Posted on August 30th, 2009 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.
Posted on August 11th, 2009 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:
Trials are sponsored by several organizations, mainly it seems, Family Health International (FHI).
FHI has produced a set of slides listing PrEP trials.
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/
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.
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