Once-daily oral FTC–TDF provided 44% additional protection from HIV among men or transgender women who have sex with men who also received a comprehensive package of prevention services. The protective effect of FTC–TDF was significant but not as high as originally hypothesized during the design of the study. Although reported pill use was high, drug exposure that was measured objectively was substantially lower. The intracellular assay that was used in this study is expected to detect TFV-DP for 14 days or more after the last dose of TDF is taken (see Methods in the Supplementary Appendix
). Other evidence of low drug exposure included the lack of drug resistance observed among emergent infections and the absence of suppression of the HIV RNA level in plasma at the seroconversion visit. There was no evidence of delayed seroconversion among subjects who were infected in the FTC–TDF group. More information will be available after the entire cohort stops receiving the study drug.
The estimate of biologic activity of FTC–TDF persists after adjustment for high-risk sexual practice, suggesting that the correlation between drug detection and protection is primarily due to the drug and not to other characteristics of subjects that may link poor adherence with higher risk. The testing of a larger number of specimens, from more subjects at more times, is needed to better define the minimum protective drug concentration. Protective drug levels may differ according to the type of exposure (rectal vs. penile). Drug level may have a role in monitoring trials, programs, and individual users. Methods for inexpensively measuring long-term drug exposure, such as that afforded by analysis of hair,19
would be helpful once such a method is fully validated.
Side effects may have contributed to low pill use among some subjects. As with treatment of HIV infection and the use of FTC–TDF in post-exposure prophylaxis,20
the initiation of FTC–TDF preexposure prophylaxis was associated with self-limited start-up symptoms in a few subjects. The trial design involving a placebo may also have contributed to lower-than-expected pill use. All subjects were counseled that the study pill might be a placebo or an active drug having no proven benefit. Open-label research and program development could provide users with clearer information about expected benefits and risks, which might increase the use and efficacy of preexposure prophylaxis. Engagement with communities and additional behavioral research are needed to develop methods of counseling that better support such use.
The initiation of chemoprophylaxis either before or after exposure should be deferred in patients with signs or symptoms of a viral syndrome, which are often present during acute HIV infection.21,22
The initiation of postexposure prophylaxis in patients who are RNA-positive but antibody-negative has been linked with acquisition of resistance to FTC and lamivudine (3TC),5
as occurred in subjects in the FTC–TDF group who were already infected at enrollment in our trial. Ways to increase recognition of acute HIV infection would include routine measurement of body temperature and testing for HIV antibodies to evaluate viral syndromes, regardless of whether the presentation suggests HIV infection or another cause. Testing for HIV RNA at the time of the initiation of preexposure prophylaxis should be considered where available.
TDF treatment is known to cause decreases in renal function,23
and there were trends toward more creatinine elevations in the FTC–TDF group than in the placebo group. Most creatinine elevations were self-limited and were not confirmed on repeat testing of a new specimen, as might occur due to dehydration, creatine use, or exercise. The ability to detect safety outcomes, including drug resistance, may have been decreased by lower-than-expected drug exposure. In light of evidence of the efficacy of FTC–TDF, more information is needed about possible subclinical effects that may affect bone mineral density, low-level drug resistance, and proximal renal tubular function. Flares of hepatitis caused by HBV after stopping preexposure prophylaxis with TDF were not seen in West African women,12
but more information is needed. These issues are being investigated in existing trials of preexposure prophylaxis.
Reported high-risk behavior decreased substantially after enrollment and remained lower than at baseline during the trial. Safer behavior was also observed in a trial of preexposure prophylaxis with TDF in West African women12
and may reflect the services (e.g., counseling, testing, and dispensing of condoms) that are provided as part of such interventions. In addition, taking a pill a day may have served as a daily reminder of imminent risk and may have promoted planning for sex, which has been associated with lower HIV risk.24
Behavioral changes during future open-label use of preexposure prophylaxis may differ because of an increased expectation of benefits, although such “risk compensation” was not observed during an open-label study of postexposure prophylaxis, during which benefits were expected.25
The optimal regimen for preexposure prophylaxis has not been established, and data from the subjects in our study cannot be applied to other populations. Alternative regimens in different populations are being studied. (Details are available in the Discussion in the Supplementary Appendix
and at www.avac.org
In our study, preexposure prophylaxis with oral FTC–TDF among men and transgender women who have sex with men addressed an important unmet need in public health. HIV prevalence is higher in this population than in other groups in almost all countries.14
In the United States, rates of HIV infection among such men and transgender women have climbed since the early 1990s, affecting in particular black and Hispanic subpopulations.26
Intensive counseling in behavioral risk reduction for such subjects has not been shown to be better than standard counseling.27
Although male circumcision partially protects heterosexual men,28–30
penile circumcision is not expected to protect those who are exposed on the rectal mucosa.31
Heterosexual women were partially protected by tenofovir 1% vaginal gel,13
but the safety and utility of tenofovir topical gels for rectal use is not yet known. In the FTC–TDF group, there was increased efficacy among subjects who reported having unprotected receptive anal intercourse, which is the main mode of HIV transmission among the subjects in our study and increases the risk of heterosexual women who engage in the practice.32
We showed that such subjects with a high risk of exposure to HIV can be mobilized to participate in prevention initiatives and that preexposure prophylaxis is effective for slowing the spread of HIV in this population.