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Use of antiretroviral drugs to prevent sexual transmission of HIV-1 has been a critical priority since their development. In the past 2 years results from seven important prevention trials have been reported (table). One of the trials, HPTN 052,1 showed nearly complete prevention of HIV transmission when viraemia was suppressed. The other studies focused on antiretroviral agents for pre-exposure prophylaxis: two used 1% tenofovir gel (CAPRISA 0042 and VOICE3), four used oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) in combination (iPrEX,4 TDF2,5 Partners in Prevention [PIP],6 and Fem-PrEP7), and two used oral TDF alone (VOICE3 and PIP6). Somewhat confusingly, the findings of these studies have led to reports both of successful prevention of HIV infection (CAPRISA 004,2 iPrEx,4 TDF2,5 and PIP6) and of futility (VOICE3 and Fem-PrEP7).
Clearly, results on pre-exposure prophylaxis will be used to inform policy and to plan future research, and so the trials’ findings need to be considered carefully. There were key differences in the pre-exposure prophylaxis trials (table): each included different populations with distinct routes of HIV transmission. For example, iPrEx4 was the first success for oral pre-exposure prophylaxis and focused on men who have sex with men. It is reasonable to assume that anal intercourse was the key route of transmission in the iPrEx trial,4 and was less frequently the source of HIV infection in the heterosexual women and men in the Fem-PrEP,7 VOICE,3 TDF2,5 and PIP6 studies. HIV acquisition is more efficient after anal intercourse,8 and more HIV variants are acquired during anal intercourse than cervicovaginal exposure.9
We have reported substantial differences in anti-retroviral drug concentrations in mucosal tissues.10–12 After oral administration of co-formulated TDF and FTC, there were 100-fold higher concentrations of tenofovir in rectal tissue compared with cervicovaginal tissue.12 Intracellularly phosphorylated tenofovir (TFV-DP) and emtricitabine (FTC-TP) are required to inhibit HIV replication.12 100-fold higher concentrations of TFV-DP were detected in the rectum as compared with cervix and vagina.12 Conversely, FTC-TP concentrations were 10–15 fold higher in vaginal and cervical tissue than in rectal tissue. Although we do not know the concentrations of TFV-DP and FTC-TP required to prevent HIV infection, the differences in tissue concentrations are substantial and suggest implications for HIV prevention. In the VOICE trial,3 the lack of protection with oral TDF could reflect low tissue concentrations of the drug. How, then, can we explain the protection provided by TDF in PIP6? It seems possible that HIV transmission in a discordant couple relationship might be prevented differently, or more readily. It is also possible, indeed likely, that adherence in a discordant relationship is better, resulting in a critical (currently unknown) tissue concentration being achieved. The protection from HIV observed with the TDF and FTC combination in TDF25 and PIP6 suggests an important role for higher FTC concentrations, perhaps in combination with the lower concentrations of tenofovir, in the female genital tract. The differences in benefit of 1% tenofovir gel in CAPRISA 0042 and VOICE3 demand further exploration; the studies used different dosage schedules, and women at different sites might differ in ways that affect study outcomes (table).
Adherence, however, will still determine the value of antiretroviral agents both in clinical trials and in clinical practice. In HPTN 0521 HIV viraemia was prospectively monitored in infected trial participants to ensure adherence, which allowed determination of the antiretrovirals’ ability to suppress transmission under ideal conditions. To date, the only prospective measurement of adherence in pre-exposure prophylaxis trials has been by self-report or pill counts, which might overestimate adherence.13 These values have then been compared to potential efficacy with post-hoc measurement of blood concentrations in a limited number of samples using a case-control design. In the iPrEx trial,4 the investigators used combined data to argue that pre-exposure prophylaxis was perhaps more than 90% protective in participants who took the treatment reliably. In CAPRISA 004,2 the effectiveness of protection was 52% with more than 80% adherence as measured retrospectively by evaluation of used gel applicators. But such retrospective analyses cannot be used to confirm the intervention’s success or failure. Less adherence to daily use of 1% tenofovir gel in VOICE3 could have compromised benefit relative to the coitally-driven use of the gel in CAPRISA 004.2 Paradoxically, daily use may confer a degree of difficulty that reduces adherence.
We believe that, before future pre-exposure prophylaxis studies are undertaken, knowledge of biological plausibility must be secure. Evidence of strong and durable tissue concentrations of active agents should be a condition of such studies taking place. Powerful antiviral agents limited in their tissue penetration, intracellular metabolism, or tissue half-life are not appropriate for pre-exposure prophylaxis. Moreover, adherence must be measured prospectively in future trials.14,15 Under these conditions trial participants who do not adhere to treatment can be counselled or the study analysis designed to incorporate these most rigorous measures of adherence. To predict success in clinical practice reliably, both the drug concentrations needed for protective efficacy and the best way to assess adherence in clinical trials must first be defined. Effectiveness trials that depend on adherence and many other factors—the real world—should await proof that antiretroviral agents work as anticipated.
ADMK has received research grants from Abbott Laboratories, GlaxoSmithKline, Jansen Pharmaceuticals, Merck, and Pfizer, and has received honoraria from Merck and Bristol-Myers Squibb. KBP has received research grants from Abbott Laboratories, GlaxoSmithKline, Jansen Pharmaceuticals, Merck, and Pfizer, and has also served on a women’s advisory board and as a consultant for Jansen Pharmaceuticals.
JBD and MSC declare that they have no conflicts of interest.