In this study of heterosexual men and women with a partner known to have HIV-1 infection, once-daily oral TDF and TDF–FTC were associated with risk reductions of 67% and 75%, respectively, against HIV-1 infection when provided in conjunction with other HIV-1 prevention services. Both TDF and TDF–FTC showed significant, and a similar magnitude of, HIV-1 protection for both women and men.

Clinical trials of tenofovir-based preexposure prophylaxis have had conflicting results. Once-daily oral TDF–FTC reduced the risk of HIV-1 acquisition by 44% in a multicountry study among men who have sex with men and by 62% among young heterosexuals from Botswana,20,21 and the use of 1% tenofovir vaginal gel decreased the incidence of HIV-1 among South African women by 39%.22 Biologic and behavioral hypotheses have been proposed to explain the failure of two trials of preexposure prophylaxis among African women to show protection against HIV-1 infection,23,24 including a lack of adherence to daily doses of preexposure prophylaxis, vaginal concentrations of tenofovir achieved with oral dosing that may be particularly sensitive to nonadherence,25 sexually transmitted infections or other cofactors affecting infection with HIV-1 in young women, high HIV-1 concentrations in the seropositive partner during primary HIV-1 infection, and innate or acquired immunologic factors that may provide adjunctive protection in long-term couples with HIV-1 serodiscordance. Further study is needed to understand which, if any, of these factors influence the efficacy of preexposure prophylaxis.

Although we studied established couples known to be HIV-1–serodiscordant, all HIV-1 transmissions ultimately occur between serodiscordant partners. Our findings provide proof of concept that preexposure prophylaxis can reduce HIV-1 acquisition in heterosexual populations.

High adherence is essential to achieve clinical benefits from antiretroviral agents for HIV-1 treatment,26 and emerging evidence suggests that adherence to preexposure prophylaxis is also important for HIV-1 prevention. In the Preexposure Prophylaxis Initiative trial involving men who have sex with men, the relative reduction in the risk of HIV-1 infection from TDF–FTC preexposure prophylaxis was 44% overall but was 73% among the participants with an adherence of 90% or more (as measured by means of pill counts) and 92% among the participants with detectable tenofovir levels in the blood — although only half the participants had detectable levels.20

In our study, retention and pill-count adherence were high, tenofovir was detected in 82% of samples from randomly selected participants, and detectable tenofovir levels were associated with a reduction in the relative risk of HIV-1 infection of more than 85%. The high proportion of samples with detectable tenofovir levels is consistent with the 92% study-drug coverage we calculated on the basis of missed visits, withholding of the study drug, and nonadherence, with the absolute difference of 10 percentage points most likely reflecting the fact that pill counts can overestimate adherence if pills are not returned.

Analyses of objective adherence measures across preexposure prophylaxis trials will be informative for understanding the relationship between adherence and protection against HIV-1 infection. In a subgroup of our study cohort, intensive monitoring of adherence by means of pill bottles with caps that electronically monitor bottle openings and monthly unannounced visits to the home for purposes of pill counting supported high adherence,27 and in-depth interviews have emphasized that trust and the support of a partner reinforce high adherence.28 Strategies to promote and achieve high adherence outside clinical-trial settings will be necessary to achieve maximum public health benefits of preexposure prophylaxis.

We found similar degrees of protection against HIV-1 with TDF and TDF–FTC, in contrast to findings in studies of animal models.11 Dual-agent preexposure prophylaxis would most likely be more expensive than single-agent preexposure prophylaxis, and the potential for differential tolerability and antiretroviral resistance in persons with HIV-1 seroconversion despite the use of preexposure prophylaxis should be considered in decision making with regard to public health policies regarding preexposure prophylaxis. We are continuing the TDF and TDF–FTC groups of our study, including offering randomization to TDF or TDF–FTC to participants originally assigned to the placebo group, to gather additional information on the relative safety, efficacy, and HIV-1 resistance of TDF as compared with TDF–FTC.

In our study, 25% (two of eight) of participants who had acute HIV-1 infection at the time of study-drug initiation had viral resistance develop (through the M184V mutation in one and the K65R mutation in the other). The initiation of preexposure or postexposure prophylaxis in persons with acute HIV-1 infection can select for resistance; strategies to improve the recognition of acute infection are needed.20,29,30 Resistance was rare in partners in whom seroconversion occurred after randomization, of whom a minority had detectable tenofovir levels.

Adherence to preexposure prophylaxis, protection against HIV-1 infection, and antiretroviral resistance appear to be tightly interwoven. Low adherence provides little HIV-1 protection but little risk of resistance if infection is acquired. High adherence potentially blocks most transmissions, and the few persons who acquire HIV-1 despite preexposure prophylaxis potentially have an increased risk of drug resistance. Four participants with HIV-1 seroconversion in our study became infected with HIV-1 that was resistant to nonnucleoside reverse-transcriptase inhibitors, which should not have been selected for by the study medication and instead probably reflects circulating resistance, which is increasingly being detected in Africa.31

When used for HIV-1 treatment, TDF is known to cause small decreases in glomerular filtration that are of uncertain clinical significance.32 In our population of HIV-1–seronegative participants without preexisting renal impairment, we found no evidence of clinically significant elevations in serum creatinine. Additional studies are needed of proximal renal tubular function, bone mineral density, and other aspects of long-term safety of TDF-based preexposure prophylaxis, as well as safety in pregnant, breast-feeding, or adolescent women, among whom HIV-1 rates are high.33,34

For couples known to have HIV-1 serodiscordance, antiretroviral treatment of the partner infected with HIV-1 provides substantial, though incomplete, protection against HIV-1 transmission; 25 to 30% of HIV-1 infection in serodiscordant couples are from infected partners outside the couple.5,7 Mathematical modeling may help guide policy decisions regarding optimal targeting and timing of treatment and preexposure prophylaxis for reducing HIV-1 incidence in couples.35 Antiretroviral-based HIV-1–prevention strategies may be particularly important for couples seeking to have children.36-38 In addition, preexposure prophylaxis offers an HIV-1 prevention strategy for uninfected persons with partners who do not know their HIV-1 status or who are infected with HIV-1 but have not begun antiretroviral therapy.

Successful prevention of HIV-1 infection on a population scale will need to incorporate multiple, evidence-based biomedical and behavioral strategies to achieve maximum benefits. The HIV-1 incidence in this study was lower than that seen in previous studies of HIV-1–serodiscordant African couples,14,39 emphasizing the importance of and synergy among HIV-1 testing in individuals and couples, risk-reduction counseling, and other prevention services, in combination with antiretroviral preexposure prophylaxis, for reducing the risk of HIV-1 infection in heterosexual populations. Potential implementation of preexposure prophylaxis as a public health measure will require clinical monitoring, methods for encouraging adherence, and ensured access to antiretroviral therapy for HIV-1–infected persons. Nonetheless, to stem the global HIV-1 epidemic, effective primary HIV-1 prevention strategies are critical.