Joseph Sonnabend, MD

If we were to express the efficacy of delayed washing in the same way that the results of PrEP trials were reported, that is as relative risk reductions, this would mean that not washing immediately, but waiting for at least 10 minutes after intercourse before washing can reduce the risk of infection by 83%. Compare this to the 44% efficacy of Truvada in the iPrEx trial, the 39 % efficacy of tenofovir gel in reducing the risk of infection in women  in the Caprisa 004 trial, and the 38-66% efficacy reported for circumcision over 24 months.

Genital washing after sex may be quite common in parts of Africa.  A study in Nairobi in 2004 found that a majority of men washed their genitals after sex.   Here is a link to a table in the report; 60% of men reported always washing their genitals after sex.

We have had evidence that this practice may contribute to the risk of HIV infection in men since 2007.  We have to wonder if the many questions this raises have been addressed, or even considered.  

Could the practice of immediate post-coital genital washing contribute to the risk of sexual transmission of HIV to men?

Are there regional variations in this practice, and could this be related to HIV prevalence to some extent?

Should there be a debate on the evidence by experts, with recommendations for further research - such as adding questions to on-going or proposed studies, laboratory testing of HIV viability in semen and vaginal fluids at body temperature or conducting  a trial to nail down the risk of immediate washing, or in other words, the protective effect of delayed washing? 

If immediate washing increases the risk of infection does this not raise the question of the extent to which infection occurs after withdrawal?

Considering how innocuous the intervention is do we have sufficient evidence now to  advise  African men at risk of HIV through heterosexual contact not to clean their penis for at least 10 minutes after sex?  Should a dry cloth without water or soap be used?

The study teams for these trials have more information on post-coital penis cleaning that they have not reported. We know that for uncircumcised men, wiping was safer than washing, and waiting at least 10 minutes to clean significantly reduced risk for HIV (see the last several slides in this reference. But we don't have similar details for circumcised men. What information has been collected but not reported?

We have evidence that a common practice, at least in certain regions can substantially increase the risk of HIV infection in men through heterosexual intercourse.  Considerable attention has been given to newer prevention methods in the past few years, notably pre - exposure prophylaxis and male circumcision, but almost none to the simplest of procedures that may be even more effective in preventing the sexual transmission of HIV.

Many other questions and concerns will no doubt arise as more people look at the evidence, and figure out what to do about it. Lives are at stake. Scientific competence and integrity are also at stake - researchers have overlooked and/or incompletely reported information that could save lives.

David Gisselquist and Joseph Sonnabend

The rating of the recommendation that people with more than 500 CD4 lymphocytes start treatment is B III.   It's a moderate recommendation supported only by the opinion of experts.

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

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

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

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 benefits have not yet been proven to outweigh their harms.

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.    

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

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 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.

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 should surely be our first priority.  It is here that treatment will also have its greatest prevention benefit.

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 12^th 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.

Data on risk reduction derived from trials can be expressed in different ways.  Too often the results of prevention trials are presented in ways that exaggerate the benefits of an intervention, and information is withheld that would allow us to more realistically understand the degree to which risk is reduced.

The most common way in which results are presented in order to throw a more favourable light than is warranted is to only present the reductions in relative risk, and to withhold information on  absolute risk reduction.

 In iPrEx for example we were told that the relative risk reduction in people taking Truvada was 44%.

But what does a 44% reduction in relative risk mean?   Certainly not a 56% risk of infection without PrEP, as several people have said when asked this question.   It's because of these answers that I'm writing this.

Relative risk reduction tells you the percent reduction in risk in the treated group compared to that in the control group, or how much lower the risk with an intervention is relative to the starting risk.

If you are not clearly told what the risk is to begin with, then you can't tell what the actual reduction of risk is when taking the intervention; all you know is how much lower it is than a number that is not clearly presented to you. 

Although it is not clearly stated in the published trial report, we can work out what the starting chance of infection is. 

It's the number of infections occurring in the placebo group during the time period of the study. We were told that   64 out of 1248 people in the placebo group were infected, which is 5.1 in 100, or 0.051 in 1.     (Since then there have been additional infections, reported at the recent conference in Rome, reflecting an increase in the number of infections over a longer time period).

The absolute risk reduction, as opposed to the relative risk reduction conferred by Truvada tells you how much lower the risk is than in the placebo group in absolute terms.

2.8% of the 1251 people in the Truvada arm became infected compared to 5.1% in the placebo group.

The reduction of risk in the Truvada group is therefore 5.1 minus 2.8, which is 2.3.

Truvada PrEP reduces the absolute risk of infection by 2.3%.

A 2.3 % reduction in absolute risk is nowhere nearly as impressive as a 44% reduction in relative risk.

Yet this lower number is a more accurate measure of the efficacy of Truvada PrEP. (1)

The actual risk of infection in the Truvada arm was 2.8%, which surely is a figure that is more useful to an individual considering PrEP.  (2)

Not clearly stating the absolute risk reduction conferred by Truvada was unfortunate.  I haven't checked, but will look to be sure that  absolute risk reductions were clearly stated in the other recent PrEP trial reports.

Maybe in Rome, the absolute risk reduction conferred by Truvada was in fact clearly stated.

Knowing the absolute risk reduction allows one to calculate another important measure, which again I did not notice in the trial report.

This is the number of people who need to be treated (NNT) in order to prevent one infection. From the information presented it appears that about 45 people need to be treated in order to prevent a single infection.  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 needs to be monitored at regular intervals for toxicity and importantly, for infection, in order to prevent the inevitable emergence of resistant viruses as a result of sub optimal treatment.

It should be possible to make a ball park estimate of what it will cost to prevent one infection. Whatever it is, it's the cost of treating and monitoring 44 people who will derive no benefit and be subjected to the adverse effects of tenofovir on their kidneys as well as other adverse effects. There will be additional costs if they generate resistant virus.

There is a great deal of information written to inform people about the differences between relative and absolute risk and how risk data can be manipulated to make the results appear to be better or worse than they really are.

I would recommend "Know Your Chances" by Steven Woloshin  and others .  The book opens with this statement.

Numbers can make people sick.

But they don't have to.

Learn how to make them help you.

(1)

I have copied this from a website in the UK addressed to patients:

Helping to decide about taking a treatment

The decision on whether to take a treatment needs to balance various things such as:

• What is the absolute risk of getting the disease to start with.
• How serious is the disease anyway.
• How much is the absolute risk reduced with treatment.
• The risks or side-effects in taking the treatment.
• How much does the treatment cost - is it worth it to an individual if the individual is paying, or is it worth it to the country if the government is paying?

To which must be added:

• More effective, cheaper and safer interventions are readily available (at least in developed countriers)

(2)

 Unfortunately even knowing absolute risk and absolute risk reduction is still of limited help.

In anal intercourse the risks of infection to receptive and insertive partners are not equal.  The receptive partner is at greatest risk, and may well be  responsible for the bulk of the overall 2.8% risk of infection in the published report.     It's probably impossible to reliably break down the risks in the trial according to self-reported sexual act. 

 The investigators were easily able to discern the unreliability of self-reports on drug adherence.   I don't know why they were so willing to trust the reliability of self-reports about specific sexual acts..     Unlike verifying adherence reports by measuring drug levels, there is no way to verify self-reports of unprotected receptive anal intercourse.      Self-reported sexual practices in epidemiological investigations have been repeatedly proven to be unreliable in several studies.

Given that the receptive partner is at greater risk, their best protection is of course to refuse sex with a partner who will not use a condom.  Among men who have sex with men there surely can only be very limited situations when the receptive partner would choose the more dangerous course. For example, in a relationship where the insertive partner cannot maintain an erection with a condom, or where a couple feels that intimacy is diminished with a condom. We should be supportive of PrEP  in these circumstances  We should also make clear what we know about risk, and provide more information than simply relative risk reduction numbers. 

Cervical cancer and anal cancer also occur more frequently in association with HIV infection. These two cancers, like KS and NHL are also caused by viruses. These viruses are members of the human papillomavirus family (HPV), types 16 and 18 being the most frequent.  Over 90% of anal cancers are associated with HPV type 16.    HPV viruses are more usually the cause of common warts.  

Potent anti-HIV therapy has reduced the incidence of KS and NHL by 80-85%.  Unfortunately treatment has not had the same effect on HPV associated cancers.   Some studies show an increasing trend in the incidence of cervical and anal cancers, an effect most likely due to increased survival.

I was prompted to write this entry after reading an important report about HIV and anal cancer which has just appeared in an advance access edition of the Journal,  Clinical Infectious Diseases.  The lead author is Alexandra de Pokomandy.

Its title is:  HAART and progression to high grade anal intraepithelial neoplasia in men who have sex with men and are infected with HIV.

Many of the article's conclusions have been reported before, but this one is important because it has the power of a prospective study.   A prospective study is one in which participants are examined at regular intervals after entering the study and checked for the development of any changes over time.  Most previous studies on the association of anal cancer and HIV infection were not prospective studies.