Renee Heffron

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.

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis:

In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.

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.

Integrated Delivery of Antiretroviral Treatment and Pre-exposure Prophylaxis to HIV-1–Serodiscordant Couples: A Prospective Implementation Study in Kenya and Uganda

Background Antiretroviral-based interventions for HIV-1 prevention, including antiretroviral therapy (ART) to reduce the infectiousness of HIV-1 infected persons and pre-exposure prophylaxis (PrEP) to reduce the susceptibility of HIV-1 uninfected persons, showed high efficacy for HIV-1 protection in randomized clinical trials. We conducted a prospective implementation study to understand the feasibility and effectiveness of these interventions in delivery settings. Methods and Findings Between November 5, 2012, and January 5, 2015, we enrolled and followed 1,013 heterosexual HIV-1-serodiscordant couples in Kenya and Uganda in a prospective implementation study. ART and PrEP were offered through a pragmatic strategy, with ART promoted for all couples and PrEP offered until 6 mo after ART initiation by the HIV-1 infected partner, permitting time to achieve virologic suppression. One thousand thirteen couples were enrolled, 78% of partnerships initiated ART, and 97% used PrEP, during a median follow-up of 0.9 years. Objective measures of adherence to both prevention strategies demonstrated high use (≥85%). Given the low HIV-1 incidence observed in the study, an additional analysis was added to compare observed incidence to incidence estimated under a simulated counterfactual model constructed using data from a prior prospective study of HIV-1-serodiscordant couples. Counterfactual simulations predicted 39.7 HIV-1 infections would be expected in the population at an incidence of 5.2 per 100 person-years (95% CI 3.7–6.9). However, only two incident HIV-1 infections were observed, at an incidence of 0.2 per 100 person-years (95% CI 0.0–0.9, p < 0.0001 versus predicted). The use of a non-concurrent comparison of HIV-1 incidence is a potential limitation of this approach; however, it would not have been ethical to enroll a contemporaneous population not provided access to ART and PrEP. Conclusions Integrated delivery of time-limited PrEP until sustained ART use in African HIV-1-serodiscordant couples was feasible, demonstrated high uptake and adherence, and resulted in near elimination of HIV-1 transmission, with an observed HIV incidence of <0.5% per year compared to an expected incidence of >5% per year.

'If I am given antiretrovirals I will think I am nearing the grave': Kenyan HIV serodiscordant couples' attitudes regarding early initiation of antiretroviral therapy.

Objectives:Early initiation of antiretroviral therapy (ART) – that is, at higher CD4+ cell counts (>350 cells/&mgr;l) – is a potent HIV prevention strategy. The WHO recommends ART initiation by all HIV-infected individuals in HIV serodiscordant relationships to prevent HIV transmission, yet the acceptability of early ART among couples has not been well studied. Design:Qualitative study exploring HIV serodiscordant couples’ attitudes toward early initiation of ART. Methods:We conducted eight focus group discussions and 20 in-depth interviews with members of heterosexual HIV serodiscordant couples in Kenya. Investigators iteratively applied inductive and deductive codes, developed matrices to identify patterns in codes, and reached consensus on key attitudes (motivations and barriers) related to early ART and one central, emerging theme. Results:Most participants expressed interest in early initiation of ART, with maintaining health and preventing HIV transmission as key benefits. However, many identified personal concerns and potential barriers to wider community acceptance, including side-effects, adherence to life-long treatment, and stigma. The meaning of ART emerged as a fundamental consideration, with initiating therapy perceived as emblematic of the final stage of AIDS, when one was ‘nearing the grave.’ One particular challenge was what early ART might signify for someone who looks and feels healthy. Conclusion:HIV serodiscordant couples recognized the potential benefits of early ART, but ART was frequently viewed as signifying AIDS and approaching mortality. Potential implementation of early ART presents challenges and an opportunity to re-orientate individuals toward a new image of ART as health-preserving for patients and partners.

A prospective study of contraceptive use among African women in HIV-1 serodiscordant partnerships

Background: Dual contraception is important for averting HIV-1 transmission, unintended pregnancy, and maternal-to-child HIV-1 transmission. Few studies have explored contraceptive use in HIV-1 serodiscordant couples, a population at high risk for HIV-1 transmission. Methods: Data from a prospective study of 3407 women in HIV-1 heterosexual serodiscordant partnerships were analyzed to describe use and correlates of contraception. Results: Among 2298 HIV-1 seropositive women, 23.5% used contraception at enrollment and 30.2% used contraception after 24 months of follow-up; among 1109 HIV-1 seronegative women, contraceptive use decreased from 21.3% to 14.2%. For both HIV-1 seropositive and seronegative women, contraceptive use was less common among women from East Africa compared to women from southern Africa (adjusted odds ratio [AOR], 0.6; 95% confidence interval [CI], 0.5-0.8 and AOR, 0.6; 95% CI, 0.4-0.8, respectively) and more common among women with at least one child (AOR, 2.4; 95% CI, 1.7-3.4 and AOR, 2.3; 95% CI, 1.2-4.5, respectively). Condom use increased significantly during follow-up from 71.2% to 92.6% and 73.5% to 95.6% among HIV-1 seropositive and HIV-1 seronegative women, respectively, at baseline and 24 months. However, contraceptive use was associated with unprotected sexual activity among both HIV-1 seropositive and seronegative women (AOR, 1.3; 95% CI, 1.1-1.5 and AOR, 1.4; 95% CI, 1.1-1.8, respectively), although not among women who initiated contraception during follow-up. Conclusions: Counseling and provision of dual contraception should receive high priority in programs that care for women in HIV-1 serodiscordant partnerships.

Assessing the effect of hormonal contraception on HIV acquisition in observational data: challenges and recommended analytic approaches.

Introduction:Determining whether hormonal contraception, particularly the injectable contraceptive depot-medroxyprogesterone acetate (DMPA), increases a womans risk of HIV acquisition is a priority question for public health. However, assessing the relationship between various hormonal contraceptive methods and HIV acquisition with observational data involves substantial analytic design issues and challenges. Studies to date have used inconsistent approaches and generated a body of evidence that is complex and challenging to interpret. Methods:In January 2013, the United States Agency for International Development and FHI 360 supported a meeting of epidemiologists, statisticians, and content experts to develop recommendations for future observational analyses of hormonal contraception and HIV acquisition. Results:Meeting participants generated recommendations regarding careful definition of exposure groups; handling potential confounders, mediators, and effect modifiers; estimating and addressing the magnitude of measurement error; using multiple methods to account for pregnancy; and exploring the potential for differential exposure to HIV-infected partners. Advantages and disadvantages of various statistical approaches to account for time-varying confounding and estimating total and direct effects were also discussed. Conclusion:Implementing these recommendations in future observational hormonal contraception-HIV acquisition analyses will enhance interpretation of existing studies and strengthen the overall evidence base for this complex and important area.

Contraceptive method and pregnancy incidence among women in HIV-1-serodiscordant partnerships.

Background:Effective contraception reduces unintended pregnancies and is a central strategy to reduce vertical HIV-1 transmission for HIV-1-infected women. Methods:Among 2269 HIV-1-seropositive and 1085-seronegative women from seven African countries who were members of HIV-1-serodiscordant heterosexual partnerships and who were participating in an HIV-1 prevention clinical trial, we assessed pregnancy incidence according to contraceptive method using multivariate Andersen–Gill analysis. Results:Compared with women using no contraceptive method, pregnancy incidence was significantly reduced among HIV-1-seropositive and HIV-1-seronegative women using injectable contraception [adjusted hazard ratio (aHR) 0.24, P = 0.001 and aHR 0.25, P < 0.001, respectively). Oral contraceptives significantly reduced pregnancy risk only among HIV-1-seropositive women (aHR 0.51, P = 0.004) but not seronegative women (aHR 0.64, P = 0.3), and, for both seropositive and seronegative women, oral contraceptive pill users were more likely to become pregnant than injectable contraceptive users (aHR 2.22, P = 0.01 for HIV-1-seropositive women and aHR 2.65, P = 0.09 for HIV-1-seronegative women). Condoms, when reported as being used as the primary contraceptive method, marginally reduced pregnancy incidence (aHR 0.85, P = 0.1 for seropositive women and aHR 0.67, P = 0.02 for seronegative women). There were no pregnancies among women using intrauterine devices, implantable methods or who had undergone surgical sterilization, although these methods were used relatively infrequently. Conclusion:Family planning programs and HIV-1 prevention trials need innovative ways to motivate uptake and sustained use of longer acting, less user-dependent contraception for women who do not desire pregnancy.

My intention was a child but I was very afraid: fertility intentions and HIV risk perceptions among HIV-serodiscordant couples experiencing pregnancy in Kenya

We sought to understand fertility intentions and HIV risk considerations among Kenyan HIV-serodiscordant couples who became pregnant during a prospective study. We conducted individual in-depth interviews (n = 36) and focus group discussions (n = 4) and performed qualitative data analysis and interpretation using an inductive approach. Although most of the couples were aware of the risk of horizontal and vertical HIV transmission, almost all couples reported that they had intended to become pregnant and that the desire for children superseded HIV risk considerations. Motivations for pregnancy were numerous and complex: satisfying desired family size, desire for biological children, maintaining stability of the union, and sociocultural pressures. Couples desired strategies to reduce HIV risk during conception, but expressed hesitation toward assisted reproductive technologies as unnatural. HIV prevention programs should therefore address conception desires and counsel about coordinated periconception risk-reduction strategies.