Understanding Referral Networks in AIDS Vaccine Trials
What is the process for referring volunteers in vaccine trials for treatment and care?
To participate in clinical trials of preventive AIDS vaccine candidates, volunteers must not be HIV infected at the start of the trial. This allows researchers to determine the safety of the vaccine candidate in healthy individuals and, in larger Phase IIb or III trials, its efficacy at preventing HIV infection.
During the course of the trial volunteers receive counseling on how they can reduce their risk of HIV infection and have access to proven prevention methods like condoms (see VAX August 2005 Primer on Understanding Risk-Reduction Counseling). None of the AIDS vaccine candidates being evaluated in clinical trials can cause HIV infection, yet some volunteers may still become HIV infected during the course of the trial through risk behaviors such as sexual activity or injection drug use. These volunteers may therefore need antiretrovirals (ARVs) to treat their HIV infection at some point in the future. The provision of this treatment to trial volunteers has been an important subject for organizations that conduct AIDS vaccine research and the communities where this work occurs.
According to two landmark documents that serve as the basis for the conduct of medical research (the Declaration of Helsinki and the Council for International Organizations of Medical Sciences guidelines), sponsors of vaccine trials are not ethically required to provide volunteers with treatment for a disease that is contracted during the vaccine trial. The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) issued guidelines in 2000 specifically for AIDS vaccine trials stating that volunteers should receive, at a minimum, the highest level of care attainable in the country where the trial is taking place and, ideally, the best proven therapy. However several questions remained about who would pay for this treatment. As importantly, researchers had to consider how offering treatment only to those taking part in the trial could unfairly influence people's decision to participate, an idea known as undue inducement.
But the landscape of HIV treatment in developing countries has changed dramatically in recent years, and sponsors are now asking how—not if—treatment should be provided to volunteers. More people have access to life-saving ARVs because of significantly lower treatment costs and programs launched by the WHO; the Global Fund to Fight AIDS, Tuberculosis, and Malaria; the President's Emergency Plan for AIDS Relief (PEPFAR); and the Clinton Foundation, among others. Although the WHO's plan to put 3 million people on HIV treatment by 2005 did not meet its goal, it did substantially improve the systems for distributing ARVs to HIV-infected people in many developing countries. This, along with the other programs, has affected the way AIDS vaccine trial sponsors are approaching the issue of providing treatment to volunteers who happen to become HIV infected during a vaccine trial through exposure in their community.
Tapping into existing networks
Now many organizations that conduct AIDS vaccine research are working together with existing treatment programs provided either by national governments or by outside organizations to ensure that volunteers have access to ARVs. Before a trial even begins sponsors will map out the treatment services that are already available in the community and then investigators at the trial site can refer individuals that become HIV infected during the trial to one of these clinics for treatment.
This process can vary among the different organizations that are conducting AIDS vaccine trials and may even be different for each trial site. Some countries have created their own policies regarding treatment of volunteers. In Uganda the government has said that volunteers in HIV prevention research that become HIV infected will be a priority for receiving ARVs through their national treatment programs. In South Africa volunteers in AIDS vaccine trials are provided with an identification card that they can present at any government clinic to get treatment. Volunteers that may become HIV infected in any of the ongoing AIDS vaccine trials conducted by the Walter Reed Army Institute of Research (WRAIR) are guaranteed to receive ARVs directly through PEPFAR grants.
The WHO and UNAIDS recommend that an agreement is reached in writing before the trial starts about the systems for providing treatment and that the sponsors, researchers, host governments, and communities are included in this process.
Preparing for the future
In all communities where treatment is available there are still obstacles to getting infected volunteers into these programs. One of these obstacles is the distance volunteers have to travel to the clinic. Participation in a vaccine trial requires regular visits to the trial site for HIV testing and counseling and even those that become HIV infected will still be followed for the remainder of the trial because researchers want to study how the vaccine might affect disease progression. Making several trips to both the trial site and to the clinic for treatment may be difficult for some volunteers and could present a barrier to them accessing ARVs.
Another complication is following up on volunteers to ensure that they receive treatment and care. In Phase I or II trials, where investigators anticipate only a very small number of volunteers will be incidentally infected and need treatment, it is possible for the trial site staff to follow up on individuals who are referred to outside clinics to make sure they are actually accessing treatment. But this will be difficult in Phase III efficacy trials when several thousand volunteers are enrolled and significantly more infections occur through exposure in the community. Trial sponsors are concerned that trial sites may be referring people to already over-burdened clinics, which may have waiting lists for ARV treatment.
To combat this problem several organizations, like IAVI and the HIV Vaccine Trials Network, are now optimizing these referral networks so that they can be prepared for large-scale trials. Other trial sponsors are working to develop new funding mechanisms to provide treatment for volunteers in the future.