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 19th, 2010 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
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 May 18th, 2009 2 comments
I’m returning to this topic yet again because the French National Commission on HIV/AIDS has now published a statement on treatment as prevention.
This document discusses treatment as prevention at the individual and the population level together.
It places great importance on individual autonomy, which includes the fundamental right individuals have to make decisions on their own behalf. I have come to see the issues in a somewhat different way after reading the French document.
This document can be seen here:
It is worth mentioning again that the term “treatment as prevention” can be applied to two different situations.
At an individual level it refers to prevention of HIV transmission by sexual contact between two individuals. The Swiss statement concentrated on this aspect.
The term is also applied at a population level, where the goal of treatment as prevention is the control of the epidemic, even as suggested by some, a means to end it.
The principle underlying the proposals to use treatment as prevention in both of these situations is the same. It is the reduction in infectivity that results from the effect of antiretroviral therapy.
Unlike the Swiss recommendations that dealt only with transmission between two individuals, the French statement deals with both aspects.
Treatment as prevention is not the same when applied to individuals as opposed to populations. For example, transmission between some individuals may be interrupted by treatment without having an effect on the epidemic.
To have an impact on the epidemic additional factors that do not apply at an individual level have to be considered.
For example, the number of infected people who must be treated in relation to the total number of people who are infected must be taken into account, if treatment is to have an effect on the epidemic.
For treatment as prevention to have a greater effect on the epidemic, a larger proportion of infected people must be treated.
Canadian studies have suggested that the proportion of infected people who must be treated in order to reduce transmission would need to be increased from 50% to 75%. Transmission would be slowed but not reversed with treatment rates below 50%.
Thus the percentage of infected people who are treated is related to the extent of the impact treatment will have on the epidemic.
At an extreme, if the stated objective is to end the epidemic, as has been proposed by some, the proportion of infected people who would need to be treated would be so large that it would have to include those who do not need treatment for their own benefit.
[ Added October 3, 2010: It appears that there are experts who believe that everybody who is HIV infected, no matter at what stage of their disease would benefit from treatment. For them, there would be no ethical problem at al. These experts believe that treatment benefits every HIV infected individual. But the practice of medicine is not a faith-based enterprise, although I imagine individuals holding this belief probably pay lip service to evidence-based medicine. As opposed to a belief that everyone will benefit from treatment there is no evidence of the best quality that for people with greater than 350 CD4 lymphocytes, the benefits of antiviral drugs will outweigh their risks. Hopefully the START trial will provide the evidence needed to help HIV infected individuals and their health care providers make a decision as to when it's best to start treatment, that will be informed with hard evidence rather than belief based interpretations of data. The San Francisco Department of Public Health now recommends that all HIV infected individuals receive treatment. so they are able to avoid having to deal with the ethical problem that arises in recommending treatment to people not known to derive a net benefit from doing so as they too rely on their belief that all benefit. For individuals starting treatment at higher CD4 numbers the harms caused by the drugs may outweigh their benefits. Such individuals may choose to receive treatment in order to make them less infectious, but surely respect for their autonomy means that we must provide them with evidence of the best quality so that their choice is informed, and this also means that where the best evidence is not yet available on when it's best to start treatment we must tell them that this is the case. The concern expressed last May about the threat of coercion may have been justified in the light of the San Francisco Department of Public Health's recommendations. While it is perfectly legitimate and even expected of them, health care providers make recommendations based on their judgement, which in turn depends on the knowledge and experience they have. This is why we turn to experts. But their respect for individual autonomy really requires that where evidence of the best quality does not yet exist to justify their recommendation, and where there is no expert consensus on the issue, that these facts be told to the individual. A failure to do so in making the recommendation, can be seen as being coercive. Consenting to the recommendation will not be fully informed, and in this way the individual's autonomy is not respected.]
I have written about the multitude of problems arising from this situation in previous posts on this topic. Lurking behind such an extreme proposal is the threat of coercion, and the possibility of an infringement of individual rights. Very disappointingly this aspect has been barely acknowledged in English language discussions of treatment as prevention.
However if, as I believe, an additional goal of treating infected people is to add a powerful tool to prevent transmission, we are then not stating an objective that would require the participation of individuals who do not themselves need treatment.
Admittedly, treating only those who need to be treated may not have such a great impact as also treating additional infected people who do not need treatment. Therefore we must also intensify and improve our efforts at targeted prevention education with the promotion of condom use.
But we will avoid the insuperable problems and threats to personal autonomy associated with treating individuals who do not need to be treated for their own benefit.
The goal of treatment as prevention as applied to controlling the epidemic is perhaps better stated in a different way.
It might be preferable to simply state that the goal is to provide treatment to every individual who needs it. This goal must therefore be coupled with enhanced efforts to facilitate regular testing.
If we can achieve this it is likely that not only will the individual benefit, but there will be an impact on the extent of the epidemic.
There is evidence of a reduction in HIV transmission in areas where antiretroviral treatment has been introduced. .
When we emphasize that our efforts are to identify infected individuals and make treatment available to all who need it, we eliminate all the problems connected with treating infected individuals who do not need treatment.
One reason why the French document is so significant is that it stresses the importance of individual autonomy.
It emphasizes the need to respect individual rights and adds a caution to avoid the temptation to employ coercive measures in the name of the public good. Testing is the key to any success of this approach to prevention, but testing must be voluntary and informed. As of course is a decision to receive treatment.
Here is an excerpt from the French statement that shows the concern for individual autonomy and recognizes that there is a potential threat of the employment of coercive measures.
” if screening and massively treating infected persons enables to reduce the epidemic, it could be tempting to consider population compulsory systematic screening and to voice more or less insistent summons for the treatment of persons identified as HIV positive. Should public authorities use all convenient means to implement efficient policies that strengthen screening, they need to be careful not to yield to such fallacious reasoning. The issue of improving screening efficiency surely does not invalidate any of the reasons that have hitherto prevailed for rejecting compulsory screening. Keeping screening hinged on free and informed consent remains a matter of respecting the fundamental right of the person; it is at the same time an obligation even from the public health viewpoint,
Pursuing a probably completely unworkable attempt to end the epidemic by yearly testing and treating everyone infected as has been suggested by some, is wrong. The problems of feasibility, adherence, resistance, and the threats to individual autonomy cannot be overcome.
Instead we should:
Offer treatment to all who need it.
Facilitate testing, identifying and removing barriers that impede it.
Intensify and improve our efforts at targeted prevention education.
Promote condom use and make them available.
There is a final issue.
Who needs to be treated? Certainly everyone with a CD4 count below 200. Apart from this we do not know, so until we obtain some guidance from prospective randomized studies, it is prudent, in general, to not delay treatment to a CD4 count below 350 as is currently recommended.
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.