Introduction Antiretroviral pre-exposure prophylaxis (PrEP) reduces the incidence of acquisition of human immunodeficiency virus type 1 (HIV-1) in men who have sex with men and is a promising approach for preventing HIV-1 in heterosexual populations. Methods We conducted a randomized, three-arm trial of oral antiretroviral PrEP among heterosexual couples from Kenya and Uganda in which one member was HIV-1 seronegative and the other HIV-1 seropositive. Seronegative partners were randomly assigned to once-daily tenofovir (TDF), combination emtricitabine/tenofovir (FTC/TDF), or matching placebo and followed monthly for up to 36 months. At enrollment, HIV-1 seropositive partners were not eligible for antiretroviral therapy under national guidelines. All couples received standard HIV-1 treatment and prevention services, including individual and couples risk-reduction counseling and condoms. Results 4758 couples were enrolled; for 62%, the HIV-1 seronegative partner was male. For HIV-1 seropositive participants, the median CD4 count was 495 cells/μL (interquartile range 375–662). Of 82 post-randomization HIV-1 infections, 17 were among those assigned TDF (incidence 0.65 per 100 person-years), 13 among those assigned FTC/TDF (incidence 0.50 per 100 person-years), and 52 among those assigned placebo (incidence 1.99 per 100 person-years), indicating a 67% relative reduction in HIV-1 incidence for TDF (95% CI 44 to 81, p<0.001) and 75% for FTC/TDF (95% CI 55 to 87, p<0.001). HIV-1 protective effects of FTC/TDF and TDF were not significantly different (p=0.23), and both study medications significantly reduced HIV-1 incidence in both men and women. The rate of serious medical events was similar across the study arms. Conclusions Oral TDF and FTC/TDF provided substantial protection against HIV-1 acquisition in heterosexual men and women, with comparable efficacy of TDF and FTC/TDF. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number NCT00557245)

BACKGROUND Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, ≥250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P = 0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log10 copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2–positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log10 copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Summary Background Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. Methods We followed 3790 heterosexual HIV-1 serodiscordant couples from seven African countries participating in two longitudinal HIV-1 incidence studies. Among hormonal contraceptive users (including injectable and oral contraceptive users) and nonusers, we compared rates of HIV-1 acquisition in women and HIV-1 transmission from women to men. Findings Among 1314 couples in which the HIV-1 seronegative partner was female, HIV-1 acquisition rates were 6.61 and 3.78 per 100 person-years among hormonal contraceptive users and nonusers (adjusted hazard ratio [AHR]=1.98, 95% confidence interval [CI] 1.06–3.68, p=0.03). Among 2476 couples in which the HIV-1 seronegative partner was male, HIV-1 transmission rates from women to men were 2.61 and 1.51 per 100 person-years in those whose partners currently used versus did not use hormonal contraception (AHR=1.97, 95% CI 1.12–3.45, p=0.02). In subgroup analysis, injectable contraceptive users had increased risk for acquiring and transmitting HIV-1 to their partner and HIV-1 seropositive women using injectable contraception had higher genital HIV-1 RNA concentrations, suggesting a mechanism for increased transmission risk. Oral contraceptives were used too infrequently to draw definitive conclusions about HIV-1 risk. Interpretation Women should be counseled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, particularly injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or lower-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. Funding National Institutes of Health (R03 HD068143, R01 AI083034, P30 AI027757, and T32 AI007140) and the Bill and Melinda Gates Foundation (26469 and 41185).

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High plasma HIV-1 RNA concentrations are associated with an increased risk of HIV-1 transmission. Although plasma and genital HIV-1 RNA concentrations are correlated, no study has evaluated the relationship between genital HIV-1 RNA and the risk of heterosexual HIV-1 transmission. In a prospective study of 2521 African HIV-1 serodiscordant couples, we assessed genital HIV-1 RNA quantity and HIV-1 transmission risk. HIV-1 transmission linkage was established within the partnership by viral sequence analysis. We tested endocervical samples from 1805 women, including 46 who transmitted HIV-1 to their partner, and semen samples from 716 men, including 32 who transmitted HIV-1 to their partner. Genital and plasma HIV-1 concentrations were correlated: For endocervical swabs, Spearman’s rank correlation coefficient rho was 0.56 (p<0.001), and for semen rho was 0.55 (p<0.001). Each 1 log10 increase in genital HIV-1 RNA was associated with a 2.20-fold (for endocervical swabs, 95% confidence interval 1.60–3.04, p<0.001) and a 1.79-fold (for semen, 95% confidence interval 1.30–2.47, p<0.001) increased risk of HIV-1 transmission. Genital HIV-1 RNA independently predicted HIV-1 transmission risk after adjusting for plasma HIV-1 quantity (hazard ratio 1.67 for endocervical swabs and 1.68 for semen). Seven female-to-male and four male-to-female HIV-1 transmissions (incidence <1% per year) occurred from persons with undetectable genital HIV-1 RNA, but in all eleven plasma HIV-1 RNA was detected. Thus, higher genital HIV-1 RNA concentrations are associated with greater risk of heterosexual HIV-1 transmission, and this effect was independent of plasma HIV-1 concentrations. These data suggest that HIV-1 RNA in genital secretions could be used as a marker of HIV-1 sexual transmission risk.

National Institute of Child Health and Human Development.

Summary Background Observational and laboratory studies suggest that some hormonal contraceptive methods, particularly intramuscular depot medroxyprogesterone acetate (DMPA-IM), might increase women's susceptibility to HIV acquisition. We aimed to compare DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant among African women seeking effective contraception and living in areas of high HIV incidence. Methods We did a randomised, multicentre, open-label trial across 12 research sites in eSwatini, Kenya, South Africa, and Zambia. We included HIV-seronegative women aged 16–35 years who were seeking effective contraception, had no medical contraindications to the trial contraceptive methods, agreed to use the assigned method for 18 months, and reported not using injectable, intrauterine, or implantable contraception for the previous 6 months. Participants were randomly assigned (1:1:1) to receive an injection of 150 mg/mL DMPA-IM every 3 months, a copper IUD, or a LNG implant with random block sizes between 15 and 30, stratified by site. Participants were assigned using an online randomisation system, which was accessed for each randomisation by study staff at each site. The primary endpoint was incident HIV infection in the modified intention-to-treat population, including all randomised participants who were HIV negative at enrolment and who contributed at least one HIV test. The primary safety endpoint was any serious adverse event or any adverse event resulting in method discontinuation, until the trial exit visit at 18 months and was assessed in all enrolled and randomly assigned women. This study is registered with ClinicalTrials.gov , number NCT02550067 . Findings Between Dec 14, 2015, and Sept 12, 2017, 7830 women were enrolled and 7829 were randomly assigned to the DMPA-IM group (n=2609), the copper IUD group (n=2607), or the LNG implant group (n=2613). 7715 (99%) participants were included in the modified intention-to-treat population (2556 in the DMPA-IM group, 2571 in the copper IUD group, and 2588 in the LNG implant group), and women used their assigned method for 9567 (92%) of 10 409 woman-years of follow-up time. 397 HIV infections occurred (incidence 3·81 per 100 woman-years [95% CI 3·45–4·21]): 143 (36%; 4·19 per 100 woman-years [3·54–4·94]) in the DMPA-IM group, 138 (35%: 3·94 per 100 woman-years [3·31–4·66]) in the copper IUD group, and 116 (29%; 3·31 per 100 woman-years [2·74–3·98]) in the LNG implant group. In the modified intention-to-treat analysis, the hazard ratios for HIV acquisition were 1·04 (96% CI 0·82–1·33, p=0·72) for DMPA-IM compared with copper IUD, 1·23 (0·95–1·59, p=0·097) for DMPA-IM compared with LNG implant, and 1·18 (0·91–1·53, p=0·19) for copper IUD compared with LNG implant. 12 women died during the study: six in the DMPA-IM group, five in the copper IUD group, and one in the LNG implant group. Serious adverse...

The HIV acquisition probability per condomless sex act steadily increased during pregnancy and was highest during the postpartum period, suggesting that biological changes during pregnancy and the postpartum period increase HIV susceptibility among women.