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How to have sex in an epidemic: 30th anniversary

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This month marks the 30th anniversary of several significant events in the history of the response to AIDS.

Most significantly, May 1983 is the 30th anniversary of the discovery of HIV. 

In the May 20th, 1983 issue of Science, Francoise Barre Sinnossi and her colleagues at the Pasteur Institute in Paris reported that they had isolated a virus from the lymph nodes of a patient with signs and symptom characteristic of AIDS.   This was how the virus, a retrovirus they named LAV, was announced to the world.  Its name was changed to HIV a few years later.

2013 is also the 30th anniversary of several other events that represent achievements by people with HIV.

A small booklet called "How to Have Sex in an Epidemic" appeared in May 1983. It was written with two HIV positive patient collaborators of mine, Michael Callen and Richard Berkowitz. 

HTHS.jpg


The entire booklet can be seen at Richard's website.

In 2008, Professor Merson and colleagues in an article entitled "The History and Challenge of HIV Prevention" wrote the following:

"That year (1983), two publications that are now seen as having invented so-called safe sex were issued: the pamphlet Play Fair! produced by the activist group Sisters of Perpetual Indulgence, and How to Have Sex in an Epidemic: One Approach, which advocated condom use and

self-empowerment and laid the foundation for a  generation of prevention approaches to follow"

(The Lancet 2008; 372:475)

 

(Play Fair appeared in 1982, not 1983).

 

At that time the cause of AIDS was unknown; isolation of the virus, yet to be named HIV, had only been reported in the same month that our booklet was published.   But by then we did know that AIDS was sexually transmitted, that exposure to body fluids was involved. We had good reasons, if not proof at that time, to believe that semen was a major vehicle of transmission.  We did not then know what it was that was being transmitted.  Was it a new virus or repeated reinfections with something known?    I had extensive experience in caring for gay men in New York, for three years before the epidemic was recognized in 1981; my patients were among the very first to become ill. Because of this experience, and because I was also a well-trained microbiologist with an interest in cytomegalovirus - CMV, I thought it possible that repeated infections by CMV, found with very high frequency in the semen of sexually  active gay men, could play a role in disease development1.

Even if we didn't have the answer to the question of what it was that was being transmitted, we felt that it was justifiable to recommend condom use, which could prevent transmission either of an as yet unrecognized new virus, or repeated infections with a known virus. 

 

Our booklet was not the first to recommend condom use; this first appeared in a pamphlet put out by The Sisters of Perpetual Indulgence in San Francisco in 1982.

 

A more detailed account of how we came to write How to Have Sex in an Epidemic (HTHS) can be seen HERE.

 HTHS originated entirely in the community of people with and at risk for AIDS, from individuals with no organizational affiliation.   It was made possible by a $5,000 donation from Randall Klose, who should be remembered for this, as well as for his support of so many worthwhile projects.  Michael added a tax refund from the IRS to Randy's contribution.

Having written the booklet we had copies printed and bound and then did our best to distribute the booklets, even leaving copies in bars. 

I rented a mail box on Greenwich Avenue and opened an account for our publishing venture which we called News from the Front.

Our efforts were met with a great deal of hostility, as well as with expressions of gratitude.  I still have a box of letters from all over the US and some from elsewhere, thanking us in different ways. There were probably different reasons for the hostility.  Some saw condoms as a means to facilitate sex in perilous times. The properties ascribed to the then theoretical new virus included a very high degree of infectiousness, such that a single exposure would lead to infection, and that the infection would always be fatal.

There is a link above to something I wrote about our work on the booklet, that includes the following:

The three of us shared a belief in the importance of sexual expression as a vital human need. It was particularly important, that at a time when it could be associated with the possibility of such dreadful consequences, sex itself be defended as one of life's joys. Michael and Richard were able to do this in their writing. Theirs was a perfect writing partnership, and the three of us had an easy and fluent collaboration. The booklet, in addition to describing the theory on which the proposals were based, describes specific sexual acts very explicitly and suggests ways in which they can be safely performed. There are additional essays on issues such as Should Aids patients have sex? and Guilt, Morality and Sex Negativity. .

To be sure, if we had not suggested condom use, it would have been proposed some years later. (2013 comment:  The following assumption is probably incorrect)  This almost certainly would have been a harm reduction proposal, although the concept of harm reduction had not yet been articulatedThe primary prevention message would most likely have been abstinence outside a stable relationship, but if one were unable to achieve this, a condom would be recommended. Thus this likely scenario would not have been supportive of sex and might have had a particularly negative impact on some gay men, and indeed on anyone engaging in sex outside marriage. Perhaps the most valuable contribution of How to have sex in an epidemic was its ability to propose condom use in a manner that was able to celebrate sex. It clearly recognized that it was not sex that caused illness, but sex with a person who was infectious

In 2003 Richard published " Stayin Alive. The invention of safe sex "in which he describes the interaction between the three of us and the process of writing the booklet.

The history of HTHS is also covered in the movie:  "Sex Positive".

There are two other 30th anniversaries this year related to the publication of HTHS.  While writing the pamphlet Michael and Richard were also working out of my 12th street office helping to establish the AIDS Medical Foundation (AMF).  The incorporation papers were prepared by a lawyer patient of mine and his partner and on the 27th April 1983 the AMF came into being, just weeks before HTHS appeared.  One of the first actions of the AMF was to provide fiscal sponsorship for Randy's donation, supporting work on HTHS.   We placed inserts into the booklet soliciting donations to the AMF.

 The other 30th anniversary that should be commemorated in 2013 is the formulation of the Denver Principles.  This happened in June, 1983.   Both Michael and Richard were signatories.  Richard is now the only surviving signatory to the Denver principles.  Michael and Dan Turner wrote an account of the formation of the PWA self-empowerment movement which can be read HERE.

 

HTHS, the creation of AMF, and the articulation of the Denver Principles were all manifestations of PWA self-empowerment.

People with HIV articulated the Denver principles; HTHS was written by two people with HIV and their community doctor, and the AMF was established by myself, a community doctor and Dr Mathilde Krim, with the essential help of people with HIV.

1:          Early evidence for a role for CMV included the following:  Most adults will have been infected with CMV.  But among gay men attending STD clinics in the 1970s prevalence of CMV antibodies was about 90% compared with a 54% prevalence among heterosexual men.  CMV could be isolated from the semen of about 40% of a cohort of gay men followed in New York in the early 1980s.  By 1981 we knew from studies in the transplantation field that CMV among herpes viruses has an important property.  Reinfections with CMV can occur, and in 1983, given the high prevalence of carriage of CMV in the semen of gay men, the prevention of CMV reinfection was one theoretical reason to propose condom use. 

  We now know that CMV, and other herpes viruses interact in multiple ways with HIV.

 

Here are some links to a description of these interactions.

CMV and immune activation

Herpes viruses and HIV

Positive feedback involving herpes viruses and HIV


Transmission of HIV From Infants To Their Mothers

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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 Collery 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 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. 


Kenya HIV2.jpg




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. (noted in the paper referenced below).

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.  

Why so few resources have been devoted to the improvement of health care facilities in developing nations is 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?

Perhaps it will be left to HIV activists who have successfully drawn public attention to other neglected issues, to alert funders and policy makers to the dangerous condition of many healthcare facilities in the developing world.

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

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

 

I realize I neglected one point,

 Exposure to saliva is not considered to be a great risk for HIV transmission, so why is it happening in the case of CBWT?

The authors suggest maternal skin fissures or infant stomatitis (inflammation of the lining of the mouth).  I'm not aware of research that would explain such transmissions in infancy. I hope it will be undertaken. 

 

 

 

(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.

 

This was written together with David Gisselquist



In 2010 there was a great deal of outraged comment about the US government's award of $823,000 to an HIV related project in Africa.    Specifically, the taxpayer dollars were to be used to teach uncircumcised African men how to wash their genitals after having sex.  The grant states; "If we find that men are able to practice consistent washing practices after sex, we will plan to test whether this might protect men from becoming HIV infected in a later study."

 

The reasoning behind the project was based on the assumption that the reported protective effect of male circumcision was due to improved genital hygiene.   This is in the project description:

"The protective effect of male circumcision on HIV acquisition may be due to improved genital hygiene. We propose to evaluate the feasibility of a post-coital genital hygiene study among men unwilling to be circumcised in Orange Farm, South Africa. Men in high prevalence settings could potentially benefit from improved genital hygiene if this intervention proved to be efficacious in reducing HIV acquisition risk"   Genital hygiene was to be improved by asking men to wash their penis after sex.

Widespread criticism of such a use of public funds might have missed the main problem.  As it turns out, not washing immediately after sex may actually have a significant protective effective for men at risk from heterosexual intercourse - including both circumcised and uncircumcised men

This was noted in two randomized studies of male circumcision to prevent HIV infection in the Rakai region of Uganda in 2003-2007.  Although the effect of washing on HIV acquisition received some media  attention  at the time its relevance to HIV prevention remained generally unnoticed. It apparently also remained unnoticed or considered to be of no consequence to the applicants as well as the funders of the $823,000 grant noted above.

Combining  results from these two trials, Tobian and colleagues in an article in AIDS in 2009 (1) report information on risks for 105  HIV seroconversions in 6,396 initially HIV-negative men observed  during 9,604 person years (PY) of follow-up.  Half the men were circumcised for the trial and half remained uncircumcised.

These 105 HIV seroconversions represent 1.09 infections per 100 PY.

Among the questions that trial participants were asked in attempting to define risks for HIV infection was whether or not they washed their genitals after sex.

Among men who did so there were 1.35 infections per 100PY compared to only 0.38 infections per 100PY among men who did not wash their genitals.  The adjusted relative risk for washing vs. not washing was 3.04 (95% confidence interval: 1.11-8.33; P = 0.031).

The authors make the following comment in their discussion,

"The finding that HIV incidence was increased with washing genitals after sexual intercourse is counterintuitive, but supports previous finding that washing the penis within 10 min of sexual intercourse increases the risk of HIV acquisition among uncircumcised men. The increased HIV acquisition with penile washing may be due to the removal of acidic vaginal secretions or the addition of water with a neutral pH may assist HIV survival and infectivity".

The "previous finding" referred to is an earlier report by Makumbi and colleagues (2)   in 2007, who interviewed 2552 uncircumcised men enrolled in the control arm of a randomized   trial of circumcision for HIV prevention in the Rakai region of Uganda (these men are included in the data reported by Tobian and colleagues in 2009).  Some of the information reported by Makumbi  and colleagues is shown in the last four slides in this presentation prepared by i-Base, UK. 

This is one of the slides showing that there were 2.32 HIV infections per 100PY among men who washed their penis within 3 minutes of intercourse, but only 0.39 infections per 100PY among men who waited for 10 minutes or longer before washing.



washing3.bmp

 

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


1.   Tobian AAR, Ssempijja V, Kigozi G, et al. Incident HIV and herpes simplex virus type 2 infection among men in Rakai, Uganda. AIDS 2009; 23: 1589-1594.

2.    Makumbi FE, Gray RH, Wawer, M, et al. Male post-coital penile cleansing and the risk of HIV-acquisition in rural Rakai district, Uganda. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, abstract WEAC1LB, Sydney, 2007. Available at:

http://www.ias2007.org/Default.aspx?pageId=11&abstractId=200705536

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

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.  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.   There are plenty of other experts who are not so certain that starting treatment above 500 CD4 lymphocytes will confer a net benefit to the HIV infected individual.

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.

Here is the rating scheme used by the DHHS panel in making their treatment recommendations.

rating system.png

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 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.

Dual HIV Infection

| 3 Comments

We have known for quite a long time that it's possible to be infected with HIV more than once.  Dual HIV infections were first reported in 2002.

However recombinant HIVs were detected long before.

Recombinant HIVs are viruses that are derived from at least two different HIVs; parts of each join together to produce a new virus. Since this can only happen in a cell infected with both viruses, the existence of recombinant HIVs means that infection with more than one HIV must have occurred.

We don't know how frequently this occurs.  Some people will have been infected with more than one virus at the same time. But others already infected may be subsequently superinfected, that is infected with a different HIV.

 

The current issue of Clinical Infectious Diseases has an article on dual HIV infection.

It demonstrates that dual infection in one particular cohort   was associated with a more rapid decline in CD4 numbers.

In the authors' own words:

Conclusions. Dual HIV-1 infection is the main factor associated with CD4+ T-cell decline in men who have untreated primary infection with HIV-1 subtype B.

 

This conclusion is based on the study of only 10 men dually infected, drawn from an already selected group of 37 untreated men who were followed after a primary HIV infection.

 

Dual infection has also been reported among long term non-progressors, so  it's impossible at this time to generalize about its effects.  

The article demonstrates that dual infection may not be that uncommon.  It was detected in 10 of a group of 37, albeit selected, men.

Superinfection in treated individuals may result in a failure of particular drug regimen should the superinfecting virus be resistant to it.

Even if we still have much to learn about dual infections, the implications regarding continued condom use among seropositive individuals are clear enough, a point made by the authors.

 

 

 

 

 

HIV and Herpes Viruses

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HIV and Herpes Viruses

 

I'm returning to this topic yet again as another paper has appeared reporting that treatment of HIV infected individuals with Valtrex lowered HIV viral loads to a greater extent than acyclovir.  As has become usual in these reports the authors only studied individuals who were infected with herpes simplex virus type 2, which therefore suggests that the effect of Valtrex results from a suppression of this virus.

 

This is perplexing.   Although prevalence of herpes simplex virus type 2 is 50%-90% in some African countries, prevalence of HSV-1 must be even higher.  There are several reports that indicate that herpes simplex virus  type 1 can activate HIV (as do other herpes viruses),  It is just as, and may even be more, sensitive to acyclovir.  EBV is also sensitive to this drug, and while CMV is resistant, the high dose of Valtrex may have had some effect on this virus.    

There is considerable evidence that CMV plays an important role in the pathogenesis of HIV disease.  It's  likely that EBV also does.  I have written about this in several previous posts, two can be seen here and here. 

These trials of the effects of anti-herpes treatment on HIV also represent missed research opportunities.    Any effect of treatment on EBV could have been investigated because this would likely be reflected in changes in EBV antibody reactivation patterns.  Although CMV is resistant to acyclovir, there may have been an effect of the dose of Valtrex used, which might have been detectable by virus isolation or quantitative PCR.  If sera and stored blood samples exist this still may be possible.

Immune activation is at the heart of the pathogenesis of HIV disease.  By now it's recognized that factors in addition to HIV contribute to the sustained immune activation that's characteristic of HIV disease. There is much evidence to implicate herpesvirus infections as one of these factors; in addition these viruses can interact with HIV in several other ways, to facilitate infection as well as replication.

The lowering of HIV viral loads by treatment of herpesvirus infections also has implications for transmission and therefore for prevention.  Transmission of HIV is enhanced when viral loads are high. 

There is a relationship between viral load and infectivity,  although this has been studied in relation to sexual transmission, there can be little question that it also applies to blood borne infection.  This is a much neglected source of HIV transmission in  regions with generalized epidemics particularly  Africa, which can occur in unsafe medical facilities and from other skin piercing procedures with reused and contaminated equipment including  the reuse of syringes.  This is well described in a recent blog on this site by Simon Collery and David Gisselquist.

It's not only herpesvirus infections that interact with HIV to increase its replication. A number of endemic and waterborne infections in Africa can also do so. I have also written about this in this POZ blog. And more extensively, here.

Treating and preventing these endemic and waterborne infections is an absolutely appropriate part of the attempt to control the HIV epidemic.  Of course doing so is important in its own right and will improve the lives of people. These infections shorten life and are debilitating, with destructive social and economic consequences.

Treating many of these infections can lower HIV viral loads to a greater or lesser extent, also noted in this blog.  

Should we not also extend the concept of treatment as prevention to the treatment and prevention of endemic and waterborne infections?  

By reducing immune activation, and thus HIV replication, this will not only lower HIV viral loads and slow disease progression, but will also improve the lives of millions of people.

PrEP Trial Reports: iPrEx

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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.

 

Or just put "absolute and relative risk" into the google search box.

(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. 

Treatment as Prevention: Protecting patient autonomy

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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.  This is because it has yet to be reliably shown 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.   START is a randomized controlled trial now enrolling that will provide needed information, but we will have to wait several years for its results.

The issue isn't whether people with greater than 350 CD4 lymphocytes should or should not receive treatment.  A respect for their autonomy means that the decision whether or not to do so is made by them and is made free from coercion.

Interferon and AIDS: Too much of a good thing

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The discovery of interferon in the circulation of people with AIDS

 

This is another historical account. It's about interferon and HIV. 

Interferon is produced in response to viral infections as a first line of defence.  But in addition to its antiviral properties interferon also has widespread effects on the immune system and elsewhere, some of which can be harmful if prolonged.  Therefore mechanisms come into play to turn interferon production off after some days as other antiviral responses come into play. 

HIV and disease causing SIV infections are different to other 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.   

As early as 1983 a suppressive effect of interferon on CD4 proliferation had been noted and published.  Stuart Schlossman  who was one of the first to devise the current method to identify T cell subsets was an author, yet there probably is no reference to this work in the literature dealing with interferon as a treatment for AIDS.

Finding interferon in people with AIDS

 

AIDS was first recognized in 1981.  Interferon was found in the blood streams of people with AIDS later that same year, making it one of the earliest of the significant AIDS associated immunologic abnormalities to be noted.    Large amounts of interferon were found that were present for very prolonged periods, a situation noted before only in auto-immune diseases like lupus.

 

In this post I'll describe how interferon came to be discovered in people with AIDS so early in the epidemic.  It's an interesting story illustrating at least one way in which science can progress, and also a way in which scientific progress can be retarded.

Anal Cancer and HIV

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Kaposi's sarcoma (KS), and non- Hodgkin lymphoma (NHL) were common AIDS associated malignancies before potent antiviral therapy became available.   The incidence of these two malignancies used to be 50-200 times higher among HIV positive individuals  than in those who were HIV uninfected.  These two malignancies are caused by herpes viruses, HHV8 in the case of KS and EBV in the case of NHL.

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.



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