Optimizing Delivery of Preexposure Prophylaxis--The Next Frontier.

Abstract

Preexposure prophylaxis (PrEP) for human immunodeficiencyvirus(HIV) infection—administeringadailytabletofaUSFood and Drug Administration (FDA)-approved HIV antiretroviral fixed-dose combination of tenofovirdisoproxil fumarate and emtricitabine (TDF/FTC) (Truvada; Gilead Sciences, Inc) to high-risk uninfected individuals—has galvanized supporters and opponents. Data show that PrEP is effective in preventing HIV infections inmenwho have sexwithmen (MSM), aswell as in heterosexually active men and women.1-3 In intention-to-treat analyses, these studies showed reductions of infections between44%and 75%, although compliancewith daily therapy did not appear to be high. When investigators restricted the analysis to personswith detectable drug levels, effectiveness rates were over 90%. An open label extension study in follow-up to the iPrEX (Iniciativa Profilaxis Pre-Exposicion) trial1 found 100% protection for those who had sustained adherence at the level of 4 or more doses per week.4 Whether adherence to daily or near-daily dosing can be achieved in real-world settings has been questioned. Moreover, there has been concern that PrEP will lead to increases in condomless sexwith attendant risk of other sexually transmitted infections. In this issueofJAMAInternalMedicine, Liuandcolleagues5 address some of these concerns as they report the results of theDemoProject, a longitudinal, open-label, single-armstudy ofdailyoralTDF/FTC inmenwhohavesexwithmenandtransgenderwomen in3cities.This report represents the firstof several demonstration projects following the 2012 FDA approval of TDF/FTC for HIV prevention. Deployed at clinics that treat sexually transmitted infections (STIs) in San Francisco and Miami, aswell as a gay-identified community health center in Washington,DC, thestudyenrolled550menwhohavesexwith menand7 transgenderwomen intoa48-week longitudinal cohort between October 2012 and February 2014. Importantly, this is the first cohort studied that received open-label TDF/ FTCwhohadnotpreviouslyparticipated in a randomized trial of PrEP, therefore, providing a better approximation of what real-world clinical PrEP delivery might look like. Overall, thenews concerningPrEPdissemination is good, but there are sobering lessons.Of the557enrolled in theDemo study,5 78% were retained over the 48 weeks of follow-up. African Americans and participants from theMiami sitewere less likely to be retained, as were those with lower socioeconomic status and the uninsured. In an attempt tomimic clinical settings,missing participantswere only contacted amaximum of 3 times in response to a missed visit, and incentives for visit attendancewerenominal, although thedrugwas free. The study used intraerythrocytic drug levels measured on dried blood spots (DBS).5 This is an elegant technology for evaluating TDF-based adherence over a 3to 4-month horizon.6 Such a measurement provides an objective biomarker for longitudinal adherence. A subset of approximately 100 participants at each site had DBS drug level assays performed. At any given time over the 48-week follow-up period, 80% to 86% of study participants had DBS levels commensurate with high levels of protection (≥4 doses per week or the adherence modeled to be predictive of 96% protection based on the iPrEX data set7 and 100% protective from iPrEX open label extension). Reassuringly, those reporting higher sexual risk were more likely to have protective biomarker levels, but consistently, the black participants and those fromMiami were less likely to have protective levels, as were participants who were unstably housed. The overall HIV incidence in the cohortwas an extremely low 0.43 per 100 person years (95% CI, 0.05-1.54). Of 2 onstudy seroconversions observed, both occurred in participants whose DBS suggested PrEP adherence levels of fewer than 2 doses per week. In the Demo study,5 the observation of poor retention and adherence inMiamiarenotexplainedbydemographicsorother measured parameters, which reminds us that community and individual acceptance of PrEP may still vary widely by region andculture, andwide-reachingandnovel educationalmessagingwill need tobeused to assure coverageof all at-risk groups. Overall, the rates of unprotected intercourse and STIs in the Demo study5 were high but stable over the course of the study. It remains unclear if the high rates of STIs are a manifestation of testing bias or a suggestion of increased rates of condomless sex. The medications were well tolerated with minimal adverse effects. The sites in theDemostudy5 are sophisticated,highlymotivated sites that arewell-versed in PrEP science, well-rooted in community activities, andexperiencedwithbehavioral and biomedicalHIVprevention strategies. Their successes inPrEP delivery may not be generalizable to other clinical settings. There are an abundance of anecdotes on the Internet of potential PrEP consumers struggling to find clinics willing to provide PrEP and knowledgeable about monitoring and concomitant services. PrEP-providing clinic registries are being developed but are largely grassroots efforts. Financial coverage of copayments and deductibles can be a substantial barrier, and self-efficacy (ie, high levels of motivation, empowerment, knowledge, and time) seems tobe anecessaryquality for patients and clinics alike to marshal the available financial resources. Whether the retention and adherence rates found in this studyaregeneralizable to lesswell-resourcedand sophisticated clinical settings remains to be seen. Related articles pages 75 and 136 Preexposure Prophylaxis for HIV Infection Original Investigation Research