The Cost of Truvada Pre-exposure prophylaxis, PrEP
In my last post I wrote about the very small reduction in the absolute risk of HIV infection in the iPrEx trial among those taking Truvada as pre-exposure prophylaxis.
The 44% reduction in relative risk conferred by Truvada was the only efficacy measurement explicitly presented by the investigators. That the absolute risk reduction was only 2.3% was not mentioned in the various presentations.
I suspect that many reading press reports of this so called breakthrough were unaware that in fact, the actual risk to people taking Truvada was 2.8%. (36 infections in 1251 participants). True, this is less than the 5.1% risk to those on placebo, but by very little. Certainly not enough to justify the bewildering acclaim given to the iPrEx trial results.
Failing to clearly state the absolute risk reduction of an intervention is something we have come to expect from salesmen to inflate the efficacy of a product, but not from clinical researchers. Large reductions in relative risk can be associated with minute reductions in absolute risk when the events prevented are low to begin with.
Another important reason why absolute risk reduction should be stated in a report is that this allows one to calculate the number of people who need to be treated to prevent one event, in this case, one HIV infection.
Although the iPrEx investigators did not explicitly provide these numbers, they can be worked out from data presented, as I did in my last post and was also done in a letter published in the New England Journal of Medicine of April 7, 2011 in response to the iPrEx trial report, where the authors report that 44 people need to be treated to prevent one infection (I got 45).
They then went on to calculate that it would cost $400,000 a year to prevent a single infection.
This figure does not even include the cost of the necessary monitoring for infection. In another letter, it was suggested that such monitoring be done monthly to prevent the emergence of resistant virus by detecting infection early.
From Sean Strub’s calculations (in his comment to my post on the POZ magazine website) which included doctor’s visits and tests, the annual cost to prevent a single infection would be about $500.000.
These figures are based on drug costs in the US.
Truvada PreP not only does not work well enough it will cost a half million dollars a year to prevent a single infection.
Maybe this is indeed a “game changer” but not in the sense intended by the triumphalist reports coming from the recent Rome AIDS conference.
There definitely seems to be a perception that PrEP is a viable prevention option for everybody; there even have been calls for its general implementation. These cost estimates alone would make it unfeasible as a public health measure but there are additional reasons, importantly its relatively low efficacy.
PrEP is a reasonable option for only a very small number of individuals at high risk for infection who are able to be regularly checked for infection. I believe there is no disagreement about this; the controversy is only about its general use.
Implementation of PrEP on a wide scale will almost certainly result in an increase in new infections. It’s not only adherence to the drug regimen that will not be maintained by all. Adherence to a schedule of regular testing for infection cannot be relied on. Facilities for performing the needed tests may not even always be available.
The way PrEP has been promoted has probably already damaged targeted prevention education programs with support for continued condom use, an activity already in great need of support.
Drugs for prevention are paid for from a different budget than prevention education programs, and health departments already under budgetary constraints may feel that prevention needs can now be paid for by those entities that pay for drugs, private insurers or Medicaid/Medicare.
The amount of almost uniformly uncritical publicity given to PrEP is completely out of proportion to its utility. It’s a hugely expensive and very poorly effective prevention intervention, of use to only a very small number of individuals, and its misleading promotion has probably already damaged prevention education programs.
Considerable resources must have been devoted to publicize and promote PrEP over many years, in a way that has not taken care to reinforce prevention education with support for continued condom use. One can only wonder why.
Drs Dong Heun Lee, M.D. and Ole Vielemeyer, M.D of Drexel University College of Medicine in Philadelphia are the authors cited.
Pre-exposure prophylaxis with Truvada just does not work nearly well enough.
Pre-exposure prophylaxis (PrEP) to prevent HIV infection with Truvada is not sufficiently effective
There is a similar
post on the POZ magazine website.
PrEP is a prophylactic intervention where uninfected people take anti HIV medications before sexual intercourse to prevent becoming infected with HIV. The use of a vaginal gel containing an anti HIV drug has also been tested.
The results of several trials of PrEP have been reported in the past year, all but one hailed as huge successes, with reported efficacies of up to 90% among those adhering to the treatment regimen.
The efficacy of PrEP in preventing HIV infection was so great that this intervention has been trumpeted as signalling a revolution in HIV prevention. A new era has opened up we are told; PrEP is a “game changer”.
With such enthusiastic coverage it may come as a surprise that none of the reports explicitly told us what the actual efficacies of the interventions were in preventing HIV infection, perhaps because they were so low as I’ll describe.
Maybe what’s even more startling is that this omission seems to have gone completely unnoticed, at least in the universally jubilant press reports and equally enthusiastic press releases from AIDS advocacy organizations.
How has this been possible?
The reason is that the results have been reported as reductions in relative risk only. This tells you nothing about actual risk reduction. What is reported is a percentage reduction in risk from a number that was never clearly stated. For example in the iPrEx trial of PrEP among men who have sex with men, the drug, Truvada, was reported to reduce the risk of infection by 44%. But 44% of what? We were not explicitly told, although it’s possible to calculate what it is.
In fact we can calculate that the absolute risk reduction conferred by Truvada is a measly 2.3%, a number nowhere to found in the trial report.
The relative risk reduction may have been 44%, but this translates into only an actual 2.3% reduction in absolute risk, as is shown below.
Reporting relative risk reduction only is the oldest trick in the book to exaggerate the effects of an intervention, used by salesmen, but apparently also by clinical researchers.
What makes the unquestioning acceptance of these reports of relative risk reductions achieved by PrEP even more remarkable is that there is a tremendous amount of material explaining the difference between relative and absolute risk reduction. Just type the words “relative risk absolute risk” into the Google search box.
Relative risk reduction tells you the percentage reduction in risk in the treated group compared to that in the group receiving placebo, or how much lower the risk with the intervention is relative to the risk to begin with.
If you are not clearly told what the risk is to begin with, then you can’t tell what the actual reduction in risk is when taking the intervention; all you know is how much lower it is than a number that’s not clearly presented to you.
Although not included in the iPrEx trial report there is information that allows one to calculate the absolute risk reduction conferred by Truvada. To do this we need to know what the risk of infection is to begin with.
This is the number of infections occurring in the placebo group over the time period of the study.
64 out of 1248 people in the placebo group were infected, which is 5.1%, or 0.051 in 1. (since then there have been additional infections reported at the Rome AIDS conference, reflecting an increase in the number of infections over a longer time period).
In the group receiving Truvada 2.8% of 1251 people were infected.
The absolute risk reduction conferred by Truvada is simply 5.1 minus 2.8 which is 2.3.
A 2.3% reduction in absolute risk conferred by Truvada is the more accurate measure of its efficacy. Hardly something to celebrate.
A 44% reduction in relative risk sounds much better, although far from spectacular,but unfortunately this number tells you nothing about actual risk reduction.
Relative risk reduction is calculated as follows:
It is the number of events in the treatment group subtracted from the number of events in the placebo group divided by the number of events in the placebo group.
On its own, relative risk reduction is not a helpful number.
Of much greater help to a person considering Truvada PrEP is knowledge of the actual risk while taking Truvada (over the period of the study, a median of 1.2 years).
That number is 2.8%.
Knowing the absolute risk reduction allows one to calculate another important measure. This is the number of people who need to be treated to avoid one infection (NNT).
From information contained in the trial report 45 people need to be treated to prevent one infection. I did not notice this number in the trial report nor was the absolute risk reduction
of 2.3% reported. NNT is a useful number as it allows one to estimate what it would cost to prevent a single infection with Truvada.
The cost of the drug is the least of it. A person taking Truvada PrEP needs to be monitored at regular intervals for toxicity and importantly, for infection, in order to avoid the inevitable emergence of resistant viruses as a result of sub optimal treatment.
If Prep is implemented on a large scale which some AIDS advocates seem to be calling for, but is unlikely to happen, then there may well be increases in new infections with viruses resistant to the drugs in Truvada in men who have sex with men, in IV drug users and in African populations.
PrEP is not a success, at least not with Truvada.
However such a failure was transformed into a triumph, part of the explanation is the use of relative risk reduction numbers with care taken to remain silent on absolute risk reduction.
Despite all the literature available to help people tell the difference between absolute and relative risk reduction, this evidently was a resource not used by those cheering along this ineffective intervention.
Treatment as Prevention: Protecting Individual Autonomy
Treatment as Prevention
Protecting patient autonomy
Patient autonomy is just a particular instance of individual autonomy, a term that may sound pretty dry and academic but if we used the term individual freedom we would essentially be talking about the same thing.
Respect for the autonomy of the individual may be the most important of the principles that form the foundation of medical ethics. (1)
One attribute of personal autonomy is: “the capacity to be one’s own person, to live one’s life according to reasons and motives that are taken as one’s own and not the product of manipulative or distorting external forces.” (2)
There is no disagreement about the importance of respect for individual autonomy but as I’ll explain, it seems that its pre-eminence is being questioned in some proposals to use antiretroviral treatment to prevent transmission of HIV.
The recent demonstration that antiretroviral treatment can prevent transmission of HIV among serodiscordant heterosexual couples is great news. However, when the person offered treatment has not yet been shown to personally benefit from it, an ethical issue needs to be addressed. It has not yet been reliably demonstrated that for people with greater than 350 CD4 lymphocytes, starting treatment immediately rather than deferring it confers a net benefit; indeed, it may even prove to be harmful. A randomized controlled trial now enrolling will provide needed information, but we will have to wait several years for its results.
The issue isn’t whether or not people with greater than 350 CD4 lymphocytes should receive treatment. A respect for their autonomy requires that the decision whether or not to do so is made by them and is made free from coercion.
A recent issue of the Journal, Public Health Ethics (3) is devoted to ethical issues associated with the proposal that a program of universal testing and treatment of infected individuals could bring an end to the HIV/AIDS epidemic. Such a proposal would involve the treatment of healthier HIV infected individuals not at this time known to personally benefit from antiviral medications which could even harm them.
In an article in the journal referred to above, public health ethics is said to require an approach where respect for individual autonomy is not paramount; a commitment to the supremacy of individual autonomy could have no place where the “primacy of collective wellbeing is the starting point”.
In that case I wonder just how desirable a collective wellbeing would be where individual rights were subservient to whatever was defined as the collective good.
I can only hope that this goes nowhere, as abandoning the pre-eminence of respect for individual autonomy opens the door to tyranny, paternalistic or otherwise. Individual freedoms have been hard won, and we should always be aware of harms that have been perpetrated in the name of the public good, even leaving alone the problem of who defines what constitutes the public good.
In public health, medical research and medical practice, concern for individual autonomy remains paramount. The only commonly agreed acceptable exemption is the restriction of personal freedoms to prevent harm to others such as limiting the movement of individuals with highly communicable diseases where the harm that may be done to others is considerable. That is, outside the criminal justice system, among individuals who are free.
People have the right to make decisions about their treatment, their participation in a research study, or in a public health intervention, free from coercion.
Providing misleading information is a form of coercion; withholding information may also be coercive.
Providers of health care have an obligation to provide patients with honest information to inform their decisions. This must include information about what is known about the risks and benefits of treatment, as well as what remains conjectural.
Information and the strength of the evidence upon which it rests:
It’s not enough to simply provide individuals with information concerning the benefits and risks of a particular treatment. In order for the information to be useful we must also indicate the strength of the evidence on which the information rests. (4)
The most reliable evidence regarding the effects of a particular treatment is provided by results of randomized controlled clinical trials. This is because the treatment in question has been put to the test in a protocol that minimizes bias; we can therefore have a greater degree of confidence that effects observed are in fact caused by the treatment.
Unfortunately information derived from randomized controlled trials is often unavailable. The clinical trial may not yet have been completed, or for whatever reasons the trial cannot be undertaken.
When this is the case we have to consider evidence of inferior quality, for example, evidence derived from reviews of patient records or observational studies, and the opinion of experts.
Observational studies are beset with interpretative difficulties because subjects are not randomly assigned to receive one or another kind of intervention. The particular reasons why participants were selected for study may influence the outcome rather than the effects of the intervention.
Expert opinion:
In all the systems I have seen that grade the quality of different kinds of evidence, expert opinion is at the bottom of the list. But expert opinion can be valuable to an individual in coming to a treatment decision when evidence of the highest quality is not available.
Respect for patient autonomy means that patients make their own decisions free from coercion. As noted, supplying misleading information is a form of coercion. To state that something is known to be the case, when it is only an opinion is misleading.
HPTN 052
HPTN 052 is the study which demonstrated the efficacy of antiretroviral treatment in preventing transmission of HIV among serodiscordant heterosexual couples. Although the result was not unexpected it is nonetheless significant because it was obtained from a randomized controlled clinical trial.
We now know that the uninfected partners of individuals with greater than 350 CD4 lymphocytes will benefit from treatment of the HIV positive partner. At this time we can only have an opinion about whether starting treatment immediately or deferring it will benefit or harm the infected partner with greater than 350 CD4s or be without effect – apart from cost.
Most of the jubilant reports of the results of HPTN 052 do not mention the problem facing the healthier HIV positive partner in coming to a decision. Do the commentators just assume that it’s been established that all infected individuals receive a net benefit from treatment irrespective of CD4 numbers? Or do they not believe it to be important that patients make their own decisions regarding their treatment?
I wish I could say I was startled to read in one newsletter that “For treatment as prevention to work….. people need to be convinced that early treatment is in their interest.”
Convincing people to take a possibly perilous course of action based merely on opinion and evidence of inferior quality is a step on a road that ends with enforcement.
A respect for individual autonomy means that we respect the right of individuals to make decisions on their own behalf, free from even subtle coercion. Our obligation as providers of health care information is to not only provide information, but also an indication of the quality of the evidence supporting it.
At this time we do not know that individuals with greater than 350 CD4 lymphocytes receive a net benefit from antiviral treatment. There is evidence that they may, but until this is put to the test in a randomized controlled trial such as START, we must not mislead them by trying to convince them that “early treatment is in their interest”.
Given adequate information, a person with greater than 500 CD4 lymphocytes may reasonably decide to take antiretroviral drugs to lessen the risk of infecting a partner even knowing that there may be no personal benefit or that there is a possibility of harm.
Whenever treatment is offered for any reason other than for a person’s benefit, and where it has not yet been reliably demonstrated that there will be a net benefit, a consent process should be required. I doubt though that this will happen.
At the end of the day what’s of central importance is that we respect our patient’s right to make choices about his or her treatment, and provide honest information to inform that choice, recognizing the difference between expert opinion and established fact.
(1) Ever since Beauchamp and Childress published the first edition of their classic text, Principles of Biomedical Ethics, in 1979 it’s been commonly accepted that beneficence, nonmaleficence, justice and respect for autonomy, are four principles that should guide medical ethics.
The Four Principles are general guides:
Respect for autonomy: respecting the decision-making capacities of autonomous persons; enabling individuals to make reasoned informed choices.
Beneficence: this considers the balancing of benefits of treatment against the risks and costs; the healthcare professional should act in a way that benefits the patient
Non maleficence: avoiding the causation of harm; the healthcare professional should not harm the patient. All treatment involves some harm, even if minimal, but the harm should not be disproportionate to the benefits of treatment.
Justice: distributing benefits, risks and costs fairly; the notion that patients in similar positions should be treated in a similar manner.
Beauchamp and Childress; Principles Biomedical Ethics, OUP, 5th edition
(2) Christman, J, 2001″Autonomy in Moral and Political Philosophy”, The Stanford Encyclopedia of Philosophy (Fall 2007 Edition) , Edward N. Zalta (ed.), URL = <http://plato.stanford.edu/archives/fall2007/entries/autonomy-moral/>.
(3) http://phe.oxfordjournals.org/content/3/3.toc
(4) Several systems have been devised to grade the quality of evidence.For example: http://www.cebm.net/index.aspx?o=1025 The GRADE working group has been working on assessing the quality of evidence since 2000. http://www.gradeworkinggroup.org/index.htm
Interferon in AIDS: Too much of a good thing
Slightly different accounts were posted on the POZ magazine blog site and on aidsperspective.net
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 a low white blood cell count.
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 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 formation.
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.
The discovery of 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 afternoons.
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
E. DeStefano, R. M. Friedman, A. E. Friedman-Kien, J. J. Goedert, D. Henriksen,O. T. Preble, J.Sonnabend* and J.Vilček (1)
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 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.
Ann NY Acad Sci 1984, 437: 65
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 fewer than 50 CD4s, 12 people with 10-49 units had fewer than 500 CD4s while 17 people without interferon had about 700.
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.
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.
Several other features recognized among our first patients could also have been effects of interferon. Elevated serum triglyceride levels were characteristically seen. We routinely centrifuged blood before sending the samples to the lab and the turbidity of our patient’s sera was striking.
Interferon inhibits an enzyme, lipoprotein lipase that could have contributed to elevated triglyceride levels (TNF can have the same effect), HDL cholesterol was characteristically low which could also be an interferon effect.
Patients were noted to have low blood tryptophan levels, and even in 1981 we knew that gamma interferon, and to a lesser extent alpha interferon could induce an enzyme (indoleamine 2,3 dioxygenase – IDO) that degrades tryptophan. This was known to be the basis of interferon’s inhibitory effect on toxoplasma gondii, an effect recognized in the 1970s. It’s also possible that tryptophan degradation may contribute to neurocognitive disorders and more recently IDO has been implicated in the suppression of CD4 proliferation. The ability of interferon to inhibit CD4 proliferation was first reported in 1983 – at least 25 years before the effect of IDO was noted.
The early zeal to use interferon as a treatment for HIV disease also created a very strange situation concerning a molecule called beta-2 microglobulin (beta 2M).
It was well known that alpha interferon is the major stimulus for the synthesis and release of beta 2M, a component of the HLA system referred to above.
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 it appeared that many AIDS researchers were either unaware of this association or remained silent about it. At a meeting I attended on prognostic indicators there was a presentation on beta 2M, but as expected the word interferon was not mentioned.
I made a comment that this omission was strange considering patients with elevated beta 2M also had elevated interferon levels. The researcher leading this session looked puzzled and asked if anyone knew what I was talking about. I was rescued from this embarrassing moment by a reply from the investigator that interferon assays, unlike tests for beta 2M, were expensive.
One might have expected some discussion but none followed. At this time interferon was being injected into people who already were producing large amounts of it. Beta 2M levels were therefore raised, so the investigators reporting that raised beta 2M levels were adverse prognostic indicators were in effect suggesting that the presence of interferon indicated a poor prognosis – something hard to reconcile with injecting more of it.
In fact the adverse prognostic significance of serum interferon had already been reported early in the epidemic, as early as 1983, in studies on gay men and people with haemophilia, but neglected as was the case with a good number of early studies.
At least one noted AIDS researcher, in 1991 reported studies undertaken to evaluate the “hypothesis” that elevated beta 2M levels were associated with the production of interferon, an association that 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 indicate an adverse prognosis should we not be concerned about administering interferon when there are already elevated beta 2M levels.
This of course doesn’t mean that beta-2M mediated any pathogenic effects, but it simply prompts the question about a role for interferon in pathogenesis.
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. We were able to detect it in patient’s sera in the first place by assays that depended on its antiviral activity. It certainly was responsible for the beta 2M elevations.
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 justification for administering interferon that 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. For example I received no response to a letter written to a writer on AIDS 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 appropriate to emphasize again that interferon has been spectacularly successful in the treatment of Hepatitis C in co-infected individuals, even at lower CD4 counts.
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.
AZT treatment was started in these three patients at time 0: HIV p24 antigen and interferon are promptly removed.
The effect of prolonged treatment with AZT on interferon is shown below.
Interestingly, interferon reappeared before HIV p24.
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.
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.
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.
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
(1)
Abstract
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.
(2)
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.
.
(3)
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.
The AZT trial that led to FDA approval
I’m moving some posts from aidsperspective.net/blog as there have been difficulties accessing that blog. This was originally posted there on January 28th 2011., with a similar but shorter article on my POZ blog.
The clinical trial that led to the approval of AZT for the treatment of AIDS in 1987 is a landmark event, not only in the field of HIV medicine but I believe it had a major impact on the drug regulatory process that has had effects in all fields of clinical medicine.
The trial reported in the New England Journal of medicine, had produced a dramatic result (1). Before the planned 24 week duration of the study, after a mean period of participation of about 120 days, nineteen participants receiving placebo had died while there was only a single death among those receiving AZT. This appeared to be a momentous breakthrough and accordingly there was no restraint at all in reporting the result; prominent researchers triumphantly proclaimed the drug to be “a ray of hope” and “a light at the end of the tunnel”. Because of this dramatic effect, the placebo arm of the study was discontinued and all participants offered 1500mg of AZT daily.
I was treating many HIV infected individuals in 1987 when the drug was approved for the treatment of advanced AIDS. I was puzzled by the results of the trial quite simply because those patients of mine who resembled trial participants would not have died in the period before the placebo arm was terminated. Many patients enrolled in the trial had experienced an episode of pneumocystis pneumonia within four months of participation. My patients and those of other experienced physicians were unlikely to die within four months of an episode of this type of pneumonia.
This means that if my patients had enrolled in the trial it’s probable that there would have been no deaths at all by the time the placebo arm was discontinued and thus an apparent dramatic effect of AZT on mortality would not have been seen.
There had to be an explanation for the discrepancy between the outcome of my patients (and those of other experienced physicians) and individuals participating in the trial; I was confident that an academic clinical researcher would sort this out.
But no explanation was forthcoming.
I was then able to obtain a copy of the application submitted to the FDA 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 reviewing 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 there would have been instances where the participant also had a personal physician. There was no analysis of trial outcomes based on this difference. Of course from what I have written, I would expect that mortality was probably confined to those participants who did not have a personal physician, but were treated by the study doctor.
But who knows? 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. I sent copies to all the clinicians who were prominent in the field – as well as to several patient advocates. There was not a single response – not even to reject the points I made. Just total silence. Realizing the difficulty in publishing independent material we – myself and mostly Michael Callen , decided to publish an independent journal. We called it AIDS Forum. Michael was the editor, and it lasted for three issues.
One last comment on the baneful effects of this trial: While it was not responsible for the undue influence industry has on medical practice, this trial probably provided the greatest impetus towards the sad situation we are in today. It is possible that in the field of HIV medicine, industry had its greatest opportunity to establish a firm hold on many different ways to influence practice. These include not only marketing strategies, but influence on guidelines committees, support of continuing medical education, the support of medical conferences and influence on reports of their proceedings, as well as the invention of the Key Opinion leader or KOL, to provide information to physicians. “Key Opinion Leader” is not the only absurd designation in this field. We also have “Thought Leader”. Needless to say these distinctions are not conferred by any academic institution; I would assume that the marketing departments of pharmaceutical companies are responsible for choosing who deserve these titles.
(1)
N Engl J Med 1987; 317:185-191July 23, 1987
iPrEx trial results of Pre exposure prophylaxis – PrEP ,
A very similar article has been posted at the aidsperspective site.
Pre-exposure prophylaxis, or PrEP, is an HIV prevention intervention in which anti-HIV drugs are taken to prevent infection. A safe, effective and affordable drug that could achieve this would be a powerful prevention intervention even possibly capable of halting the spread of the epidemic.
Last week we were told the results of the iPrEx trial that tested the efficacy of PrEP with Truvada, a combination of two anti-HIV drugs, in reducing new HIV infections among a group of men who have sex with men considered to be at high risk for HIV infection.
The announcement of the results was greeted with almost universal jubilation.
“That’s huge,” said a prominent AIDS researcher, “That says it all for me.”
“Today marks a major step forward in our quest to combat HIV among MSM
“This discovery alters the HIV prevention landscape forever,”
“….. the new data “represents the most promising development in HIV/AIDS since the introduction of triple combination drug therapy in 1996.”
“This is a game-changing trial result,”
Science magazine reported that..
“The researchers applauded and some even cried when they heard the bottom line”; “I have not cried this hard in years” – said one researcher.
These exultant cheers are usually reserved for the most momentous of breakthroughs.
Demonstrating that a drug could be safe and effective in preventing infection would indeed be a momentous breakthrough as already noted.
But the iPrEx results, far from representing such a breakthrough, indicated that PrEP, at least with Truvada, together with counselling and provision of condoms, reduced new HIV infections among men who have sex with men only modestly. It’s unlikely that the 44% reduction in new infections that was seen is of sufficient magnitude to make PrEP with Truvada viable as a public health prevention intervention. Moreover, as will be described there are significant safety concerns, a demonstrated danger of the emergence of drug resistant HIV, and the drug is far from affordable.
A 44% reduction in new infections is not huge; even those extolling the trial results would agree (at least I think they would, but who knows considering the over-the-top responses).
But what is most troubling is that the researchers have squeezed an efficacy of Truvada of over 90% by a questionable statistical sleight of hand, an improper use of sub-group analysis, a technique of data dredging that has been soundly discredited. I’ll return to this.
This has resulted in headlines such as “PrEP works – if you take your pills”, I don’t know if this will persuade some people to abandon condoms and religiously take their pills. Unfortunately, as will be explained, the type of subgroup analysis that apparently allowed investigators and commentators to confidently claim a greater efficacy of PrEP is not reliable. Maybe consistent use of Truvada will reduce new infections by over 90%. Maybe not.
For the moment staying with the ability to reduce new infections by 44%: As a public health intervention to be used on a wide scale, this degree if efficacy is just not good enough to justify using Truvada to prevent a life threatening infection. Even if the risk of infection is low this must be balanced against the gravity of the infection. About 3% of participants in the Truvada arm of the trial became infected as opposed to about 5% among those receiving placebo.
Perhaps it’s on this issue that I’m at odds with the huge acclaim given to the trial results. Maybe the prevailing view is that a 44% reduction in new infections is indeed good enough; some commentators are even discussing implementation.
PreP proponents like to compare it to malaria prophylaxis. If the efficacy of malaria prophylaxis were of the same order as that of Truvada in relation to HIV, I suspect many people might think twice before visiting an area where there was a risk of malaria.
Let’s take a closer look at the trial results, particularly the claimed greater degree of efficacy in compliant participants reported in the New England Journal of medicine.
I have commented briefly on this in my blog on the POZ magazine website.
The medication used in the trial, Truvada, is a combination of two anti-HIV drugs, FTC and tenofovir. It was compared with placebo in over 2000 men who have sex with men, considered to be at high risk for HIV infection.
The 44% reduction in new infections was achieved in conjunction with counselling, provision of condoms and monthly tests to monitor for infection.
This is not a good enough performance to justify widespread use of Truvada to protect against infection. The investigators then looked at blood and tissue levels of the drugs in people who became infected and those who did not. They found that those who remained uninfected had detectable drug levels while those who became infected did not.
They incautiously trumpeted this result as proving that Truvada works well if the pills are taken consistently – stating that in those who took their pills more consistently the relative risk reduction was well over 90%.
On the surface this sounds good. Almost all the commentators thought so.
However looking at the results in a sub-group of participants can be misleading. Most particularly in a sub-group that is defined after randomization; who would or would not comply with treatment could not have been known. The problems with subgroup analyses will be clearer after a short account of intention to treat analysis.
Intention to treat analysis is the most reliable way to analyse clinical trial data. In such an analysis participants are analysed in the group to which they were randomized, irrespective of whether they dropped out, or didn’t adhere to the treatment or strayed from the protocol in other ways. This seems counter-intuitive, but there are sound reasons why intention to treat is regarded as the best way to analyse trial data, among them that it more reliably reflects what happens in real life, rather than in a clinical trial. For example, one reason why pills may not work is because they are not taken. If they are not taken in a trial we have to be concerned that they may not be taken in real life. Take a look at this excellent explanation of intention to treat: Making sense of intention to treat.
As noted, the trial investigators made a lot of the sub-group analysis showing greater efficacy in those who took Truvada pills as measured by finding the drugs in blood and tissue samples.
This is surprising as the pitfalls inherent in such post-hoc sub-group analyses have been recognized for years. Commentators, some of whom are clinical researchers, in their over-the-top exultation at the results of the analysis in those compliant with Truvada may have forgotten about the treachery inherent in sub group analysis. A few commentators give the problem only passing acknowledgement.
This is a classic paper on sub group analysis:
Yusuf S, Wittes J, Probstfield J, Tyroler HA: Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials.
Journal of the American Medical Association 1991 , 266:93-98
This is from that paper:
“Analysis of improper subgroups, though seductive, can be extremely misleading, because a particular treatment effect may influence classification to the subgroup. Thus, an apparent subgroup effect may not be a true effect of treatment but rather the result of inherent characteristics of patients that led to a particular response or to the development of side effects”.
In iPrEx the subgroups were categorized by events that happened after randomization, so the adherent group is an “improper” subgroup. “Subgroups of clinical trial subjects identified by baseline characteristics … is a proper subgroup while a subgroup determined by post randomization events or measures is an improper subgroup”.
In actuality the attention given to the subgroup that had blood and tissue drug levels is an example of the treachery of such sub-group analyses.
As an illustration, the reduction in new infections seen in this group may well have resulted from the following possibility.
People who take their pills consistently are more likely to use condoms consistently and in general are more attentive to risk. So if it were possible to do a subgroup analysis of people who adhered to placebo we might conclude that the placebo also works – (and it’s cheaper).
This is not so fanciful.
“In one study [3], those who adhered to the trial drug (clofibrate) had reduced
mortality; but those who adhered to the placebo pill had the same reduction in mortality”.
This is from:
Coronary Drug Project Research Group. Influence of adherence to treatment
and response of cholesterol on mortality in the coronary drug
project. Engl J Med 1980;303:1038-1041
A classic example of the pitfalls of subgroup analysis is what it demonstrated in ISIS-2, a trial examining the effects of aspirin after myocardial infarction. A subgroup analysis showed it was of benefit to all except people who were either Libras or Geminis.
Maybe Truvada taken consistently can reduce new infections by over 90%; maybe not. There was no basis for the investigators and commentators to present the first possibility with such overwhelming confidence.
We must accept that a 44% reduction in new infections is at this time the most reliable estimate of Truvada’s efficacy as PrEP. Although, the confidence interval , a measure of reliability, was wide.
We have an intervention that can reduce new infections by 44%, if taken in conjunction with a program of counselling, condom use, and monthly tests for HIV infection. That is the benefit. What about the down side?
The two most important are the development of resistance of HIV to the component drugs of Truvada and the toxicity of the drugs.
The utility in treating HIV infection of FTC and tenofovir – Truvada’s component drugs is lost if the virus becomes resistant to the drugs. Moreover, some mutations conferring resistance to these drugs can also affect sensitivity to some other drugs. The danger of resistance, and even cross resistance to other drugs developing when Truvada is used as PrEP is not a trivial concern. Truvada used as PrEP provides a suboptimal dose in treating established HIV infections. This is precisely the situation in which resistance is likely to develop. There were in fact two instances of developed resistance in the iPrEx trial in individuals who became infected, but undetected before the trial began.
Resistant viruses in the community are a danger to all, so the risk of generating resistance is not confined to the individual taking Truvada as PrEP.
What about safety?
The claim in many reports that Truvada is without significant toxicity is also misleading.
Maybe poor adherence has some bearing on the lack of significant toxicity.
A median of 1.2 years exposure to Truvada can tell us little about cumulative and long term effects. Experience with long term use of Truvada in HIV infected people makes concern about toxicity realistic. Renal toxicity, sometimes severe occurs not uncommonly. It’s mostly but not always reversible on stopping the drug. Thinning of bones, osteopenia and osteoporosis is also seen. There are additional adverse effects associated with the drugs.
There were small abnormalities in some parameters measuring kidney function among those treated with Truvada. Although these changes were reversible on stopping the drug, the fact that they were seen at all is a reason for great concern about the effects of longer term treatment.
With the experience we have gained from longer term treatment with Truvada, it is disingenuous to stress its overall safety from just 1.2 years of very inconsistent use.
It’s important to point out that for HIV infected individuals, the benefits of treatment with Truvada far outweigh the risks. For uninfected individuals, an entirely different risk benefit analysis must be made.
Despite the disappointing results of iPrEx, PrEP is important.
Why is PrEP important?
There are at least two important reasons.
1:
PrEP could protect receptive partners in sexual intercourse, both men and women, who are unable to ensure that a condom is used by their partner and for a variety of reasons are unable to refuse sex . The best and most respectful way of addressing this would be to find ways to empower these individuals; in some way providing them with the means to protect themselves could be seen to also have the effect of perpetuating their subjugation and abuse.
But there are women and men who need protection now and providing them with a means to prevent infection that they can control is vital. This can go hand in hand with working to empower them and helping them to try to ameliorate or leave abusive relationships.
2:
Sex is one of life’s joys. It is vitally important to the human experience.
Condoms can be a barrier to intimacy which for many is the most essential aspect of sexual intercourse, for both receptive and insertive partners. So recommending the use of condoms without acknowledging the significant obstacle they may present to a fulfilling sexual experience is a real problem. Pleasure is part of that fulfilment and for some insertive partners condoms are a significant impediment to experiencing it. A fully effective and safe means of pre-exposure prophylaxis may also allow the removal of a barrier to conception.
But people are different; for example some individuals have found that condoms can increase intimacy in the reassurance they provide concerning their and their partners safety.
We should never minimize or trivialize the difficulties condoms can present. We should also keep in mind that their use is the most effective means of preventing sexual transmission of HIV.
Their use will remain necessary in order to remain uninfected until we are free from HIV or a safe an effective PrEP method can be found.
These considerations, a prevention method that the receptive partner can control, allow conception and remove an impediment to full sexual expression are some reasons to work towards finding a safe and effective form of PrEP.
Truvada unfortunately has not proved to be sufficiently effective and safe.
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A few words about prevention education and condoms:
The consistent use of condoms is the most effective means to prevent sexual transmission of HIV.
PrEP proponents agree but many go on to say that people just don’t use condoms consistently. This is an attitude that has apparently concluded that prevention education does not work, and more importantly, cannot work.
But how can one conclude that it cannot work when there has been so little of it? This has some analogy with the claims made for the efficacy of Truvada. It works, if you take the pills
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If prevention education has been a failure, it’s not because it doesn’t work, but because we have not provided it well enough. There has been too little and most has not been properly targeted.
Proper targeting to those most at risk is critical. I have written about this. We need more and better prevention education.
The CDC now tells us that the group at greatest risk by far in the US is men who have sex with men. Nothing has changed except the ethnic distribution, so why are they only telling this to us now? For over twenty years we were told that AIDS was an equal opportunity infection making prevention education targeted to those at greatest risk even more difficult.
It’s only now, 25 years too late, that the CDC appears to recognize the urgency of providing prevention education to gay men.
Neglect of properly targeted prevention education, with encouragement for condom use and continuing support to sustain their use helped to allow the spread of HIV into African American communities in plain view while millions were spent on “America Responds to AIDS” a vacuous prevention message.
Similarly we have known for years that in the US younger men who have sex with men are at particular risk. We know where to target prevention messages, but we don’t it well enough.
We know that highly targeted prevention education, when crafted by the communities at greatest risk can work. This was demonstrated in the earliest years of the epidemic in San Francisco and New York City.
In 1982 when Michael Callen, Richard Berkowitz and I first recommended condom use to gay men in New York City, we stressed that in doing so it was important to celebrate sex, recognizing that for some individuals condom use, or perhaps more precisely, HIV, could present a barrier to its full expression. We have come far in freeing ourselves from long standing societal constraints that for too many have stood in the way of a fulfilling sexual experience burdening it instead with guilt. It’s important to take care in providing continuing support for condom use and recognize that for many they do get in the way. But it’s really HIV that’s getting in the way, and consistent condom use can help to bring it to an end.
Finding conditions where sex without condoms is safe is important. On the showing of iPrEx – despite its ecstatic reception, PrEP unfortunately is not yet ready.
At the moment consistent condom use is the best protection there is.
The often uncritical response to iPrEx should not persuade anyone that Truvada is a safe and effective alternative.
iPrEx is a large and complicated study. The investigators deserve the highest praise for completing this phase and having provided a result. It may not be the result so many hoped for. But providing clear information is a major advance.
Treatment of HIV/AIDS. The revised USPHS guidelines. May, 2010
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.
AIDS pathogenesis: HIV disease and Positive feedback: An additional comment.
This blog more or less duplicates that at the aidsperspective.net site, explained in the “about” page above.
HIV Disease and Positive Feedback. An additional comment.
AUGUST 31ST 2010
A previous post focussed on the positive feedback interaction between HIV replication and immune activation. HIV replication and immune activation reciprocally enhance each other.
While HIV infection is an essential cause of the immune activation that’s characteristic of HIV disease, there are other factors that also contribute to it. In that post as well as in the blog I write on the POZ magazine website, I described some of these additional factors that can add to immune activation. As noted, viruses of the herpesvirus family, cytomegalovirus (CMV) in particular are the most important of these worldwide, while in parts of Africa certain endemic infections may be of great significance in contributing to immune activation.
Since sustained immune activation, involving both innate and adaptive immunity is at the heart of the pathogenesis of HIV disease an understanding of how it is perpetuated is critical.
Evidence for activation of innate immunity was noted in 1981, the year that AIDS was first reported, in the detection of large amounts of alpha interferon in the circulation of patients. We even knew then that interferon alpha and gamma could induce an enzyme, indole 2,3-dioxygenase (IDO), (IDO was known to be responsible for the inhibition of toxoplasma gondii by depletion of tryptophan in cells treated with gamma interferon) but we did not know then that this enzyme could contribute to the loss of T lymphocytes. Another observation of historical interest is that even before AIDS was first reported in 1981, interferon was known to preferentially inhibit CD4 lymphocyte proliferation in mixed lymphocyte culture.
Since immune activation and its effects, including inflammation, are harmful if sustained, there are mechanisms that can dampen it.
But in HIV disease, immune activation persists with continued deleterious consequences.
The reason I’m revisiting this now is that there is a question that continues to be bothersome.
HIV disease is not the only infection associated with long standing immune activation.
Several endemic infections in Africa are also associated with sustained immune activation, certainly not all – some even have a dampening effect on immune responses. TB is another example of an infection associated with chronic immune activation. In none of these conditions is there such a profound loss of CD4 lymphocytes as in HIV disease. While individuals with active pulmonary TB have been reported to have lower CD4 counts than healthy individuals, the numbers were well above 500.
Is the difference between sustained immune activation associated with HIV and that associated with other chronic infections in HIV negative individuals a matter of degree – is it a quantitative difference?
Could the mechanisms that dampen and check immune activation be impaired in HIV disease? These mechanisms include the secretion of cytokines that have anti-inflammatory properties, such as IL-10, IL-13, and TGF-beta, among others. Specialized immune system cells can also dampen immune activation. Tregs, a subset of T lymphocytes, have such a dampening effect. Although there are conflicting reports on the relationship of Tregs to HIV disease, it is known that HIV targets some of these particular T lymphocytes.
This graphic comes from my earlier post on positive feedback characteristics of HIV disease.
In this diagram HIV pathogenesis is represented by a circular process moving in a clockwise direction. It is started by HIV infection and can be propelled by a positive feedback association between HIV replication with immune activation. Immune activation is reinforced by CMV, and in certain settings, by some endemic infections. This is represented by the + sign in the diagram. Immune activation is retarded by those influences that dampen the immune response, including anti-inflammatory cytokines and Tregs, represented by the – sign in the diagram.
Here is a revised version of this diagram:
HIV disease progression is represented as moving clockwise in a circle, reinforced by sources of immune activation other than HIV and retarded by Tregs and other mechanisms that dampen immune responses. Tregs act as brakes, but HIV can directly make the brakes less effective.
Could critical differences between HIV disease and other infectious causes of long standing immune activation where CD4 numbers are relatively preserved, be the preferential targeting of Tregs by HIV and a different pattern of cytokine secretion?
I wonder if this revised representation of HIV disease lends itself to a more formal modelling process.
In this particular model a disease process is represented by a circular motion in a clockwise direction, with forces that both propel and retard it. Some predictions can be made.
The degree of immune activation at the time of HIV seroconversion would favour more rapid HIV disease progression. The set point – the level from which CD4 lymphocytes decline following an acute HIV infection, would be lower, and the subsequent rate of CD4 decline higher when HIV infection occurs in a person where there already is a higher degree of immune activation, compared to an individual where this is not the case. There already is some evidence in support of this possibility.
It’s well established that HIV disease progresses more rapidly with increasing age. Could an explanation for this be that immune activation increases with age – indeed, it’s been suggested that immune activation contributes to the aging process.
HIV disease progresses more rapidly in individuals with active TB. CMV viremia was noted to carry an adverse prognostic significance in HIV disease very early in the epidemic. There are but two examples, but there are many more of of a more rapid course of HIV disease in the setting of other infections caused by bacteria, protozoa, viruses and helminthes. Some are referred to in a previous post.
Are Treg numbers at seroconversion and for a period immediately afterwards related to subsequent disease progression?
Could treatment with anti CMV agents during acute HIV infection retard subsequent disease progression?
There already is some evidence that treatment of HIV during acute infection might slow the subsequent course of HIV disease.
The utility of any model of a disease process lies in its ability to provide a common explanation for disparate observations as well as to make predictions that can be tested by an analysis of available data or by experimentation.
Viewing HIV disease as a process with a positive feedback interaction between HIV replication and immune activation with forces that both enhance and retard this interconnection, provides a useful descriptive framework as well as testable predictions.