In this study, there was no significant reduction in HIV acquisition among women in the TDF–FTC group, as compared with the placebo group. Drug-level analyses revealed that less than 40% of the HIV-uninfected women had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion. If such low adherence levels prevailed for the entire cohort, the trial was substantially underpowered to detect an effect of TDF–FTC on the risk of HIV acquisition. Although women in the TDF–FTC group had higher rates of some known side effects than those in the placebo group, the prevalence of these events was modest and consistent with the overall low adherence. However, the rate of adverse events might have been higher if the level of adherence had been higher.
Relatively low adherence levels were also observed in the case–control analysis in the Preexposure Prophylaxis Initiative study involving men who have sex with men,9
in which tenofovir was detected in 44% of the uninfected controls. This finding might indicate that TDF–FTC is more forgiving of imperfect use with rectal exposure to HIV than with vaginal exposure, possibly because of a difference in concentrations of the active metabolites in rectal and vaginal tissues after oral administration.10
In the Partners Preexposure Prophylaxis study,2,11
there was a highly significant protective effect of both TDF and TDF–FTC in the overall study population and among female participants. Among uninfected controls, drug-level analyses revealed adherence rates of 81% in the TDF–FTC group and 83% in the TDF group. Thus, if there are biologic differences between drug responses in men and those in women or between HIV exposure with vaginal and rectal sex, it appears that these differences may be overcome with high rates of adherence.
In the Vaginal and Oral Interventions to Control the Epidemic (VOICE, or MTN-003) trial among women,12
treatment with daily oral TDF was stopped early because of a lack of effectiveness, a finding that is similar to ours for TDF–FTC and that contrasts with the findings for both TDF and TDF–FTC in the Partners Preexposure Prophylaxis study. One of the hypotheses is that low adherence may have played a role. In the VOICE trial, participants continue to receive daily oral TDF–FTC.
It is important to understand why so many women came for the monthly visits and underwent frequent blood testing but did not take their pills. We hypothesize that the women’s perception that they were at low risk for HIV infection may have contributed to the poor adherence. In addition, the high pregnancy rate among women receiving oral contraceptives may indicate difficulty with daily pill regimens. Understanding these issues and identifying characteristics predictive of high adherence will be important in developing strategies for adherence counseling for future studies and programs.
Self-reported behaviors and data regarding the prevalence of sexually transmitted infections do not suggest increased risk behavior among women in the TDF–FTC group. Although there were slightly higher rates of study-drug discontinuation owing to adverse events in the TDF–FTC group, the percentage of days on which women had a study drug available for use was high in the two groups.
There were no major safety concerns in the trial, although low adherence may have compromised our ability to identify a safety concern or an effect on the CD4+ T-cell count and viral load in participants with seroconversion. Five participants had HIV infections that were resistant to FTC, one of them in the placebo group. Among these five participants, one in the TDF–FTC group had not received the study drug for 48 weeks because of early toxicity, leaving three cases of resistant infection in the TDF–FTC group among participants who may have had access to the study drug around the time of acquiring the infection. Sero-conversion was discovered in these three participants within 12 weeks after enrollment. Thus, despite intensive testing, we cannot definitively rule out the possibility that the participants were already infected at enrollment.
It has been suggested that the use of TDF–FTC may mask HIV infection by modifying the viral load and antibody production. However, the similarity in the rates of HIV infection in the two study groups after study-drug discontinuation is not consistent with this concern.
Although we suspect that the lack of efficacy of TDF–FTC in our study population was due to low adherence, biologic factors may also be involved. The protective effect of TDF–FTC might be diminished in the presence of a very high viral load in the infecting partner, as occurs in the acute phase of HIV infection. Another possible reason for the lack of efficacy of TDF–FTC is a high cytokine level. It has been reported that the effect of vaginal tenofovir 1% gel may be lower in women with an elevated vaginal cytokine profile.13
Our trial has several limitations. The low adherence impairs our ability to make clear conclusions regarding the effectiveness and safety of TDF–FTC in the study population. In addition, 13% of the participants were lost to follow-up. Although we were able to document that a third of these women had relocated outside the study area, the absence of HIV testing at the final visit means that we cannot rule out the possibility that a difference in rates of HIV acquisition existed between the two study groups among those who were lost to follow-up.
In conclusion, prophylaxis with TDF–FTC did not reduce the rate of HIV infection and was associated with increased rates of side effects, as compared with placebo. However, we were unable to accurately assess the effect of TDF–FTC on HIV acquisition or safety because of low study-drug adherence, which may be an indication that a daily pill-taking regimen will be difficult for some populations. A better understanding of indicators of adherence among women at high risk for HIV infection is needed to ensure the effectiveness of future preexposure prophylaxis programs.