Tenofovir (TDF) is currently approved for treatment of HIV disease, and is also being studied to determine whether it is appropriate for use as pre-exposure prophylaxis (PREP) for the prevention of HIV infection. If TDF demonstrates safety and effectiveness in PREP studies, it could be a powerful new HIV prevention tool to be used in conjunction with existing HIV prevention interventions.
There are currently six ongoing or planned human clinical trials testing TDF as PREP. Several of these trials encountered difficulties when host communities or advocacy groups raised concerns about what they perceived to be ethical shortfalls in trial design and implementation and inadequate consultation with the communities involved. To date, because of these difficulties, one TDF PREP trial has been closed and another has been put on hold. A further PREP study in Nigeria was stopped due to an inability to meet protocol requirements.
The International AIDS Society (IAS) convened a meeting May 19-20, 2005, in Seattle on behalf of the trial sponsors: the Bill and Melinda Gates Foundation, the US Centers for Disease Control and Prevention (CDC), and the US National Institutes of Health (NIH). Over 50 stakeholders attended, representing the diverse communities participating in the TDF prophylactic trials, host governments from the respective countries, leading advocacy groups, senior researchers, all trial sponsors, and representatives from TDF's manufacturer, Gilead Sciences.
The objectives of the meeting were to:
The fundamental goal of the meeting was to promote successful and ethical PREP research that is relevant, respectful, and acceptable to the host communities within which these trials are taking place. The meeting highlighted the four key challenges that have been identified as significant obstacles to these studies; namely, providing treatment and care to trial participants, the standard of care for prevention interventions offered to participants, research literacy for potential participants and community advocates, and mechanisms for community involvement. Principal investigators of PREP trials, trial sponsors, researchers, and community advocates addressed these issues through formal presentations followed by group dialogue. Several times during the course of the meeting attendees broke into smaller working groups that focused specifically on issues related to trial-site countries: Botswana, Cameroon, Ghana, Malawi, and Thailand.
The meeting was characterized by a sense of willingness among participants to work collaboratively to address concerns with current PREP trials. One theme that clearly emerged was the importance of involving community members, advocates, and researchers within the trial countries early in the trial planning process, and creating systems to respond effectively to concerns raised during the course of the trial. Importantly, the country-specific working groups produced a series of recommendations on the four challenge areas posed. They also specified the challenges particularly relevant to their country trial sites and suggested ways of addressing these.
There were several issues that were consistent across trial sites. Regarding the standard of care for prevention support, it was felt that some of the trial sites need immediate review and improvement to ensure that the current level of counseling support that participants receive is significantly improved, and that there is access to male and female condoms. All groups felt that mechanisms were required to ensure access to treatment and care for individuals screened for enrollment in the trials who are found to be HIV-positive, as well as trial participants who become infected during the course of the trial. A number of country groups recognized the need for national guidelines to be established to inform and improve civil society engagement. It was acknowledged that, while efforts were made by researchers, this process was at times ill-informed and inconsistent. Similarly, all groups reinforced the need for clear mechanisms for feedback and conflict resolution when problems arise at research sites. A shared concern regarding the registration status, and availability and price of TDF was highlighted. The representative from Gilead Sciences confirmed that in many of the countries where these studies are taking place, TDF is already being made available at cost. In countries where intellectual property protection does not apply, such as South Africa, generic drug manufacturers are free to produce generic versions of TDF.
Each group raised specific [issues] unique to the situation within that country. For provision of treatment and care, the Cameroon working group suggested a number of recommendations, including referral to the National AIDS Treatment Program for those individuals who are found to have HIV infection at the time of screening for entry into the trial (and [who are] therefore ineligible for enrollment in the trial). A recommendation was made by this group that the cost of the laboratory tests that are needed to qualify for the national treatment program should be met by the study sponsors. Further recommendations included provision of prevention of mother-to-child transmission (PMTCT) services for trial enrollees who become infected with HIV during the trial, as well as treatment for hepatitis B and hepatitis C virus coinfection with HIV, if needed.
Of great concern to many was the issue of research literacy to ensure that participants and advocates understand clinical research and are able to fully engage in the consultation process. In the Botswana working group, the development of a range of educational resources in multiple languages and media was considered necessary. This included not only raising awareness of the processes of clinical research, such as informed consent, but also understanding and improving the process by which research ethics are agreed [upon] and implemented. The importance of training researchers and protocol reviewers to improve their communication with community members, trial participants, and the media was strongly emphasized.
Following both collective and country group discussions, specific follow-through actions were agreed [upon] with members of the working groups. The Thai group agreed to hold a community meeting later in May  and to hold meetings that involve multiple stakeholders later in the year to discuss issues of concern. The group agreed that having begun the process, the issue of promoting participant safety, especially for injecting drug users and commercial sex workers, would be addressed at specific meetings over the coming months. The Thai group also asked the Joint United Nations Programme on HIV/AIDS (UNAIDS), as part of its ongoing consultation on HIV prevention research ethics, to develop best practices on trial counseling and other issues. There was agreement to hold training on research ethics later in the year, with the probable involvement of the Global Campaign for Microbicides, the AIDS Vaccine Advocacy Coalition, and Treat Asia.
The Cameroon group planned a two-day stakeholder meeting to be held in Cameroon at the end of June 2005. A variety of invitees, representing many different stakeholder groups, were identified. Consultations will be held and a smaller working group will be formed to prepare for the meeting.
The Botswana group agreed to initiate a process spearheaded by the Ministry of Health to develop a guidance document. It also agreed to consult with others on the educational materials needed, and to assess the interest of journalists in media training. The group agreed to work with the Ministry of Health to determine the content of research literacy training, and those to be invited.
Several speakers expressed satisfaction with the outcome of the meeting and interest in continued collaborative efforts. A variety of ideas were suggested for follow-up, including more funding to foster capacity of local community members, discussion of the issues [to be] raised at the XVI International AIDS Conference [to be held in 2006] in Toronto, better involvement of developing country researchers as full partners in research, and analysis of national ethical review boards.
There appeared to be broad support for creation of a global stakeholders group on PREP research that would take these issues forward, and all the trial sponsors expressed willingness to consider resourcing additional consultation forums. A small steering committee will be formed to make recommendations on the best way to maintain greater communication and coordination of these trials. It was agreed that progress in the field could be monitored by periodic updates of the country-level activities suggested at the meeting. A full meeting report from this consultation will be issued in the summer of 2005.
It was acknowledged that many of the concerns discussed during the meeting may have already become important issues in HIV prevention research studies beyond PREP. Many delegates confirmed that the shared challenges identified at this meeting and the resolution strategies suggested will help promote the successful, ethical implementation of other critical health research, particularly in the prevention of HIV infection. The results of the meeting will be incorporated into the broader ongoing UNAIDS consultation towards revised ethical guidance for HIV prevention research in resource-constrained countries. The commitment, passion, and diligence of the researchers, advocates, and all those that make up the stakeholder community were deeply acknowledged.
The success of the TDF PREP trials rests on the execution of many of the recommendations discussed at this meeting. The meeting closed with the clear message that all those engaged in TDF PREP research [must] take responsibility to engage in continued and meaningful dialogue with all stakeholders, and [to] influence action to deliver these commitments.
Yasmin Halima is a program manager at the International AIDS Society (IAS), and is responsible for the coordination of the IAS Industry Liaison Forum (IAS-ILF). Chris Collins is a New York-based consultant specializing in health policy and communications.