Adherence is Critical
Optimizing adherence and its measurement in prevention clinical trials is critical for trial outcomes and interpretation. The CAPRISA 004 study of tenofovir vaginal gel provided an important proof of concept that antiretroviral agents can prevent HIV acquisition . However, the trial also demonstrated the importance of adherence in ultimate PrEP effectiveness: self-reported high adherers (>80% adherence as measured by returned gel applicators) had a significant protective effect (54% effectiveness, 95% confidence interval (CI) 4–80%), while low adherers (<50% adherence) had no significant protection (28% effectiveness, 95% CI 40–64%). Data from the iPrEx trial of oral daily Truvada® in MSM is not yet available at the time of this writing. However, analyses are planned to evaluate the effect of adherence (as measured both by self-report and drug levels) on PrEP efficacy.
One challenge to interpreting efficacy results is the veracity of self-reported measures, where over-reporting may commonly occur. In the Carraguard vaginal microbicide trial, for instance, adherence to prescribed microbicide use was 96% via self-report but only 42% on the basis of applicator testing . Data from a sub-study of the US-based MSM safety trial found relatively poor correlation between various adherence and drug exposure measures . Many factors may be responsible for these discrepancies, including misunderstanding of study questions, memory lapses, social desirability bias, or differences in drug absorption, metabolism, or penetration into various tissues. Adherence and drug exposure measures will be most useful if they can reproducibly define patterns or thresholds of pill-taking required for maximum effectiveness, and point to mechanisms by which effectiveness may be impaired. Strategies to promote pill use in PrEP trials and to facilitate accurate reporting of product use are currently being explored .
Only limited data to date have been presented on adherence patterns in oral PrEP trials. Preliminary analysis from a comparison of daily versus fixed plus post-coital dosing in Kenya and Uganda suggested that adherence to daily and fixed-dose regimens were relatively high and better than post-coital dosing, although accurate measurement of post-coital pill use may have been an issue . It is not yet known what schedule of PrEP dosing will be most effective, nor what level of adherence will be required for maximum tolerability and efficacy.
Importance of Community Engagement in All Stages of Research
Early planned PrEP trials (efficacy trials in Cambodia, Cameroon, Malawi, and three West African sites) were not launched or were stopped prematurely because of ethical, political, and logistical issues raised by community members, advocates, government officials, and clinical trial sponsors . Difficult as these situations were for all parties involved, the resulting discussions that arose as a result of these challenges strengthened the next generation of trials, which included full involvement of community members, support of government officials, and strong oversight of clinical study operations. Community consultation must start early and involve multiple community groups, which may have distinct perspectives and interests. These engagement efforts should promote communication between researchers and community as well as among different community groups through transparent discussions . UNAIDS has recently issued a revised version of good participatory practice (GPP) for biomedical HIV prevention trials ; this document highlights the importance of stakeholder engagement at each stage of the research life-cycle.
Attention to Trial Planning and Conduct is Paramount
In addition to the importance of community engagement, the successful conduct of PrEP research requires great attention to the mechanics of clinical trial implementation. PrEP trials are highly complex, and successful conduct of PrEP trials depends on talented investigators with access to appropriate populations to achieve rapid accrual rates, adequate seroincidence in the context of best prevention strategies, and adherence to protocol requirements. PrEP clinical trials have faced numerous challenges on these fronts. For example, the US PrEP trial among MSM experienced slower than projected enrollment; important lessons learned included the importance of centrally coordinated recruitment strategies and campaigns, and the need for streamlined regulatory approvals and support for innovative strategies, including use of the Internet . Lower seroincidence was observed in both the West African PrEP study  and CDC Botswana trial , but may have been due to overall secular trends in the community, inaccurate pre-trial estimates of HIV incidence, and intensive prevention services provided in the trial. Adherence to protocol requirements is also critical. Missed visits and pregnancy were primary reasons for time off study drug in the West African PrEP study. Low retention in the CDC Botswana PrEP study contributed to the premature closure of that trial. Ideally, plans to achieve rapid enrollment, adequate HIV seroincidence, and excellent retention rates in trials should begin prior to study launch, and adequate resources should be in place to address difficulties.
Many Questions Will Remain After the First Round of PrEP Studies
Even if all of the first and second generation PrEP studies are conducted with excellent adherence to study procedures, many questions will remain after results are available (Table 2). Data to date suggest that oral tenofovir is relatively well-tolerated in HIV-negative individuals, with no substantial safety concerns after up to 12 months of use in women in West Africa  and up to 24 months in MSM in the US . However, only preliminary safety analyses were presented on the US MSM safety trial; additional analyses, including studies of the effect of daily tenofovir or Truvada® on bone mineral density have not yet been completed. In addition, safety data have not yet been reported for other populations, including IDU and youth, and are not collected comprehensively in pregnant or lactating women, or in persons with underlying medical conditions. Also, the long-term safety of ongoing use of antiretrovirals for prevention is unknown.
All PrEP efficacy studies will measure drug resistance in breakthrough infections. However, numbers of infections on PrEP may be small, and pooling data across PrEP studies will help identify resistance issues. All current studies focus on tenofovir-based regimens; there is interest in developing other antiretroviral agents for PrEP to improve on the safety and/or efficacy profile, or to reduce the possibility of drug resistance.
Some of the most substantive questions will need to be addressed if PrEP is found to be efficacious in clinical trials. Modeling exercises suggest that PrEP could substantially reduce new infections at a population level, but that efficacy could suffer if risk practices also increase [26, 27]. If PrEP is found to be efficacious, additional studies to measure the effect of knowledge of PrEP efficacy on risk behavior and adherence will be needed. PrEP impact may be highest if delivered to those at highest risk of acquiring HIV. Several studies have surveyed MSM about their interest in taking PrEP if found to be efficacious, and these suggest that men with substantial risk may be willing to take PrEP [28–30]. However, whether and how these men might use PrEP is not yet known. Substantial work is required to determine how best to deliver PrEP to various populations in various settings . PrEP delivery will require coordination of different PrEP delivery components, including outreach, screening, drug prescribing and delivery, HIV and additional safety testing, and interventions to sustain pill use and behavioral risk reduction over the long term . In addition to consideration of various political, legal, and cultural issues, questions remain about the frequency and intensity of clinical monitoring and HIV testing, how best to identify and engage high-risk populations, methods of reimbursement, and the types of clinical or community-based facilities that may be best equipped to deliver PrEP in various settings.