Covid-19: Can the initial response to HIV teach us anything?

Many of us who participated in the early response to HIV/AIDS have been asked if any useful lessons were learned that might help us in dealing with Covid 19.  Implicit in the way that question was sometimes asked was the assumption that the medical response to AIDS was exemplary, a contention I most certainly do not agree with.  Instead and more to the point, the question might have been: Can we avoid repeating the mistakes made in the medical response to HIV/AIDS?

The mistakes that were then made, both with respect to steps that were taken and those that were not taken were numerous and easily documented. As examples, they include the failure to make recommendations and pursue studies on the prevention and treatment of opportunistic infections, most strikingly the failure to provide guidance on the prevention of pneumocystis pneumonia until 1989, when the means to do this had been known even before 1981;  the very inappropriate use of interferon to treat people with AIDS when it was already present in patients and in large quantities, and when evidence already existed that interferon could play a role in pathogenesis; the failure to respond to the movement of the epidemic into African American communities, that was happening in plain sight as early as the late 1980s.  There are many more examples.

It’s difficult to see where responsibility for this dismal response lies.  Medical scientists who could see these failings also remained largely silent, or perhaps were not successful in advancing their criticisms.

Should we not try to understand how the indifferent federal medical response to AIDS was able to continue?

How is a medical leadership established in times of crisis?  How should it be established, keeping in mind the wellbeing of the public as its goal, safe as possible from political influence?

Sadly, it’s unlikely that this question will ever be addressed let alone answered. With the increasing privatisation of public services over the past 40-50 years there is now almost nothing left to defend the public interest.

 

Whatever goes into the establishment of a medical leadership in times of crisis, in the case of HIV/AIDS, it failed miserably.  Can we trust that it will not fail us today?

 

Unlike the mediocre medical response to HIV/AIDS, the scientific response was spectacularly successful, resulting in major advances in virology and molecular cell biology with implications well beyond HIV/AIDS. The same appears to be true of the scientific response to Covid 19.  Maybe virologists, immunologists and molecular cell biologists have performed so much better than the doctors partly because they are to a greater extent, shielded from political influence.

 

There has been much recent publicity reassuring us that we are in good hands with Dr Fauci leading the medical response. Maybe this is indeed a good thing, but in extoling his virtues, one can’t help but note that the less than lustrous performance of the medical response to HIV/AIDS under his leadership has somehow been transformed into a triumph.   We should not be taken in by this attempt to obscure a less than exemplary past.

We have to admit to what went wrong as a first step to getting it right.

 

 

 

 

 

 

An unwise recommendation by the WHO.

July 20, 2014 1 comment

 

PrEP is an HIV prevention intervention in which antiviral medications are taken to interrupt sexual transmission of the virus. It is now being recommended by the WHO for, it seems all   sexually active gay men.  Actually it’s not quite that stark – they continue to recommend condom use as well.   Despite this, many will probably see this as a recommendation to rely on PrEP as an alternative to condoms.

 

The WHO recommendation is a population based proposal, a public health recommendation as opposed to recommendations for specific individuals.   Recommendations for individuals are different because they take into account individual circumstances, such as the extent to which a specific person is at risk.  Population based recommendations are recommendations made across the board, in the case of the WHO, addressed to all men who have sex with men.

 

While assuring us that the recommendations are evidence based and providing the customary explanation of how the strength of evidence is graded, we learn that the WHO has made a sweeping worldwide population based recommendation on evidence provided by just one randomized study!    This was the iPrEx study, which was beset with interpretative difficulties, not least because few took the medication as directed, if at all.

 

We simply do not know enough about PrEP to make a sweeping population based recommendation. .  We have little idea of what adherence to the medication might look like in various populations, we know little about the degree of protection in specific sexual acts.  Different sex acts carry different risks, for example, to the receptive or insertive partner in anal sex.   Also, how effective is PrEP  in situations of exposure to high and low viral loads.  In addition we have little idea of the extent to which condom use will be abandoned.

 

It’s clear that there is a widespread view that PrEP is an alternative to condoms, despite official recommendations stating that PrEP  should be part of a comprehensive prevention approach that includes condom use.

 

 

A more balanced response would have been a call for more research, and importantly, for a fuller description of those individual situations where PrEP use is a rational preventative intervention at the present time.

 

 

The use of PrEP by an individual is very different.     The degree of risk to individuals will vary considerably and on an individual basis PrEP use can be a completely appropriate intervention in situations of very high risk, even if we do not have precise information of its efficacy without condom use.   The use of  PrEP could also be considered when there is an inability to maintain an erection with a condom.  It might be an option to enable a fuller sexual expression among what is probably   a large number of men whose difficulty with condoms, for whatever reason,  stands in the way of satisfactory   sex.      Medical supervision is also more likely in individual situations. It is important to check for HIV infection and to monitor for sexually transmitted infections and drug toxicities.

 

 

Monitoring for sexually transmitted infections is important.  Since PrEP alone offers no protection from the transmission of infections that might be interrupted by condoms we might expect an increase in such infections with a wide roll out of PrEP.  The current increase in sexually transmitted infections among gay men in some cities is most likely attributable to an increase in unprotected sex.    Many sexually transmitted infections facilitate the transmission of HIV which may be another factor that could drive an increase in new HIV infections.

 

 

 

The way PrEP has been promoted during the past few years has surely contributed to the poor support received for prevention education.   One way in which this has happened is the shifting of budgets for prevention to those entities, private or government insurers that pay for drugs used in biomedical prevention.

 

There seems to be a widespread view that prevention education does not work.  But we know that it can work. The adoption of safe sex practices including condom use in the early 1980s curbed the spread of the epidemic, although admittedly conditions are not the same today.  There is little support for continued condom use, and rather than take the view that condoms don’t work, we might try to understand the obstacles that stand in the way of effective prevention education.

 

 

 

If prevention education has been ineffective it’s  be because there has been so little of it, and what little there is has not been properly targeted.  The move of the epidemic into African American communities during the 1990s  was occurring in plain view yet the federal government was churning out expensive vacuous untargeted prevention messages in the form of “America responds to AIDS,” a futile exercise that helped to discredit prevention education.

I get the sense that some younger gay men feel they have missed out in not experiencing the abandon of the 1970s and see PrEP as a way to make up for this.  The real lesson of the 1970s is that sex with multiple different partners on such a vast scale, as occurred in NYC in the 1970s, permits any pathogen that can be transmitted sexually to disseminate widely. That’s what started to happen with amebas and other intestinal parasites and HIV, and is happening with syphilis, gonorrhoea, herpes, hepatitis and many other infections.  There surely will be others beyond HIV.

 

Since we really have very little information about PrEP, and almost none about its use on a population level  such a broad recommendation by the WHO is absolutely inappropriate, so maybe  faced with increasing HIV  infections among gay men,  the WHO is simply giving up  and proposing an unproved intervention out of desperation.  When I say unproven, I mean it is unproven as a viable population based intervention.    Looked at this way, it’s a put down –  a response that may be no more than gestural to people who continue to harm themselves by refusing to use condoms in sex with partners of unknown sero status.

 

This unwise WHO recommendation may also have the effect of increasing new HIV infections if it results in an increase in unprotected sex where adherence is inadequate.

 

I hope there will be a critical look at the WHO panel and funders responsible for producing such unhelpful recommendations.

 

 

 

 

Transmission of HIV from infants to women who breastfeed them

Transmission of HIV from infants to their mothers.

 

This title may surprise some.   In a paper (abstract, below) from a group at CDC I learned yet another HIV/AIDS related acronym.  It’s CBWT, Child-to-Breastfeeding-Woman Transmission.

There have been several reports over many years of HIV infected infants born to mothers who were HIV uninfected.   These infections were noted as early as the late 1980s in the former Soviet Union, in Libya in 1998, in Kyrgyzstan, Kazakhstan, Romania as well as in Africa.   In every instance except in Africa, there cases were investigated with varying degrees of thoroughness.   The sources of infection were invariably associated with contaminated blood,   either from transfusions, or from procedures in unsafe healthcare settings, where for example sterilization of instruments is inadequate, or injection equipment is reused.

The infections noted in infants that were investigated occurred as outbreaks and all were determined to be nosocomial.    Although infected infants born to uninfected mothers have been noted in Africa, remarkably, it appears that none have been investigated.

It will probably remain for a future historian to understand why cases of HIV infection in infants, horizontally rather than vertically transmitted, have yet to be investigated in Africa.

In those non-African outbreaks that were investigated transmission occurred through unsafe medical care, so what do we know of the safety of health care facilities in Africa ?

Unfortunately unsafe health care remains a problem in many facilities in high prevalence areas in Africa.

Taking Kenya as an example, Simon Colley has written in one of my blogs

“Where does Kenya fit into this picture? As UNAIDS admit, there’s not much data. But there is a document called the Service Provision Assessment which looks at conditions in various kinds of health facility, such as hospitals, clinics and pharmacies.

A few samples from this document may suffice to illustrate Kenya’s women capacity to prevent HIV transmission through unsafe injections and other healthcare practices: Between 10 and 15% of facilities don’t have adequate supplies of needles, syringes or latex gloves; between 55 and 70% don’t have running water or soap; many don’t have facilities for disposing of contaminated equipment or supplies of disinfectant; less than half have guidelines for infection prevention and less than 10% have guidelines for sterilization.

Although this document dates from 2004, we don’t know if there has been any change

There’s little doubt that unsafe health care is still a problem in Kenya and other high HIV prevalence countries. What’s not clear is how big a problem it is. Because, despite admitting that they don’t have the sort of data on unsafe health care that would allow an estimate to be made, UNAIDS and the WHO have failed to investigate or to carry out the research required”

 

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As the title of this post indicates, infants infected either vertically or through exposure to contaminated blood are able to transmit HIV to seronegative women who breast feed them.

Mother to child transmission is the leading cause of HIV infection in infants. Some of these infected infants will be orphans and so place seronegative women who breastfeed them at risk.  Wet-nursing is the complete nursing of another woman’s infant and still occurs as does cross-nursing which is the nursing of another infant by a woman  while still nursing her own child.  Estimates of the prevalence of these practices vary by region and the overall prevalence is not known.

Worldwide the greatest risk for CBWT is carried by seronegative mothers whose infants become infected through exposure to contaminated blood.  Rates of CBWT were as high as 40-60% among mothers  breastfeeding infants who became infected after birth.

This report on CBWT highlights the importance of unsafe health care facilities in the transmission of HIV.   Of course HIV is not the only pathogen that can be transmitted in such settings.

A question that is unlikely to be addressed – it’s so rarely even asked, is: Why are infections acquired by exposure to blood, particularly in health care settings barely acknowledged, and never investigated when they occur in sub-Saharan Africa, but are investigated should they occur in Kyrgystan, Libya, Romania and elsewhere?

Why so few resources have been devoted to the improvement of health care facilities in developing nations is also puzzling.  Could it be that like the provision of clean water and sanitation, improving health care facilities is not something that can generate much profit?

The benefits of improving infection control in these facilities extend far beyond effects in HIV transmission.

Perhaps it will be left to HIV activists in sub-Saharan African countries to alert funders and policy makers to the dangerous condition of many healthcare facilities in the developing world.  HIV activists in the past have succeeded in bringing attention to important issues.

A group of individuals have been trying to bring attention to this issue for many years and I do recommend looking at the website that has been created to directly alert people in Africa to dangers in health care facilities with no or poor infection control procedures.

Unsafe medical practices in equatorial Africa about eighty years ago probably helped to set the epidemic in motion.  Unsterile injections and transfusions by well-meaning colonial doctors provided conditions that enabled the initial   spread of HIV (as well as of Hepatitis C and HTLV), before sexual transmission became the predominant way the epidemic advanced. This is described by Jaques Pepin whose account of the origin of AIDS is by far the most plausible.

To a greater or lesser extent, unsafe health care procedures are still contributing to the spread of HIV in parts of Africa. At least this source of HIV infections could be easily stopped.

(1)

A Review of Evidence for Transmission of Human Immunodeficiency Virus from Children to Breastfeeding Women and Implications for Prevention.

Kirsten M Little, Peter Kilmarx, Allan Taylor, Charles Rose, Emilia Rivadeneira. And Steven Nesheim.

The Pediatric Infectious Disease Journal Publish ahead of print.

DOI:10.1097/INF.0b013e318261130f

Abstract

Background: Child-to-Breastfeeding-Woman Transmission (CBWT) of HIV occurs when an HIV-infected infant transmits the virus to an HIV-uninfected woman through breastfeeding. Transmission likely occurs as a result of breastfeeding contact during a period of epithelial disruption, such as maternal skin fissures and/or infant stomatitis. Despite extensive epidemiologic and phylogenetic evidence, however, CBWT of HIV continues to be overlooked.

Objective: This paper summarizes the available evidence for CBWT from nosocomial outbreaks, during which nosocomially HIV-infected infants transmitted the virus to their mothers through breastfeeding. This paper also explores the CBWT risk associated with HIV-infected orphans and their female caretakers, and the lack of guidance regarding CBWT prevention in infant feeding recommendations.

Methods: We searched online databases including PubMed and ScienceDirect for English language articles published from January 1975 to January 2011 using the search terms “HIV”, “perinatal”, “child-to-mother”, and “breastfeeding”. The citations from all selected articles were reviewed for additional studies.

Results: We identified five studies documenting cases of CBWT. Two studies contained data on the number of HIV-infected women, as well as the proportion breastfeeding. Rates of CBWT ranged from 40 – 60% among women reporting breastfeeding after their infants were infected.

Conclusions: Poor infection control practices, especially in areas of high HIV prevalence, have resulted in pediatric HIV infections and put breastfeeding women at risk for CBWT. Current infant feeding guidelines and HIV prevention messages do not address CBWT, and fail to provide strategies to help women reduce their risk of acquiring HIV during breastfeeding.

Conflicts of interest in HIV medicine: The 2012 revised DHHS HIV treatment guidelines and what’s wrong with expert opinion

April 12, 2012 Leave a comment

The most recent revision of the DHHS guidelines on the use of antiretrovirals in HIV infected adults and adolescents now recommends starting therapy at a CD4 lymphocyte count greater than 500/ mm3.,

For those with greater than 500 CD4 lymphocytes the recommendation is only supported by expert opinion – the opinions of the experts on the DHHS panel.  Almost all of the non-governmental researchers on the panel have financial arrangements with entities that stand to gain from the decisions they make.  There are plenty of other experts who are not members of the DHHS panel who are not so certain that starting treatment above 500 CD4 lymphocytes will confer a net benefit to the patient..

This particular recommendation is unlike those made for individuals with lower CD4 numbers where more reliable evidence from clinical trials clearly demonstrates a benefit to the patient

Evidence based medicine has brought us a long way from the days when clinical decisions were based on authority and tradition (“expert opinion”); it attempts to use the best available evidence on which to base clinical recommendations.  The term “best available evidence “means that not all types of evidence are of equal quality.  There are several systems that grade the relative strengths of evidence derived from different sources.    All agree that evidence provided by randomized controlled clinical trials is of the highest quality and therefore the most reliable.  Applied to HIV medicine, a strong recommendation that antiviral treatment be initiated at 350 or fewer CD4s can be confidently made because the evidence of substantial benefit is derived from a randomized controlled clinical trial.

At the other end of the scale rating the quality of evidence, is evidence based on “expert opinion”.   This may not even be a marginal improvement on the bad old days when the doctor knew best; when there was no need to justify a recommendation other than by the authority of the doctor or by tradition.

The rating of the recommendation that people with more than 500 CD4 lymphocytes start treatment, according to the system used by DHHS is B III.   It’s a moderate recommendation supported only by the opinion of experts.

But when expert opinion is the basis for a recommendation, this does not even mean that the opinion represents a consensus of all experts.   It only represents the opinion of those experts chosen by the organization making the recommendation.

Making a recommendation based solely on expert opinion is particularly troublesome when the means exist to obtain evidence of the highest quality.  The START trial that directly addresses the question of when it’s best to begin antiviral treatment is enrolling, and one must wonder why the panel did not defer making a recommendation concerning individuals with greater than 500 CD4 lymphocytes until the trial results become available.  This is even more puzzling as individuals who have waited to start at CD4 numbers between 350 to 500 have in general done very well, so waiting to make a recommendation for some years until the START trial results are available seems to be a much more reasonable and prudent option than jumping the gun and making a recommendation based on  evidence of the weakest quality.

Bur when we come to look at the associations of the experts on the DHHS panel, a recommendation based on expert opinion is even more problematic.  We note that almost all of the non-governmental researchers have financial arrangements with entities that can benefit from the decisions they make. Some of these arrangements are quite extensive.

Take a look at them.

A conflict of interest becomes particularly troublesome when it’s only the opinion of the expert that supports a recommendation. Since people with greater than 500 CD4 lymphocytes represent a huge proportion of the HIV infected population, treating them will have an impact on expanding the market for antiviral drugs.  With greater efforts to encourage testing, greater numbers of individuals with higher CD4 numbers will be identified, and now recommended to receive lifelong treatment with expensive and potentially toxic drugs whose benefit has not yet been proven to outweigh their harms.

The conflicts of interest of panel members are duly noted in the DHHS financial disclosures.

Early AIDS activists performed a great service for all individuals who must deal with illness, in asserting their right to make informed decisions concerning their care, and that the decisions are made free from coercion.   Withholding information and supplying misinformation are forms of coercion.

Although the guidelines ask physicians to inform patients with high CD4 numbers that evidence for benefit is  not conclusive    I   think it’s safe to conclude that individuals with greater than 500 CD4s will not always, and may only rarely informed   be informed  of this important caveat. As to informing patients of the conflicts of interest noted above, this isn’t even a consideration.   They are also unlikely to be told that the recommendation that they start treatment is based on the opinion of certain experts only, and that there are other experts with a different opinion.  In fact, the DHHS guidelines   may be the only ones in the world to make this recommendation.

Undoubtedly the DHHS panel members believe that people with higher CD4 numbers will receive a net benefit from treatment.    But the recommendations would have greater authority if the non-governmental researchers on the panel were better balanced with respect to members who had no financial arrangements with entities that stand to benefit from their decisions;  in fact many would agree that such conflicts of interest should be a disqualification for panel membership.

The recommendations also refer to the prevention benefit of treatment.  The greatest prevention benefit will result from the treatment of individuals with lower CD4 numbers who will have the highest viral loads.   These individuals need treatment. On this point there is no doubt or debate. For those with higher CD 4 numbers, not known at this time to benefit from treatment, the prevention benefit is likely to be much lower as their viral loads will also, on average be much lower than those with more advanced HIV disease.

Providing treatment to everybody who needs it to stay alive should surely be our first priority.   It is here that treatment will also have its greatest prevention benefit.

Conflicts of interest are of course common among those making treatment recommendations.  However HIV medicine seems to be unique in that these conflicts of interest, which may be among the most egregious, seem to go almost completely unnoticed.  In every other field of clinical medicine they occasion extensive discussion.    The apparent indifference to conflict of interest issues and the  influence drug marketing practices   in HIV medicine is unfortunate, as precedents in that field may go unnoticed but will have implications for other fields  of clinical medicine.   The rapid approval of zidovudine by the FDA in 1987 may be such an example.

Two years ago in a tribute to Michael Callen  I responded to similar recommendations to treat all HIV infected individuals irrespective of CD4 numbers.

I cannot express my reservations more clearly than with the words I used then:

I miss Michael Callen. He was my patient when AIDS began, but soon became my collaborator and friend.

For a time, Michael and Richard Berkowitz, another patient collaborator, were able to work out of an office adjoining my practice on W 12th street in New York City. It was in this setting that Michael and Richard learned about the medical aspects of this new disease and participated in the creation of some of the earliest organized community responses to the epidemic.

Michael and Richard helped in the formation of the AIDS Medical Foundation; they wrote the very first publication to recommend condom use by gay men. Michael played a role in the first attempt to protect the confidentiality of people with AIDS, and he helped to create both the Community Research Initiative and the PWA Health group.

A thread running through all of these endeavours is the notion of self empowerment. This extends beyond the belief that individuals who are fighting a disease should actively participate with their doctors in making decisions about the care they receive. Empowerment also means the inclusion of affected individuals at all levels of the response to the disease, from research to the provision of services.

The Community Research Initiative was sponsored by the PWA Coalition of which Michael was President. This is the very embodiment of self empowerment. It is people with a disease sponsoring research into that disease themselves and not waiting for some benevolent institution to come to the rescue.

Michael understood that his interests and priorities as a person living with AIDS might sometimes be at odds with those of some scientists conducting research into this new disease. He knew very well that he was living in a world that was still capable of cruel and discriminatory behavior towards him. Who better to protect the interests of those who had the most to lose than people living with AIDS themselves?

Self empowerment found expression in the Denver Principles. Michael and Richard were both signatories to this historic document. Michael played a major role in crafting the words of the Denver Principles.

Almost thirty years later these Principles remain as important as when they were first articulated.

One of the Denver principles asserts the right to obtain full explanations of all medical procedures and risks.

I wish Michael Callen were here today to bring attention to the violation of this right.

This is happening with little protest in places like San Francisco where antiviral medications are now recommended for healthier HIV positive individuals for whom the benefits of treatment have not been shown to outweigh the risks.

As always, you can’t beat the truth, and the truth is that for people with more than 350 CD4 lymphocytes, the best time to start treatment is not known. This may seem surprising as potent antiretroviral drugs have been available for fifteen years.

We have not yet done the kind of study that would most reliably provide the information those HIV positive individuals with higher CD4 numbers and their doctors need to make the best decisions about when to start treatment.

With information provided by a properly designed and conducted prospective randomized trial, we could know with confidence when in the course of HIV infection the benefits of treatment absolutely outweigh the risks.

Some feel that a decision can be made with less reliable information. But surely all would agree that a decision to start treatment or to defer it must always be an informed one voluntarily made by the individual considering treatment.

It is here that the principle asserting the right to a full explanation of the risks of medical interventions is being violated.

The San Francisco Department of Public Health in advising all HIV infected individuals to receive treatment is in effect telling them that at all stages of HIV disease the benefits of treatment outweigh the risks. This may be so, but apart from those with 350 or fewer CD4 lymphocytes, we just do not have the most reliable evidence to support this contention.

People with higher CD4 numbers have the right to know not only what evidence there is that immediate treatment will have a net benefit compared to deferring it, but also the quality of that evidence. They surely should also be made aware that experts hold differing opinions on whether treatment should begin immediately or be deferred.

A physician in San Francisco who recommended that all HIV infected individuals should start treatment immediately was reported to have said:

“If I’m wrong, we’ll start people [on treatment] a couple years earlier than we otherwise would. But if I’m right and we don’t start early, there’s no going back,”

Others who are concerned about drug side effects might feel that more may be at stake for HIV positive individuals with higher CD4 numbers. This also includes the possibility that fewer options may be available when treatment is definitely known to be needed.

This doctor is also reported to have said:

“The old paradigm was that drugs are toxic so we should wait as long as possible. The new paradigm is that while today’s drugs are not totally benign, they are less toxic than the virus.”

“The” paradigm? Is it not misleading to give an impression that his views on drug toxicities represent a consensus?

How on earth can the longer term toxicities of the newer drugs be known?

Just a few days ago it was reported that AZT and 3TC based therapies produced a metabolic abnormality called hyperhomocysteinemia. This is a condition associated with vascular abnormalities including a greatly higher risk of heart attacks. We have been prescribing AZT and 3TC for about twenty years, so what information does the San Francisco doctor have that gives him such confidence that the drugs in use for only a few years are less toxic?

Empowerment means that HIV positive individuals make their own decisions to start or to defer treatment. They have the right to clear and honest information to enable them to make this decision. Those with higher CD4 counts have the right to know that there still is uncertainty about when it is best to start treatment.

The views of the San Francisco Department of Public health and those who share them are just opinions; healthier HIV positive individuals should also know that these opinions are not held by all experts. Respect for the autonomy of healthier HIV positive individuals requires that opposing views on when it’s best to start treatment be presented together with the evidence supporting these views, so those who have most at stake can decide for themselves.

There will continue to be opposing views on when it’s best to start antiviral therapy as long as the question has not been put to the test.

The best way to resolve uncertainty in clinical medicine is by conducting prospective randomized trials. A properly designed and conducted trial could reliably and safely answer the question of whether, on average, immediate or deferred treatment is better or worse or makes no difference.

HIV positive individuals deserve the most reliable information to inform them in making treatment decisions. The START trial is a randomized prospective study that directly asks the question about the best time to start antiviral medications. We could really finally know what’s best, and no longer rely on opinions based on data of inferior quality.

Is an immediate or deferred initiation of treatment better or worse, or does it make no difference? If knowledge is power a demand to complete the START trial is the embodiment of the self empowerment of HIV positive individuals. The very antithesis of self empowerment is to allow researchers to persuade us with evidence of inferior quality, such as their personal opinions, presented as if there were a consensus, or with the results of embarrassingly uninterpretable studies such as NA-ACCORD so often used to justify earlier starts to treatment. NA-ACCORD was not a prospective randomized trial. It was a review of a large number of medical records. Such retrospective observational studies are beset with interpretative difficulties because subjects are not randomly assigned to receive one or another kind of intervention, in this case, to start treatment early or to defer it. We don’t know why a particular course of action was chosen. The reasons why decisions were made to start treatment early or to defer it may have determined the outcome rather than the time treatment was started.

In situations where prospective randomized trials cannot be conducted for whatever reasons, then we have to do the best with data of inferior quality. But fortunately this is not the case with HIV infection.

I miss Michael Callen. He would have reminded us that HIV positive individuals must demand that the best evidence be obtained to inform their treatment choices.

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The Cost of Truvada Pre-exposure prophylaxis, PrEP

August 17, 2011 1 comment

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.

August 6, 2011 2 comments

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/&gt;.

(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