During the last two years, the scientific community documented the efficacy of ART to prevent sexual transmission. The quantity of HIV in plasma and genital secretions is the prime determinant of HIV transmission risk and initiation of ART in HIV-infected individual’s results in early and sustained reductions in plasma and genital HIV levels [31
]. Therefore, it was hypothesized that treating HIV-infected individuals with antiretroviral medications reduces their infectiousness and risk of transmission to partners.
In Pre-Exposure Prophylaxis (PrEP), an HIV-uninfected individual uses an antiretroviral medication prior to an HIV exposure. By having therapeutic levels of the antiretroviral medication already in their blood and tissues, PrEP may prevent HIV from establishing infection, analogous to prophylaxis for malaria in travelers. There are several published observational studies documenting the use of ART in preventing transmission of HIV in discordant couples [32
]. Tenofovir-based PrEP use either with tenofovir (TDF) alone or in combination with emtricitabine (TDF/FTC) sold under the trade name Truvada®
is a daily oral pill with broad and potent activity against all HIV subtypes with favorable safety and tolerability.
To date, five important PrEP trials have been completed. The first two trials included the Centre for the AIDS Program of Research in South Africa 004 trial (CAPRISA004), which tested pericoitally applied 1% tenofovir (TDF) vaginal gel among 889 South African young sexual active women [33
], and the PreExposure Prophylaxis Initiative (iPrEx) trial, which evaluated daily oral TDF/FTC among 2,499 men who have sex with men and transgender women from six countries (US, Brazil, Ecuador, Peru, South Africa, and Thailand) [34
]. In CAPRISA 004, TDF gel reduced HIV acquisition risk by 39% (95% Confidence Interval [CI]: 6–60%; P=0.017). In iPrEx, oral TDF/FTC reduced HIV risk by 44% (95% CI, 15–63%; P=0.005). In both trials, protection against HIV was substantially higher among those with high ART adherence: 54% efficacy in CAPRISA 004 among participants with >80% adherence and 73% efficacy in iPrEx for participants with >90% adherence. These results clearly demonstrate that the success of PrEP as a public health intervention will necessitate monitoring ART adherence and interventions to improve or maintain adherence to optimal levels.
Five months after the announcement of iPrEx’s promising results, a large trial of oral preexposure prophylaxis in women 18–35 years of age in South Africa, Kenya, and Tanzania called FEM-PrEP was closed in April 2011 due to futility [35
]. At the time the study was stopped, 2120 HIV-uninfected African women were enrolled, with 68 incident infections, 33 in the TDF/FTC arm and 35 among placebo recipients. Use of TDF/FTC was associated with increased gastro-intestinal side effects but not increased creatinine levels. Poor adherence seemed the likely explanation for non-efficacy since patient self-reported adherence (around 95%) and pill count (around >85%) were discrepant with drug levels assessed in a subset of patients, showing that detectable TDF levels were seen only in <40% of those tested, and <30% among those randomized to active drug. It was clear that with this low level of adherence, it would have been impossible for this study to demonstrate any efficacy of TDF/FTC for HIV prevention in this study population. At the same time, the data underscored the importance of adherence as well as the difficulty in making accurate assessments of therapy-taking behaviour. In late 2011, the assessment of oral and vaginal tenofovir in the Microbicide Trial Network (MTN)-003 trial called VOICE (Vaginal and Oral Interventions to Control the Epidemic) was stopped for futility [36
] in Uganda, Zimbabwe and South Africa but the TDF/FTC versus placebo arm are still ongoing () and results are expected in 2013. Final results about why oral and vaginal tenofovir did not show efficacy in VOICE are not known fully understood yet, but it is likely that low adherence played a crucial role as well.
PrEP Trials Efficacy Results and Levels of Adherence.
The results of two other PrEP trials were announced in July 2011 at the international AIDS Society Conference in Rome. Both showed efficacy higher than the iPrEx trial. The TDF2 study compared TDF/FTC against placebo in 1,200 heterosexual men and women (600 per arm) in Francistown, Botswana, one of the world’s highest-prevalence locations for HIV. In the primary analysis, there were nine HIV infections among the 601 participants who received TDF/FTC and 24 among the 599 who received placebo, translating into a statistically significant 62.6% (95% CI 20.3% to 82.5%) reduction in infections. Of note, a secondary analysis excluding infections that occurred among participants who had run out of their pills and who had not taken one for at least 30 days showed 77.9% fewer infections in people taking TDF/FTC [37
]. The Partners for PrEP Trial took place in Kenya and Uganda. It recruited 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group, 13 in the TDF-FTC group, and 52 in the placebo group, a relative reduction of 67% in the incidence of HIV-1 with TDF (95% CI: 44 – 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55–87; P<0.001). Of note, protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23) [38
There is a clear relationship between PrEP adherence use and HIV protection in all five clinical trials. Divergent PrEP trial results appear to be correlated with PrEP adherence behaviors (). A clear premise is that PrEP cannot work if it is not taken and there is a clear dose-response between evidence of PrEP use and efficacy. When PrEP was taken as prescribed and detected in blood, protection was very high (). Of note, overall, relatively low adherence levels were observed in the iPrEx and FEM-PreP trials. Yet evidence of benefit was found in the former. This observation may suggest that Truvada is more forgiving of imperfect use for rectal rather than vaginal exposure to HIV, possibly due to differential concentration of the active drug in rectal compared to vaginal tissues [34
Adherence as Evaluated by Blood Concentrations and Efficacy in PrEP Trials.
Risk perceptions seem to play a potential powerful driver of adherence in PrEP studies. Adherence counseling was offered to both partners in the Partners for PrEP trial, and overall, high levels of adherence was documented in this trial using intensive adherence monitoring and followed by an intervention for participants with less than 80% adherence [39
]. Qualitative data by Ware and colleagues suggest that trust and commitment within the partnership were critical for supporting adherence in this study [40
]. Known HIV+ partner, ongoing exposure, and a decision to maintain relationship, were all associated with high adherence. In FEM-PrEP which enrolled young women, about 70% perceived themselves to be at little or no HIV risk, and had documented very low adherence. In iPrEx, men who practiced unprotected receptive anal intercourse had higher PrEP use than other men, and received highter HIV protection (58% in subgroup efficacy). Men not having sex were least likely to take PrEP. Of note, there was no evidence of risk compensation in these PrEP clinical trials. Understanding the interface of risk perception and HIV prevention is key for any strategy. Also, it is important to consider the temporal patterns of adherence and sexual exposure such as isolated lapses combined with high-risk sexual exposures can lead to transmission, while low adherence confers little risk in the absence of sexual exposure [41
]. Finally, in addition to non-adherence, variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection have been reported as potential explanations for divergent PrEP trial results to date [41