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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

  • The Cost of Pre-exposure Prophylaxis with Truvada

    Posted on August 17th, 2011 admin No comments

    In my last post I wrote about the very small reduction in the absolute risk of HIV infection in the iPrEx trial among those taking Truvada  as pre-exposure prophylaxis.

    The 44% reduction in relative risk conferred by Truvada was the only efficacy measurement explicitly presented by the investigators.  That the absolute risk reduction was only 2.3% was not mentioned in the various presentations.

    I suspect that many reading press reports of this so called breakthrough were unaware that in fact, the actual risk to people taking Truvada was 2.8%.  (36 infections in 1251 participants).  True, this is less than the 5.1% risk to those on placebo, but by very little.  Certainly not enough to justify the bewildering acclaim given to the iPrEx trial results.

    Failing to clearly state the absolute risk reduction of an intervention is something we have come to expect from salesmen to inflate the efficacy of a product, but not from clinical researchers.  Large reductions in relative risk can be associated with minute reductions in absolute risk when the events prevented are low to begin with.

    Another important reason why absolute risk reduction should be stated in a report is that this allows one to calculate the number of people who need to be treated to prevent one event, in this case, one HIV infection.

    Although the iPrEx investigators did not explicitly provide these numbers, they can be worked out from data presented, as I did in my last post and was also done in a letter published in the New England Journal of Medicine of April 7, 2011 in response to the iPrEx trial report, where the authors report that 44 people need to be treated to prevent one infection (I got 45).

    They then went on to calculate that it would cost $400,000 a year to prevent a single infection.

    This figure does not even include the cost of the necessary monitoring for infection.  In another letter, it was suggested that such monitoring be done monthly to prevent the emergence of resistant virus by detecting infection early.

    From Sean Strub’s calculations (in his comment to my post on the POZ magazine website) which included doctor’s visits and tests, the annual cost would be about $500.000.

    These figures are based on drug costs in the US.

    Truvada PreP not only does not work well enough it will cost a half million dollars a year to prevent a single infection.

    Maybe this is indeed a “game changer” but not in the sense intended by the triumphalist reports coming from the recent Rome AIDS conference.

    There definitely seems to be a perception that PrEP is a viable prevention option for everybody; there even have been calls for its general implementation.  These cost estimates alone would make it unfeasible as a public health measure but there are additional reasons, importantly its relatively low efficacy.

    PrEP is a reasonable option for only a very  small number of individuals at high risk for infection who are able to be regularly checked for infection.  I believe there is no disagreement about this; the controversy is only about its general use.

    Implementation of PrEP on a wide scale will almost certainly result in an increase in new infections.  It’s not only adherence to the drug regimen that will not be maintained by all.  Adherence to a schedule of regular testing for infection cannot be relied on.

    The way PrEP has been promoted has probably already damaged targeted prevention education programs with support for continued condom use, an activity already in great need of support.

    Drugs for prevention are paid for from a different budget than prevention education programs, and health departments already under budgetary constraints may feel that prevention needs can now be paid for by those entities that pay for drugs, private insurers or Medicaid/Medicare.

    The amount of almost uniformly uncritical publicity given to PrEP is completely out of proportion to its utility.  It’s a hugely expensive and very poorly effective prevention intervention, of use to only a very small number of individuals, and its misleading promotion has probably already damaged prevention education programs.

    Considerable resources must have been devoted to publicize and promote PrEP over many years,  in a way that has not taken care to reinforce prevention education with support for continued condom use.    One can only wonder why.

    Drs Dong Heun Lee, M.D.  and Ole Vielemeyer, M.D of Drexel University College of Medicine in Philadelphia are the authors cited.

  • Pre-exposure prophylaxis against HIV with Truvada, PrEP, just does not work nearly well enough

    Posted on August 5th, 2011 admin No comments

    Prevention of HIV infection by pre-exposure prophylaxis (PrEP) is not sufficiently effective

    PrEP is a prophylactic intervention where uninfected people take anti HIV medications before sexual intercourse to prevent becoming infected with HIV. The use of a vaginal gel containing anti HIV drugs has also been tested.

    The results of several trials of PrEP have been reported in the past year, all but one hailed as huge successes, with reported efficacies of up to 90% among those adhering to the treatment regimen.

    The efficacy of PrEP in preventing HIV infection was reported to be so great that this intervention has been trumpeted as signalling a revolution in HIV prevention.  A new era has opened up we are told; PrEP is a “game changer”.

    With such enthusiastic coverage it may come as a surprise that none of the reports explicitly told us what the actual efficacies of the interventions were in preventing HIV infection. Perhaps because they were so low, as I’ll explain.   Maybe what’s even more startling is that this omission seems to have gone completely unnoticed, at least in the universally jubilant press reports and equally enthusiastic press releases from AIDS advocacy organizations.

    How has this been possible?

    The reason is that the results have been reported as reductions in relative risk only.   This tells you nothing about actual risk reduction.  What is reported is a percentage reduction in risk from a number that was never clearly stated.  For example in the iPrEx trial of PrEP among men who have sex with men, the drug, Truvada, was reported to reduce the risk of infection by 44%.  But 44% of what?  We were not explicitly told, although it’s possible to calculate what it is.

    In fact we can calculate that the absolute risk reduction conferred by Truvada is a measly 2.3%, a number nowhere to found in the trial report.  The relative risk reduction may have been 44%, but this translates into only an actual 2.3% reduction in risk, as is shown below.

    Reporting relative risk reduction only is the oldest trick in the book to exaggerate the effects of an intervention, used by salesmen, but apparently also by clinical researchers.

    What makes the unquestioning acceptance of these reports of relative risk reductions achieved by PrEP even more remarkable is that there is a tremendous amount of material explaining the difference between relative and absolute risk reduction.   Just type the words “relative risk absolute risk” into the Google search box.

    Relative risk reduction tells you the percentage reduction in risk in the treated group compared to that in the group receiving placebo, or how much lower the risk with the intervention is relative to the risk to begin with.

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

    Although not included in the iPrEx trial report there is information that allows one to calculate the absolute risk reduction conferred by Truvada.  To do this we need to know what the risk of infection is to begin with.

    This is the number of infections occurring in the placebo group over the time period of the study.

    64 out of 1248 people in the placebo group were infected, which is 5.1%, or 0.051 in 1.  (since then there have been additional infections reported at the Rome AIDS conference, reflecting an increase in the number of infections over a longer time period).

    In the group receiving Truvada 2.8% of 1251 people were infected.

    The absolute risk reduction conferred by Truvada is simply 5.1 minus 2.8 which is 2.3.

    A 2.3% reduction in absolute risk conferred by Truvada is the more accurate measure of its efficacy.    Hardly something to celebrate.

    A 44% reduction in relative risk sounds much better, although far from spectacular,  but unfortunately it’s a number that tells you nothing about actual risk reduction.

    Relative risk reduction is calculated as follows:

    It is the number of events in the treatment group subtracted from the number of events in the placebo group divided by the number of events in the placebo group.

    On its own, relative risk reduction is not a helpful number.

    Of much greater help to a person considering Truvada PrEP is knowledge of the actual risk while taking Truvada (over the period of the study, a median of 1.2 years).

    That number is 2.8%.

    Knowing the absolute risk reduction allows one to calculate another important measure.  This is the number of people who need to be treated to prevent one infection (NNT).   From information contained in the trial report 45 people need to be treated to prevent one infection.  I did not notice this number in the trial report nor was the absolute risk reduction of 2.3% reported.   NNT is a useful number as it allows one to estimate what it would cost to prevent a single infection with Truvada.

    The cost of the drug is the least of it.  A person taking Truvada PrEP needs to be monitored at regular intervals for toxicity and importantly, for infection, in order to avoid the inevitable emergence of resistant viruses as a result of sub optimal treatment.

    If Prep is implemented on a large scale which some AIDS advocates seem to be calling for, but is unlikely to happen, then there may well be increases in new infections with viruses resistant to the drugs in Truvada  in men who have sex with men, in IV drug users and in Africans.

    PrEP is not a success, at least not with Truvada.     However such a failure was transformed into a triumph, part of the explanation is the use of relative risk reduction numbers with care taken to remain silent on absolute risk reduction.   Despite all the literature available to help people tell the difference between absolute and relative risk reduction, this evidently was a resource not used by those cheering along  this ineffective intervention.

  • Treatment as Prevention: Protecting Individual Autonomy

    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

  • HIV pre-exposure prophylaxis (PrEP): A misguided guidance issued on its use.

    Posted on February 23rd, 2011 admin No comments

    Full contents of this blog:

    Pre-exposure prophylaxis – called PrEP, is an HIV prevention intervention where antiviral drugs are taken by HIV uninfected individuals in the hope that sexual transmission of HIV will be prevented.   A recent trial of daily Truvada, a combination of two anti-HIV drugs demonstrated only a 44% reduction in the risk of becoming HIV infected by sexual transmission among men who have sex with men (MSM).     I have written about this trial a few months ago.

    Unbelievably, the use of this intervention has in effect been endorsed by the US Centers for Disease Control (CDC).   True, the CDC call their recommendations on the use of daily Truvada as PrEP an “interim guidance”.    But anything short of “don’t risk your life by taking an intervention that cannot even halve the chance of becoming HIV infected” is in effect an endorsement.    Simon Collery has also written about this calling the CDCs recommendations a “mixed message”.

    The CDC is not alone in regarding an intervention that is only 44% effective in preventing a potentially lethal infection to be good enough to be implemented.  Quite surprisingly some groups claiming to represent the interests of those at risk share this bizarre view.  One implication is that these groups, supposedly representing people at risk for sexually transmitted HIV, as well as the CDC have given up on persuading MSM to use a condom, as described by Michael Weinstein in a recent article .

    In reality groups calling for an implementation of an insufficiently effective intervention to prevent a life threatening infection may be a  small minority whose real influence is probably insignificant in relation to their noisy irrational advocacy.

    People on the ground, dealing with risk are often wiser than those who claim to advocate on their behalf, but do not have the means to influence the way issues are reported in the media.  They know that a 44% efficacy in reducing the chance of acquiring a life threatening infection is just not good enough.  They know that condoms are the most effective way to prevent sexual transmission of HIV.

    But when this insufficiently effective measure was first announced in November of 2010, it was hailed as a triumph.    Time magazine even called this ineffective intervention the most significant medical breakthrough of 2010!     I suspect these accolades may have resulted from the skill of publicists rather than of independent investigative reporting.

    But of course I may be part of a  minority in considering that a trial demonstrating that an intervention that is only 44% effective in preventing a potentially lethal infection is far from a triumph and  rather is an emphatic failure because a much more effective protective measure is readily available that’s cheaper and safer.

    Concerns that condoms may not be used regularly in appropriate situations to prevent the sexual transmission of HIV are better expressed by a support for extended properly targeted prevention education.

    PrEP trials began in the early 2000s and have had a troubled history.  Trials were planned and even several started in African countries and in Thailand and Cambodia.  Some never got off the ground, and several were stopped for a variety of reasons.  There were vigorous activist demonstrations in connection with some.     The varied concerns of activists included provision of care to trial participants who became infected, or the provision of sterile injection equipment to IV drug users in Thailand.

    I posted a blog on the POZ magazine website in August 2009 describing an ethical problem   with  PrEP trials,  essentially that  PrEP would have to be tested with an imperative to provide and encourage the use of effective means already available to prevent HIV transmission, namely condoms and sterile needles.  If these measures are conscientiously provided and their use encouraged it’s unlikely that any effect solely attributable to PrEP could be measured.  iPrEx  told us that self-reported adherence to medication is unreliable, so there is no reason to believe that self-reported frequency of unprotected sexual intercourse is any less so.

    In that post there are links to two significant articles published in 2005.   The first represents the view sympathetic to those who demonstrated against PrEP trials.  It can be seen by following this link:

    The Tenofovir pre-exposure prophylaxis trial in Thailand: Researchers should show more openness in their engagement with the community

    The second is the view of  PrEP researchers.

    The Abandonded Trials of PreExposure Prophylaxis for HIV: What went wrong?

    We Must Not Let Protestors Derail Trials of Pre Exposure Prophylaxis for HIV

    One of the ways suggested to forestall the problems that have beset so many PrEP trials in the past was to solicit a greater degree of community involvement early in the process with a view to obtaining their commitment.

    An effort was made to obtain community support for PrEP  trials  with the help of UNAIDS.      There have been many teleconferences and many publications about PrEP best seen by looking at this website. http://www.avac.org/

    .

    It’s evident that much effort and expense has been placed into engaging communities in the design and conduct of PrEP trials.  Apparently with some success as I believe the earlier upheavals associated with PrEP trials have not been repeated.

    As for as expenditure on PrEP trials and PrEP promotion, the following figure indicate funding amounts and sources.

    Despite this expenditure, it’s most unlikely that PrEP with Truvada will be used by more than a very small minority of individuals.

    Apart from the cost of the medication, it will be necessary to pay for regular tests for HIV infection and for monitoring for drug toxicity.  It’s likely that some of those who choose to use Truvada as PrEP will forgo these regularly needed tests, because of cost and other reasons.   Not only are these individuals risking infection with an insufficiently effective preventative measure, they also risk the development of virus resistant to the antiviral drugs in Truvada because of receiving a suboptimal dose during an unidentified infection.

    With only a 44% reduction in the risk of becoming HIV infected, unidentified infections are a very real possibility among individuals who choose to use daily Truvada as PrEP.  It’s realistic to be concerned that some of these individuals will not be tested regularly to detect infection.  Individuals with an undetected infection could then pose a risk to their uninfected sexual partners.    Who knows how suboptimal treatment will influence the course of initial HIV infection?.   Even the illness of primary infection that could be an alert,  may be less likely to occur.     Failure to be tested regularly would also mean that drug toxicity, specially to the kidneys is less likely to be detected.

    With all these hazards, not only to the individual using PrEP, and with the likelihood that   Truvada, and indeed other antiviral medications can be  obtained without a prescription,  the CDC’s  interim guidance is unwise.   It’s also unfortunate that there may be  some who will see additional significance in that the guidance  is specifically directed at “high risk” MSM.

    Properly targeted prevention education with the promotion of, and support for condom use  needs all the support it can receive.

    Daily Truvada as PrEP is a really bad idea.

  • iPrEx trial results of preexposure prophylaxis – PrEP

    Posted on December 12th, 2010 admin No comments

    Full Contents of this blog

    Pre-Exposure prophylaxis –  PrEP –  iPrEx  trial results.

    Pre-exposure prophylaxis, or PrEP, is an HIV prevention intervention in which anti-HIV drugs are taken to prevent infection.    A safe, effective and affordable drug that could achieve this would be a powerful prevention intervention even possibly capable of halting the spread of the epidemic.

    Last week we were told the results of the iPrEx trial that tested the efficacy of PrEP with Truvada, a combination of two anti-HIV drugs, in reducing new HIV infections among a group of men who have sex with men considered to be at high risk for HIV infection.

    The announcement of the results was greeted with almost universal jubilation.

    “That’s huge,”  said a prominent AIDS researcher,  “That says it all for me.”

    “Today marks a major step forward in our quest to combat HIV among MSM

    “This discovery alters the HIV prevention landscape forever,”

    “….. the new data “represents the most promising development in HIV/AIDS since the introduction of triple combination drug therapy in 1996.”

    “This is a game-changing trial result,”

    Science magazine reported that..

    “The researchers applauded and some even cried when they heard the bottom line”; “I have not cried this hard in years” – said one researcher.

    These exultant cheers are usually reserved for the most momentous of breakthroughs.

    Demonstrating that a drug could be safe and effective in preventing infection would indeed be a momentous breakthrough as already noted.

    But the iPrEx results, far from representing such a breakthrough, indicated that PrEP,  at least with Truvada, together with counselling and provision of condoms, reduced new HIV infections among men who have sex with men only modestly.   It’s unlikely that the 44% reduction in new infections that was seen is of sufficient magnitude to make PrEP with Truvada viable as a public health prevention intervention. Moreover, as will be described there are significant safety concerns, a demonstrated danger of the emergence of drug resistant HIV, and the drug is far from affordable.

    A 44% reduction in new infections is not huge; even those extolling the trial results would agree (at least I think they would, but who knows considering the over-the-top responses).

    But what is most troubling is that the researchers have squeezed an efficacy of Truvada  of over 90%  by a questionable statistical sleight of hand,  an improper use of sub-group analysis, a technique of data dredging has been soundly discredited.  I’ll return to this.

    This has resulted in  headlines such as “PrEP works – if you take your pills”, I don’t know if this will persuade some people to abandon condoms and religiously take their pills.  Unfortunately the type of analysis that provides confidence to do so is not reliable.  Maybe consistent use of Truvada will reduce new infections by over 90%. Maybe not.

    For the moment staying with the ability to reduce new infections by 44%, as a public health intervention to be used on a wide scale, this degree of efficacy is just not good enough to justify using Truvada to prevent a life threatening infection.   Even if the risk of infection is low this must be balanced against the gravity of the infection. About 3% of participants in the Truvada arm of the trial became infected as opposed to about 5% among those receiving placebo.

    Perhaps it’s on this issue that I’m at odds with the huge acclaim given to the trial results.  Maybe the prevailing view is that a 44% reduction in new infections is indeed good enough; some commentators are even discussing implementation.

    PreP proponents like to compare it to malaria prophylaxis.  If the efficacy of malaria prophylaxis were of the same order as that of Truvada in relation to HIV, I suspect many people might think twice before visiting an area where there was a risk of malaria.

    Let’s take a closer look at the trial results, particularly the claimed greater degree of efficacy in compliant participants   reported in the New England Journal of medicine.

    I have commented briefly on this in my blog on the POZ magazine website.

    The medication used in the trial,   Truvada,  is a combination of two HIV anti-HIV drugs, FTC and tenofovir.  It was compared with placebo in over 2000 men who have sex with men, considered to be at high risk for HIV infection.

    The 44% reduction in new infections was achieved in conjunction with counselling, provision of condoms and monthly tests to monitor for infection.

    This is not a good enough performance to justify widespread use of Truvada to protect against infection.  The investigators then looked at blood and tissue levels of the drugs in people who became infected and those who did not.  They found that those who remained uninfected had detectable drug levels while those who became infected did not.

    They incautiously trumpeted this result as proving that Truvada works well if the pills are taken consistently – stating that in those who took their pills more consistently the relative risk reduction was well over 90%.

    On the surface this sounds good. Almost all the commentators thought so.

    However looking at the results in a sub-group of participants can be misleading.  Most particularly in a sub-group that is defined after randomization; who would or would  not comply with treatment could not have been known.    The problems with subgroup analyses will be clearer after a short account of intention to treat analysis.

    Intention to treat analysis is the most reliable way to analyse clinical trial data.   In such an analysis participants are analysed in the group to which they were randomized, irrespective of whether they dropped out, or didn’t adhere to the treatment or strayed from the protocol in other ways. This seems counter-intuitive, but there are sound reasons why intention to treat is regarded as the best way to analyse trial data, among them  that it more reliably reflects what happens in real life, rather than in a clinical trial.  For example, one reason why pills may not work is because they are not taken. If they are not taken in a trial we have to be concerned that they may not be taken in real life.  Take a look at this excellent explanation of intention to treat:  Making sense of intention to treat.

    As noted, the trial investigators made a lot of the sub-group analysis showing greater efficacy in those who took  Truvada pills as measured by finding the drugs in blood and tissue samples.

    This is surprising  as the pitfalls inherent in such post-hoc sub-group analyses have been recognized for years.  Commentators, some of whom are clinical researchers, in their over-the-top exultation at the results of the analysis in those compliant with Truvada  may have forgotten about the treachery inherent in sub group analysis.  A few commentators give the problem only passing acknowledgement.

    This is a classic paper on sub group analysis:

    Yusuf S, Wittes J, Probstfield J, Tyroler HA: Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials.

    Journal of the American Medical Association 1991 , 266:93-98

    This is from that paper:

    “Analysis of improper subgroups, though seductive, can be extremely misleading, because a particular treatment effect may influence classification to the subgroup. Thus, an apparent subgroup effect may not be a true effect of treatment but rather the result of inherent characteristics of patients that led to a particular response or to the development of side effects”.

    In iPrEx  the subgroups were categorized by events that happened after randomization, so the adherent group is an “improper” subgroup.  “Subgroups of clinical trial subjects identified by baseline characteristics … is a proper subgroup while a subgroup determined by post randomization events or measures is an improper subgroup”.

    In actuality the attention given to the subgroup that had blood and tissue drug levels is an example of the treachery of such sub-group analyses.

    As an illustration, the reduction in new infections seen in this group may well have resulted from the following possibility.

    People who take their pills consistently are more likely to use condoms consistently and in general are more attentive to risk.   So if it were possible to do a subgroup analysis of people who adhered to placebo we might conclude that the placebo also works – (and it’s cheaper).

    This is not so fanciful.

    “In one study [3], those who adhered to the trial drug (clofibrate) had reduced

    mortality; but those who adhered to the placebo pill had the same reduction in mortality”.

    This is from:

    Coronary Drug Project Research Group. Influence of adherence to treatment

    and response of cholesterol on mortality in the coronary drug

    project. Engl J Med 1980;303:1038-1041

    A classic example of the pitfalls of subgroup analysis is  what it demonstrated in the ISIS-2, a trial examining the effects of aspirin after myocardial infarction.  A subgroup analysis showed it was of benefit to all except in people who were either Libras or Geminis.

    Maybe Truvada taken consistently can reduce new infections by over 90%; maybe not.  There was no basis for the investigators and commentators to present the first possibility with such overwhelming confidence.

    We must accept that a 44% reduction in new infections is at this time the most reliable estimate of Truvada’s efficacy as PrEP.   Although, the confidence interval , a measure of reliability, was wide.

    We have an intervention that can reduce new infections by 44%, if taken in conjunction with a program of counselling, condom use, and monthly tests for HIV infection.  That is the benefit.   What about the down side?

    The two most important are the development of resistance of HIV to the component drugs of Truvada and the toxicity of the drugs.

    The utility in treating HIV infection of FTC and tenofovir – Truvada’s component drugs is lost if the virus becomes resistant to the drugs.  Moreover, some mutations conferring resistance to these drugs can also affect sensitivity to some other drugs.  The danger of resistance, and even cross resistance to other drugs developing when Truvada is used as PrEP is not a trivial concern.    Truvada used as PrEP provides a suboptimal dose in treating established HIV infections.  This is precisely the situation in which resistance is likely to develop.   There were in fact two instances of developed resistance in the iPrEx trial in individuals who became infected, but undetected before the trial began.

    Resistant viruses in the community are a danger to all, so the risk of generating resistance is not confined to the individual taking Truvada as PrEP.

    What about safety?

    The claim in many reports that Truvada is without significant toxicity is also misleading.

    Maybe poor adherence has some bearing on the lack of significant toxicity.

    A median of 1.2 years exposure to Truvada can tell us little about cumulative and long term effects. Experience with long term use of Truvada in HIV infected people makes concern about toxicity realistic. Renal toxicity, sometimes severe occurs not uncommonly. It’s mostly but not always reversible on stopping the drug.   Thinning of bones, osteopenia and osteoporosis is also seen. There are additional adverse effects associated with the drugs.

    There were small abnormalities in some paramaters measuring kidney function among those treated with Truvada.  Although these changes were reversible on stopping the drug, the fact that they were seen at all is a reason for great concern about the effects of longer term treatment.

    With the experience we have gained from longer term treatment with Truvada, it is disingenuous to stress its overall safety from just 1.2 years of very inconsistent use.

    It’s important to point out that for HIV infected individuals, the benefits of treatment with Truvada far outweigh the risks.  For uninfected individuals, an entirely different risk benefit analysis must be made.

    Despite the disappointing results of iPrEx, PrEP is important.

    Why is PrEP important?

    There are at least two important reasons.
    1:

    PrEP could protect receptive partners in sexual intercourse, both men and women, who are unable to ensure that a condom is used by their partner and for a variety of reasons are unable to refuse sex .   The best and most respectful way of addressing this would be to find ways to empower these individuals; in some way providing them with the means to protect themselves could be seen to also have the effect of perpetuating their subjugation and abuse.

    But there are women and men who need protection now and providing them with a means to prevent infection that they can control is vital.  This can go hand in hand with working to empower them and helping them to try to ameliorate or leave abusive relationships.

    2:

    Sex is one of life’s joys.  It is vitally important to the human experience.

    Condoms can be a barrier to intimacy which for many is the most essential aspect of sexual intercourse, for both receptive and insertive partners.  So recommending the use of condoms without acknowledging the significant obstacle they may present to a fulfilling sexual experience is a real problem.   Pleasure is part of that fulfilment and for some insertive partners condoms are a significant impediment to experiencing it.

    A fully effective  and safe means of pre-exposure prophylaxis may also allow the removal of a barrier to conception.

    But people are different; for example some individuals have found that condoms can increase intimacy in the reassurance they provide concerning their and their partners safety.

    We should never minimize or trivialize the difficulties condoms can present.  We should also keep in mind that their use is the most effective means of preventing sexual transmission of HIV.

    Their use will remain necessary in order to remain uninfected until we are free from HIV or a safe an effective PrEP method can be found.

    These  considerations, a prevention method that the receptive partner can control,allow conception  and  remove an impediment to full sexual expression are reasons to work towards finding a safe and effective form of PrEP.   If this can be achieved safely and affordably it could even help to bring the epidemic to an end.

    Truvada unfortunately has not proved to be sufficiently effective or safe to be of utility as a general recommendation.  The use of condoms still  remains the most efficient way to prevent the sexual transmission of HIV.

    .

    A few words about prevention education and condoms:

    The  consistent use of condoms is the most effective means to  prevent sexual transmission of HIV.

    PrEP proponents agree but many go on to say that people just don’t use condoms consistently.  This is an attitude that has apparently concluded that prevention education does not and  cannot work.

    But how can one conclude that it does not work when there has been so little of it?   This has some analogy with the claims made for the efficacy of Truvada.   It works, if you take the pills

    .

    If prevention education has been a failure, it’s not because it doesn’t work, but because we have not provided it well enough.  There has been too little and most has not been properly targeted.

    Proper targeting to those most at risk is critical. I have written about this.  We need more and better prevention education.

    The CDC now tells us that the group at greatest risk by far in the US is men who have sex with men.  Nothing has changed except the ethnic distribution, so why are they only telling this to us now?     For over twenty years we were told that AIDS was an equal opportunity infection making prevention education targeted to those at greatest risk even more difficult.

    It’s only now, 25 years too late, that the CDC appears to recognize the urgency of providing prevention education to gay men.

    Neglect of properly targeted prevention education, with encouragement for condom use and continuing support to sustain their use helped to allow the spread of HIV into African American communities in plain view while millions were spent on “America Responds to AIDS” a vacuous prevention message.

    Similarly we have known for years that in the US younger men who have sex with men are at particular risk.  We know where to target prevention messages, but we don’t do it well enough.

    We know that highly targeted prevention education, when crafted by the communities at greatest risk can work.  This was demonstrated in the earliest years of the epidemic in San Francisco and New York City.

    In  1982 when Michael Callen, Richard Berkowitz and I first recommended condom use to gay men in New York City, we stressed that in doing so it was important to celebrate sex, recognizing that  for some individuals condom use, or perhaps more precisely, HIV,  could present a barrier to its full expression.      We have come far in freeing ourselves from long standing societal constraints that for too many have stood in the way of a fulfilling sexual experience burdening it instead with guilt.   It’s important to take care in providing continuing support for condom use and recognize that for many they do get in the way. But it’s really HIV that’s getting in the way, and consistent condom use can help to bring it to an end.

    Finding conditions where sex without condoms is safe is important.   On the showing of iPrEx – despite its ecstatic reception, PrEP unfortunately is not yet ready.

    At the moment consistent condom use is the best protection there is.

    The often uncritical response to iPrEx should not persuade anyone that Truvada  is a safe and effective alternative.

    iPrEx is a large and complicated study.  The investigators deserve the highest praise for completing this difficult phase and for havine provided a result.  It may not be the result that many had hoped for.  But providing clear information is a great achievement and a major advance . iPrEx results clearly show that continued condom use is still necessary to prevent the sexual transmission of HIV.

  • HIV Prevention Education and Pre-Exposure Prophylaxis Against HIV. August 2009

    Posted on August 30th, 2009 admin No comments

    Since my last post on this subject I have heard a variety of different views as well as discussed the issue with several  interested individuals.

    As a result I have come to see the issue somewhat differently; I suppose I could just amend my last post, but it’s better to leave it as it is and  describe the differences in how I now view PrEP efficacy trials after having heard several different descriptions of  ways in which these are seen.

    I listened to presentations at two conferences during the  last few weeks.  A teleconference organized by CHAMP, a community group, and one organized by the Centers for Disease Control (CDC).  These conferences attempted to engage and inform individuals about PrEP.       As a consequence I realize that I was mistaken in stating so categorically that efficacy trials of PrEP,  unlike safety trials, could not be undertaken in human research subjects.   However I do not think that if all the ethical requirements are met, that is to provide condoms, consistent counseling and sterile injecting equipment, a generalizable result will be obtained indicating that it is an effective prevention strategy.  Of course I don’t know this, and was wrong in my view that trials of PrEP efficacy should not proceed.

    The most important concern with the way the promotion of PrEP, at least as a concept, is being pursued is the neglect of encouraging  prevention education.

    Prevention education remains the most important tool we actually have, as opposed to theoretical and unproven approaches.  The latter include PrEP, and the test and treat every infected person proposal.   We absolutely know that in principle prevention education, including the use of condoms can work.   It worked in curbing the increase in the epidemic among gay men in the late 1980s .

    The principle is thus established, admittedly without application to those who have no control over the use of condoms by the male partner.  This group is therefore in need of prevention strategies they can control themselves, and PrEP may be the only realistic possibility.

    For everyone else, the sexual transmission of HIV can be controlled by the use of condoms, even if not with 100% efficacy.  We have a powerful tool in our hands, and if there are new infections, this is certainly not an indication that it does not work well enough.   It indicates that it is an activity that receives insufficient support, or  it may well be that some of those doing it are just not very good at it.  Maybe there is little societal support for HIV prevention education, even little support from individuals at risk who could use condoms but would like not to.

    Unfortunately, from what I have experienced, the several groups supporting and promoting PrEP seemed to have given little thought to prevention education in presenting this intervention to stakeholders. .  They may be diligent in the context of efficacy trials, in ensuring the availability of condoms and counselling to participants.

    But what seems to be missed is this:  Unless the promotion of PrEP is accompanied by very clear advocacy of prevention education with condom use,  PrEP can be seen as an alternative to safer sex practices as now recommended.

    This cannot be the intention, but from comments I have heard after the CHAMP and CDC conferences this seems to be a dangerous conclusion that some have drawn.

    The explanation of the utility of PrEP must be accompanied by a strengthening of prevention education to avoid this unfortunate misinterpretation. The very promotion of the concept of PrEP in the way it has so far been done can actually be seen as an undermining of condom use.  A possible alternative to condoms is presented. One can only hope that in the absence of accompanying prevention education there will not be instances sex with available antiretroviral drugs rather than with condoms.

    Prevention education is in a dismal state as it is, and we should be aware of any activity that can undermine it further, unless care is taken in how it is presented.

    I have commented in other posts that in HIV medicine a one-size-fits-all approach seems to be the norm.  Admittedly it’s cheaper to deal with populations rather than individuals. A single size that fits everybody is even cheaper  than providing  small, medium or large varieties, let alone customizing the size to fit individual needs.

    So in HIV medicine, treatment recommendations have been made for all infected individuals, without considering the rate of disease progression, and many other characteristics applicable to any given person.

    So it is with PrEP.  Its relevance is different to different constituencies.

    At one extreme, for those who have no power to control the use of a condom by their male partner, PrEP may be the only realistic possibility of avoiding infection with HIV.  PrEP to these individuals is obviously of vital importance.

    In fact it is so important that it would be useful even if its efficacy, if this can be demonstrated, proves to be inferior to the consistent use of condoms.   Such individuals have no alternative.

    The situation of people who are perfectly capable of consistent condom use is different.

    The power of the receptive partner in this case is the power to say no. No condom, no sex.   Both partners have an effective means of preventing the sexual transmission of HIV.  There is no need for PrEP to prevent infection, except that some may welcome an additional layer of protection.

    There are others whose hopes for PrEP are different.  The desire to conceive is one.

    Yet others hope that PrEP will make sex without condoms safe with respect to HIV transmission.   In this case the efficacy of PrEP would have to be known to be at least equal to the consistent use of condoms (and free from toxicity and affordable).   Of course  individuals decide to take risks that involve danger to  themselves only, but full information should be available, and certainly we should take care not to disseminate material that can  mislead, even if only by implication.   We do not have full information on the efficacy of PrEP, and I can see no way of testing its efficacy without the use of condoms.   But it is here that we need to take great care not to mislead, even by implication, that PrEP is as safe as using condoms unless in the unlikely event, it is actually  proven to be so.

    Even a modest degree of efficacy is better than nothing for those who are unable to avoid sex with a partner who cannot be relied on to use a condom. There actually is nothing else to protect them.

    A modest degree of efficacy is insufficient for those who are well able to refuse to have sex if a condom is not used.   That’s my opinion, and I would believe that of many others, but as  always risking  harm to oneself only,  is an individual choice;  our obligation is not to mislead, and ensure  that full and accurate information is available.

    So, PrEP is of undoubted importance to individuals who have no control over the use of a condom by their male partner.  Apart from the female condom, it is the insertive partner who has to use a condom.  All the receptive partner has as protection now,  is the ability to just say no.  We recognize that there are situations when this is not possible, and no practical remedy is available to change this.

    Of course there are other situations when it is possible to attempt a change.  If an individual just cannot say no to a partner who cannot be relied on to use a condom because he or she is ignorant of safer sex practices this is something we must try to remedy with intensive prevention education.  This will include imparting the knowledge of the lapses in judgement that can accompany the use of drugs or alcohol.

    Getting away from the one-size-fits-all approach, there probably will be some individual situations in which PrEP, even if less effective than consistent condom use may be considered.  An example noted by one commentator is when condom use may be associated with sexual dysfunction.

    Prevention education with consistent condom use is the best available means we have to prevent the transmission of HIV.   Prevention education should be strengthened and care taken not to undermine it.

    Where individuals have no control over the use of a condom by their male partners  we should do what we can to provide them with the means to protect themselves, and PrEP may be all we have to work on at present.

    Others may look to PrEP as a means to avoid the use of condoms.  The price of failure seems to be an extraordinary high one, considering that condom use is known to be highly effective in preventing HIV transmission.

    There are people who need PrEP. There are also people perfectly able to use condoms but who want PrEP.

    In promoting PrEP studies we must take great care not to undermine efforts at prevention education, even by implication.  Promotion of PrEP must go hand in hand with promotion of HIV prevention education.

  • 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. Another postscript.

    Posted on April 19th, 2009 admin 1 comment

    This additional postscript was prompted by an article that appeared a few days ago in the Washington Post. It was written by Dr Anthony Fauci, who adds his voice to support a policy of universal HIV testing and treatment of all those infected, adding also the treatment of uninfected people at high risk.

    He points to the dire situation in DC, and states that our prevention efforts have been insufficient. That is perfectly true. But he, with all of us, have watched  this terrible situation developing over the past 20 years;  as my first post, AIDS and Minorities  indicates, we did little to prevent it.

    We get Dr Fauci’s point that probably more than 56,000 Americans have been infected with HIV every year for the past decade. But if we look at the graph in my first post we can see that over the years, the proportion of infections in African Americans rose, while it fell in white Americans, although the numbers have levelled in the past 6-7 years.

    So, when we are told that our prevention efforts have been insufficient, are we not really being told that we just neglected or were unable to develop adequate prevention education programs for some populations? Or are we being told that this is inherently an impossible task?

    It is not. Gay men were able to make a significant impact of the spread of AIDS in the early years of the epidemic. Safer sex with the use of condoms did make a difference.

    Safer sex originated in this community without the slightest outside help.  I would also guess that the armies of behavioral psychologists who entered the field found that within this community, essential behavioral modifications had been already learned without much need for their interventions or recommendations.

    We might learn something from this experience.  Empowered communities can respond to threat, and maybe we should be providing  the support communities need to achieve this.

    Dr Fauci’s “three pronged” approach is fraught with danger. Firstly it implies that prevention education cannot work.  This is very unfortunate as it provides an excuse to diminish, rather than intensify our efforts. We absolutely have not exhausted all the potential there is to create persistent and effective highly targeted prevention education programs. It is possible that with adequate support communities can best do this themselves.

    Then there is the problem discussed in an earlier post  “Treatment as Prevention”  that deals with the many implications of providing treatment to individuals for a social good, but where the treated individuals will derive no benefit themselves.

    Infected individuals who do not need treatment will therefore be asked to receive it and thus be exposed to the risks of the drugs but derive no personal benefit from them.

    The first of the three bold approaches suggested is the treatment of uninfected people at high risk; this is called pre-exposure prophylaxis (PrEp).

    This of course includes sexually active gay men, IV drug users, and heterosexual female and male partners to an infected person. If this means intermittent use of PrEp I would agree that this may well be a useful, if as yet unproven approach.  The persistent use of PrEp is another matter as drug toxicity is an issue.

    Here it can certainly be argued that the uninfected  individual taking  antiviral drugs may certainly  benefit from their use, unlike the treatment of healthy HIV infected people with higher CD4 counts who may be slow or even non progressors.

    For the uninfected individual at risk the persistent use of PrEp  is something that individuals should decide on themselves,  given adequate information.  I doubt whether this will make the slightest difference to the state of the epidemic, but may provide individual benefit.

    The multitude of problems associated with the second and third approaches were simply ignored.  I will not repeat the problems that exist in treating people, not for their benefit, but for a social benefit; these are discussed in my previous post.

    It is far from clear – as the article categorically states that benefit will be derived from starting treatment as soon as possible after infection. There is no direct evidence to support this contention. We simply do not know if very prolonged exposure to antiviral drugs will prolong, shorten or have no effect on an individual’s life span.

    As far as toxicity is concerned, it is often stated that the newer drugs are less toxic.  How on earth do we know this with only a few years use? We have enough experience of severe toxic effects only being recognized after years of use.  The drugs that block the HIV co-receptor are particularly worrisome.   CCR5 does not exist on the cell surface for the convenience of HIV. It serves a physiological function and time will tell if blocking its natural function has deleterious effects, and if these outweigh the benefits the drugs confer in inhibiting HIV replication.

    As far as eradication is concerned – which appears to be the third new bold approach, this possibility is so far in the future, if it ever can be achieved, that it is absolutely unrealistic to base any practical policy on its success.  The difficulties in killing all cells that harbour stable integrated HIV DNA, or of excising it from the human genome are enormous.

    Before undertaking such a “three pronged” project we would need some assurance of success; we would need to know, for example what degree of compliance would be necessary for it to work. But these issues are discussed in my previous post.

    At the moment the only winners in this approach will be the drug and testing equipment manufacturers.

    We should renew and redouble our efforts towards producing and persistently disseminating prevention education messages, appropriately targeted to specific populations. We should provide communities with adequate support so that they can craft their own prevention education materials, and disseminate them.

    We should remove all barriers to testing. This includes the most difficult of undertakings which is to fight the stigmatization still associated with this disease.

    This will entail an avoidance of policies and legislation that have the effect of increasing stigmatization.  Among other disincentives to testing is the lack of assurance of a link to medical care.  The cavalier approach to informed consent recently demonstrated by some providers and community groups is misguided:

    http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=58009

    It is likely that the consequences of “streamlining” the consent process for testing will actually have the effect of dissuading individuals from being tested.

    Those proposing “streamlining” the consent process may think HIV testing is routine.  Those testing positive may soon come to a different conclusion when they learn that HIV disease is serious, can be associated with stigmatization, treatments may not be affordable or available, may have adverse effects, jobs may be lost, and  families may abandon infected individuals.

    Can a test that  opens the door to such difficulties be regarded as routine?

    As long as these consequences of testing remain possible, we absolutely must obtain informed consent for testing so that our patients will know  of the implications of both a negative and positive test.  We all gain from  doing  everything possible to be supportive and retain the trust of our patients.   This will not be achieved by misleading them.

    In conclusion: Providing antiviral drugs to people who do not need them is no substitute for developing a variety of highly targeted prevention education strategies.