Helping at-risk patients stick to a daily regimen of antiretrovirals can be a powerful tool for preventing the spread of HIV, according to results from a recently completed component of a larger clinical trial.
The test of this pre-exposure strategy, called PrEP, enrolled uninfected people in East Africa who had an HIV-positive sexual partner. A combination of objective monitoring of how often participants took their daily medications and intensive counseling of those with lower rates of adherence prevented any HIV infection among those receiving active medication during an average follow-up period of nearly one year.
“Our study shows that PrEP can be extremely effective in preventing HIV infection when adherence to daily dosing is high,” said Jessica Haberer, HMS assistant professor of medicine at Massachusetts General Hospital and lead author of the article published in PLOS Medicine. “Previous studies of PrEP have found considerable variance in efficacy, ranging from as high as 75 percent to no effect at all. We think that the different levels of adherence in those trials explain the differences in their findings, a hypothesis that is supported by this new study.”
The larger Partners PrEP Study was conducted from July 2008 until July 2011 at nine clinical sites in Kenya and Uganda. It enrolled almost 5,000 couples, of which only one member infected with HIV. Uninfected participants were prescribed daily oral medications: either one of two different antiretroviral formulations or a placebo. At the outset of the trial and at monthly intervals during the study period, both members of the couples received counseling on the importance of following the trial protocol, including consistently taking the study drug, and other ways to prevent HIV transmission.
Since early experience in PrEP trials indicated that limited adherence might be a significant problem, the Partners PrEP team added a substudy focused on improving adherence. But because preliminary results of the overall Partners PrEP Study were so strong—showing a 62 to 75 percent reduction in the incidence of infection—the larger trial was stopped early.
As a result, the adherence component was applied only to a subgroup of almost 1,150 couples enrolled at three sites in Uganda. The earlier clinical trials of PrEP that included any measures of adherence relied on such information as participants’ reports of how many pills they had taken, pill counts, or blood tests on the day of scheduled clinic visits. These measures may be unreliable because participants can misreport how well they followed a protocol, discard extra, unused pills or take medications only on the days before a scheduled visit.
The adherence substudy adopted two objective measures known to reflect more accurately how well participants follow a study protocol: unannounced in-home visits to count the pill supply and an automated microchip-based system that records each time the pill bottle is opened. Participants whose pill-count-measured adherence for a three-month period dropped below 80 percent received more-intense counseling, with additional information on the importance of adherence and help with strategies to identify and overcome factors that reduced adherence. Their HIV-infected partners were also included in these counseling sessions, if they chose, and participants could schedule as many sessions as they felt would be helpful.
At the end of the clinical trial, only 14 of the 1,147 uninfected participants in the adherence substudy had contracted HIV. All of them had been in the placebo group, a finding that equates to 100 percent efficacy of PrEP. Average adherence rates over the whole trial were 99 percent, measured by unannounced pill count, and 97 percent, measured by the automated monitoring system. Among participants who were assigned the adherence intervention early enough in the study period to have subsequent pill counts, 92 percent had a greater than 80 percent adherence at the next count, and 82 percent maintained that level for the rest of the study period.
“This study suggests that PrEP is highly effective when taken,” said study senior author David Bangsberg, HMS professor of medicine at Mass General and professor in the Department of Global Health and Population at the Harvard School of Public Health. “We believe that studying participants in committed relationships, where both partners are supporting adherence, was part of the reason that participants in this study experienced such a high degree of protection.”
Adherence to the study protocol was most strongly influenced by relationship factors, the researchers found. Participants who reported having no sexual activity during the previous three months were more likely to report not having taken their pills—perhaps because they felt they were not at risk of infection. People who reported having more than one sexual partner or not consistently using condoms were also more likely to report not having taken their pills.
In contrast, participants in stable polygamous marriages, which are culturally accepted in the parts of Africa where the study was conducted, were more likely to follow the study protocol closely. Other factors associated with lower adherence were youth and heavy alcohol use. Adherence also decreased over time, possibly reflecting a drop-off in motivation during the study period.
“PrEP is another important biomedical tool for the prevention of HIV infection in sub-Saharan Africa or anywhere in the world where people are at high risk for acquiring the virus,” Haberer said. “No one tool will work for all people in all settings, so it’s important to have options. PrEP may make sense for couples like those in this study, particularly if they want to have children—in which case they would not be using condoms or abstaining from sex—but not for individuals who have trouble taking pills on a daily basis. It also may be a good option for couples in which the HIV-infected individual doesn’t qualify for antiretroviral therapy, which was the case for most couples in this study.”
Haberer is now collaborating on the PrEP Demonstration Project in East Africa, which includes comprehensive counseling on treatment safety, efficacy and the importance of adherence. The project does not include the intensive adherence intervention, so it should more accurately replicate “real world” clinical treatment, he said.
“We think that this project and others like it will be highly informative of how well people can take PrEP outside the structured settings of clinical trials,” she says. “The data on the acceptability and efficacy of PrEP that these projects will yield should help public officials make difficult decisions about where to spend their limited funds for HIV prevention.”
The study was supported by the Bill and Melinda Gates Foundation.
Adapted from a Mass General news release.
