Understanding the Recruitment of Volunteers at Risk of HIV Infection
Why are volunteers who are at high risk of HIV infection necessary participants in late-stage AIDS vaccine trials?
While there are many chapters in the development of a vaccine, its success or failure ultimately rests on its ability to protect the individuals who are at the greatest risk of becoming infected with the pathogen, either virus or bacteria, that the vaccine protects against.
Most routine vaccinations against diseases are now given to infants because they are most susceptible to many viral and bacterial infections. For example, the virus that causes measles primarily infects children, and so the vaccine against measles is administered to infants. This required testing the vaccine in precisely this population. Similarly, for AIDS vaccine trials it is imperative that vaccine candidates are tested in the populations at greatest risk of becoming infected with HIV. This allows researchers to be sure that the vaccine is safe and effective in these individuals.
Phase III efficacy trials of AIDS vaccine candidates require several thousand HIV-uninfected individuals drawn from populations where the HIV incidence—defined as the number of individuals infected with HIV annually—is high. Phase IIb test-of-concept trials, including the recently conducted STEP study, may also involve at-risk volunteers. Phase I and II trials, which are focused primarily on the safety of the vaccine candidate and its ability to induce an immune response, do not traditionally require the involvement of volunteers at increased risk of HIV infection.
Defining high risk
Populations of individuals who are at high risk of HIV infection vary from place to place, and before an efficacy trial can begin, researchers must identify which individuals should be included in a trial. This requires having reliable HIV incidence data in the population in which the trial will be conducted (see VAX July 2007 Primer on Understanding HIV Incidence). When HIV incidence rates are outdated or calculated using old or unreliable methods, it is possible to overlook volunteers who are at risk.
People living in some regions of sub-Saharan Africa, where the HIV prevalence is so high, may be considered at high risk of contracting HIV just by living in a certain place or community. Others are placed at risk of HIV infection by their personal behaviors or occupations, for example injection-drug users (IDUs) who share needles, or commercial sex workers. In the US, men who have sex with men are at the greatest risk of HIV infection (see Spotlight, this issue). All of these populations are essential participants in late-stage AIDS vaccine efficacy trials, as their response to candidate vaccines may vary because of the different routes of HIV transmission.
Across the globe, women have been disproportionately affected by HIV. Close to 60% of HIV-infected individuals in South Africa are women, and the number of new HIV infections in women is on the rise in many other countries as well. For this reason it is also imperative that women be equally represented in AIDS vaccine trials (see VAX March 2008 Primer on Understanding the Recruitment and Retention of Women in Clinical Trials). To improve women’s participation, trial sites have been encouraged to use counselors and staff who are sensitive to gender, class, and cultural barriers, and to provide transportation and child care for participants.
While it is necessary for high-risk individuals to participate in AIDS vaccine efficacy trials, their involvement is not taken lightly. Researchers work very hard to ensure that all participants understand what puts them at risk of HIV infection and what they can do to reduce this risk (see VAX August 2005 Primer on Understanding Risk-Reduction Counseling). Risk-reduction counseling is offered to participants throughout the duration of the trial and volunteers are encouraged to be diligent and consistent about protecting themselves against HIV. Despite this, some volunteers will inevitably still become HIV infected through natural exposure to the virus.
Large-scale trials typically measure vaccine efficacy by randomizing study participants into two groups—those who receive a vaccine and those who receive an inactive placebo—and comparing the rate of new HIV infections in each group. For researchers to conclude whether or not a vaccine candidate is effective, some individuals in the placebo group must become HIV infected. But importantly, volunteers are never purposely exposed to HIV.
Aside from providing intensive risk-reduction counseling, there are still several other ethical, scientific, and even geographical challenges that need to be addressed for an AIDS vaccine trial among at-risk individuals to be successful. Often the groups most severely impacted by the AIDS epidemic feel stigmatized and marginalized, and this makes them more difficult to reach. In some places it can be challenging to recruit men who have sex with men, or women, for trials. Most, if not all, study protocols prohibit women from becoming pregnant or breast-feeding during a vaccine trial and this can make it more difficult to recruit women, particularly in cultures where a high value is placed on women’s fertility.
Some high-risk communities, such as IDUs, also tend to be more transient, making it difficult to track them through the duration of a multi-year trial. In sub-Saharan Africa, where heterosexual sex is the most common mode of HIV transmission among adults, migratory patterns, low literacy rates, and political unrest are additional impediments to recruiting volunteers at the greatest risk of HIV infection.
The clinical design of efficacy trials is complex, and in response to all of these challenges, counselors and investigators at AIDS vaccine trial sites are continually working to improve their recruitment methods and strategies. Approaches vary depending on where the vaccine site is based and the high-risk population that is being sought. Vaccine sites also rely heavily on community advisory boards and local leaders to assist them in this process (seeVAX May 2005 Primer on Understanding Community Advisory Boards).