow people who are randomly assigned to start treatment immediately or to defer it.

    Some of the problems associated with interpreting retrospective observations are outlined at the end of this post1.

    The “when to start” issue of course only applies to infected persons who are not symptomatic and have a CD4 count above 200. For those with fewer CD4 cells there is no doubt at all that such individuals should be on therapy.

    If the antiviral drugs were completely harmless, with no toxicity, we would have no problem at all, apart, of course from the financial toxicity. However the drugs are not without problems, particularly if we are dealing with taking the medicines for a life time. The newer drugs are touted as being less toxic. However it takes years for some toxicities to become manifest. How many years were people taking Zerit, (D4T,stavudine) before we knew about its effects on fat distribution? Another example of toxic effects only becoming apparent after years of use is thinning of bones caused by some antiviral drugs.

    When potent antiretroviral agents were introduced in the 1990s their impact on reducing mortality was unequivocally demonstrated in persons with more advanced disease. This immediately left us with a question regarding the effect of starting these drugs in individuals with less advanced disease.

    Rather than admitting that the answer to this question was unknown, and required to be studied in a prospective fashion, the Department of Health and Human Services issued a set of guidelines. It is understandable that issuing guidelines, in the face of uncertainty is reasonable, but they must be regarded as interim, pending the outcome of studies.

    In 1997 I wrote a letter in response to the publication of these guidelines; it was received by the Guidelines Committee, but I was sent absolutely no response. The letter can be seen here: http://aidsperspective.net/articles/guidelines1.pdf

    Despite attempts to rely on retrospective observations to resolve clinical uncertainty, – such as uncertainty about when to start antiviral treatment, prospective randomized trials remain the best way to achieve this. They minimize bias, and thus misinterpretation, and are therefore the most reliable way to resolve uncertainty. There is no getting over this. Such trials may be expensive, and last a long time, but in the end, probably more time and money is lost by repeating inconclusive and conflicting retrospective studies.

    As always, you can’t beat the truth. Regarding the “when to start” question, the truth was and still is that the answer to the question is unknown. Again, if the drugs were harmless there would be no problem. But it is quite possible that a person starting treatment at say 700 CD4 cells, even 500 CD4 cells, who may be a slow progressor may well have his or her life shortened by long exposure to the medications.

    If, for whatever reason one presumes to favour a particular answer one can always select snippets of data to support one’s bias. Many would like to believe that it is better to start early. I have even read on one web site, that a New York physician stated that he would start any infected person on treatment no matter what the CD4 count was. I suppose this physician, and those who share this view are happy to practice with only their unsupported beliefs as a guide. This is as reliable as using a crystal ball and sick people deserve more from their health care advisers. In this respect the writers reporting such nonsense generally make no comment on the danger of views based only on belief, thereby adding credibility to these statements of faith. The practice of medicine is not a faith based activity.

    The scientists who attach unwarranted importance to retrospective studies are also doing a disservice to clinical research. Some at the recent CROI meeting did admit that a prospective randomized trial was the best way to obtain reliable evidence on the issue of when to start. But as reported on one web site:

    “Professor Doug Richman of the University of California San Diego questioned whether a ‘when to start’ trial was worth the expense. “Rather than spend millions on a trial, given that most people aren’t diagnosed until much later, why not use all that money to identify people who have the higher risk?” he asked”.

    Similarly:

    “He [Bartlett] also believes that the field is not willing to wait the 5 to 10 years necessary to generate an answer on when to start therapy.”

    Discovering what is in the best interests of the infected person is not worth the expense? Waiting 5 to 10 years to find out is unacceptable?

    So if we dispense with the truth to inform our actions, what could it be that guides us? Whatever it is, it is certainly no more reliable than consulting a palm reader.

    Interpretations of associations found in retrospective studies presented as reliable indicators of a cause and effect relationship, rather than possibly suggestive of such a relationship, have as much meaning as the interpretations of an astrologer. Of course such data may be useful in suggesting hypotheses.

    At a recent ICAAC meeting Dr Kitahata presented an analysis of a large retrospective study comparing outcomes among people starting at a higher as compared to a lower CD4 count. There was little meaningful criticism of the interpretation that the improved outcome in those starting treatment earlier was actually due to medications taken. Dr Kitahata felt that it was possible by some statistical magic for retrospective observations to mimic a randomized prospective study.

    Here is an illustration of the interpretive pitfalls in such studies; it is a comment I sent to the web site reporting the results and conclusions of retrospective studies. I used the name James Mello, and pointed out that, as an example people who started treatment earlier were more likely to be under medical care than those who started later, and this might have contributed to their better survival. Another possibility is that most of the mortality might have occurred in those with the lowest CD4 counts; the examples I gave in my comment were a CD4 count of 1 compared to 349, when in fact the study concentrated on individuals with counts above 350. There are other possible explanations. There was one comment that suggested the possibility that people who choose to start treatment early are more likely to be concerned with their health in general and thus more prudent, and presumably more cautious in risk taking.

    This is the comment of James Mello:

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

    Another retrospective study actually showed no survival benefit in people with CD4 counts above 450. Here is a report of this study and that of Dr Kitahata:

    http://www.medpagetoday.com/MeetingCoverage/CROI/12819

    Surely we need to know, and not guess when it is best to start treatment.

    There are those who favour an earlier start and may have reasonable ideas to support these views. But they remain views – not proven ways to proceed that are in the patient’s best interests.

    Let us find out if it is a fact that there is a benefit to starting earlier. All of us – HIV infected people and their advocates should be calling for appropriate prospective studies to guide us. We need to know the truth about when it is best to start.

    Even if we were to conduct an appropriate large randomized prospective study we would only know if in asymptomatic HIV infected people with greater than 350 CD4 cells, it is on average better or worse to start treatment early or to defer it or if it makes no difference, of course apart from the expense.

    This brings up an associated extremely important but neglected issue. This is the need to individualize therapy, which will be the subject of the next post.

    1.

    The causative interpretations of retrospective observations are made difficult by what are called confounding factors and some are impossible to overcome. For example we don’t know why people choose or agree to start treatment early or defer it. The different decisions may reflect the possibilities that those choosing an earlier start may have better access to medical care, and receive better care in general, or may be more likely to be people concerned with their overall health.

    Here is another example of something that might make interpretation of retrospective observations difficult.  A retrospective study  comparing mortality in people starting treatment above and below 500 CD4 cells finds that  those who start treatment at  higher CD4 numbers have a lower risk of risk of death.  If, in those who delayed treatment and died, we are not told what the median CD4 count was at the time treatment was started the overall conclusion that antiretroviral drugs improve survival if started above 500 CD4 cells, would be unwarranted. It might well be that those most who died delayed treatment until a CD4 count of 100 or less.  Had`they started at 450, 350, or 300 – numbers of course`all below 500, the outcome might have been very different.

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    The importance of individualized treatment.