Posted on April 12th, 2012 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.
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.
Posted on June 5th, 2011 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.
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 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/>.
(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
Posted on May 12th, 2011 No comments
Interferon and AIDS: Too much of a good thing
This discovery of interferon in AIDS
AIDS was first recognized in 1981. Interferon was found in the blood streams of people with AIDS later that same year, making it one of the earliest of the significant AIDS associated immunologic abnormalities to be noted. Large amounts of interferon were found that were present for very prolonged periods, a situation noted before only in auto-immune diseases like lupus.
The interesting story of how interferon came to be discovered in people with AIDS so early in the epidemic illustrates at least one way in which science can progress; it also demonstrates a way in which scientific progress can be retarded.
The production of interferon following viral infections is part of the innate immune response that is the immediate first line of defence against viral infections. Interferon has potent antiviral activity against a broad range of viruses. It also has widespread effects on the immune system as well as effects on other organ systems. Some of these effects are harmful if prolonged, so there are mechanisms for turning off the interferon response after a few days as other antiviral mechanisms come into play.
HIV and disease causing SIV infections differ from most viral infections in that the production of interferon is not turned off; it continues to be produced, sometimes at very high levels. The prolonged presence of interferon contributes to the disease process and is a factor in the loss of CD 4 cells.
The sustained activation of both innate and adaptive immune responses is now understood to be at the heart of AIDS pathogenesis.
Interferon continues to be produced, sometimes in large amounts, in HIV infected individuals. In untreated HIV disease we have the unusual situation where increasing amounts of interferon are associated with increased HIV replication.
Interferon can’t be exerting much of an antiviral effect in HIV infected individuals, but this did not deter investigators from injecting yet more of it into people with AIDS early in the epidemic.
This is even more puzzling as by 1983 we had evidence that interferon was able to suppress CD4 lymphocyte proliferation. Long before this we knew that treatment with interferon was associated with low white blood cell counts, and a low white blood count is characteristic of advance HIV disease.
But if interferon was of no use against HIV it has been spectacularly successful against Hepatitis C, curing many people of this infection. It also may still have a place in treating some people whose Kaposi’s sarcoma is unresponsive to antiretroviral drugs, possibly through its ability to inhibit angiogenesis, which is the process of new blood vessel growth.
Although there were lots of reasons to consider that prolonged exposure to high levels of interferon might have something to do with this newly recognized illness even in 1981, serious work on this possibility was delayed for many years. The zeal to administer yet more interferon to treat AIDS is surely part of the reason for this neglect.
The inexplicable enthusiasm to treat AIDS with interferon resulted in no benefit to patients; it probably accelerated the disease process in some.
It also had the unfortunate effect of delaying research into interferon’s role in the pathogenesis of HIV disease.
It’s only in the past ten years that we have gained some information on how prolonged exposure to interferon can contribute to the loss of CD 4 lymphocytes.
Finding interferon in people with AIDS
This is how we came to find interferon in people with AIDS so early in the epidemic.
Early in 1981 I had referred one of my patients to Dr Joyce Wallace. A biopsy taken of lesions seen in his stomach indicated that these were Kaposi’s sarcoma. Joyce called to tell me that she had contacted the National Cancer Institute to help identify experts in New York City who were familiar with Kaposi’s sarcoma because this was the first time she was confronted with this diagnosis (the first time for me as well). She had been told that over twenty gay men had been diagnosed with Kaposi’s sarcoma and that Dr Alvin Friedman Kien at NYU was treating a number of them. I knew Alvin through my association with Jan Vilcek, a long-time colleague in the field of interferon research. Alvin is a dermatologist but also worked in the NYU lab that Jan headed.
I immediately called Jan who confirmed that Alvin was treating a number of gay men with Kaposi’s sarcoma. Jan very kindly allowed me to work in his lab. I then arranged my time so that I worked in the virology lab in the mornings and saw my patients in the afternoon.
I was one of several scientists who thought it likely that cytomegalovirus (CMV) played a role in this newly recognized disease so initially my lab work centered on this virus.
In the early months of the epidemic Alvin had sent blood samples to Pablo Rubenstein at the New York blood center for HLA typing. HLA refers to the human leukocyte antigen system which allows the immune system to differentiate foreign antigens from self-antigens. It’s important in organ transplantation, where a match in HLA antigens between recipient and donor can prevent organ rejection.
HLA typing is important in investigating a newly recognized disease as there is an association of certain HLA types with some diseases, even some infectious diseases.
A serologic method was then used for HLA typing. It depended on the attachment of HLA specific antibodies to HLA antigens on the surface of leukocytes.
HLA typing of our first patients with Kaposi’s sarcoma proved to be difficult because the patient’s own antibodies were already coating the surface of their leukocytes, interfering with the test.
At the same time I had come across a preprint of a paper reporting an important observation by Jan Vilcek. The CD3 antigen is present on the surface of T cells. Jan had reported that an antibody against the CD3 antigen was a powerful inducer of gamma interferon.
As I read this report it occurred to me that Pablo Rubenstein’s observation that antibodies were attached to our patient’s leukocytes could mean that these blood cells were secreting gamma interferon, which we might be able to detect in their sera.
I discussed this possibility with Jan and Alvin and we immediately set out to test the sera of Alvin’s patients. This idea was to bear fruit, but not what we had expected. Rather than gamma interferon, large amounts of alpha interferon were found.
Jan Vilcek has also described this event, which can be seen by clicking here.
Maybe what’s important is to have a reasonable idea that can be tested, not that the idea need be correct. In fact much later, using more sensitive tests gamma interferon was eventually found in AIDS sera.
Robert Friedman is a colleague from the early days of interferon research, with whom I had published work on the mechanism of interferon’s antiviral action. He was – and still is ,chairman of the pathology department at the Uniformed Services University of the Health Sciences in Bethesda. He, Jan and I have been colleagues since the 1960s when Alick Isaacs, a discoverer of interferon was still alive. We joined forces to study the association of interferon with AIDS.
Our extended findings including data obtained at both Jan Vilcek’s and Bob Friedman’s lab was published in the Journal of Infectious diseases in 1982.
Since there were so many names, it was left to me to decide their order, and I chose that they be listed alphabetically. Thus Gene DeStefano became lead author. He was a technician in Jan’s lab and I believe he went on to become a dentist. This is the title.
Acid-Labile Human Leukocyte Interferon in Homosexual Men with Kaposi’s Sarcoma and Lymphadenopathy
This early discovery prompted a pretty obvious question: could the sustained presence of interferon have anything to do with the pathogenesis of this newly recognized disease? From what was then known about the effects of interferon it was a question that certainly needed to be explored.
Although interferon had been discovered in 1957 through its antiviral properties, by the 1970s it was already known that it had widespread effects on the immune system.
In the first few years of the epidemic I was in a position to begin to begin to explore the possibility that interferon played a role in this newly recognized disease.
I was able to obtain interferon assays on sera from my patients at Robert Friedman’s lab. Further interferon tests were done by Mathide Krim, then head of the interferon lab at Memorial Sloan Kettering cancer center.
I also was able to obtain quite extensive immunological tests on my patients through my collaboration with David Purtilo at the University of Nebraska in Omaha. As a result I had (and still have) a small database of my own and so was able to produce further evidence for the association of high interferon levels with low CD4 counts, as well as some other associations with interferon. (2).
The numbers of patients was not huge but the following graphic shows that 7 people with over 50 units of interferon/ml had under 50 CD4s, 12 people with 10-49 units had under 500 CD4s while 17 people without interferon had about 700.
There are several other interesting correlations. Interferon levels correlate with IgA levels and not surprisingly there is an inverse correlation between CD4 counts and IgA levels.
This was a CRIA presentation in the 1990s from the days when I was the medical director, but the data had first been presented in 1986.
Being familiar with the adverse immunological effects of prolonged exposure to interferon I was puzzled by the attempts to conduct trials of alpha interferon to treat AIDS. This is very different to the benefits of interferon in treating Hepatitis C and some cases of Kaposi’s sarcoma.
The zeal to use interferon as a treatment for HIV disease created a strange situation concerning a molecule called beta-2 microglobulin (beta 2M).
In the early years of the epidemic various markers were sought that could act as prognostic indicators. It was soon found that a raised beta 2M level in the serum of patients was an adverse prognostic indicator. High levels were indicative of a poor prognosis. But interferon is the major stimulus for the synthesis and release of beta 2M, something that was known in the 1970s.
In fact the adverse prognostic significance of serum interferon had already been reported early in the epidemic.
A 1991 paper by a noted AIDS researcher, reported studies undertaken to evaluate the hypothesis that elevated beta 2M levels were associated with the production of interferon. But this association had been well known for about 20 years!
Beta 2M levels can be elevated in certain conditions where interferon is not detectable. But even before the onset of the epidemic we knew that when interferon levels are elevated we expect to see increases in beta 2M. Nonetheless this particular paper was noteworthy in that it discussed this association. Few others papers dealing with beta-2M during those years made any mention of it, thus avoiding the following question. If elevated beta-2M levels indicated an adverse prognosis should we not be concerned that administering interferon will result in yet further increases in beta-2M?
This of course doesn’t mean that beta-2M mediated any pathogenic effects, but it simply prompts a question. Of course we now know that interferon mediates some of the pathological effects of HIV disease, and beta-2M can properly be regarded as a surrogate marker for interferon.
How is it possible to explain why in a disease characterised by low CD 4 lymphocyte counts and the presence of large amounts of interferon, it was thought that injecting yet more interferon could possibly be of help?
Dr Fauci and other investigators tried to explain the paradox of administering interferon to people who already had huge amounts of it in their blood stream by claiming that the endogenous interferon was different. The difference referred to was that the AIDS associated interferon could be partially inactivated by acid, whereas the administered interferon was resistant to acid (3).
But we knew that AIDS associated interferon was neutralized by monoclonal antibodies against administered interferon, meaning that the molecules were identical, and the interferon in patients’ blood had the antiviral activity expected of alpha interferon when tested in cell cultures. It certainly was responsible for the beta 2M.
In fact the sensitivity to acid is not a property of the interferon molecule but is conferred by other components. Interferon from patients that is partially purified loses its sensitivity to acid.
This explanation which cannot stand up to even the most cursory scrutiny was apparently good enough for community writers on AIDS treatment.
I repeatedly tried to bring attention to the probable contribution of interferon to pathogenesis without success. I received no response to a letter that can be seen by clicking here.
In 1990 I was able to organize a meeting to bring basic researchers and clinicians together to discuss the role of interferon in pathogenesis and in treatment.
The meeting was very well attended, but I have no idea if it accelerated interest in interferon’s role in pathogenesis.
I probably angered a number of investigators when I tried – with the help of Michael Callen and Richard Berkowitz to inform people of the risks of receiving very high doses of interferon in clinical trials. We felt that information about interferon should be included in the consent form. We even went to the lengths of taking out a paid advertisement in the New York Native to inform people about potential problems associated with receiving high dose interferon. This can be seen here. Richard Berkowitz has posted the complete ad on his website, Richardberkowitz.com
It’s now more difficult to undertake studies that can investigate correlations between endogenous interferon levels and various immunological abnormalities. It would have to be done on material stored before AZT was introduced or on individuals not receiving antiretroviral drugs.
The reason for this is that antiviral therapy promptly removes interferon from the circulation. This is something that the group I worked with at Roosevelt hospital, including Elena Klein and Michael Lange found shortly after AZT was introduced. We had access to sera from clinical trials of AZT. In one of these trials AZT was administered for a week on alternate weeks.
We found that interferon promptly disappeared during the week on AZT, only to reappear just as promptly when AZT was discontinued.
Another report studying sera from the same trial looked at the effect of intermittent AZT therapy on beta 2M. The same saw tooth response of beta 2M was unsurprisingly seen, but my recollection is that the word interferon was not mentioned.
Undoubtedly researchers today are looking at the significance of this almost immediate turning on and off of the interferon response in pin pointing the mechanism of its induction.
With continuous AZT therapy interferon remains suppressed for about 5 weeks and then reappears and increases steadily. Interestingly HIV as measured by p24 antigen reappears many weeks after interferon
One interesting implication of the effect of AZT (and other antiretroviral drugs) on endogenous interferon levels relates to hepatitis C. It’s been noted that in coinfected individuals starting anti HIV drugs, sometimes there is an increase in liver enzymes as well as an increase in hepatitis C RNA. It’s possible that in some individuals, hepatitis C is controlled to some extent by endogenous interferon, and flares up when interferon is removed by the anti HIV drugs. Some researchers have commented on this although I don’t know it this possibility has actually been studied. There are also other reasons why liver enzymes can increase on starting anti HIV drugs.
We presented these results at a meeting I organized in New York in 1990.
The innate immune response is a first line of defence against infection coming into play within hours. Secretion of interferon is an important part of this response which also includes the inflammatory response. Innate immune responses are immediate attempts to localize and overcome infections. These beneficial responses last for a brief period because they become harmful if prolonged. There are mechanisms that turn them off. But in HIV infection and in pathogenic SIV infections innate immune responses are not turned off. Persistent immune activation involving the adaptive immune system as well is at the heart of HIV disease pathogenesis.
Several important research questions that I’m sure are being pursued are: Why is the interferon response not turned off in HIV disease? Why does the innate immune response continue to be activated? What are the mechanisms that normally turn off interferon production and why are they not working?
The precise role of interferon in contributing to CD4 loss remains to be worked out, although several mechanisms by which this can occur have been elucidated.
But for years there was almost no work on identifying what induced such high levels of interferon and on determining which cell produced it. It took over twenty years since interferon was first identified in AIDS sera for work to be undertaken to identify the ways in which it contributes to pathogenesis. There is still much to be learned, and hopefully the findings can be translated into new therapeutic possibilities.
The reasons why the role of interferon in pathogenesis has been neglected for so long are undoubtedly multiple and complex. But one reason for this neglect was surely the early enthusiasm to administer it as treatment.
But many years have been lost by the neglect of a critical line of research the importance of which was evident in the same year that AIDS first came to attention.
I have chosen these three references from a growing literature to illustrate what we are beginning to learn about interferon’s role in the pathogenesis of HIV disease.
- Herbeuval JP, Shearer GM. HIV-1 immunopathogenesis: How good interferon Turns Bad.Clinical Immunology (2007); 123920:121-128
- Boasso A,Hardy AW et al. HIV-1 induced Type 1 interferon and Tryptophan Catabolism Drive T Cell Dysfunction Despite Phenotypic Activation. PLoS ONE (2008); 3(8): e2961
- Stoddart CA, Keir ME et al. IFN-α-induced upregulation of CCR5 leads to expanded HIV tropism in vivo, PLoS pathogens (2010); 6(2) e1000766
Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with SLE have an unusual acid-labile form of human leukocyte interferon (HuIFN-α) in their serum. Sera from 91 homosexual men were tested for the presence of HuIFN. Of 27 patients with KS, 17 had significant titers of HuIFN in their serum. Ten of 35 patients with lymphadenopathy and three of four patients with other clinical symptoms also had circulating HuIFN. In contrast, only two of 25 apparently healthy subjects had serum HuIFN. All 32 samples of HuIFN had antiviral activity on resemble findings in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Many patients with bovine cells, a characteristic of HuIFN-α, and all of 14 representative samples tested were neutralized by antibody to HuIFN-α. In addition, the HuIFN-α in six of eight representative patients was inactivated at pH 2 and therefore appears to Some immunologic parameters in homosexual patients with Kaposi’s sarcoma (KS) or unexplained lymphadenopathy be similar to the HuIFN-α found in patients with SLE. These findings suggest that an autoimmune disorder may underly lymphadenopathy and KS in homosexual men.
Sonnabend J., Saadoun S., Griersen H., Krim M., Purtilo D. Association of serum interferon with hematologic and immunologic parameters in homosexual men with AIDS and at risk for AIDS in New York City.
2nd International Conference on AIDS Paris 1986. Abstract 100
There were several other interesting associations including a positive correlation between IgA and interferon, so needless to say, there is an inverse correlation between CD4 counts and IgA. In the early days I used easily obtainable IgA measurements as an unproven prognostic indicator.
I found a transcript of a meeting in New York where Dr Fauci answered questions posed people with AIDS and their advocates, where he explains this.
You can see this at the very end of another article I wrote about interferon and AIDS in 2009 that contains some of the same material in this blog.
Posted on January 28th, 2011 No comments
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.
N Engl J Med 1987; 317:185-191July 23, 1987
Posted on May 19th, 2010 No comments
The revised USPHS guidelines for the treatment of HIV/AIDS
Guidelines for the treatment of HIV/AIDS were first issued by the US Department of Health and Human Services (DHHS) in 1998. They have undergone numerous revisions since then; the most recent was in December 2009.
The first guidelines were issued shortly after potent antiviral medications became available. We knew very little about how best to use these drugs at that time, and with only a few years experience our knowledge of their adverse effects was understandably limited.
Perhaps the only reliable information we then had was that individuals with fewer than 200 CD4 lymphocytes received a life saving benefit from their use.
Despite such limited information the panel that had been convened to write the guidelines made firm recommendations for the use of antiviral drugs in groups of patients for whom evidence of a net benefit was lacking.
Even in the absence of experience with the newer antiviral agents, at least two probable problems associated with their use could have been anticipated in 1997. The propensity of just about any microorganism to develop resistance to antimicrobial agents was no mystery. Nor was it a surprise that adverse reactions to new drugs appeared as they were used for longer periods.
As might have been anticipated healthier HIV infected individuals have not infrequently had to deal with both of these problems.
Why then did the first HIV/AIDS treatment guidelines panel not propose and encourage the conduct of a randomized prospective clinical trial to answer the question of whether immediate or deferred treatment with antiviral drugs could or could not prolong life and improve its quality or made no difference apart from cost?
Since the problems that were to arise could have been anticipated, if not their extent, the guidelines committee must have accepted that whatever evidence existed was sufficient to reassure them that there would be a net benefit to starting treatment at 500 CD4 lymphocytes.
The most recent revision of the DHHS guidelines now propose, as the first guidelines did, that treatment be initiated at a CD4 count of 500. A prospective randomized trial that directly addresses the question of when treatment is best initiated has yet to be completed. In the absence of information from such a trial the committee has relied on evidence from some large retrospective observational studies.
In the next post John Falkenberg writes about some previous experiences where advice based on results of retrospective analyses of observational data had to be reversed when the results of randomized controlled studies became available.
I believe the biggest mistake made in 1997 by the guidelines committee was in not responding to the very real possibilities of dangers associated with early treatment initiation by encouraging the completion of a prospective randomized trial, such as START, that could by now have reliably provided an answer to the question of whether immediate or deferred treatment is better or worse or makes no difference that is, apart from cost.
It’s not the benefits of early treatment that are in question. Of course there are benefits, but the question we need an answer to is when in the course of HIV disease the benefits of treatment outweigh the risks.
Long term exposure to antiretroviral drugs can have harmful effects. It can take many years to recognize some of these adverse effects. For example we learned only in the last few months that under certain circumstances neurocognitive function improved in some people who stopped antiviral drugs (ACTG 5170).
So the challenge is to find out how best to use the drugs. Put another way, we must find ways to safely minimize exposure to the drugs, which until we have drugs without significant adverse effects, is what determining the optimal time to start treatment is all about. We don’t know if a person deferring treatment until a CD4 count of 350 will or will not live longer with an overall better or worse quality of life than someone starting at 800 or even 500 CD4s.
We do know that at 350 CD4s, benefits of treatment far outweigh risks. But no matter what NIH guidelines committee members may feel, we do not yet have the most reliable evidence that benefits of treatment will outweigh risks when starting at higher numbers.
The wording of the USPHS guidelines is such that depending on whose vote one goes with, I suppose might even be interpreted to mean a recommendation for every HIV positive individual to receive treatment irrespective of CD4 count.
A letter written to the DHHS panel in 1997 suggesting that a randomized prospective trial be encouraged to provide guidance for individuals with greater than 200 CD4 lymphocytes remained unanswered although received.
Sadly the repeated changes to the guidelines since their first appearance in 1998 appear to indicate a retreat from evidence-based recommendations. Maybe this should be stated as a retreat from attempting to find the most reliable evidence on which to base recommendations. The guidelines panel go to great lengths to reassure us that their recommendations are indeed evidence based.
But as they recognize, the quality of evidence can vary. They also recognize that evidence of the highest quality is derived from the results of prospective randomized trials. Yet not only do they not vigorously encourage the completion of such trials, their recommendations actually inhibit enrolment into START which is such a trial.
Unfortunately the DHHS recommendations while not binding have a huge influence. Remarkably they are even regarded by some as setting an ethical standard, so that fears have been expressed that enrolment into START might be considered unethical as the current guidelines revision recommend starting treatment at 500 CD 4 lymphocytes.
Thirteen years after the first guidelines were issued, the DHHS panel has now made revisions that continues to threaten enrolment into a randomized controlled trial that will provide clear guidance to HIV positive individuals and their doctors about when to initiate antiviral therapy.
Surely, when we recognize that reliable evidence is lacking to inform a very important clinical decision, is it not our obligation to seek the evidence, rather than settle for the uncertainties associated with evidence of inferior quality? This is not only for the benefit of our patients but also to affirm that our stated respect for evidence-based recommendations is more than lip service.
At this time the DHHS guidelines are the only ones that recommend a start to treatment at 500 CD4 lymphocytes.
The DHHS guidelines have been of benefit to people with HIV/AIDS. But on the issue of when to start antiviral therapy they have not best served the interests of HIV positive individuals.
We need a randomized controlled trial to answer this question, not the votes of a committee.
I believe that many health care providers would welcome the opportunity to be able to present an option to their patients with greater than 350 CD4s, to enrol in a study such as START.
At the end of the day, determining when it’s best to start is not something you vote on. It’s something so important that you nail it down with a trial such as START.
Posted on April 13th, 2009 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
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
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.