Daily oral tenofovir (as PREP) was one of the first products to move into large-scale efficacy studies for the prevention of HIV. But in 2004 and 2005, several of the studies were derailed largely due to pressure from ACT UP Paris and in some cases, local organisations that claimed that the trials were unethical. Ultimately, the choice of whether this study or any study should continue should be left up to the community in which it is being performed — as long as that community is speaking with a unified voice.
In the case of the tenofovir studies, the story is somewhat mixed. http://www.aidsmap.com/en/news/3BAF85DA-3C18-49F1-A8A1-49F37C94F8D7.asp, http://www.aidsmap.com/en/news/53066193-F3CA-4B1A-8E1E-7B99A7698E76.asp, http://www.aidsmap.com/en/news/deab5309-e626-476e-8df8-50d836b26d66.asp.
In general, activists felt that the community had not been adequately involved in the preparation, design and implementation of the tenofovir trials — and to some extent the problems encountered by the trials are evidence of this. The activists also had several specific complaints especially concerning the standard of care for prevention being offered in the studies and the provisions for standard of care treatment during and after the study.
Activists had the right to be concerned about the adequacy of prevention services offered participants in these studies, however, the issues can be complex. The activists sited Guideline 29 of the Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects (http://www.wma.net/e/policy/pdf/17c.pdf), which states that new products should be tested against the best treatment or prophylactic interventions available. In the case of HIV prevention, this would clearly include counselling and condoms as well as clean needles.
For example, one complaint, about a jeopardised PREP study in injection drug users (IDUs) in Thailand, is that the study does not provide clean needles to the participants. In this case, the IDU activists are absolutely right — clean needle distribution would markedly reduce HIV transmission in the study population, however, US government policy currently bars federally funded organisations (such as the Centers for Disease Control and Prevention) from supporting needle exchange.
This is a bad policy, and yet, it does not necessarily follow that the trial should be discontinued. One of the goals of the Helsinki Declaration is to try avoid modern day Tuskeegee experiments but there is a danger that if guideline 29 were to be interpreted too strictly, trials would be never be able to generate results that are applicable to real world settings. The best way to get useful results is to use a control arm that matches actual practice in the community — although in this case, the IDU community clearly wants the freedom to do more to protect themselves (to access clean needles without police harassment).
But this isn’t always the case. For example, ACT UP Paris complained that the tenofovir studies in Cameroon did not provide female condoms. And indeed, female condoms could reduce transmission and supplying them would optimise the standard of care for prevention in the trial. However, even though acceptability of female condoms was reportedly high in clinical trials, their real world uptake has been very limited perhaps, as mentioned by participants in one Population Council study, because it takes too long to insert (destroying spontaneity), looks ugly and squeaks noisily during sex. Although lowering the price and increased social marketing have led more people to try the product, these efforts have had no impact on increasing consistent use.
Holding up a trial because it does not offer a prevention intervention which is not in widespread use would seem not to be in the best interest of people. And if you took this approach (requiring the highest standard of care in the prevention control arm) to its logical conclusion, then prevention studies would have to get women to bring in their male partners for circumcision -- as this has also been shown to reduce HIV acquisition in the man, and transmission of HIV to his partner (see http://www.aidsmap.com/en/news/d775d204-7155-4cdf-acb5-8caa1c6730fa.asp, and http://www.aidsmap.com/en/news/37A87885-0A35-431B-8C8C-6D7A4B1BB9F6.asp.)
But this would be unworkable.
ACT UP Paris also had another related complaint — that there were too few prevention counsellors in the Cameroon study — arguing that one doctor and five counsellors to 400 women was an unacceptably low ratio. (see http://www.aidsmap.com/en/news/53066193-F3CA-4B1A-8E1E-7B99A7698E76.asp)
But just how many counsellors and how much counselling is necessary? Five full-time counsellors to 400 people is a lot better than many communities have. That’s about two hours of prevention counselling and support for each person per month; certainly much more than the participants would receive outside of the trial.
On top of this, at their monthly clinic visits participants would have received free condoms, repeated tests for hepatitis and for HIV (in itself, a pretty strong incentive to practice safer sex) and free treatment for sexually transmitted infections. In reality, anyone participating in this study would have received prevention that was better than in the real world treatment. Instead, the study in Cameroon was shut down, and those people got nothing.
With the benefit of hindsight, trials presented at Microbicide 2006 suggest that activist concerns about inadequate prevention interventions were unwarranted. For example, participation in a prevention trial in Ghana (of the microbicide Savvy, see http://www.aidsmap.com/en/news/E31C54A1-F80E-4155-A2CB-0852AF6A04B6.asp), which offered the same standard of care interventions that were being offered in Cameroon, resulted in extremely low seroconversion rates of ~0.9-1.0 in both the placebo and Savvy arm — and many other trials are also observed lower than expected rates of transmission (Link) .
Unfortunately, misinformation about the study in Cameroon and oral tenofovir received considerable press in in sub-Saharan Africa and did immeasurable harm beyond the permanent closure of the trials. Many people are now convinced that the investigators were trying to give the participants HIV, and that the tenofovir pills — or even microbicides that Western investigators now want to study in them — might actually contain HIV.
Even on the other side of the continent, in Uganda, activist Miriam Katende of TASO said during the panel discussion on standard of care, the first thing that people want to know about a study is “is the product free of HIV.” It has affected trust, and people in Katende’s community are worried about who is conducting trial “Who is administering the product, and this matters a lot. Where is this person coming from? Is he coming from the North or the South?” she said.
But the other major concern for the activists and the major reason for the suspension of the tenofovir trials was the absence of a system to guarantee long term provision of ART to those who seroconverted during the trial (in every setting). And the investigators and study sponsors didn’t really have a good answer.
One of the difficulties for the tenofovir studies was that it didn’t really have a pharmaceutical sponsor. Gilead Sciences, maker of tenofovir, provided free drug but offered no other backing for the studies. The actual trial sponsors/organisers including Family Health International and the US National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID) will never be selling the product, nor are they in the business of providing long term treatment. “Not all sponsors are created equal. Our missions can be quite different,” said Dr Monica Ruiz of the US National Institutes of Health. “What we can do in terms of standard of care is determined by our mission.” And the NIH and NIAID do research. To provide longer care, they generally have to partner with other organisations.
And at the time, options were limited in Cambodia and Cameroon. At first, the trials tried to set up a programme of care only for the course of the study or for a two or three year period afterwards; and yet, some of the sponsors now admit that withdrawing support for treatment after a couple of years just wouldn’t have been right. “It is neither ethical or practical to offer a standard of care that cannot be sustained after the trial has finished — to do this would be unfair to participants and the community in which the research took place.” said Dr Ruiz.
Of course, it wasn’t acceptable to the activists either.
If there are any silver linings in the debacle of these tenofovir trials, it is that researchers have now realised that community participation is absolutely necessary to move forward with this sort of research — and that that will require more than token efforts at inclusion. At the Microbicides meeting, a whole track is now devoted to community involvement, which is seen not only as necessary for trials to run smoothly but as potential allies in the educational programmes, and to sustain support of microbicide research efforts. “Community mobilisation for microbicides should not be limited to awareness raising but should aim at building the capacity of communities to enhance development and/or improving community healthcare systems,” said Katende. The community can thus become a much richer resource for prevention researchers to draw on.
Finally, the controversy has forced researchers and sponsors to consider what is their obligation to provide quality treatment where it is not available. And even if they reject the moral arguments, “existing social and political realities make access to care an essential factor in a trial’s ability to go forward,” said Anna Forbes of the Global Campaign for Microbicides.
“Worldwide there is consensus among researchers and sponsors that care should be provided to participants who volunteer for screening and are excluded due to their HIV status and especially to those who become HIV positive during the course of the trial,” said Prof. Ramjee. Who should do it? Increasingly, it is being seen as a collaborative effort between the investigator, sponsor, pharmaceutical company, community and the local health department. Even the NIH is now routinely looking for partnerships to provide long-term care to the participants in its studies, and Dr Ruiz noted, agreeing that “research doesn’t happen in a vacuum.”