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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.

    .

  • Treatment as Prevention: Protecting Individual Autonomy

    Posted on June 5th, 2011 admin No comments

    Treatment as Prevention

    Protecting patient autonomy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Expert opinion:

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

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

    HPTN 052

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

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

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

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

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

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

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

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

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

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

    The Four Principles are general guides:

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

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

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

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

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

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

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

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

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

    Posted on July 9th, 2009 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

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

    The finding regarding cardiovascular disease is particularly relevant.

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

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

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

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

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

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

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

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

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

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

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

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

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

    Here it is:

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

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

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

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

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

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

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

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

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

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

    stop treatment. The LOTTI study does not justify a

    recommendation in that regard, but it does give clinicians

    useful information that it is probably safe to stop

    treatment within the limits of CD4 cell counts of

    LOTTI. Continued vigilance is needed so that excellent

    adherence is maintained when patients are on HAART

    to prevent the emergence of resistance.

    The LOTTI study adds important information to the

    continued question of whether there is a role for

    interrupted therapy. Further study is justified, particularly

    with newer combination therapies, which may well

    have less toxicity and therefore shift the balance towards

    continuous treatment. Clinicians will welcome the

    information from LOTTI because it can allay some of

    the concerns regarding the safety of treatment interruptions

    at high CD4 cell counts”.

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

    So, further study is absolutely warranted.

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

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

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

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

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

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

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

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

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

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

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

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

    Kuller 2

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

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

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

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

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

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

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

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

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

    This lack of interest is really puzzling.

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

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

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

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

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

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

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

    Refs

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

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

    3:    Staccato                           Lancet 2006   368: 459-465

    4:    LOTTI                                AIDS     2009   23:799-807

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

    6:      AIDS  2003    17:2257-2258

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

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

  • Treatment as Prevention. A last short postscript

    Posted on May 1st, 2009 admin No comments

    I have written several posts dealing with “Treatment as Prevention”  referring to proposals that the epidemic could be controlled by testing and treating all infected people.   However, as this phrase is also used in a different, although related context, I am adding this last postscript.

    Thus,  “treatment as prevention” has a context that concerns populations and considers a strategy to  control and even end the epidemic.    The same phrase  also has a context that deals with prevention of infection at an individual level, and focuses on transmission risks  between two people.

    The latter context was brought to attention in 2008 by the Swiss Federal Commission on HIV/AIDS.  Their publication essentially states that, under certain conditions,  with effective antiviral treatment achieving an undetectable viral load, the risk of sexual transmission without condom use is not greater than that with the use of condoms.

    Among the conditions stipulated is that there is no sexually transmitted infection, and that the viral load has been undetectable for at least six months.

    http://www.aids.ch/e/fragen/pdf/swissguidelinesART.pdf

    Now a German voluntary organization, Deutsche AIDS-Hilfe, has added support – with some modifications to the Swiss statement.

    http://www.aidshilfe.de/media/de/0904_DAH-Papier_HIV-Therapie_und_Praevention_Englisch.pdf

    There was a huge controversy when the Swiss recommendations were first made public in 2008.  Their conclusions were rejected  by groups  in the US,  even by those who promoted the application of the same principle – the reduction in infectivity conferred by treatment – as a means of controlling the epidemic.

    I was – and am – absolutely supportive of the Swiss recommendations as applied to individuals.  Here is an excerpt from a letter I wrote when the Swiss document was published:

    “The report is absolutely reasonable. There are caveats and cautions in it, and since I can see no reasonable objection to them, we have to look elsewhere to try and understand why the report has provoked such a furious response. I know it is a bit pedantic and pretentious but I’m going to add a quotation that is over 100 years old that recognizes that scientists can be as irrational as anyone else (especially about sex), here it is:

    In Man Adapting, Rene Dubos notes that:

    “The presuppositions on which medicine operates are thus conditioned by the general philosophy of the social group as a whole” and adds the words of Oliver Wendell Holmes in 1860:

    “The truth is that medicine, professedly founded on observation, is as sensitive to outside influences, political, religious, philosophical, imaginative, as is the barometer to the changes in atmospheric density”10
    I would bet that some who have commented have not even read the cautious Swiss text, and have allowed their prejudices and squeamishness about sex in general to surface at the very mention of sex without condoms.

    The Swiss authors do deserve some recognition for their courage. There are circumstances in which it is not irresponsible to have sex without condoms. And even for those for whom these circumstances do not apply, the knowledge of the possibility of sex without condoms will be an encouragement, in at least two ways.

    Firstly, to continue using condoms when this is necessary, and then as a support with treatment adherence and monitoring.

    I say these things as someone who had something to do with the original introduction of condom use for AIDS prevention in 1983, – briefly described here:

    http://aidsperspective.net/articles/Callen-Berk_collaboration4.pdf

    and until now thought – as probably most did, that condom use  would be forever.

    Knowing that this is not necessarily so is a tremendous encouragement and I believe this thought alone will help our prevention efforts”.

    I have continued to encourage the use of condoms, but I do welcome the Swiss document for pointing out, with appropriate documentation and caution, that there are circumstances when it is not irresponsible to dispense with them.

    This also means that there are circumstances when conception is possible. There are also implications in situations where there are laws that criminalize sexual contact with HIV infected people under certain circumstances.

    A large part of the irrational responses to the proposal are I believe based on a disparaging attitude towards sex.

    For many, the use of condoms is a barrier to intimacy.  The knowledge that if certain circumstances can be met, an infected person is not endangering their sexual partner by dispensing with condoms is in fact a life affirming celebration of sex, one of life’s joys.

    Admittedly, dispensing with condoms will not be possible for most individuals.  It is probably most relevant to serodiscordant couples in a stable relationship – that is where only one of the partners is HIV infected.

    But knowing that this might be achieved could be a great support to most HIV infected people  who must continue to use condoms   It will also be a greater incentive to remain adherent to one’s treatment regimen.

    Of course the diminished infectivity of effectively treated individuals is the basis for the proposals to use treatment of all infected people as a means of controlling the epidemic.

    This is a very different situation, most importantly because it will involve treating people who do not need to be treated for their own personal benefit. These healthier people will derive no benefit from the medications and only be exposed to their side effects.  I have written about this in previous posts on treatment as prevention.

    Except for the relatively uncommon situations outlined in the Swiss document, and more cautiously and explicitly, in the German document, the consistent use of condoms remains one of the most important measures we have to prevent infection.

  • The Not So SMART Study

    Posted on April 27th, 2009 admin 2 comments

    I have borrowed this title from a comment in the journal, Lancet Infectious Diseases, entitled “Not so Smart?” by Justin Stebbing and Angus Dalgleish.

    The SMART study as many will recall was a randomized comparison of two antiretroviral treatment strategies.

    HIV infected individuals were randomized to receive either  continuous antiviral treatment or to receive it intermittently while the CD4 count had fallen below 250. This trial received a tremendous amount of publicity.  Deaths from all causes – including those that were not obviously related to HIV infection, were significantly increased in the group that were treated intermittently.  This seemed to dampen enthusiasm for treatment interruptions and brought attention to a possible relationship between HIV infection and deaths from causes previously not associated with it.

    5,472 patients participated in this study at 318 sites in 33 countries.

    There were a total of 85 deaths in the study.

    79 of these 85 deaths occurred in the US where 55% of the patients were randomized.

    There were only 6 deaths among the 45% of patients randomized in countries outside the US.

    .

    It would seem that treatment interruptions are quite safe, as long as they occur in countries outside the US.

    Did I miss this information in the original report of the study published in 2006?

    There were numerous discussions of the SMART study on websites and newsletters addressed to HIV infected people and their health care providers.  Did I miss those that reported on the fact that only 6 of the 85 deaths occurred in countries outside the US?

    Of course I looked at the original report again but could not find this information – perhaps it was buried in a supplementary appendix?

    For some reason, it seems that the authors of the report on the SMART study did not feel it necessary to draw attention to this information – at least not with the prominence that it deserved, if it was mentioned at all.

    Most of the deaths on the study were not from AIDS associated opportunistic infections or malignancies.

    With a presumption (maybe this  suggestion is too harsh) that despite this, the deaths were indeed related to HIV,  a possible relationship with this virus was sought. One obvious possibility of connecting these deaths with HIV was by linking them with the inflammation that is associated with HIV disease.

    Thus, as a follow up to the SMART study, various markers of inflammation were looked at in both groups, and not surprisingly these were increased in the group with the most deaths, those receiving intermittent treatment rather than continuous treatment. As mentioned almost all of these deaths were confined to the US.

    So, what we have is the observation that people who were to die within a relatively short period had increases in markers of inflammation. Of these, D-dimer, CRP and IL 6 had already been associated with all cause mortality, even in people not infected with HIV.

    With respect to the cardiovascular deaths in the study, here is a quotation from PM Ridker:  “In apparently healthy men, elevated levels of IL-6 are associated with increased risk of future MI. These data thus support a role for cytokine-mediated inflammation in the early stages of atherogenesis”.

    IL-6 is a pro inflammatory cytokine and levels were increased in those receiving intermittent therapy.  IL-6 promotes HIV replication,  and can be produced by HIV infected cells but also by many other stimuli.

    So IL 6, which is associated with atherogenesis,  also directly increases the replication of HIV.  IL 6 secretion is increased by numerous and diverse factors. For example bacterial toxins induce IL 1 which in turn stimulates IL 6 release and  hepatitis C virus core proteins induce IL 6.  HIV infected cells can also release IL 6.

    But with so many different agents able to do this it is difficult to attribute IL 6 production to HIV.  This is of course muddied by the fact that whatever stimulates IL 6 secretion, IL 6 itself will accelerate the replication of HIV.

    But possibly the most intriguing feature of the report of this follow up study  is the first sentence of the Results section:

    “Most of the deaths (79 of 85) occurred in the US”.

    Having made this rather startling statement, the authors never return to it.  It remains undiscussed,  as if it is of no consequence!

    Are we to believe that intermittent therapy with antiviral agents  promotes inflammation with its lethal consequences only in the US?

    The outcome measurement of the SMART study included death from all causes. Only 8% were the result of opportunistic disease.

    There were 16 deaths from cancer ( 11 in the intermittent therapy(IT) group and 5 in the continuous therapy group(CT)), 11 deaths from cardiovascular   disease  (7, IT, 4,  CT);

    8 people died from substance abuse, 7 from violence.

    18 deaths were from causes that could not be determined. Of these 18, 15 occurred in those on intermittent treatment and only 3 in those receiving continuous treatment.  This last rather large difference leads one to ask if it is possible that the two groups were treated differently. At least, in the US, where almost all the deaths occurred.

    This may seem like an outrageous question. But unintentional bias in unblinded studies cannot be ignored and I will return to this.

    Many of the deaths reported -  certainly far from all, were caused by  conditions that might have been ameliorated by appropriate medical care ( this does not only mean from the point of view of the physician. The patient is also involved – for example, were medical visits made? Did the patient pay attention to symptoms? Was there compliance with prescribed treatment?)

    With almost all of the mortality confined to the US,  it looks like something else must be at play here, something other than the antiretroviral treatment strategies, and the first place to look is the overall quality of medical care – which,as mentioned, includes issues that may entirely be related to the patient – such as poor compliance with recommendations, despite adequate support.

    There are two distinct  questions to be asked.

    Firstly,  why was there such  a difference  in  the trial outcomes between US and non US sites?

    Secondly, in the US can we reliably attribute the differences in outcomes in the two treatment arms to the differences in the antiviral treatment strategies?

    The first two questions one would ask in trying to explain the difference between 6 deaths and 79 deaths is related to the quality of general medical care in the US as compared to the non US countries, and then to possible differences in the patient populations.   The patient populations may have differed for example in the extent of co- morbidities,  and in the degree of compliance with recommended treatments.

    But  I don’t know that one can come up with an answer about the quality of medical care.   We must assume that there were probably no great differences.  However there was some information on co- morbidities such as Hepatitis b and C,  but not enough to attribute the differences in the number of deaths to this factor.  [Note`added on April 4 2010. The difference in co-morbidities is in fact probably  the reason for the striking difference in mortality between US and non US sites. Here is a link to a later post where a table is reproduced  from the paper describing the mortality difference referenced below. The population enrolled in US sites, where most of  the deaths occurred,  were much more likely to suffer from non HIV related health problems than those enrolled in non US sites.  Here are two sentences from the later post:  ”The study was conducted in US sites on what appear to have been a group of individuals in whom disorders unrelated to HIV were overrepresented.  As mentioned earlier, these disorders include diabetes, hepatitis B and C, high blood pressure and a history of heart disease:

    I conclude with a few more comments on the SMART study with a possible explanation for the huge discrepancy in the number of deaths in US sites, 79, compared to only 6 in non US sites.   At least there is a very clear reason why the results observed in this study should not be generalized to all HIV infected individuals”. This current entry on the SMART study, which I'm leaving unchanged,  should be looked at in conjunction with my subsequent post. LINK TO LATER POST ]

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

    I doubt if information on compliance is available.

    Even if one could show differences between the US and non US sites ,  how would  this  affect the study outcome?  More people died in the intermittent treatment arm compared to those receiving continuous treatment. So this is the second question.

    Could there be an explanation for the differences noted between the study arms (albeit only in the US) other than the antiviral treatment strategies?

    There could be a connection with general patient care.

    In order to minimize bias in a study, where possible when treatments are compared, participants and those conducting the trial do not know what treatment is being received by particular participants.

    The study is blinded, so that as far as it is possible, we can attribute any effects observed to the treatment, not to any anything else.  For example, if patients knew what they were or were not receiving in a treatment trial, they may behave differently, and  in ways that may affect the outcome, which then could not be attributed to the particular treatment being studied.

    For example if a patient knew they were receiving a placebo, they may then take other medications that might affect the outcome of the trial, or if doctors knew patients were taking a medicine they believed worked they might treat their patients with greater care or with less care.  We do recognize that some behaviors that may alter the outcome of a study are  certainly not intentional.

    It was impossible to blind the SMART study.  So, both participants and physicians knew which arm of the study patients were randomized to.

    If the study doctor was also the person who provided  general  care than the specter of bias unfortunately is lurking and may confound interpretations.

    This is not to say that differences in general care between both study arms, if indeed there were differences, were intentional.

    To put the questions in another way:

    1: Can general patient management strategies ( not the strategy of antiviral treatment being studied) have an impact on all cause mortality?  In other words, can the way health care providers manage the general  health of their patients make a difference to survival?

    2: Can bias influence the ways physicians take care of their patients?

    The answer is of course yes., although we may not like to admit this.    So bias might be a factor in an unblinded study and affect the outcome.

    So we are still in the dark regarding regarding the value or danger  of treatment interruptions.

    As a postscript, a similar problem hangs over the original AZT study – the study that led to the approval of this drug by the FDA.  Of course the dramatic life saving effect of zidovudine seen in this trial  has never been observed again.

    This placebo controlled study was also in effect unblinded. Patients and doctors knew who was receiving placebo or active drug.

    Deaths were mostly due to opportunistic infections. Patient management strategies can make the difference between life and death with regard to these infections. Rapid diagnosis, effective treatments obviously make a difference. Can bias influence patient management strategies?

    I wrote about this in – I think 1989, and the article can be seen by clicking here.

    I suppose that one must conclude that the fact that almost all the deaths in the SMART study occurred in the US was not known to journalists and those who specialize in informing us about issues related to AIDS.  I also missed it when it was  published in 2008 [iii].

    The report of Dr Kuller may be the first public mention of this odd result. But it is just mentioned and not discussed at all.

    Here is what Justin Stebbing and Angus Dalgleish wrote in the Lancet Infectious diseases about this report:

    ” The follow-on case-control study by Kuller and colleagues showed that it is apparently safer to be off  HAART outside the USA rather than on HAART within the USA”

    As a clinician I don’t know what to make of the SMART results. In the lamentable absence of firm evidence one has to use one’s best judgment in caring for patients.  Numbers of my patients have – at their request and at my recommendation, temporarily interrupted their treatments, using a variety of strategies, with no harm, and with a better quality of life.

    I imagine that some will have been persuaded to stop this practice  by their new physicians. But I am still in touch with one, who had a CD4 count of 0 when first seen, who still regularly interrupts his treatment.  He is extremely well, leading an active and productive life.


    The Lancet Infectious Diseases, Volume 9, Issue 5, Pages 268 – 269, May 2009

    The New England Journal of Medicine [NEJM 355(22): 2283-96 (2006)

    PLoS Medicine 5 (10); e203.doi:10.1371/journal.pmed.0050203

    Kuller LH, et al. (2008) Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV infection.

    HarrisTB et al 1999  Association of elevated IL6 and CRP levels with mortality in the elderly, Am J Med 106: 506

    Ridker PM et al 2000 Plasma concentrations of IL 6 and the risk of future myocardial infarction among apparently healthy men.  Circulation  101 1767

    Shorr AF et al 2002 D-dimer corerelates with proinflammatory cytokine levels and oycomes in critically ill patients, CHEST 121: 1262

    HIV disease is in fact characterized by multiple examples of positive feedback systems – a subject for another post.




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

    Posted on April 23rd, 2009 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    A few introductory words are needed.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    img0822

    img083

    img084

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Surely the payors, will want to know.


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

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

  • When is it best to start antiretroviral treatment: an update April 2009

    Posted on April 13th, 2009 admin 2 comments

    “Starting HIV Therapy Earlier Saves Lives”

    “Study: Treatment for HIV Should Start Earlier”

    “Starting Therapy Earlier Found to Improve Survival”

    “Earlier HIV Treatment Boosts Survival”

    With headlines like these you would think that there is a clear answer to the question of when is it best for HIV infected people  to start antiretroviral treatment.  There can be no doubt at all that starting antiviral therapy early – in this case at a CD4 count above 500 improves survival.  These headlines, addressed to HIV infected individuals their physicians and the public are a unanimous response to a study that just appeared in the New England Journal of medicine (NEJM).  http://content.nejm.org/cgi/content/full/NEJMoa0807252

    But is this confidence justified?

    Unfortunately, despite these headlines, the study which occasioned them was absolutely unable to justify the conclusion ; we still do not know when it’s best to start treatment.

    The study examined data that had been previously collected.  It was a retrospective observational study with all the problems inherent in such studies. These have been outlined in a previous post.

    About a week after this study appeared in the NEJM, another large retrospective observational study was published in the Lancet (April 9th 2009

    doi:10.1016/S0140-6736(09)60612-7http://www.thelancet.com/images/clear.gif ).

    While both studies support the desirability of not delaying a start to antiviral therapy to a CD4 count below 350, they do differ with respect to the reported benefits of starting above that number.  The Lancet study, whose lead author is Jonathan Sterne, finds a decreasing benefit at start times increasing above a CD4 count of 350, with nothing   at starting around 400.

    The authors of both reports  agree that prospective randomized studies are the best way to approach a resolution of the “when to start” question – a question that might have already  received a reliable general answer had we begun these studies in 1997, as some of us suggested we do at that time.

    Obviously we cannot just wait for the results of randomized prospective studies.  We do need guidelines now, but any recommendation based on available information must be regarded as provisional, until the results of prospective randomized studies are in.  It is important that this be clearly stated. If we are ever going to be able to enrol a prospective randomized study then we cannot afford to delude ourselves that the answer to the when to start question is already known.

    While the lead author of the New England Journal of Medicine did pay homage to prospective randomized trials – and a kind of ritualized homage is exactly what it sounded like, this gesture most certainly did not inhibit her from unreservedly recommending an earlier start to treatment, a start even at a CD4 count above 500, without conducting such a prospective study.  Her conclusion:

    “The early initiation of antiretroviral therapy before the CD4+ count fell below two

    prespecified thresholds significantly improved survival, as compared with deferred

    therapy

    One of these prespecified thresholds was a count 500 CD4 lymphocytes.

    This categorical statement, arrived at by the kind of study that cannot possibly justify such confidence, will have a negative  effect on  enrolment in proposed randomized trials, which are in fact the kind of study that can provide conclusions in which we can have justified confidence.

    This study may well be the last coffin nail in any hopes there may have been for the completion of prospective randomized trials designed to address the “when to start” issue.  It may now be impossible to enrol, and will never get off the ground. This difficulty is made so much worse by the kind of uncritical headlines shown above

    I wonder how the commentators who rushed so uncritically to announce Dr Kitahata’s conclusion on the benefits of starting treatment at CD4 counts even greater than 500 will respond to the Lancet report, which did not find a benefit with starting at such high CD4 numbers?   I hope I’m wrong in suspecting that this study will be largely ignored; the headlines trumpeting the survival benefit of starting treatment early – even above a CD4 count of 500 will not be marred by any doubt introduced by the study reported in the Lancet.

    Among the problems with the New England Journal of Medicine study is that a significant number of people were left out of the analysis, because their HIV disease failed to cooperate with preconceived notions about the course of this disease.

    This is a significant criticism and I will try to explain why.  The study examined two groups of people, one with over 500 CD4 lymphocytes, and one with CD4 counts between 351 and 500.

    Let’s just take the 351 to 500 group.    Here, deaths in those starting at counts between 351 and 500 were compared with deaths in those starting below 350. Sounds reasonable?   Maybe, until we learn that significant numbers of people with 351 – 500 CD4 cells who did not start treatment  also did not progress to below 350 CD4 cells.   So the authors just left these people out of their calculations. They in effect did not exist for the investigators.

    The recommendations the authors make are meant for all people, including those who did not progress and were left out of the analysis.  These people are also going to be treated with drugs they don’t need, as they cannot be identified.

    I suppose this will do wonders for drug sales, but there will be individuals taking drugs for no reason and some may only suffer their ill effects as well as cost while deriving no benefit.

    Here is another serious problem with this study.

    Among those people with CD4 counts between 351 and 500, it is important to know just how long treatment was delayed in those who waited until their counts fell below 350.   This information was provided; the median count at the time of starting treatment among all who waited was 286.   But what was the CD4 count at starting treatment among those in this group who died?

    This information was not given – at least I was unable to find it.

    Could there have been those starting treatment with counts below 100, below 50 – maybe even below 20.   In an extreme example, if a person waited to start treatment to a point close to death, there would not be much surprise that delaying treatment   initiation is associated with a worse outcome.

    Many physicians are proud that the field has abandoned uncritical authority as a guide to practice and has now embraced evidence based medicine. David Sackett, one of its originators, has stated that one pillar of evidence based medicine is the use of the best external evidence in making clinical decisions.

    All too frequently physicians, while priding themselves on practising evidence based medicine,  somehow are still able to make decisions based solely on their unproven beliefs, as if they have a private source to the truth, some special access to an oracle.  I have  heard one physician state that anyone with a viral load should be treated, another saying essentially the same thing in stating that he would treat every HIV infected patient no matter what the CD4 count. How on earth have they arrived at these conclusions?  Patients might just as well seek advice from a palm reader.

    As always you can’t beat the truth. No matter what the private sources of information to which  some physicians and patients apparently have access, the truth remains  that apart from people with under 200 CD4 cells the best time to initiate antiviral therapy is unknown.

    I have once before faced this kind of opposition to conducting a randomized prospective study to address the question of when is it best to start treatment.  In the early 1990s I participated in an effort to conduct a trial of early versus deferred treatment with AZT.  A pilot study was initiated, and I participated with some statisticians in describing the study to numbers of physicians in New York City, with the hope of encouraging them to enrol patients.  Despite expressions of enthusiasm, the response was so dismal that the trial could never take place.  However there was one physician – just a single physician in San Jose who was able to recruit many more patients than all the others combined.  He was so successful that we asked him to come to New York City to explain how he was able to enrol so many patients.  His answer was simple.  He told patients the truth. He did not know when it was best to start treatment, so he and his patients let the toss of a coin determine this, as a means of finding out what was best by participating in a study.

    This means that the other doctors were unable to say they did not know.  Maybe, as is the case today some actually felt that they did know, as they had complete faith in their intuition, or perhaps had some private access to the truth. For these physicians the practice of medicine is more akin to a faith based activity.  Maybe other physicians  did not know when it was best to start treatment, but might have felt unable to admit this; maybe some patients felt they knew and physicians acceded to their wishes.

    The rational response to uncertainty – having first overcome the hurdle of being able to admit that there is uncertainty – is to try to resolve this by the best means available.

    I fear we are not even close to recognizing that there is uncertainty about when to start treatment in people with over 200 CD4 cells.  The NEJM article exacerbates the problem with its assumption of certainty, an assumption very sadly shared by some health care providers, some journalists and community commentators to whom HIV infected people turn to for advice.

    In conclusion I cannot lose an opportunity to yet again bring attention to the need to individualize therapy.   The rate of HIV disease progression is so widely variable that there are limitations in setting a fixed CD4 count as a guide to start therapy.  A prospective appropriately designed trial can tell us if on average it is better to start above rather than below a certain CD4 count, or on average it is better to start treatment immediately or to defer it.

    It is the “on average” limitation that needs fine tuning for each individual patient.

    Not only will the rate of disease progression vary widely between patients, but there are other individual considerations that impact the decision to start treatment. For example, adequate housing, mental health issues, co morbidities and many other factors need to be considered.

    These two aspects, the general and the particular, fit so very neatly into David Sackett’s description of evidence based medicine that I will quote a passage:

    The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice“.

    BMJ 1996;312:71-72 (13 January) : Evidence based medicine: what it is and what it isn’t.  David L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson

    The best available external evidence will be the  results of a prospective randomized trial; these  will provide general guidance.  Individual clinical expertise will apply this to particular patients,  taking into account many factors, not least of which is the patient’s rate of disease progression.

    A previous post discusses the  issue of individualization of treatment.


    If we took individualization of treatment seriously, we could in fact come some way to identifying rapid and slow/non progressors.  See previous post on individualization of treatment.

    Often forgotten, the second pillar is individual clinical judgement.

  • Individualization of HIV therapy

    Posted on March 8th, 2009 admin 1 comment

    Why treatment of HIV infection must be individualized.

    HIV disease is usually a progressive disease. That is, it has a starting point; the time of infection. The disease then progresses, and without treatment will generally end fatally. There are some very fortunate HIV infected individuals who are able to control viral replication and remain disease free. But for most, HIV disease does progress. But, for each individual, the rate at which it progresses varies widely. Disease progression is reflected in the fall in the numbers of CD4 lymphocytes.

    So any single CD4 count measurement is really a point on a descending curve, one that does not necessarily proceed in a straight line, and falls at widely differing rates in different individuals.

    Recommendations for the treatment of HIV infected individuals are issued periodically by DHHS and bodies such as the International AIDS Society. These recommendations, particularly those concerning when to start antiviral treatment, have always included a particular CD4 count as a signal to start or to consider starting antiviral treatment.

    All individuals with a CD4 count of less than 200 should be on therapy. They are in great danger of acquiring a possibly fatal opportunistic infection and evidence derived from clinical studies makes it absolutely clear that antiretroviral treatment is life saving.

    But what about people with higher CD4 counts? Here there is uncertainty about when in the course of HIV infection it is best to start treatment. Of course, if the drugs were completely harmless (including cost) it might be less important to have an answer to this question. However the drugs can have significant adverse effects, some of which only become evident after years of use. For people with fewer than 200 CD4 lymphocytes, the benefit of antiviral treatment overwhelmingly outweighs the risks.

    For others, a very mixed group, with CD4 cells anywhere from 200 to over 1000, and each with a different rate of disease progression, we cannot, with any security, make a “one size fits all” recommendation as to when it is best to start treatment.

    The best way to resolve clinical uncertainty remains randomized prospective clinical trials. By now we might already have obtained reliable evidence as to whether, on average, it is best for infected individuals with more than 200 CD4 lymphocytes, and who have no symptoms, to start antiviral treatment immediately, or to defer it. (A suggestion made in 1997 when the first guidelines were issued: http://aidsperspective.net/articles/guidelines1.pdf )

    The current recommendations, regarding people with greater than 200 CD4 lymphocytes, and who are without symptoms, propose a CD4 count of 350 as a point to start treatment ( many believe this number should be 500). This recommendation is made for all individuals – it is a one size fits all approach[1]. This kind of approach is appropriate for some aspects of treatment; for others it is very wrong[2].

    Perhaps the most important  example of a  recommendation, where its application across the board  is problematic,  is that which deals  with the time when antiretroviral treatment should be started in individuals with greater than 200 CD4 lymphocytes.  This recommendation specifies a specific CD4 count at which to start. As noted, for individuals with a CD4 count below 200, there is no doubt that they will benefit from therapy. For others who have no symptoms, specifying a CD4 count for all is mistaken. It is here that individualization is necessary.

    The reason is that no two HIV infected people are the same with respect to the rate of disease progression. During the early years of the epidemic, before antiretroviral treatment was introduced, we soon noted that the CD4 count declined at different rates in different people, and not necessarily in a straight line. As noted, at one extreme, there were the few fortunate individuals in whom there seemed to be no disease progression, at the other there were the few people whose CD4 cells fell very rapidly after infection, and who did not survive for more than 2-3 years, but most fitted somewhere between these extremes .

    To illustrate this I have considered four possible situations. This is a picture of the possible rates of CD4 decline in four different individuals. . It is true that these pictures are constructs, but they do accurately reflect the observed variability in disease progression; real examples showing this variability would be easily found in my medical records, and of course in those of other physicians during the period between 1981 and about 1993.

    The dip in CD4 cells following infection is usually seen when there is an opportunity to observe this. CD4 cells then rebound to a level called the set point, which will be different in relation to the pre infection level in different people. From then on it declines, but at a very variable rate, and can remain steady for varying periods before declining, again at varying rates.

    img049

    Look at where three of them (A ,B and C) reach a count of 450 CD4 lymphocytes; A (an unusual rapid progressor) gets there in about one year, B in about 3 years, C in 7 years, and D, who is a fortunate non progressor is nowhere close after 18 years.

    The arguments for starting early are not only to forestall reaching the dangerous level of 200 CD4 lymphocytes. The continuous deterioration of the immune system and diminished chances of recovery at lower counts are also arguments for an earlier start. There is also the possibility that there is a greater incidence of cancer, – other than lymphoma and Kaposi’s sarcoma, at higher CD4 counts in HIV infected people. If this is so then it remains to be shown how frequently these events occur and whether antiviral therapy can avert them.

    Treatment itself, particularly if extended over many years, is not without risks, some of which cannot even be completely known yet, particularly with the newer antiviral agents. We have to do the best we can in making a risk benefit assessment. In order to do this we should attempt to obtain information on the rate of disease progress in any one individual. This may not be entirely possible, as the rate of disease progression in any one individual may not be steady; it may accelerate or slow down. But it is possible to obtain a good, if not perfect, picture of the course of HIV disease in any one person.

    How might we obtain some information about a given individual’s rate of disease progression? Apart from obvious exceptions, and in people below 200 CD4 cells, there are no emergencies in HIV medicine. For each person we generally will have time to observe the CD4 count and viral load over a period of 6 to 12 months and obtain some idea of the rate of progress. A rapid fall in CD4 count might result in a decision to start in less than six months of observation. Or a consistent fall in CD4 count might lead to a decision to start treatment at CD4 numbers higher than even 500. This is far from perfect, as changes in CD4 cell numbers do not necessarily follow a straight line. But it is far better than basing a decision on a snapshot – which is what the experts are telling us to do.

    Individualization involves more than considering the rate of disease progression. There are other factors, such as associated diseases, domestic and social circumstances such as a lack of housing, as well as mental health issues, and many other considerations that are involved in individualization. Observing people also provides the time to establish a doctor patient relationship and for the physician to become familiar with the patients particular circumstances.

    The natural history of untreated HIV disease is relevant to the “when to start treatment” issue and will be the topic of the next post.


    [1] Evidence supporting the recommendation is derived in part from retrospective observations. The reasons why these are unreliable guides are outlined in the previous post. It is critical to as far as possible, eliminate bias in study designs because this increases the probability that a particular outcome can be interpreted as indeed resulting from a particular intervention. In this case it would be that improved survival is due to an earlier start of antiviral therapy and that the medications mediate the effect – and not for example, from simply being under the supervision of a physician. Retrospective observations, that is, looking back at information already gathered cannot be free of confounding factors as described in the previous post. In a prospective study people would be randomly assigned to receive immediate treatment or to defer it. This will give us the most reliable answer to the question of which approach is better on average.

    [2]Examples of measures that should be taken in the treatment of every HIV infected person, irrespective of the rate of disease progression are the types of tests that are performed on the initial assessment of an infected person. For example, the initial assessment of an HIV infected person should always include not only CD4 counts and HIV viral load measurements, but also tests for hepatitis, toxoplasmosis, and many other investigations. Another example of an intervention that is appropriate for categories of infected people is treatment to prevent Pneumocystis pneumonia in people with less than 200 CD4 cells. And of course, people in this category must always be offered antiretroviral therapy.