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Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention

van der Straten, Arianea; Van Damme, Lutb; Haberer, Jessica E.c; Bangsberg, David R.d

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doi: 10.1097/QAD.0b013e3283522272
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Although the balance of recent evidence supports the efficacy of antiretroviral-based pre-exposure prophylaxis (PrEP) against HIV-1 infection, recent negative trial results are perplexing [1–3]. Of seven trials with available HIV endpoints, three different products have been tested: tenofovir 1% vaginal gel, oral tenofovir disoproxil fumarate (TDF) tablets, and TDF/emtricitabine (Truvada; Gilead Sciences, Foster City, California, USA) tablets. Six of these trials were conducted exclusively in sub-Saharan Africa; all found the products to be safe, and four (the Centre for the AIDS Program of Research in South Africa 004 trial (CAPRISA004); the Preexposure Prophylaxis Initiative (iPrEx); Partners for PrEP; TDF2) demonstrated effectiveness (we define ‘efficacy’ as the biological efficacy of a product used under optimal trial conditions, whereas ‘effectiveness’ is defined as the intention-to-treat estimate obtained from a trial under less-than-perfect conditions, with presence of source of bias or dilution effect [4]) (Table 1) [1–3,5–13]. Furthermore, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission to HIV-negative partners in HIV-serodiscordant couples [14]. These results, along with human and animal data [15,16], provide substantial evidence for the efficacy of antiretroviral-based HIV prevention [17]. Yet assessment of oral Truvada in the FEM-PrEP study and of oral and vaginal tenofovir in the Microbicide Trial Network-003 trial (VOICE) was stopped for futility. How do we make sense of these discrepant results? Expanding upon a recent editorial in the Lancet[18], we discuss the impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection as potential explanations for divergent PrEP trial results to date.

Table 1:
Antiretroviral-based oral and vaginal topical HIV prevention trials with HIV endpoint findings, conducted, completed, or ongoing to date.


Adherence measured by different methods has been variable in the four PrEP trials with demonstrated effectiveness (Table 1). Applicators were used pericoitally in 72% of reported sex acts in CAPRISA004 (90% by self-report), with more protection (54%) among high adherers [6]. Moreover, adherence by pill count was 84% in TDF2 [11] and 89–95% in iPrEx [7], although drug levels were detectable in only 54% of a random subsample of men [8]. Drug levels correlated with protection in the CAPRISA and iPrEx trials [7,19], strongly suggesting that adherence determines the level of protection. Yet the heterogeneity of adherence estimates within studies calls for improved and standardized adherence measures in order to better characterize the relationship between adherence and protection.

Partners for PrEP was the only trial that enrolled HIV-serodiscordant couples, offered adherence counseling to both partners, and had the highest adherence in the study overall and in a substudy using intensive adherence monitoring followed by an intervention for individuals with less than 80% adherence [20]. Early qualitative data [21] suggest that trust and commitment within the partnership are critical for supporting adherence. Although not all trials can or should enroll partners, encouraging the involvement of partners or other influential individuals in supporting product use should be integral to adherence interventions. This may be especially important when targeting women [22,23], given the lack of effectiveness seen to date in two trials recruiting exclusively women. Although theory-based adherence support interventions were implemented in several trials, estimating their effect has been limited, in part, by their late implementation, the absence of an experimental design, and/or the lack of objective measures to evaluate success [Next Step Counseling in iPrEX [24]; VOICE Adherence Strengthening Program [25]; and an adherence support program with motivational interviewing in CAPRISA [6]].

Mode and frequency of administration may explain the heterogeneity in adherence across study populations in addition to the level of involvement of a stable partner. In one cross-over study of 144 women, American women strongly preferred tablets over gel, whereas African women had no clear preference [26]. Limited data exist on preference of different dosing regimens, although some evidence suggests that daily or intermittent dosing yields higher adherence than coitally related dosing [27,28]. However, daily use is more costly and possibly more burdensome on users with higher risks of lapses or stopping altogether [29]. Other causes of nonadherence, such as gaps in product refill due to missed study visits or protocol-driven holds, may also contribute to efficacy dilution and warrant further cross-trial analyses.

Heterogeneity in adherence has a profound impact on the interpretation of trial results. Mathematical models of efficacy from randomized controlled trials often assume 100% adherence [4,30], and these estimates are biased toward the null as adherence levels fall. For example, at 60% adherence, the trial estimate is less than half of the true biological efficacy. Yet, explaining the futility findings in VOICE and FEM-PrEP simply based on low average adherence (defined by the percentage of study product taken during the study) may be overly simplistic. Temporal patterns of adherence and sexual exposure will influence the degree of PrEP protection (Fig. 1); isolated lapses combined with high-risk sexual exposures can lead to transmission. Conversely, low adherence confers little risk in the absence of sexual exposure. Unfortunately, cost and complexity of measurement have so far precluded any PrEP study to address this issue.

Fig. 1:
Two hypothetical patterns of adherence and sexual exposure with pre-exposure prophylaxis daily regimen.The figure presents two hypothetical patterns of adherence and sexual exposure among users of a daily pre-exposure prophylaxis regimen over 60 days. The first table illustrates a participant with high adherence; however, a period of product nonuse (8 consecutive days) coincides with a period of high-risk sexual activity. The second table illustrates a participant with low adherence and low risk (no sex).

Explaining discrepant findings by differences in adherence is difficult in the absence of comparable and accurate measures across studies. Participant's self-report has limited accuracy and overestimates adherence compared to objective measures that minimize opportunities for participant manipulation (these include measures such as electronic devices for medication monitoring, unannounced home-based product counts, and biomarkers of gel applicator insertion) [31,32]. Although drug levels are helpful, they represent a combination of behavioral and biologic factors and they do not inform patterns of adherence. In the absence of a gold standard, achieving accurate behavioral reporting remains a challenge. Triangulating multiple objective measures provides the best possible estimate of true adherence. Although they add to the cost and operational complexity of trials, objective behavioral measures of adherence are necessary to monitor use and target adherence interventions to those participants needing additional support. Objective behavioral measures combined with drug levels will be critical for the interpretation of future study results.

Drug concentration at the exposure site

Antiretroviral medications must reach a concentration high enough in the exposed tissue to provide protection [19]. Available antiretroviral drugs offer varying levels of drug concentration within the cervicovaginal fluids (CVFs), blood plasma, and vaginal and rectal tissues [33]. Tenofovir reaches slightly higher levels in the CVF and a 33 times higher concentration in rectal tissue compared with blood plasma after one single oral dose [34]. For emtricitabine, slightly higher levels are seen in the rectum, and much higher levels (42 times) in the CVF than in plasma. Tenofovir levels in the CVF and in genital tissues are more than 100-fold higher after vaginal gel insertion than after oral tablet ingestion [26,34,35]. Although we do not know the effective tissue concentration needed to prevent HIV infection, less than 1000 ng/ml of tenofovir in CVF was associated with no significant protection in CAPRISA004 [19].

Products applied vaginally may also penetrate into the rectum [36], although it is not known whether these levels confer protection against anal HIV acquisition. Differential drug levels in the vagina and rectum combined with differences in sexual practices across study populations may also inform the interpretation of conflicting trial results.

Integrity of the vaginal epithelium and cofactors of infection

A number of biologic risk factors may increase women's HIV susceptibility, including genital inflammation and sexually transmitted infections (STIs). There is high degree of variation in herpes simplex virus type 2 (HSV-2) prevalence by location and populations [37–39]. STIs may selectively decrease PrEP potency by compromising the vaginal epithelium or through other immunological mechanisms. For example, in CAPRISA004 the effectiveness of tenofovir gel was decreased among women with high cytokine levels, such as occurs with STIs [40]. On the contrary, tenofovir 1% gel was 51% protective against HSV-2 acquisition in CAPRISA004 [6]; an effect not observed with oral TDF administration [41].

Vaginal practices that interfere with PrEP tissue coverage (for topical gels), compromise the vaginal mucosa and/or microflora, or create drug-to-drug interactions may influence protection. A meta-analysis confirmed that intravaginal use of soap, cloth, paper, or drying products increased risk of acquiring HIV [42]. These practices vary by location and population [43,44] and may contribute to contradictory trial results.

Another consideration is that the hyperosmolarity of tenofovir gel has been associated with epithelial disruption of cervical and colorectal explants in vitro[45]. Side-effects following rectal application prompted a recent change in formulation to improve rectal safety [46]. Although the vaginal epithelium is much thicker than the rectum's, daily application of active gel for long durations could theoretically affect the integrity of cervical or vaginal epithelium (the placebo gel used in the VOICE vaginal control arm, is isotonic and isosmolar [47]).

Not enough is known about the role of women's exogenous and endogenous hormones in PrEP effectiveness and in their risk of HIV infection. Some hormonal contraceptives may increase susceptibility to HIV via several biological mechanisms, including epithelial thinning due to progesterone [48,49]. More studies should examine potential drug-to-drug interactions between hormonal contraceptive and antiretroviral-based PrEP [50–52] and the effect of hormonal contraceptives on antiretroviral activity in the genital tract.

Acute HIV infection

HIV-RNA levels are much higher during acute compared with chronic infection and confer greater risk of sexual transmission [53]. Empirical and modeling studies from sub-Saharan Africa indicate that acute infection may account for 13–25% of new HIV transmission events [54,55]. Acute infection was presumably uncommon in stable serodiscordant partnerships in Partners for PrEP in which the baseline plasma viral load in the index partner was relatively low (3.9 log10 copies/ml) and HIV incidence was only 1.92 per 100 person-years in the placebo group [12]. In contrast, the HIV incidence was 6% per year in VOICE's vaginal gel group [3] and 5% in FEM-PrEP [1]. In high seroincidence settings, trial participants are sexually exposed to high viral loads that may overwhelm antiretroviral-based protection, particularly among women with varying adherence levels.


Differences in adherence behavior combined with biologic determinants of drug concentration at the exposure site, integrity of the vaginal epithelium, and/or stage of infection of the index partner are potential explanations for the current divergent PrEP trial findings. Despite these contradictory findings, the Partners for PrEP study demonstrates that significant protection can be achieved with high adherence to oral antiretroviral within heterosexual couples. Behavioral studies, which include objective and comparable adherence measures, are needed to explore the reasons why women at high risk of HIV infection may not have been sufficiently adherent for protection. Establishing the minimum level of adherence to achieve adequate drug levels in the female genital tract or in the rectum for reliable protection is critical to guide interventions and will require more detailed assessment of patterns of adherence and sexual exposure. Such findings will help identify optimal populations for PrEP and develop effective adherence counseling interventions. Concurrently, the development of more user-independent antiretroviral delivery methods, such as vaginal rings, should continue. Accurate adherence measures should be combined with epidemiologic and laboratory studies on the determinants of drug concentration in sites of exposure to understand how behavioral and biologic factors impact antiretroviral-based protection and, thereby, guide future prevention strategies.


A.S. conceived of the idea and led the writing of this manuscript. All authors wrote at least one section of the manuscript and contributed to editing and modifying the content of the manuscript as a whole.

The authors thank Miriam Hartmann for her help in preparing and editing this manuscript, and Tim Mastro, Connie Celum, and Jared Baeten for reviewing an earlier draft of the manuscript.

Conflicts of interest

Support for preparation of this manuscript was provided by a Professional Development Award from RTI International for A.S. L.V.D. was supported by USAID funding. J.E.H. and D.R.B. were supported by the Bill and Melinda Gates Foundation. J.E.H. was supported by K-23 087228 and D.R.B. was supported by K-24 MH87227

The authors declare no conflicts of interest. A.S. is a member of the Behavioral Research Working Group of the Microbicide Trial Network, and a co-investigator on the VOICE trial. L.D. is the principal investigator of FEM-PrEP. D.R.B. is the principal investigator and J.E.H. is a co-investigator for the adherence substudy within the Partners for PrEP study.


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antiretrovirals; biomedical HIV prevention trials; microbicide; pre-exposure prophylaxis

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