Members of the HIV Vaccine Trials Network (HVTN) have a job with global implications. The international collaboration of scientists and educators — from more then 25 research institutions — was formed in 1999 to search for an effective and safe HIV vaccine. Headquartered at the Hutchinson Center, HVTN members coordinate trials of new vaccines all over the world. While doing so, they must make sure that their study populations represent a wide spectrum of humanity to ensure that the eventual vaccine product is safe and effective for as many people as possible. To get the results they need, they want all their trial participants to stay for the duration of a study to ensure the validity of the study and the ability to generalize results.
With more than 42 million people worldwide now infected with HIV and an estimated 90 million human carriers by 2010, there is undisputed need for the work.
A new study published by HVTN researchers examined the retention of participants in HIV-vaccine trials taking place across the United States between 1988 and 1999. Although the trials under consideration were limited to participants in the United States, the researchers hope that their results will be applicable to continuing work coordinating trials all over the world — work that includes recruitment and retention efforts to remove barriers to trial participation. Among the study findings were that retention in HIV-vaccine trials was high overall and that no subpopulations were lost preferentially. However, it also showed that the age of participants and the length of trials were significant factors in predicting loss to follow-up, or the failure of a volunteer to complete a trial program. The study was published in the Aug. 1, 2005, issue of the Journal of Acquired Immune Deficiency Syndrome.
"Our aim is always to retain as close to 100 percent of the study participants as possible," said Dr. Ann Duerr, an author of the paper and associate director for Scientific Support at the HVTN. "So it's important to know the characteristics of the people who are lost and where we should focus our efforts in trying to retain people."
Of the 3,033 HIV-negative volunteers who took part in 48 early-phase vaccine trials in the United States, 282 (about 9 percent) did not complete follow-up. The vaccine trials analyzed in the recent study took place under the auspices of the AIDS Vaccine Evaluation Group and the HIV Network for Prevention Trials — two predecessors of the HVTN.
The first author of the paper, Dr. Guy deBruyn, who worked at the HVTN and the University of Washington while in Seattle, has since returned to his native South Africa. He now works at the HVTN site in Soweto, an urban area in Johannesburg.
Although they couldn't judge why some participants dropped out, HVTN researchers were encouraged by the fact that there no factors other than age and length of trial were associated with higher loss to follow-up.
Improving future trials
Duerr explains that significant losses of volunteers during a trial, and uneven losses between a test group given a vaccine and a control group given a placebo, could skew results.
"You didn't see any red flags that say certain populations that we would like to have in these trials are not being retained," Duerr said. "It is encouraging that the loss to follow-up was low, that we didn't find very many things associated with loss to follow-up, and that there weren't certain populations that seemed to be lost preferentially, with the exception of young people."
Along with the positive news, the research indicates areas for possible improvement in the design of future trials.
First, the researchers suggest that trials be planned to last only as long as necessary to answer scientific questions at hand. Duerr notes that these results underscore the importance of considering two opposing elements in trial design. The need to run trials over extended periods of time to increase the data recorded and to assess the duration of a vaccine's effectiveness should be weighed against the decrease in retention seen in longer trials.
Second, there may also be a price paid for focusing trials on only the youngest individuals. Regulatory bodies often recommend limiting study participants to those younger than 40 years old because of low rates of underlying illness in this population, but one effect of this might be an increased loss to follow-up.
"We don't really have enough data to say what it is that makes younger people less likely to be followed," Duerr said. But, for example, future research might show that students move around more than other young people. If true, researchers could make doubly sure before a study began that the student could finish the trial.
There are valid reasons to limit some trials to young participants — for example, to avoid chances that vaccine effects would be indistinguishable from natural changes associated with aging. So Duerr suggests that researchers need to increase efforts to keep young people and other groups most affected by HIV/AIDS involved.
To make sure that current and future HVTN trials continue to retain a broad range of participants, the HVTN includes a community-education department to provide links between research scientists and the public.
Steve Wakefield, who works at the Hutchinson Center as associate director for Community Education for the HVTN, said that it takes a continuing effort to make sure trials are made accessible to all communities.
"There are marginalized populations who aren't interested in participating in research or don't think that they have the ability to participate in research and so you end up usually with a smaller proportion of those people in your trials," Wakefield said. "Because the vaccines being tested could benefit members of these populations, their participation is essential."
Adjustments to meet cultural needs
In order to continue to recruit and retain diverse participants, research and language used in trial materials should be culturally appropriate, Wakefield said. Peer outreach workers can provide clear information about the studies. And the clinical environment can be adapted to fit a wide variety of people's needs — for example, involving counselors who understand lifestyle issues of various sexual orientations or providing daycare for parents who might otherwise miss appointments.
"There are a number of adjustments that you have to make to your clinical atmosphere," Wakefield said. "You can't just say 'follow the yellow line down to the ninth floor to the seventh pavilion.'"
Duerr agrees. "This is the kind of thing that's evolving," she said. "You need to keep working at it to ensure that we have higher retention and that we're developing appropriate messages and facilitating participation for people who will be less likely to be retained."
As the HVTN continues to make strides in international vaccine trials, the researchers recognize that high retention of trial participants in the United States may or may not hold true for international trials that have just begun.
"What's important to understand is we are doing something that is cutting edge and new for most of the people with whom we work," Wakefield said. "We're asking people to participate in something that's not been done before and we are making the effort to ensure that our research protects and respects their lives in every way that's possible: that our trials are safe, that our trials are respectful and that they have the resources needed to maintain their participation. Whatever it takes."
The HIV Vaccine Trials Network brought together a Community Advisory Board (CAB) member from each of the 25 HIV Vaccine Trial Units around the world for a two-and-a-half day intensive CAB Retreat last week. The goal: to help CAB volunteers increase their knowledge of the science behind HIV-vaccine research so that the volunteers will be able to more effectively interact with and advise researchers regarding the work of the network. Designed in a train-the-trainer format, CAB members received training in vaccinology, immunology, epidemiology, research ethics, laboratory assays, reading research protocols, media relations and public speaking. Six of the CAB attendees partnered with HVTN scientists to deliver presentations at the retreat. The six CAB members worked with the scientists by telephone and e-mail in advance of the retreat to plan the presentations, enabling the scientists to better understand the needs of laypersons and helping them to understand how difficult concepts could be explained in lay language.
Each CAB member received workshop materials, including handouts and PowerPoint slides, so that they can return home and provide a minimum of two training presentations to their local CAB members.