Reports from the Frontlines

AIDS vaccine trial site experiences from a busy year

By Emily Bass

Bangkok may be remembered as a meeting of scaled-back expectations and, in some quarters, outright pessimism regarding the short-term future of AIDS vaccine research. But in the bustling poster hall there was a more energized mood as many sites reported on their community outreach, recruitment and retention efforts in the record number of trials launched in 2003.

While these presentations didn’t reveal any scientific breakthroughs, there was news of innovative enrollment strategies—many of which were tested for the first time—that will likely provide a foundation for future efforts. Many of these reports from the frontlines also gave a sense of the time-consuming and challenging process this can be, even when the trial is being conducted by an experienced team.

The HIV Vaccine Trials Unit at Chris Hani Baragwanath Hospital in Soweto, South Africa has so far launched two Phase I preventive AIDS vaccine trials. A poster (Abstract number ThPeC7436) detailed the results of its recruitment strategy, which uses the “Bara” voluntary counseling and testing (VCT) center and other community-based VCT centers to identify potential volunteers. This approach initiates recruitment at existing community VCT centers, rather than VCT sites that have been established specifically by or for a vaccine trial. HIV uninfected individuals were offered the opportunity to participate in vaccine discussion groups, which met on a monthly basis to provide information on a range of topics related to vaccine research and trial participation. When the trial was ready for enrollment, discussion group members were offered a chance to be screened for participation and were enrolled if found to be eligible.

In total, more than 3000 people were seen at the VCT center and 1581 individuals were found to be HIV uninfected. Of the 336 individuals who chose to enroll in the vaccine discussion groups, 194 completed the required number of group sessions and 32 were finally determined to be eligible for participation in the trial. Ultimately this approach yielded a 10:1 ratio of screening to enrollment, a typical ratio that is indicative of the effort and resources required for trial recruitment efforts, even at experienced sites. Principal investigator Efthyia Vardas says that the “Bara” vaccine trials will in future work with VCT counselors to ensure that information about enrolling in vaccine trials is given to all HIV uninfected individuals during post-test counseling. On a positive note, the Soweto trials unit showed that it is still possible to enroll HIV uninfected individuals (who are at relatively low risk of contracting infection) from a community with very high rates of HIV infection—nearly 50 percent of the individuals screened for this study were already HIV infected.

Roughly 12 percent of individuals were not eligible for the trial because their blood tests for liver or kidney function fell outside of reference ranges. Other reasons for ineligibility included loss to follow-up (15%), chronic illnesses (9%) and participant decision to withdraw (7%).

Blood tests also accounted for the exclusion of a large proportion of individuals screened for the first vaccine trial in South Africa’s neighbor, Botswana; 36 of 76 volunteers screened were ineligible due to results outside of reference ranges (ThPeC7450). These reference ranges are based on normal values in developed countries, and Site Director Tonya Villafana says that developing local reference ranges that reflect the values found in healthy persons under prevailing conditions in the country is a large undertaking that may soon be tackled by Botswana’s Ministry of Health. “It is something that the country is interested in doing given the multiple research studies being undertaken in healthy individuals, as well as the ongoing implementation of national programs for the treatment of HIV-infected people.”

Another poster from the trial in Botswana described their media outreach strategy (ThPeC7429), which played a crucial role in trial recruitment. Of 192 potential volunteers who came forward, 48 reported the media as their primary source of information; Villafana says that 11 of the 14 volunteers who ultimately enrolled first learned about the trial through the newspaper or media. The poster listed the key messages that the trial site had worked to convey through the media: An experimental AIDS vaccine cannot treat or cure HIV in people who are already infected; an experimental AIDS vaccine cannot cause HIV infection or AIDS; the experimental vaccine being tested in Botswana had been designed to work against several subtypes of HIV; Botswana has played a key role in HIV prevention research worldwide; and that community involvement was vital to the success of the trial.

Media was also the focus of a poster presented by IAVI and the Brazilian National AIDS Control Program (ThPeC7441). The investigators surveyed the quantity and quality of media coverage of AIDS vaccine research in the country. The project, which was complemented by a national journalist workshop, provided important leads to guide press outreach strategies in the country, identifying gaps and priority areas for future action.

A report from the Kenya AIDS Vaccine Initiative (KAVI)-IAVI trial site in Nairobi described yet another approach to enrolling volunteers (ThPeA6999). Following its first vaccine trial, during which it took six months to enroll 18 volunteers, the site developed a peer leader program. Individuals nominated by the communities earmarked for trial recruitment participated in training on HIV/AIDS, AIDS vaccine research and clinical trials that lasted two months, with follow-up for a further six months. These peer leaders then conducted outreach and education events in their communities, after which interested individuals could visit the KAVI clinic for one-on-one counseling and information. Recruitment rates increased to 14 volunteers per month—up from 3 per month prior to the initiation of the program.

These reports also suggest some important challenges facing the field. First and foremost there is the need to acknowledge that recruitment may proceed more slowly than anticipated. Perhaps the most dramatic example of this comes from the ongoing Phase III “Prime-Boost” trial in Thailand. Principal investigator Supachai Rerks-Ngarm gave an update (ThOrC1428) on enrollment for the study, which aims to recruit 16,000 volunteers in the provinces of Rayong and Chon Buri. All adult residents of these provinces are eligible to enroll in this community-based cohort, which is using existing health facilities as the entry point for recruitment.

Recruitment began in late September 2003 and, as of June 2004, only 2571 volunteers had enrolled in the trial, a slower rate than originally anticipated. Enrollment will be extended by another year. “Even though we are enrolling slowly, we are confident that we will achieve enough volunteers after this extension,” said Rerks-Ngarm. [At time of press, 8,315 volunteers had been enrolled and had received at least one immunization.]

Recruiting women is a challenge at some sites, such as the Uganda Virus Research Institute-IAVI site in Entebbe, Uganda (ThPeA7006). The site’s Phase I trial enrolled 42 men and 8 women; during the recruitment process 7 women withdrew after giving informed consent, many citing their partners’ objections. Trial sites in Botswana and Kenya have also reported low numbers of women participants.

A related issue is the involvement of adolescents in vaccine trials. Across sub-Saharan Africa, adolescent girls are disproportionately infected compared to their male counterparts; in South Africa, for example, 25% of South African women are infected with HIV by the time they are 22 years old. To prevent HIV infections in this age group, once a vaccine has been proven safe and effective it will be important to vaccinate adolescents or, possibly, pre-pubescent girls who have not yet become sexually active. Most licensed vaccines for other diseases have been tested in children (after preliminary safety tests in adults) since they are the primary recipients of protective vaccinations, but AIDS vaccines are likely to be tested extensively in adult populations first. To be routinely used in children or adolescents, an AIDS vaccine efficacious in adults would have to be tested for safety in adolescents, and the immune response would have to be shown to be similar to that in adults and to last long enough so that it’s still strong years after vaccination, when they may be exposed to HIV infection. It may be necessary to enroll some adolescents in key efficacy trials if it is possible to identify a group at sufficiently high risk, obtain truly informed consent and to ensure that they are effectively counseled.

Another challenge to enrolling young people in trials of HIV prevention strategies is that many countries have varied or conflicting regulations regarding young people’s participation in trials. Ann Strode of South Africa’s HIV/AIDS Vaccine Ethics Group presented a review of that country’s heterogenous legal statutes regarding adolescents (WeOrC1249). South Africa is one example of a country where “children have limited but evolving legal capacity,” she reported. For example, young people can obtain contraceptives at age 14 without parental consent, the legal age of sexual consent is 16, and young women are allowed to terminate a pregnancy at any age. However, Strode noted, South Africa has “no independent age for [children to] consent to research.”

Strode recommended that countries develop national systems to help assist in recruitment of adolescents for HIV prevention trials and that research and human rights groups work together on advocacy for legal and ethical reform of age of consent laws. She also recommended further research on children’s ability to understand the risks and benefits of trial participation.