In this substudy of adherence nested within a randomized clinical trial of PrEP among African HIV serodiscordant couples, where participants received a combination of both adherence monitoring and intensive counseling when adherence dropped below 80%, adherence to PrEP was high by two objective, validated measures and efficacy of PrEP was 100% (95% CI 83.7%–100%). Because high adherence is a prerequisite for measured efficacy to approximate biologic efficacy 
, these results provide confidence in the high efficacy estimate for protection against HIV found in the larger Partners PrEP Study. The lack of seroconversions among the adherence study participants randomized to PrEP provides further support that PrEP is highly efficacious against HIV acquisition among highly adherent PrEP users.
Despite the overall high levels of adherence, adherence <80% was observed at some point during a quarterly follow-up interval in as many as 25.8% of participants over an average of 11.3 mo of follow-up. Sexual behavior was closely associated with PrEP adherence. Those participants who reported not having sex were less likely to adhere to PrEP during that study quarter than those reporting sex, presumably because they did not perceive themselves to be at risk during periods of no sexual activity. Similarly, participants who reported having sex with another partner (with or without having sex with the primary partner) may perceive themselves to be at lower risk, especially if their outside partner is known to be HIV-uninfected. Additionally, partners within a formal polygamous marriage were more likely to adhere, suggesting a desire to reduce the risk of HIV acquisition within multiple stable and committed partnerships.
Younger age and heavy alcohol use in the HIV-uninfected partner were associated with a greater likelihood of low PrEP adherence; these factors are well established as being associated with lower adherence to antiretroviral treatment in HIV-infected people 
. The finding of higher adherence in the first 6 mo of use may reflect initial enthusiasm for a novel prevention method that may be challenging to sustain over time. Waning adherence patterns have been seen with daily oral contraceptive pills 
and strategies to maintain good adherence over time may be needed.
Adherence counseling, both in the routine sessions and in the adherence intervention, may have played a role in the high adherence seen in this study. Adherence for most participants did increase after the intervention, although the study was not designed to assess the efficacy of the intervention. Implementation challenges, however, may influence the extent of counseling to be provided as PrEP becomes available in demonstration projects and ultimately clinical care. Further research should focus on identifying key adherence counseling messages, standardized approaches for providing appropriate counseling within the “real world” context, and the cost-effectiveness of adherence interventions. Identifying appropriate counseling approaches will be critical to ensure the behavioral success of this biological agent for HIV prevention.
Adherence is difficult to compare among the PrEP clinical trials that lack comparable measures of adherence behavior. That said, our data and previously reported data suggest that the degree of HIV protection is highly correlated with adherence. The highest levels of PrEP efficacy have been reported for the HIV serodiscordant couples in the Partners PrEP Study with 75% protection from FTC/TDF and 67% from TDF 
. In the TDF-2 study, FTC/TDF conferred 62% protection in young, heterosexual men and women from Botswana who were recruited regardless of their partner's serostatus 
, and the iPrEX study found 44% protection against HIV infection from FTC/TDF among men who have sex with men 
. The degree of protection and corresponding adherence may be the highest in the Partners PrEP Study because the HIV-uninfected partner taking PrEP received a higher level of adherence support from his or her HIV-infected partner and both partners recognized the risk of HIV transmission 
. Given that up to 20% of couples in sub-Saharan Africa are serodiscordant 
, this population may be an ideal target for initial PrEP implementation strategies. Counseling of the couple, or another identified support partner for individuals taking PrEP outside of a partnership, may be a key factor for the success of PrEP beyond clinical trials. It is important to note, however, that fewer than 40% of individuals living with HIV know their serostatus 
. Further efforts will therefore be needed to scale up counseling and testing services to identify serodiscordant couples.
The strengths of this study include the use of two objective behavioral adherence measures; a large sample size; a robust set of socio-demographic, biological, and behavioral factors potentially associated with adherence; and the availability of HIV seroconversion data within a clinical trial. This study also has important limitations. First, no adherence measure is perfect. Although UPC and MEMS are significantly correlated and both indicate high adherence, UPC is consistently somewhat higher than MEMS. This relationship suggests systematic biases, which have been similarly reported in the literature 
. We believe this difference primarily reflects the removal of multiple doses from the MEMS pill bottle during a single opening, as may occur when an individual travels without their pill bottle (often due to inconvenience and/or stigma) 
. Pills lost in between pill counts may also contribute to misclassification. Pill sharing could also contribute to misclassification; however, there was no self-reported pill sharing in this substudy. While social desirability may cause such self-report to be an underestimate, the high efficacy reported here and in the clinical trial would be hard to achieve with widespread pill sharing (see Baeten et al., supplementary materials) 
. True adherence likely lies somewhere in between the two measurements. Second, due to the small numbers of participants with low adherence as measured by UPC, the power to identify factors associated with that measure of adherence was limited. Factors such as abuse may also be underreported and therefore difficult to identify. Third, this substudy was conducted within a blinded randomized controlled trial and recruitment was performed without regard to study arm. Although there were some differences in the baseline participant characteristics between the adherence substudy and the clinical trial, these differences were relatively minor, especially when data are restricted to those sites at which the substudy took place, and no meaningful differences were seen across the study arms. It is, however, possible that these differences influenced the efficacy estimate. Finally, the 80% threshold may or may not reflect the optimal level of adherence for protection against HIV acquisition. This study cannot assess whether non-adherence correlated with HIV infection because no individuals in the treatment groups became infected.
Identifying participants with <80% adherence for intensification of adherence counseling may have played an important role in achieving high efficacy in this adherence study. However, timely identification of adherence problems in general is a challenge even within clinical trials. Incomplete adherence is typically detected weeks to months after it occurs, which in the case of PrEP may result in seroconversion. Real-time adherence monitoring has recently been shown to be feasible within developing settings 
. If affordable, such monitoring could be used to identify people taking PrEP for targeted, enhanced adherence support.
In summary, we found both high levels of adherence and a high degree of protection against HIV infection in a substudy within a clinical trial of oral PrEP using two objective and validated measures of adherence. These data provide further support that PrEP is highly efficacious at preventing HIV acquisition when it is taken. Our data also suggest that future development of risk reduction strategies and adherence interventions in the implementation setting should address sexual behavior, risk perception, and heavy alcohol use, especially for young PrEP takers and prolonged PrEP use. Proper support and assessment of adherence will be critical for determining efficacy of PrEP outside of clinical trials. This data will be important for guiding ethical decisions about resource allocation for both prevention and treatment of HIV.