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  • Have we ignored a very simple procedure that could significantly reduce the risk of heterosexual transmission of HIV to men?

    Posted on May 8th, 2012 admin No comments

    By  David Gisselquist and Joseph Sonnabend


    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[i] 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[ii] 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 man 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.

    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.


    [i] 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.

    [ii] 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

  • Treatment as Prevention: Protecting Individual Autonomy

    Posted on June 5th, 2011 admin No comments

    Treatment as Prevention

    Protecting patient autonomy

    Patient autonomy is just a particular instance of individual autonomy, a term that may sound pretty dry and academic but if we used the term individual freedom we would essentially be talking about the same thing.

    Respect for the autonomy of the individual may be the most important of the principles that form the foundation of medical ethics. (1)

    One attribute of personal autonomy is: “the capacity to be one’s own person, to live one’s life according to reasons and motives that are taken as one’s own and not the product of manipulative or distorting external forces.” (2)

    There is no disagreement about the importance of respect for individual autonomy but as I’ll explain, it seems that its pre-eminence is being questioned in some proposals to use antiretroviral treatment to prevent transmission of HIV.

    The recent demonstration that antiretroviral treatment can prevent transmission of HIV among serodiscordant heterosexual couples is great news. However, when the person offered treatment has not yet been shown to personally benefit from it, an ethical issue needs to be addressed. It has not yet been reliably demonstrated that for people with greater than 350 CD4 lymphocytes, starting treatment immediately rather than deferring it confers a net benefit; indeed, it may even prove to be harmful. A randomized controlled trial now enrolling will provide needed information, but we will have to wait several years for its results.

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

    A recent issue of the Journal, Public Health Ethics (3) is devoted to ethical issues associated with the proposal that a program of universal testing and treatment of infected individuals could bring an end to the HIV/AIDS epidemic. Such a proposal would involve the treatment of healthier HIV infected individuals not at this time known to personally benefit from antiviral medications which could even harm them.

    In an article in the journal referred to above, public health ethics is said to require an approach where respect for individual autonomy is not paramount; a commitment to the supremacy of individual autonomy could have no place where the “primacy of collective wellbeing is the starting point”.

    In that case I wonder just how desirable a collective wellbeing would be where individual rights were subservient to whatever was defined as the collective good.

    I can only hope that this goes nowhere, as abandoning the pre-eminence of respect for individual autonomy opens the door to tyranny, paternalistic or otherwise. Individual freedoms have been hard won, and we should always be aware of harms that have been perpetrated in the name of the public good, even leaving alone the problem of who defines what constitutes the public good.

    In public health, medical research and medical practice, concern for individual autonomy remains paramount. The only commonly agreed acceptable exemption is the restriction of personal freedoms to prevent harm to others such as limiting the movement of individuals with highly communicable diseases where the harm that may be done to others is considerable. That is, outside the criminal justice system, among individuals who are free.

    People have the right to make decisions about their treatment, their participation in a research study, or in a public health intervention, free from coercion.

    Providing misleading information is a form of coercion; withholding information may also be coercive.

    Providers of health care have an obligation to provide patients with honest information to inform their decisions. This must include information about what is known about the risks and benefits of treatment, as well as what remains conjectural.

    Information and the strength of the evidence upon which it rests:

    It’s not enough to simply provide individuals with information concerning the benefits and risks of a particular treatment. In order for the information to be useful we must also indicate the strength of the evidence on which the information rests. (4)

    The most reliable evidence regarding the effects of a particular treatment is provided by results of randomized controlled clinical trials. This is because the treatment in question has been put to the test in a protocol that minimizes bias; we can therefore have a greater degree of confidence that effects observed are in fact caused by the treatment.

    Unfortunately information derived from randomized controlled trials is often unavailable. The clinical trial may not yet have been completed, or for whatever reasons the trial cannot be undertaken.

    When this is the case we have to consider evidence of inferior quality, for example, evidence derived from reviews of patient records or observational studies, and the opinion of experts.

    Observational studies are beset with interpretative difficulties because subjects are not randomly assigned to receive one or another kind of intervention. The particular reasons why participants were selected for study may influence the outcome rather than the effects of the intervention.

    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.

    At the end of the day what’s of central importance is that we respect our patient’s right to make choices about his or her treatment, and provide honest information to inform that choice, recognizing the difference between expert opinion and established fact.

    (1) Ever since Beauchamp and Childress published the first edition of their classic text, Principles of Biomedical Ethics, in 1979 it’s been commonly accepted that beneficence, nonmaleficence, justice and respect for autonomy, are four principles that should guide medical ethics.

    The Four Principles are general guides:

    Respect for autonomy: respecting the decision-making capacities of autonomous persons; enabling individuals to make reasoned informed choices.

    Beneficence: this considers the balancing of benefits of treatment against the risks and costs; the healthcare professional should act in a way that benefits the patient

    Non maleficence: avoiding the causation of harm; the healthcare professional should not harm the patient. All treatment involves some harm, even if minimal, but the harm should not be disproportionate to the benefits of treatment.

    Justice: distributing benefits, risks and costs fairly; the notion that patients in similar positions should be treated in a similar manner.

    Beauchamp and Childress; Principles Biomedical Ethics, OUP, 5th edition

    (2) Christman, J, 2001″Autonomy in Moral and Political Philosophy”, The Stanford Encyclopedia of Philosophy (Fall 2007 Edition) , Edward N. Zalta (ed.), URL = <http://plato.stanford.edu/archives/fall2007/entries/autonomy-moral/>.

    (3) http://phe.oxfordjournals.org/content/3/3.toc

    (4) Several systems have been devised to grade the quality of evidence.For example: http://www.cebm.net/index.aspx?o=1025 The GRADE working group has been working on assessing the quality of evidence since 2000. http://www.gradeworkinggroup.org/index.htm

  • PrEP: Pre exposure prophylaxis to prevent HIV infection. August 2009

    Posted on August 11th, 2009 admin No comments

    Pre exposure prophylaxis in relation to HIV infection refers to the administration of anti HIV medications to uninfected people as a means of protecting them from becoming infected with HIV.     It is not known if this intervention will succeed in achieving its goal.   Several trials have been underway to test it for safety and efficacy, and many more are planned worldwide.

    I have paid little attention to these initiatives but was prompted to do so by notices of a meeting to discuss pre exposure prophylaxis – now known as PrEP – in the coming weeks.   The wording of this notice is quite vague, but the notice suggests that it is urgent to start planning for the implementation of PrEP as the analysis of initial safety and efficacy trials are expected within the next year.

    This is quite startling in its implication that PrEP actually works and presumably is safe.  The actual words of the notice are:

    “Results and analyses of initial safety and efficacy trials are expected within the next year, which highlights the urgency to beginning to plan now for how PrEP might be used to maximize its public health impact”.

    This is a convoluted statement, to the point of being quite unintelligible. It can be misleading in the implication that can easily be drawn from it that PrEP works. Why else begin to plan for how to use it?

    I had not been aware of just how extensive the PrEP initiative has been.   To get some idea of the many trials that are underway or planned, take a look at this website:

    http://www.prepwatch.org/

    Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).

    http://www.fhi.org/en/Topics/preexposure_prophylaxis.htm

    FHI has produced a set of slides listing PrEP trials.

    http://www.prepwatch.org/pdf/Meetings/Cates_TDF_slides_May.2006.pdf

    Among the “research consortia” listed as involved in PrEP research are the Bill and Melinda Gates Foundation, Gilead Sciences, the Centers for Disease Control (CDC), The National Institutes of Health (NIH),  and UCSF. These trials are conducted  in many countries, including Peru, Botswana, Thailand, the US and Malawi.

    Organizations listed under “community consortia” are GMHC,  AVAC, Global Campaign for Microbicides, CHAMP, and the IAS.

    The websites of these organizations contain information about PrEP.

    AVAC :   http://www.avac.org/

    Global Campaign for Microbicides:  http://www.global-campaign.org/

    CHAMP:  http://www.champnetwork.org/about

    The International AIDS Society:  www.iasociety.org

    All the trials use a once daily drug, tenofovir, with or without emtricitabine (FTC). Tenofovir is manufactured by Gilead in the US although I believe a generic version is produced in India.

    The trials vary in design.   Some require daily tenofovir, some are used intermittently or specifically before sexual intercourse. Some use a gel formulation.

    Previous trials had run into difficulties; several were stopped for different reasons.  For example a trial in Cameroon was stopped amid allegations that those who seroconverted did not receive adequate treatment.  A trial in Nigeria was stopped because of inadequate standards in laboratory testing.

    A trial of PrEP among Cambodian sex workers was stopped in 2004 by the Cambodian government.  This was perhaps the most publicized of the several PrEP trials that were stopped, because several activist groups brought attention to it at the XV International AIDS Conference in Bakgkok.   Among the many reasons stated for pressure by activist groups to stop the trial were poor HIV prevention counselling, and a lack of medical services to those who seroconverted.    Act Up-Paris was active in stopping PrEP trials both in Cambodia and Cameroon, although it is reported that this organization is supportive of tenofovir trials in general.

    These events are described in an article entitled “The Abandoned Trials of Pre-Exposure Prophylaxis for HIV: What Went Wrong?”  The authors are Jerome Singh and Edward Mills.  It can be seen here.

    http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.0020234

    For reasons I will describe I do believe that there is no way to design a trial of the efficacy of PrEP that can meet acceptable ethical standards.   On the other hand, it is perfectly possible to conduct trials to determine the safety of tenofovir for pre exposure prophylaxis.

    So maybe an answer to Drs Singh and Mills as to what went wrong with the abandoned trials of pre exposure prophylaxis is that the question of efficacy, unlike that of safety, cannot and should not be tested on human research subjects.

    Here are the reasons why this cannot be done, at least regarding the use of tenofovir to prevent sexual transmission of HIV.

    No ethically designed and conducted trial can definitely prove that PrEP works.  Definite proof of course may be an unattainable goal, but even credible evidence regarding efficacy  would not be found if the trial were to be conducted in an ethical manner, simply because with the availability of condoms, and the imperative to provide counselling  that they be consistently  used,  such  a trial could not answer the question asked of it. This is essentially because the consistent use of condoms will ensure that insufficient seroconversions occur in participants receiving  placebo.

    In any trial that studies the ability of a new intervention to prevent sexual  transmission of HIV, participants must receive persistent counselling about the need to use condoms.  These must be provided, with ongoing support for their continued use.  This is the ethical requirement.

    Quite clearly if great care is taken to meet this requirement there will be few infections in people receiving placebo.  The investigators are presented with a conflict of interest that no amount of verbal assurance can resolve.  The conflict is that on the one hand the investigator must always be cognisant of the importance of doing all that’s possible to encourage condom use to prevent the sexual transmission of HIV infection, and on the other hand the investigator has an interest in demonstrating an effect of PrEP in preventing it.

    It is only when condom use falls below a certain level that the effect of another preventative measure can be assessed.  We are obliged to do all we can to ensure that this does not happen.

    The Centers for Disease Control (CDC) are sponsoring several trials of PrEP[i].  They are very sensitive to the need to provide risk reduction counselling to participants.

    Here is an excerpt from material published by CDC:

    “One of the greatest risks, as efforts progress to identify new biomedical prevention approaches, is that individuals at risk will reduce their use of existing HIV prevention strategies. It will therefore be crucial to reinforce proven behavioral prevention strategies, both within and beyond these trials. All three trials are taking multiple steps to address this issue during the education and enrolment of trial participants and through ongoing participant counselling.

    First, it is critical to ensure that participants understand that trial participation may not protect them from HIV infection—either because they may receive a placebo or because they may receive a study drug, the efficacy of which remains unproven. This and other key aspects of the trial, including the potential risks and benefits of participation, are explained to potential volunteers in the language of their choice, prior to their enrolment. To ensure participants fully understand all aspects of their participation, all volunteers are required to pass a comprehension test prior to providing written informed consent. Study participants are also free to withdraw from the trial at any time and for any reason”.

    So there is clear recognition that there may be a falling off in the use of proven prevention approaches, importantly, the use of condoms.

    Here is another excerpt:

    “To assist participants in eliminating or reducing HIV risk behaviours, extensive counselling is provided at each study visit, and more often if needed. This interactive counselling has proven effective in reducing the risk of HIV and other STDs in multiple populations, including past participants of similar HIV prevention trials. Participants are also offered free condoms and STD testing and treatment to reduce their risk for HIV infection”.

    If such counselling is effective, the prevention of sexual transmission of HIV particularly through the consistent use of condoms will make it impossible to detect an effect of PrEP.   As mentioned the investigators are presented with a conflict that it is not possible to resolve.

    PrEP is an experimental approach to prevention, while consistent condom use is an established method to substantially reduce the sexual transmission of HIV.

    The argument that may be presented by those who are proponents of PrEP is that condom use is not consistent, and that we need an alternative

    The implication of such an argument supporting PrEP is that prevention education, essentially the use of condoms, has not been sufficiently effective.  This cannot be known to be true of prevention education in principle.

    What is definitely true is that those responsible for prevention education have not been sufficiently effective.

    Our efforts  should be focussed on improving prevention education and support for the consistent use of condoms,

    There is so much more that can be done with persistent, culturally sensitive, highly targeted prevention education.  In order to improve our efforts at prevention education we have to first confront the fact that we may have not been too successful in this endeavour, understand why,  and absolutely not take the position that the undertaking is an impossible one.

    Every new infection today represents a failure, not of prevention education as an undertaking, but a failure to provide it effectively.  The introduction of condom use among gay men in the US in the 1980s originated in this community, it was promoted and effectively advocated for by this community and proved to be effective..   In those early years there was certainly no help from the Government which was to spend enormous sums on a vacuous and ineffective untargeted campaign “ America responds to AIDS” which did absolutely  nothing to stop the advance of this disease into African American communities , although this was happening in plain sight.

    What we can learn from this is that different affected communities are best able to understand the  issues specific to their communities that must be emphasized  and  promote prevention education that is most effective for each of them. Their input is therefore  absolutely vital.

    The design and implementation of well funded and highly targeted prevention education has been neglected.   These initiatives need to be specifically targeted to different groups, the needs of which must be assessed,  barriers identified, continuing support provided, as well as some instrument developed to evaluate the success of the programs. .   It is an enormous challenge.

    We know that gay men were able to make it work for them before the concept of risk reduction had even been articulated. It can work and this is where our efforts must be concentrated.  Not on trials of the efficacy of PrEP that are impossible to conduct in an ethical fashion.

    However It is entirely possible  that PrEP may add an additional layer of safety to condom use during sexual intercourse.  This may be of  particular importance in certain circumstances such as among sex workers.  This is also the case among some women who are unable to rely on the use of a condom by their male partners.   Trials of the safety of once daily tenofovir are absolutely possible and even desirable.  Such trials would be unburdened with the ethical problems that make efficacy trials impossible to conduct.  It will be clear that the trials are to determine the safety of tenofovir when used with condoms to provide an additional level of safety.   It is true that we may never be able to firmly establish its efficacy, but if it proves to be safe, there is sufficient – if far from conclusive evidence to justify its use.

    It is clear that all that has been written about concerns the sexual transmission of HIV.    For those in whom the risk of infection  is through intravenous drug use there is an entirely different set of considerations.  The only known prophylactic measure, the reliable provision of sterile injecting equipment is probably just unavailable for most, and efficacy trials are therefore not burdened with the same ethical constraints.

    One cannot help but note that at least  in two initiatives, pharmacological rather than behavioural approaches to prevention are now being emphasized.  Of course PrEP to prevent  transmission of HIV is one. The other is the attempt to end the HIV epidemic by testing and treating all HIV infected people, whether or not a particular infected individual needs treatment for his or her benefit.  Both are beset with ethical problems.

    The use of condoms can significantly reduce the sexual transmission of HIV.  We know this.   Therefore  our greatest efforts should be placed in improving prevention education.  It is a tremendous challenge given the cultural diversity of the populations involved, and the special difficulties experienced by some. This is particularly true where women are disempowered.

    We know that untargeted efforts such as “America Responds to AIDS” do not work.  We need to understand the barriers to effective prevention education.

    A denial of  the importance of sexual expression to the human experience, stigmatization of those infected, homophobia, racism, bigotry in general and the fact that unlike the use of drugs, prevention education provides no financial return,  are surely amongst them.


    [i] [i]    http://www.cdc.gov/hiv/prep/resources/factsheets/index.htm

  • Treatment as Prevention. A last short postscript

    Posted on May 1st, 2009 admin No comments

    I have written several posts dealing with “Treatment as Prevention”  referring to proposals that the epidemic could be controlled by testing and treating all infected people.   However, as this phrase is also used in a different, although related context, I am adding this last postscript.

    Thus,  “treatment as prevention” has a context that concerns populations and considers a strategy to  control and even end the epidemic.    The same phrase  also has a context that deals with prevention of infection at an individual level, and focuses on transmission risks  between two people.

    The latter context was brought to attention in 2008 by the Swiss Federal Commission on HIV/AIDS.  Their publication essentially states that, under certain conditions,  with effective antiviral treatment achieving an undetectable viral load, the risk of sexual transmission without condom use is not greater than that with the use of condoms.

    Among the conditions stipulated is that there is no sexually transmitted infection, and that the viral load has been undetectable for at least six months.

    http://www.aids.ch/e/fragen/pdf/swissguidelinesART.pdf

    Now a German voluntary organization, Deutsche AIDS-Hilfe, has added support – with some modifications to the Swiss statement.

    http://www.aidshilfe.de/media/de/0904_DAH-Papier_HIV-Therapie_und_Praevention_Englisch.pdf

    There was a huge controversy when the Swiss recommendations were first made public in 2008.  Their conclusions were rejected  by groups  in the US,  even by those who promoted the application of the same principle – the reduction in infectivity conferred by treatment – as a means of controlling the epidemic.

    I was – and am – absolutely supportive of the Swiss recommendations as applied to individuals.  Here is an excerpt from a letter I wrote when the Swiss document was published:

    “The report is absolutely reasonable. There are caveats and cautions in it, and since I can see no reasonable objection to them, we have to look elsewhere to try and understand why the report has provoked such a furious response. I know it is a bit pedantic and pretentious but I’m going to add a quotation that is over 100 years old that recognizes that scientists can be as irrational as anyone else (especially about sex), here it is:

    In Man Adapting, Rene Dubos notes that:

    “The presuppositions on which medicine operates are thus conditioned by the general philosophy of the social group as a whole” and adds the words of Oliver Wendell Holmes in 1860:

    “The truth is that medicine, professedly founded on observation, is as sensitive to outside influences, political, religious, philosophical, imaginative, as is the barometer to the changes in atmospheric density”10
    I would bet that some who have commented have not even read the cautious Swiss text, and have allowed their prejudices and squeamishness about sex in general to surface at the very mention of sex without condoms.

    The Swiss authors do deserve some recognition for their courage. There are circumstances in which it is not irresponsible to have sex without condoms. And even for those for whom these circumstances do not apply, the knowledge of the possibility of sex without condoms will be an encouragement, in at least two ways.

    Firstly, to continue using condoms when this is necessary, and then as a support with treatment adherence and monitoring.

    I say these things as someone who had something to do with the original introduction of condom use for AIDS prevention in 1983, – briefly described here:

    http://aidsperspective.net/articles/Callen-Berk_collaboration4.pdf

    and until now thought – as probably most did, that condom use  would be forever.

    Knowing that this is not necessarily so is a tremendous encouragement and I believe this thought alone will help our prevention efforts”.

    I have continued to encourage the use of condoms, but I do welcome the Swiss document for pointing out, with appropriate documentation and caution, that there are circumstances when it is not irresponsible to dispense with them.

    This also means that there are circumstances when conception is possible. There are also implications in situations where there are laws that criminalize sexual contact with HIV infected people under certain circumstances.

    A large part of the irrational responses to the proposal are I believe based on a disparaging attitude towards sex.

    For many, the use of condoms is a barrier to intimacy.  The knowledge that if certain circumstances can be met, an infected person is not endangering their sexual partner by dispensing with condoms is in fact a life affirming celebration of sex, one of life’s joys.

    Admittedly, dispensing with condoms will not be possible for most individuals.  It is probably most relevant to serodiscordant couples in a stable relationship – that is where only one of the partners is HIV infected.

    But knowing that this might be achieved could be a great support to most HIV infected people  who must continue to use condoms   It will also be a greater incentive to remain adherent to one’s treatment regimen.

    Of course the diminished infectivity of effectively treated individuals is the basis for the proposals to use treatment of all infected people as a means of controlling the epidemic.

    This is a very different situation, most importantly because it will involve treating people who do not need to be treated for their own personal benefit. These healthier people will derive no benefit from the medications and only be exposed to their side effects.  I have written about this in previous posts on treatment as prevention.

    Except for the relatively uncommon situations outlined in the Swiss document, and more cautiously and explicitly, in the German document, the consistent use of condoms remains one of the most important measures we have to prevent infection.

  • HIV TREATMENT AS PREVENTION

    Posted on March 27th, 2009 admin 2 comments

    The proposal that testing and treating everyone who is HIV infected would end the epidemic is back in the news.

    It is not a new idea. It has been discussed at HIV/AIDS conferences. At the beginning of the year an exercise in mathematical modelling was presented in the Lancet providing some support for this notion of universal testing and treatment. Now some experts in molecular biology and virology have added their personal opinions in favour of this approach; I notice that at least on one web site addressed to HIV and Hepatitis virus infected individuals, the views of these pioneer researchers are reported with, as seems to be usual, no analysis or criticism. http://www.hivandhepatitis.com/recent/2009/032409_a.html

    It begins to look almost like an advertising campaign, with the touch of a skilled publicist; an idea is gradually brought to public attention, it is widely endorsed and the hope is that public support will ensure that funders and politicians will move the project forwards.

    The merits of the proposal, and the way it is being promoted are two different issues.

    Regarding the proposal, in principle it is certainly a worthwhile idea that deserves consideration.
    But there are several problems, not mentioned in public reports of this proposal, and barely dealt with in the professional literature, which may constitute insuperable barriers to its implementation.

    Leaving aside for the moment the question of whether such a project is even feasible, perhaps the most important problem is that infected people who do not need treatment will be asked to receive it to achieve a social benefit.

    This proposal then involves the general concept of a public health intervention on individuals who will not themselves derive any benefit from the intervention, but will only be exposed to its risks.

    We have thankfully not yet reached the point where enforced testing and treatment can be seriously proposed. (We may be getting close in the removal of written informed consent for HIV testing).

    Certainly the spectre of mandatory testing and treatment is lurking behind this proposal to test and treated everyone infected. This would do wonders for drug and testing equipment sales.

    So we would have the situation where some individuals will voluntarily take treatments that despite what we may be told can most certainly not be regarded as absolutely free of possible adverse effects, Many infected people will of course benefit from this. Others however will agree to take risks, with no benefit to themselves but for the benefit of others. Quite apart from many other issues, we can only ask these individuals to participate in the project if there is an overwhelming chance of success. At the moment we do not have this assurance.

    It is not a digression to compare this situation with that in which an individual is asked to join a clinical trial and who may be randomly assigned to receive a new treatment of as yet only conjectural benefit. We are absolutely obliged to ensure that the trial design is such that reliable information will be obtained from the study.

    Since the testing and treatment of all infected individuals to end the epidemic can in no way be regarded as an undertaking with an assured successful outcome, it really is a trial, based on an hypothesis somewhat supported perhaps by mathematical modelling. As such it will require written informed consent from the participants.

    I wonder what such a consent form would look like. It is possible, actually likely, that a consent form outlining possible risks and benefits would dissuade many from participating.
    The disincentive would be felt by those infected individuals who do not themselves require antiretroviral treatment.

    This inconvenient obstacle can be easily eliminated.

    All that is needed is for treatment guidelines to include a recommendation that antiviral treatment should be offered to all infected individuals, even those with greater than 500CD4 lymphocytes. A precedent has now been set where treatment recommendations can be made on the flimsiest of evidence. The inappropriate use of retrospective observations to justify an earlier start to antiretroviral treatment is a good example.

    So all one needs to do is to move the goal posts a little further and declare that antiretroviral treatments should be given to all HIV infected individuals, irrespective of CD4 count. There should be no difficulty in selecting retrospective observations that will support this recommendation. In the field of HIV/AIDS you can probably find retrospective data to fit whatever idea you are interested in promoting.

    There is another tool available to promote the contention that every HIV infected individual, irrespective of CD4 count will benefit from antiviral therapy. This useful tool is called “expert opinion”. (Actually, people billed as “experts” have already expressed this opinion).

    The problem with this is: what does it take to be regarded as an expert?

    We may well be in an era where we have “experts” for hire.

    Defining what was meant by “expert” was once much easier. Years of experience and significant contributions to the field might have been required attributes. But no longer.

    Experts can seemingly be created overnight, at least by commercial entities interested in marketing a product. Their credentials are easily supplied. These instant experts will give talks at conferences, they will appear on educational programs, and even put their names to ghost written articles.

    [http://healthcare-economist.com/2008/05/03/ghostwriting-by-pharmaceutical-companies/

    Revealed: how drug firms ‘hoodwink’ medical journals Pharmaceutical giants hire ghostwriters to produce articles – then put doctors’ names on them.
    http://www.guardian.co.uk/society/2003/dec/07/health.businessofresearch
    ]

    As for the practice of ghost writing , there is a great deal of evidence for this, a little shown above. I’m ashamed to admit that I once (only once many years ago) allowed an employee of a drug company to write an article which carried my name. But I had done the work without their support, and in my defense, I checked every word, changing some, – an experience the writer was evidently not used to. This was my first (and only) personal encounter with this practice

    I will hazard a prediction; before the year is out we will have arrived at the point that experts will state that every HIV infected person benefits from treatment, irrespective of CD4 count. If required we will see retrospective observational studies which show that in people who started treatment above a CD4 count of 500, mortality from all causes was reduced as compared to those starting below 500 CD4 cells. It should be just as easy to find retrospective data that shows that starting treatment immediately on diagnosis confers a benefit not seen when treatment is delayed to CD4 count of 350.

    Of course these expert views will be very widely disseminated in press reports and on numerous web sites – some will even provide the opportunity for doctors to earn CME credit. In this way conjectures are transformed into established facts.

    I don’t know how we might obtain real evidence that testing and treating all infected people is not only feasible, but would achieve its goals. The two are related.

    For example, how does one ensure that all people are tested? Or that they will agree to be treated? Or that they will adhere to their treatments?
    As imperfect as this is maybe one approach is to test these issues in a limited setting where mobility in and out of the selected areas can be controlled for.

    This could more usefully be a trial where two different strategies were compared – the present practice of starting treatment at 350 CD4 cells, and treating everyone infected, while promoting HIV tests in both groups. Despite complications introduced by the movement of people, we might get an idea if this is a feasible and effective approach.

    Sadly those bodies that instruct physicians on how to treat HIV infected people, and who tell HIV infected people what is best for them, seem to be averse to calling for prospective studies, designed to shed some light on what may in fact be best for infected people. Those who manufacture the treatments appear to prefer trials that are designed to provide them with the answer most congenial to them. Here is an account of the practice of designing trials to provide the answer most desired.
    [http://www.washingtonpost.com/wp-dyn/content/article/2008/07/14/AR2008071402145.html]

    They can also rummage in retrospective data collections selecting observations best suited to the outcome they have already decided on. Of course there is always an expert to be created to promote this outcome.

    When the mathematical modeling referred to above supporting the idea of a “test and treat everyone infected” approach appeared, I wrote a reply to the Lancet which published the article. Not my letter, which was politely rejected.
    I am adding a slightly edited copy of that letter here.

    A recent Lancet article suggests that we could end the HIV epidemic by testing and treating all who are infected, irrespective of whether or not the individual would benefit from such treatment (R. Granich et al. 2009 Lancet 373:48).

    This represents an intervention on individuals, primarily for a public health benefit. At the present time, ethical considerations make this proposal a completely indefensible approach.
    The available drugs are far from benign; for a particular individual, their use is desirable and justified when their benefits clearly outweigh their risks. Treating individuals to achieve a population benefit requires a similar risk benefit assessment. F M Hodges and colleagues have addressed this issue. (EM Hodges, JS Svoboda, RS van Howe
    Prophylactic interventions in children: balancing human rights with public health. J Med Ethics 2002; 28: 10-26)

    To protect individual liberties they propose six conditions that should be met before for such interventions are taken. All of these are reasonable. I quote a passage from their article that outlines them.

    “PROPHYLACTIC INTERVENTIONS FOR PUBLIC HEALTH BENEFIT”
    Prophylactic medical interventions are frequently performed on healthy individuals who have given informed consent. …..
    The most common example arises when the patient is at significant risk of contracting a life- and public health-threatening illness for which the proposed prophylaxis is a proven preventive. In order to safeguard individual liberties, the situations in which such procedures may be undertaken for public health benefit must meet the following requirements:
    1. The danger to public health must be substantial.
    2. The condition must have serious consequences if transmitted.
    3. The effectiveness of the intervention in safeguarding the majority of the public against the particular malady must be well established.
    4. The intervention must be the most appropriate, least invasive, and most conservative means of achieving the desired public health objective.
    5. The individual must be provided with appreciable benefit not dependent on speculation about hypothetical future behaviours of the patient.
    6. The burden to the individual’s human rights and health must be balanced against and found to be substantially outweighed by the benefit to society in helping prevent a highly contagious disease or other potentially calamitous condition from affecting the public health”.
    Clearly the proposal to treat all infected people will include some in whom the fifth consideration will not be met, but the concerns are covered in the sixth one. But here the benefit to society must be assured, or more practically, be considered to be highly probable, with credible evidence produced to support the contention (as stated in the third consideration).

    While the first two criteria are very clearly met, the present proposal to treat all who test positive fails utterly on the third point. It is far from well established that antiviral treatment of all who are infected will protect the “majority of individuals” in diverse settings. Among problems acknowledged by the authors are those related to toxicity, adherence and the development of resistance to the antiviral drugs. To this must be added the possible negative effects on behaviour deriving from a perception of being non infectious. The fourth condition is also not met. We cannot state that we have exhausted the utility of prevention education and promotion of condom use.

    Let alone the questionable wisdom of mounting an extensive and expensive public health intervention that is based only on mathematical modeling, we are very far from possessing information that would supply the slightest confidence that such a measure would effectively meet its objective.
    Regarding adherence, the optimism presented by the authors based on studies in Malawi is hardly justified. Adherence by individuals who may be ill, and certainly know they are receiving medications for their own benefit tells us nothing about adherence by people who feel healthy and know they are not taking the medications to benefit themselves.

    The general relationship between viral load and infectivity is well established. The success of the proposed strategy according to the model presented depends on achieving a significant reduction in viral load from the pre-treatment value. The solid evidence of the potent ability of antiviral drugs to very substantially reduce viral loads in a sustained fashion derives predominantly from observations in settings where untreated endemic or concurrent infections are uncommon. The ability to achieve a sustained significant drop in viral load may be more difficult where there is a high prevalence of untreated endemic or associated infections. This is the case in parts of Sub Saharan Africa. Many of these infections are able to activate and enhance HIV replication, through the action of pro inflammatory cytokines. Should these infections be associated with genital ulceration there are additional uncertainties.
    HIV disease is characterized by an enormous variability in the rates of disease progression. There is no such thing as a standard course of disease progression that is one of the assumptions used in the modeling. We know very little about the distribution of different rates of disease progression among infected individuals, or about the influence on this of associated untreated infections.
    Risking individual harm for a public benefit is a slippery slope. Will we see a proposal to administer (with consent, of course) antiretroviral medication to the whole sexually active population, HIV infected or not?

    AIDS is a preventable disease. We have far from exhausted less conjectural, as well as less speculative approaches to its prevention.

    Addendum
    Apart from this proposed strategy to treat all infected people, there definitely are situations where treatment as prevention is absolutely appropriate and desirable. One is post exposure prophylaxis (PEP), where individuals who have been exposed to HIV attempt to prevent infection by rapidly taking antiretroviral drugs – that is within 72 hours of exposure. This applies to both occupational and sexual exposure. Regarding sexual exposure – where feasible, which is certainly the case in N America Europe and in many other regions, a 3 day supply of drugs should be available 24 hours of the day, given the limited time frame for action. Measures to immediately start PEP immediately should of course be available where occupational exposure is a risk. Emergency departments should be equipped and ready to start the protocols for PEP. People at risk should even be encouraged to keep a 3 day supply of drugs at home to cover times when medical care is not available – at night or weekends. .Very importantly people at risk must be informed of the availability of PEP.

    The second is pre exposure prophylaxis. This is taking antiretroviral drugs on specific occasions when there might be a risk of exposure. This absolutely cannot replace the use of condoms, but some individuals may wish to take an additional even if unproven preventative measure. This really is a matter for individual choice. Our obligation is to make it very clear that this is not a substitute for condoms.