PrEP Adherence Issues Kick Off CROI 2014
What do people need to be able to adhere to daily oral PrEP? And how can scientists understand, measure, and support adherence in clinical trials?
These questions were at the heart of a workshop that kicked off Day 1 of the 21st Conference on Retroviruses and Opportunistic Infections.
David Bangsberg of Massachusetts General Hospital Center for Global Health described the wildly different estimates of “efficacy,” or how well PrEP worked in a trial’s controlled setting, among the various studies of daily oral PrEP.
“It’s striking that, depending upon the study, we could get ranges of efficacy estimates from ‘nothing’ to ‘quite good,” Bangsberg said. (Estimates of efficacy address how well a product works in a clinical trial; effectiveness, on the other hand, refers to how well the product works in “real world” settings.)
Differences in population, HIV exposure routes (i.e., anal sex, vaginal sex, and injecting drugs), biological factors, and rates of participant drop-out are potential sources for the “heterogeneity,” or diversity, in estimates of PrEP efficacy, Bangsberg noted. However, he added, “as the dust has settled on interpreting these trials, I think the most likely explanation is that this wide heterogeneity in efficacy estimates is due to differences in adherence between these studies.”
Support for this idea comes from blood sample data: The lower the proportion of trial participants with detectable levels of the study drug in their blood, the lower the efficacy estimate for the trial. For example, in the VOICE study of PrEP for women, analysis of blood samples from 773 participants revealed that 58% of those in the oral tenofovir (Viread) arm had no detectable tenofovir in any sample. The oral tenofovir arm of the trial was halted early due to lack of ability to demonstrate efficacy.
“So how do we understand adherence to PrEP?” queried Bangsberg. “How do we understand adherence so we can, going forward, improve adherence to not only get better efficacy estimates but also better effectiveness?”
To address these questions, Bangsberg turned to trial participants’ own understandings of adherence. Interviews with 60 participants in the Partners PrEP trial of pre-exposure prophylaxis for serodiscordant couples (in which one partner is HIV positive and the other HIV negative) revealed that PrEP helped resolve tension—nicknamed the “discordance dilemma”—in these couples. Taking the daily pill helped couples preserve their relationship while reducing risk of HIV acquisition for the negative partner; both partners were therefore invested in good adherence.
By contrast, interviews and focus groups with a subset of VOICE participants revealed that the unknown efficacy of the trial products, stigma around using drugs associated with HIV infection, and lack of support from partners and significant others all discouraged use of the study products.
Given that using a study drug or product is clearly culturally loaded, Bangsberg advocated for greater attention to evidence-based approaches to monitoring and supporting adherence. Self-reported data on adherence is the measure most commonly employed, but as shown by comparisons against drug levels in blood, self report can dramatically overestimate adherence.
Additional adherence measures are called for, he explained. Currently available options include:
- “medical event monitoring systems,” or MEMS caps, which create an electronic time stamp when a pill bottle is opened;
- unannounced home visits to count participants’ pills, random pill counts by phone, or clinic-based pill counts;
- tracking pharmacy refills;
- measuring drug levels in blood or hair samples;
- and real-time adherence monitoring (i.e., Wisepill), which relays data on pill bottle openings to a server and thence to the provider or study investigator, allowing adherence patterns to be tracked and addressed.
Better measures of adherence would create more opportunities to intervene when trial participants are finding it challenging to stick to the study regimen. For example, an ancillary study of Partners PrEP tested an intervention with intensified adherence counseling in a subset of participants whose adherence had dropped below 80% according to unannounced pill counts. A series of roughly thirty-minute counseling sessions focused on education about adherence, participants’ daily routines, barriers to adherence, support systems and reminder strategies, and other aspects of adherence.
The result? At the first unannounced pill count following the intervention, 92% of substudy participants had increased their adherence to greater than 80%. Although adherence after the intervention wasn’t perfect, “people who had trouble adhering had reasonable adherence through the remainder of the study,” said Bangsberg. The research team is currently honing the intervention down to 15-minute sessions to better fit real-world settings and help boost adherence to PrEP.
Bangsberg also proposed conducting small-group studies to understand pill-taking behavior and anticipate adherence issues before launching large and costly randomized controlled trials. “It’s as important to find out if people will take a drug as it is to find out whether the drug actually works,” he stated. “I would suggest, just as we do Phase 2 dose-finding studies to see what is the range of doses that are both potentially efficacious as well as tolerable for a patient, we should do Phase 2 adherence behavior–finding studies to see if small groups of patients will take the drug—or if they don’t take the drug, what is the range of adherence behavior in that population—before we move forward to large-scale, randomized efficacy trials.”
Integrating social science into biomedical trials could go a long way toward addressing this “Achilles’ heel” in PrEP research.
David R. Bangsberg. Adherence: The Achilles Heel for Trial Interventions. 21st Conference on Retroviruses and Opportunistic Infections. Boston, March 3–6, 2014. Abstract 7.
Background: Recent studies of HIV pre-exposure prophylaxis (PrEP) in HIV-negative individuals revealed heterogeneous estimates of efficacy from 0% to 77%. Efficacy estimates in randomized clinical trials presume adherence to the intervention. Nonadherence biases efficacy estimates to the null and differences in adherence between studies will lead to differing efficacy estimates. Antiretroviral drug level data obtained during PrEP studies suggest that the heterogeneity in PrEP trial efficacy estimates can be explained by differences in adherence amongst the studies. This presentation will review the impact of nonadherence on efficacy estimates, and the approaches to measure adherence.
Conclusions: The presentation will conclude with post-hoc analyses that suggest that the level of protection against HIV transmission conferred by PrEP in HIV-negative individuals is comparable to the level of protection conferred by antiretroviral therapy in HIV-positive individuals.