Even the most effective products are ineffective when requirements for self-administration are not met. The magnitude and scope of nonuse of products in blinded trials and anticipated impact of this in open-label trials of effective self-administered biomedical prevention strategies have received considerable attention in the wake of several positive preexposure prophylaxis (PrEP) trial findings. Adherence has demonstrated a strong relation to reduction in HIV risk, with perhaps the most dramatic example of this exemplified by iPrEx's modified ITT risk reduction estimate of 42% , contrasted to the estimated 92% obtained through case-control analysis of those with drug detected . Additionally, null findings in FemPrEP were attributed to nonuse of study product; less than 26% of the sample had a detectable level of drug (daily TDF/FTC) [3▪]. Concerns that poor adherence to PrEP may substantially dilute intent-to-treat efficacy estimates, as well as the ultimate success of PrEP in communities, have been well represented in the literature [4▪,5–7]. With the USA recently approving the use of FTC/TDF for the prevention of HIV, there is an urgent need to survey what we know to date concerning product use in PrEP trials and what we might expect to see in terms of open-label PrEP use. In this brief review, the current evidence base and associated cautions concerning both study product use from major prevention trials and potential open-label PrEP use are summarized and gaps in knowledge identified. A burgeoning research agenda has emerged that requires careful attention to the multitude of behavioral factors that can promote or challenge PrEP success.
ADHERENCE TO BLINDED STUDY PRODUCT
Rates of study product use assessed via self-report or product return are consistently high in the major PrEP trials, typically falling in the 80 and 90% range [3▪,8–10,11▪,12–16,17▪]. However, drug detection data present a picture of substantial variability both between those who did and did not seroconvert in PrEP trials and between different trials [3▪,8–10,11▪,12–16,17▪]. As indicated in Table 1, in daily oral PrEP trials, adherence estimates obtained via self-report or product count appear to overestimate (to varying degrees) actual product use, a finding consistent with over-reporting seen in other areas of research (cf. ).
Recent work in this area further suggests that drug detection is generally lower in active arm participants who seroconvert [as low as 8% in iPrEx randomized controlled trial (RCT)  and as high as 36% with detectable drug in the genital tract in CAPRISA 004] [15,16] in contrast to ‘controls’ who remained HIV-negative (with highest levels of drug in 82% in Partners in PrEP  and 96% in CAPRISA 004 ; see Table 1). Estimating daily use of oral PrEP in studies evaluating this regimen, only 18% of iPrEx participants  and as high as 71% in Partners in PrEP  may have been taking PrEP daily. Recent results using electronic drug monitoring in a small study with men who have sex with men (MSM) and female sex workers in Kenya suggest about 92% daily adherence to study product . The dramatic range between self-report and product count-based adherence and drug detection, and the consistent relation between adherence and protective effects, position adherence as not only difficult to estimate using common strategies (self-report or product returns) but critical to PrEP success.
At least two patterns from the evidence base currently available should be noted as areas in need of further exploration. First, the variability in proportions of participants with drug detected between studies should be investigated. Evaluating potential unique contributions amongst the groups of individuals involved in these different research trials may provide some guidance in terms of factors promoting and posing potential barriers to product use. For example, is there something about the participants in the Partners in PrEP trial that distinguishes them from other trial groups? Certainly, vulnerability to HIV as being part of a serodiscordant couple may have influenced use of study product, but other relationship dynamics facilitating product use have also been noted [21▪]. Differences between sites within a single trial may also help to identify potential facilitators of product use. iPrEx  reported far higher levels of drug detection in their United States cohort (73%) versus other sites (50%). CAPRISA 004  reported higher overall efficacy in rural (43%) rather than urban (26%) sites. Presently, factors influencing adherence have largely focused on the individual. For example, in iPrEx RCT's United States sites, adherence has been related to beliefs in the efficacy of the drug, low experience of side effects, older age, reported potential exposure to HIV (recent unprotected anal sex with an HIV-positive partner), and not reporting frequency alcohol use or methamphetamine or cocaine use . In Partners in PrEP, a substudy using a combination of adherence measures found that adherence was related only to older age . However, focusing on individual-level correlates has been criticized for promoting a myopic focus on the individual to the exclusion of systems-level factors that exert influence on product use. In line with calls to better understand socio-cultural and structural context in which product use occurs and rates of efficacy are established , exploration of factors that may have influenced high and lower rates of product use that go beyond the individual, community and health-systems are needed.
Secondly, the discrepancy between reported product use and drug detection  requires focused attention. The most common strategy for on-going clinical monitoring of use of antiretroviral therapy (ART) for in treatment settings, outside of a clinical trial, is self-report (cf. [19,25]), and many of the interventions found effective for supporting adherence to ART for treatment or other regimens require open and accurate discussion of potential difficulties (cf. [26–28]). The level of discrepancy observed in some studies suggest that inaccuracies in reporting are beyond that which would be expected due to cognitive or recall errors (cf. ). The disconnect between reported use and actual use could pose substantial problems in providing targeted or generalized support to promote high rates of product use. Gaining a better understanding of the factors that facilitate or, alternatively, dissuade the reporting of nonuse when it does occur is essential to providing guidance for ongoing research studies and practice.
FROM BLINDED STUDY PRODUCT TO OPEN-LABEL PrEP USE
Many have argued that rates of adherence are often higher in the well controlled RCTs and thus open-label PrEP use is likely to be worse than what has been documented for blinded study product use. Alternatively, adherence amongst those opting in to use a demonstrated, open-label prevention strategy may actually be better. The realities of trial participation in PrEP RCTs may work against adherence, often involving well over a year of frequent visits, clinical procedures, and reminders of the chance of being on a placebo, and, even if on the active arm, on a product with unknown efficacy and continued evaluation of safety. The costs/benefits of taking a product of unknown safety are highly skewed towards costs if little potential gain can be attributed to the best case scenario (being in the active arm and the product being effective). Further, the socio-cultural context of trial participation in which certain benefits of participation are simply otherwise unavailable in the community creates samples in which PrEP use may not be a primary consideration. Open-label use of PrEP will likely differ in many ways from use of a blinded study product under investigation. We simply do not know what adherence will look like for open-label PrEP, but it seems likely that PrEP use among the first adopters of a new innovation might actually be higher than what has been reported in many trials for blinded product use. Whether or not PrEP adherence will pattern similar to ART for treatment (∼60% with optimal adherence ), use of oral contraceptives (∼40% adherent ), other types of as-needed prevention (e.g. ∼30% adhere to recommended use of sunscreen ), or what has been established for blinded study product use in PrEP trials remains to be determined. Further, if initial adherence declines generally over time similar to ART for treatment adherence  or if that decline is followed by a rise and stabilization as has been found with adherence to warfarin , it will not be known until several years after introduction of PrEP into communities.
MONITORING ADHERENCE TO PrEP
The CDC's interim guidance for oral PrEP use with MSM  clearly identifies the need to monitor and provide support for high rates of adherence. However, as previously noted, monitoring of PrEP use has been difficult to accomplish with accuracy in blinded trials. Monitoring of adherence to ART has a long history of active inquiry and continues to be best described as elusive and generally lacking of a gold standard .
Monitoring of sex event-dependent PrEP poses a number of unique challenges, and advances in research-appropriate tools to objectively determine gel-applicator use are promising. However, whether topical or oral, intermittent PrEP use ultimately requires self-report of sex events to determine how much product ‘should’ have been used. In practice, it remains unclear if drug levels in the genital tract will be a feasible methodology and use of blood level detection may offer less accuracy .
Specific to oral daily PrEP, monitoring PrEP use must include not only the extent to which individuals ‘execute’ the regimen (doses taken) but also whether or not individuals stopping and re-starting PrEP get tested for HIV prior to re-starts. For execution, drug detection is presently a gross-level strategy, although recent advances in assigning values reflective of daily use versus any recent use [10,12] offer needed refinement. The feasibility of using drug detection as a regular part of PrEP prescribing may pose challenges. Similarly, use of electronic drug monitoring (EDM) devices appears promising with feasibility uncertain. In research projects, EDM has demonstrated feasibility and acceptability , as well as accuracy . The most common approach in practice is likely to be self-report despite limited data to support its accuracy with PrEP use. Research to identify optimized methods for assessing open-label PrEP in demonstration projects and in ‘regular’ care is needed but generally absent in the literature presently available. Monitoring of ‘as-recommended’ PrEP restarts is an area that has not yet received attention but will likely be quite important to ensure that individuals starting PrEP, for the first time or as a re-start, are not HIV-infected.
Emerging technologies include use of hair and electronic monitoring for gel applicator bags. Similar to drug detection and other electronic monitoring strategies, these may prove more feasible for research rather than practice [36▪]. However, these as well as drug detection methods have a critical role in research as a ‘standard’ for developing better methods that could be generalized easily into practice (e.g. self-report measures that do map onto drug levels or EDM data).
SUPPORTING PrEP ADHERENCE
In terms of supporting open-label PrEP use, the most immediate guidance is needed for oral PrEP use, as the efficacy of topical PrEP continues to be under investigation in a number of trials. For oral PrEP use, dynamics of uptake and use are under investigation presently in at least four demonstration trials . Emerging information from the iPrEx study's open label extension was recently presented  that was extracted from the tracking tool used by counselors during their conversations with participants receiving. Results from 3345 documented conversations amongst 1274 unique participants suggested that common facilitators of open-label daily PrEP use included matching daily dose to an existing routine (81%) and use of carrying devices or strategies that allowed consistent access to a PrEP dose (22%). Barriers to PrEP use included forgetting the dose entirely or forgetting to have a dose available (31%) as well as disruptions in routine (31%). Reported difficulties due to drug or alcohol use, lack of privacy, or experience of side effects were uncommon (<10%). Strategies to promote integration of PrEP use into daily life included use of a memory aid (46%) followed by those that ensure consistent access to PrEP doses (27%).
Although important in providing initial guidance on factors that appear relevant to individuals participating in PrEP demonstration projects, individual-level correlates of PrEP uptake and use must be situated within the larger context of the communities and care-providing systems incorporating PrEP as a prevention strategy. Numerous models of adherence or adoption of health promotion behaviors can be adapted and applied to PrEP use (cf. [39–41]); however, models that seek to address protection of sexual health more globally through a compendium of approaches that represent the lived realities of managing HIV risk in the context of socio-cultural and structural influences and community-level HIV risk are needed.
Bio-medical HIV-prevention strategies that require on-going self-administration are necessarily bio-behavioral interventions, and further may, in fact, be better understood as bio-psycho-social interventions when considered at the aggregate level as strategies to decrease HIV transmission in whole communities. Even in the context of available PrEP, nonadherence will limit personal protection from HIV. Further, should protective effects of PrEP be over-estimated by an individual or by a community as a whole, safety gains will suffer potential offsets . Whereas we continue to explore what rates or patterns of oral PrEP use are in fact needed to provide high levels of protection (cf. [10,43], current demonstration projects of open-label oral PrEP request daily use. Presently, we do not know whether the rates of PrEP uptake, use, or the use of HIV-testing when re-starting PrEP after a ‘break’ will provide the level of impact on the HIV epidemic that many are hoping for. Nor do we have a strong sense of how to promote effectively either as-recommended PrEP use or product use in blinded trials.
Limitations in our current knowledge base are noted in Table 2, with an emphasis on key questions that need to be addressed by ongoing research. Obviously, there are numerous areas in need of further inquiry, but the development of research agendas that seek to definitively answer some of the questions concerning factors influencing PrEP adherence and establishing evidence-based interventions to promote high rates of adherence are needed. In addition to developing a specific evidence base for behavioral support approaches and measurement for both blinded study product use and open-label PrEP use, culling across available literatures and guidance for support of daily adherence for treatment [47▪] or other prevention strategies  may also help to shape the research agenda.
Whereas the ‘biological’ component in the bio-behavioral equation has received considerable attention and is in many ways the necessary condition for bio-behavioral prevention strategies to even offer a potential impact, in itself it is also insufficient. The bridge from potential to realized efficacy is ‘behavioral’ (social, cultural, structural, and individual) and ultimately plays a critical role in the personal and population-level impact of even the most effective agents.
Conflicts of interest
Dr Amico received no external funding relating directly to the writing of this manuscript; however, she is a consultant for the iPrEx and VOICE studies and works on the following Prep trials as part of her work at the University of Connecticut: HPTN067 ADAPT, HPTN069 NEXT PrEP, and EPIC.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 610).
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