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  • 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

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

    Posted on January 28th, 2011 admin No comments

    Full contents of this blog

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

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

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

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

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

    But no explanation was forthcoming.

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

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

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

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

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

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

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

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

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

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

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

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

    A note about patient management strategies:

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

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

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

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

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

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

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

    Returning to the original AZT trial:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    (1)

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

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

    Posted on May 19th, 2010 admin No comments


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

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

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

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

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

    —————————————————————————————

    John Falkenberg  New York, NY

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

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

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

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

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

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

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

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

  • HIV Treatment as Prevention. March 2010

    Posted on March 4th, 2010 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    Posted on July 9th, 2009 admin No comments

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

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

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

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

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

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

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

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

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

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

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

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

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

    The finding regarding cardiovascular disease is particularly relevant.

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

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

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

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

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

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

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

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

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

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

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

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

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

    Here it is:

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

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

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

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

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

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

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

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

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

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

    stop treatment. The LOTTI study does not justify a

    recommendation in that regard, but it does give clinicians

    useful information that it is probably safe to stop

    treatment within the limits of CD4 cell counts of

    LOTTI. Continued vigilance is needed so that excellent

    adherence is maintained when patients are on HAART

    to prevent the emergence of resistance.

    The LOTTI study adds important information to the

    continued question of whether there is a role for

    interrupted therapy. Further study is justified, particularly

    with newer combination therapies, which may well

    have less toxicity and therefore shift the balance towards

    continuous treatment. Clinicians will welcome the

    information from LOTTI because it can allay some of

    the concerns regarding the safety of treatment interruptions

    at high CD4 cell counts”.

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

    So, further study is absolutely warranted.

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

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

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

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

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

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

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

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

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

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

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

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

    Kuller 2

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

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

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

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

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

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

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

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

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

    This lack of interest is really puzzling.

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

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

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

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

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

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

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

    Refs

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

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

    3:    Staccato                           Lancet 2006   368: 459-465

    4:    LOTTI                                AIDS     2009   23:799-807

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

    6:      AIDS  2003    17:2257-2258

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

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

  • The not so SMART study: a very short postscript

    Posted on June 12th, 2009 admin No comments

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

    The not so SMART study.

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

    Here is the relevant part:

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

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

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

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

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

    Did they think it was of no significance?

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

  • HIV TREATMENT AS PREVENTION

    Posted on March 27th, 2009 admin 2 comments

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

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

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

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

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

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

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

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

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

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

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

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

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

    This inconvenient obstacle can be easily eliminated.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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