Edwin Were

Antiretroviral Prophylaxis for HIV Prevention in Heterosexual Men and Women

BACKGROUND Antiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations. METHODS We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services. RESULTS We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study. CONCLUSIONS Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.).

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

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, > or = 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 log(10) 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 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study.

BACKGROUND Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear. We aimed to assess the association between hormonal contraceptive use and risk of HIV-1 acquisition by women and HIV-1 transmission from HIV-1-infected women to their male partners. METHODS In this prospective study, we followed up 3790 heterosexual HIV-1-serodiscordant couples participating in two longitudinal studies of HIV-1 incidence in seven African countries. Among injectable and oral hormonal contraceptive users and non-users, we compared rates of HIV-1 acquisition by women and HIV-1 transmission from women to men. The primary outcome measure was HIV-1 seroconversion. We used Cox proportional hazards regression and marginal structural modelling to assess the effect of contraceptive use on HIV-1 risk. FINDINGS Among 1314 couples in which the HIV-1-seronegative partner was female (median follow-up 18·0 [IQR 12·6-24·2] months), rates of HIV-1 acquisition were 6·61 per 100 person-years in women who used hormonal contraception and 3·78 per 100 person-years in those who did not (adjusted hazard ratio 1·98, 95% CI 1·06-3·68, p=0·03). Among 2476 couples in which the HIV-1-seronegative partner was male (median follow-up 18·7 [IQR 12·8-24·2] months), rates of HIV-1 transmission from women to men were 2·61 per 100 person-years in couples in which women used hormonal contraception and 1·51 per 100 person-years in couples in which women did not use hormonal contraception (adjusted hazard ratio 1·97, 95% CI 1·12-3·45, p=0·02). Marginal structural model analyses generated much the same results to the Cox proportional hazards regression. INTERPRETATION Women should be counselled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, especially injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or low-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1. FUNDING US National Institutes of Health and the Bill & Melinda Gates Foundation.

Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples.

Background:Physiologic and behavioral changes during pregnancy may alter HIV-1 susceptibility and infectiousness. Prospective studies exploring pregnancy and HIV-1 acquisition risk in women have found inconsistent results. No study has explored the effect of pregnancy on HIV-1 transmission risk from HIV-1-infected women to male partners. Methods:In a prospective study of African HIV-1-serodiscordant couples, we evaluated the relationship between pregnancy and the risk of HIV-1 acquisition among women and HIV-1 transmission from women to men. Results:Three thousand three hundred and twenty-one HIV-1-serodiscordant couples were enrolled, 1085 (32.7%) with HIV-1 susceptible female partners and 2236 (67.3%) with susceptible male partners. HIV-1 incidence in women was 7.35 versus 3.01 per 100 person-years during pregnant and nonpregnant periods [hazard ratio 2.34, 95% confidence interval (CI) 1.33–4.09]. This effect was attenuated and not statistically significant after adjusting for sexual behavior and other confounding factors (adjusted hazard ratio 1.71, 95% CI 0.93–3.12). HIV-1 incidence in male partners of infected women was 3.46 versus 1.58 per 100 person-years when their partners were pregnant versus not pregnant (hazard ratio 2.31, 95% CI 1.22–4.39). This effect was not attenuated in adjusted analysis (adjusted hazard ratio 2.47, 95% CI 1.26–4.85). Conclusion:HIV-1 risk increased two-fold during pregnancy. Elevated risk of HIV-1 acquisition in pregnant women appeared in part to be explained by behavioral and other factors. This is the first study to show that pregnancy increased the risk of female-to-male HIV-1 transmission, which may reflect biological changes of pregnancy that could increase HIV-1 infectiousness.

Regional Differences in Prevalence of HIV-1 Discordance in Africa and Enrollment of HIV-1 Discordant Couples into an HIV-1 Prevention Trial

Background Most HIV-1 transmission in Africa occurs among HIV-1-discordant couples (one partner HIV-1 infected and one uninfected) who are unaware of their discordant HIV-1 serostatus. Given the high HIV-1 incidence among HIV-1 discordant couples and to assess efficacy of interventions for reducing HIV-1 transmission, HIV-1 discordant couples represent a critical target population for HIV-1 prevention interventions and prevention trials. Substantial regional differences exist in HIV-1 prevalence in Africa, but regional differences in HIV-1 discordance among African couples, has not previously been reported. Methodology/Principal Findings The Partners in Prevention HSV-2/HIV-1 Transmission Trial (“Partners HSV-2 Study”), the first large HIV-1 prevention trial in Africa involving HIV-1 discordant couples, completed enrollment in May 2007. Partners HSV-2 Study recruitment data from 12 sites from East and Southern Africa were used to assess HIV-1 discordance among couples accessing couples HIV-1 counseling and testing, and to correlate with enrollment of HIV-1 discordant couples. HIV-1 discordance at Partners HSV-2 Study sites ranged from 8–31% of couples tested from the community. Across all study sites and, among all couples with one HIV-1 infected partner, almost half (49%) of couples were HIV-1 discordant. Site-specific monthly enrollment of HIV-1 discordant couples into the clinical trial was not directly associated with prevalence of HIV-1 discordance, but was modestly correlated with national HIV-1 counseling and testing rates and access to palliative care/basic health care (r = 0.74, p = 0.09). Conclusions/Significance HIV-1 discordant couples are a critical target for HIV-1 prevention in Africa. In addition to community prevalence of HIV-1 discordance, national infrastructure for HIV-1 testing and healthcare delivery and effective community outreach strategies impact recruitment of HIV-1 discordant couples into HIV-1 prevention trials.

Daily aciclovir for HIV-1 disease progression in people dually infected with HIV-1 and herpes simplex virus type 2: a randomised placebo-controlled trial

Background Well-tolerated medications that slow HIV-1 disease progression and delay initiation of antiretroviral therapy (ART) are needed. Most HIV-1-infected persons are dually-infected with herpes simplex virus type 2 (HSV-2). Daily HSV-2 suppression reduces plasma HIV-1 levels, but whether HSV-2 suppression delays HIV-1 disease progression is unknown.BACKGROUND Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression. METHODS In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519. FINDINGS At enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002) INTERPRETATION The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration. FUNDING Bill & Melinda Gates Foundation.

Characteristics of HIV-1 Discordant Couples Enrolled in a Trial of HSV-2 Suppression to Reduce HIV-1 Transmission: The Partners Study

Background The Partners HSV-2/HIV-1 Transmission Study (Partners Study) is a phase III, placebo-controlled trial of daily acyclovir for genital herpes (HSV-2) suppression among HIV-1/HSV-2 co-infected persons to reduce HIV-1 transmission to their HIV-1 susceptible partners, which requires recruitment of HIV-1 serodiscordant heterosexual couples. We describe the baseline characteristics of this cohort. Methods HIV-1 serodiscordant heterosexual couples, in which the HIV-1 infected partner was HSV-2 seropositive, had a CD4 count ≥250 cells/mcL and was not on antiretroviral therapy, were enrolled at 14 sites in East and Southern Africa. Demographic, behavioral, clinical and laboratory characteristics were assessed. Results Of the 3408 HIV-1 serodiscordant couples enrolled, 67% of the HIV-1 infected partners were women. Couples had cohabitated for a median of 5 years (range 2–9) with 28% reporting unprotected sex in the month prior to enrollment. Among HIV-1 susceptible participants, 86% of women and 59% of men were HSV-2 seropositive. Other laboratory-diagnosed sexually transmitted infections were uncommon (<5%), except for Trichomonas vaginalis in 14% of HIV-1 infected women. Median baseline CD4 count for HIV-1 infected participants was 462cells/mcL and median HIV-1 plasma RNA was 4.2 log10 copies/mL. After adjusting for age and African region, correlates of HIV-1 RNA level included male gender (+0.24 log10 copies/mL; p<0.001) and CD4 count (−0.25 and −0.55 log10 copies/mL for CD4 350–499 and >500 relative to <350, respectively, p<0.001). Conclusions The Partners Study successfully enrolled a cohort of 3408 heterosexual HIV-1 serodiscordant couples in Africa at high risk for HIV-1 transmission. Follow-up of this cohort will evaluate the efficacy of acyclovir for HSV-2 suppression in preventing HIV-1 transmission and provide insights into biological and behavioral factors determining heterosexual HIV-1 transmission. Trial Registration ClinicalTrials.gov NCT00194519

Characteristics of HIV-1 Serodiscordant Couples Enrolled in a Clinical Trial of Antiretroviral Pre-Exposure Prophylaxis for HIV-1 Prevention

Introduction Stable heterosexual HIV-1 serodiscordant couples in Africa have high HIV-1 transmission rates and are a critical population for evaluation of new HIV-1 prevention strategies. The Partners PrEP Study is a randomized, double-blind, placebo-controlled trial of tenofovir and emtricitabine-tenofovir pre-exposure prophylaxis to decrease HIV-1 acquisition within heterosexual HIV-1 serodiscordant couples. We describe the trial design and characteristics of the study cohort. Methods HIV-1 serodiscordant couples, in which the HIV-1 infected partner did not meet national guidelines for initiation of antiretroviral therapy, were enrolled at 9 research sites in Kenya and Uganda. The HIV-1 susceptible partner was randomized to daily oral tenofovir, emtricitabine-tenofovir, or matching placebo with monthly follow-up for 24–36 months. Results From July 2008 to November 2010, 7920 HIV-1 serodiscordant couples were screened and 4758 enrolled. For 62% (2966/4758) of enrolled couples, the HIV-1 susceptible partner was male. Median age was 33 years for HIV-1 susceptible and HIV-1 infected partners [IQR (28–40) and (26–39) respectively]. Most couples (98%) were married, with a median duration of partnership of 7.0 years (IQR 3.0–14.0) and recent knowledge of their serodiscordant status [median 0.4 years (IQR 0.1–2.0)]. During the month prior to enrollment, couples reported a median of 4 sex acts (IQR 2–8); 27% reported unprotected sex and 14% of male and 1% of female HIV-1 susceptible partners reported sex with outside partners. Among HIV-1 infected partners, the median plasma HIV-1 level was 3.94 log10 copies/mL (IQR 3.31–4.53) and median CD4 count was 496 cells/µL (IQR 375–662); the majority (64%) had WHO stage 1 HIV-1 disease. Conclusions Couples at high risk of HIV-1 transmission were rapidly recruited into the Partners PrEP Study, the largest efficacy trial of oral PrEP. (ClinicalTrials.gov NCT00557245)

Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial.

IMPORTANCE Antiretroviral preexposure prophylaxis (PrEP), using tenofovir disoproxil fumarate (TDF) and combination emtricitabine/tenofovir disoproxil fumarate (FTC+TDF), is efficacious for prevention of human immunodeficiency virus (HIV) acquisition. PrEP could reduce periconception HIV risk, but the effect on pregnancy outcomes is not well defined. OBJECTIVE To assess pregnancy incidence and outcomes among women using PrEP during the periconception period. DESIGN, SETTING, AND PARTICIPANTS Randomized trial among 1785 HIV-serodiscordant heterosexual couples (the Partners PrEP Study) in which the female partner was HIV uninfected that demonstrated that PrEP was efficacious for HIV prevention, conducted between July 2008 and June 2013 at 9 sites in Kenya and Uganda. INTERVENTIONS Daily oral TDF (n = 598), combination FTC+TDF (n = 566), or placebo (n = 621) through July 2011, when PrEP demonstrated efficacy for HIV prevention. Thereafter, participants continued receiving active PrEP without placebo. Pregnancy testing occurred monthly and study medication was discontinued when pregnancy was detected. MAIN OUTCOMES AND MEASURES Pregnancy incidence, birth outcomes (live births, pregnancy loss, preterm birth, congenital anomalies), and infant growth. RESULTS A total of 431 pregnancies occurred. Pregnancy incidence was 10.0 per 100 person-years among women assigned placebo, 11.9 among those assigned TDF (incidence difference, 1.9; 95% CI, -1.1 to 4.9 [P = .22 vs placebo]), and 8.8 among those assigned FTC+TDF (incidence difference, -1.3; 95% CI, -4.1 to 1.5 [P = .39 vs placebo]). Before discontinuation of the placebo treatment group in July 2011, the occurrence of pregnancy loss (96 of 288 pregnancies) was 42.5% for women receiving FTC+TDF compared with 32.3% for those receiving placebo (difference for FTC+TDF vs placebo, 10.2%; 95% CI, -5.3% to 25.7%; P = .16) and was 27.7% for those receiving TDF alone (difference vs placebo, -4.6%; 95% CI, -18.1% to 8.9%; P = .46). After July 2011, the frequency of pregnancy loss (52 of 143 pregnancies) was 37.5% for FTC+TDF and 36.7% for TDF alone (difference, 0.8%; 95% CI, -16.8% to 18.5%; P = .92). Occurrence of preterm birth, congenital anomalies, and growth throughout the first year of life did not differ significantly for infants born to women who received PrEP vs placebo. CONCLUSIONS AND RELEVANCE Among HIV-serodiscordant heterosexual African couples, differences in pregnancy incidence, birth outcomes, and infant growth were not statistically different for women receiving PrEP with TDF alone or combination FTC+TDF compared with placebo at conception. Given that PrEP was discontinued when pregnancy was detected and that CIs for the birth outcomes were wide, definitive statements about the safety of PrEP in the periconception period cannot be made. These results should be discussed with HIV-uninfected women receiving PrEP who are considering becoming pregnant. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00557245.

A Prospective Study of Frequency and Correlates of Intimate Partner Violence among African Heterosexual HIV Serodiscordant Couples

Background:Intimate partner violence (IPV) is common worldwide and is an important consideration in couples HIV voluntary counseling and testing (CVCT), especially for HIV-serodiscordant couples (i.e. in which only one member is HIV-infected). Design:Prospective study of 3408 HIV-serodiscordant couples (2299 in which the HIV-infected partner was female) from seven countries from East and Southern Africa. Methods:At quarterly visits during up to 2 years of follow-up, participants were asked, separately, about IPV perpetrated against them by their partner during the prior 3 months. Correlates of IPV were determined by generalized estimating equations. Results:The majority of couples were married and living together, with an average duration of partnership of approximately 5 years. More than 39 000 quarterly visits were recorded. IPV was reported in 2.7% of visits by HIV-infected women, 2.2% by HIV-uninfected women, 0.9% by HIV-infected men, and 0.7% by HIV-uninfected men. The majority of IPV reports were verbal or a combination of verbal and physical violence. Those who were HIV-infected were more likely to report IPV [for women adjusted odds ratio (AOR) 1.33, P = 0.043; for men AOR 2.20, P = 0.001], but IPV was not significantly associated with risk of HIV seroconversion in HIV-uninfected participants. IPV incidence decreased during follow-up (P < 0.001). Conclusion:During up to 2 years of prospective follow-up, most persons in stable HIV-serodiscordant partnerships who had undergone CVCT did not report IPV. A modest increased risk of IPV was seen for HIV-infected partners, both female and male.