Joelle Brown

Hormonal contraception and the risk of HIV acquisition

Background:Combined oral contraceptives (COC) and depot-medroxyprogesterone acetate (DMPA) are among the most widely used family planning methods; their effect on HIV acquisition is not known. Objective:To evaluate the effect of COC and DMPA on HIV acquisition and any modifying effects of other sexually transmitted infections. Methods:This multicenter prospective cohort study enroled 6109 HIV-uninfected women, aged 18–35 years, from family planning clinics in Uganda, Zimbabwe and Thailand. Participants received HIV testing quarterly for 15–24 months. The risk of HIV acquisition with different contraceptive methods was assessed (excluding Thailand, where there were few HIV cases). Results:HIV infection occurred in 213 African participants (2.8/100 woman-years). Use of neither COC [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.69–1.42] nor DMPA (HR, 1.25; 95% CI, 0.89–1.78) was associated with risk of HIV acquisition overall, including among participants with cervical or vaginal infections. While absolute risk of HIV acquisition was higher among participants who were seropositive for herpes simplex virus 2 (HSV-2) than in those seronegative at enrolment, among the HSV-2-seronegative participants, both COC (HR, 2.85; 95% CI, 1.39–5.82) and DMPA (HR, 3.97; 95% CI, 1.98–8.00) users had an increased risk of HIV acquisition compared with the non-hormonal group. Conclusions:No association was found between hormonal contraceptive use and HIV acquisition overall. This is reassuring for women needing effective contraception in settings of high HIV prevalence. However, hormonal contraceptive users who were HSV-2 seronegative had an increased risk of HIV acquisition. Additional research is needed to confirm and explain this finding.

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.

Intravaginal Practices, Bacterial Vaginosis, and HIV Infection in Women: Individual Participant Data Meta-analysis

Pooling of data from 14,874 women in an individual participant data meta-analysis by Nicola Low and colleagues reveals that some intravaginal practices increase the risk of HIV acquisition.

Disentangling contributions of reproductive tract infections to HIV acquisition in African women.

Objective: To estimate the effects of reproductive tract infections (RTIs) on HIV acquisition among Zimbabwean and Ugandan women. Methods: A multicenter prospective observational cohort study enrolled 4439 HIV-uninfected women aged 18 to 35 attending family planning clinics in Zimbabwe and Uganda. Participants were interviewed, and tested for HIV and RTIs every 3 months for 15 to 24 months. They received HIV risk reduction counseling, male condoms, and treatment for curable RTIs. Results: Despite HIV risk reduction counseling and regular screening and treatment for RTIs, the HIV incidence did not decline during the study. Positive HSV-2 serostatus at baseline (hazard ratio [HR] = 3.69, 95% confidence interval = 2.45–5.55), incident HSV-2 (HR = 5.35, 3.06–9.36), incident Neisseria gonorrhoeae (HR = 5.46, 3.41–8.75), and altered vaginal flora during the study (bacterial vaginosis [BV]: HR = 2.12, 1.50–3.01; and intermediate flora: HR = 2.02, 1.39–2.95) were independently associated with HIV acquisition after controlling for demographic and behavioral covariates and other RTIs (Treponema pallidum, Chlamydia trachomatis, Trichomonas vaginalis, and vaginal yeasts). For N. gonorrhoeae, C. trachomatis, T. vaginalis, and vaginal yeasts, the risk of HIV acquisition increased when the infection was identified at the visit before the HIV-detection visit or with the duration of infection. Population attributable risk percent (PAR%) calculations show that HSV-2 contributes most to acquisition of new HIV infections (50.4% for baseline HSV-2 and 7.9% for incident HSV-2), followed by altered vaginal flora (17.2% for bacterial vaginosis and 11.8% for intermediate flora). Conclusions: A substantial proportion of new HIV infections in Zimbabwean and Ugandan women are attributable to RTIs, particularly HSV-2 and altered vaginal flora.

Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe

Background:An association has been demonstrated between herpes simplex type 2 (HSV-2) and HIV infection among men, but prospective studies in women have yielded mixed results. Objective:To estimate the effects of prevalent and incident HSV-2 infection on subsequent HIV acquisition among women in two African countries. Design:Prospective cohort study. Methods:HSV-2 and HIV serostatus were evaluated at enrollment and quarterly for 15–24 months among 4531 sexually active, HIV-uninfected women aged 18–35 years from Uganda and Zimbabwe. The association between prior HSV-2 infection and HIV acquisition was estimated using a marginal structural discrete survival model, adjusted for covariates. Results:HSV-2 seroprevalence at enrollment was 52% in Uganda and 53% in Zimbabwe; seroincidence during follow-up was 9.6 and 8.8/100 person-years in Uganda and Zimbabwe, respectively. In Uganda, the hazard ratio (HR) for HIV was 2.8 [95% confidence interval (CI), 1.5–5.3] among women with seroprevalent HSV-2 and 4.6 (95% CI, 1.6–13.1) among women with seroincident HSV-2, adjusted for confounding. In Zimbabwe, the HR for HIV was 4.4 (95% CI, 2.7–7.2) among women with seroprevalent HSV-2, and 8.6 (95% CI, 4.3–17.1) among women with seroincident HSV-2, adjusted for confounding. The population attributable risk percent for HIV due to prevalent and incident HSV-2 infection was 42% in Uganda and 65% in Zimbabwe. Conclusions:HSV-2 plays an important role in the acquisition of HIV among women. Efforts to implement known HSV-2 control measures, as well as identify additional measures to control HSV-2, are urgently needed to curb the spread of HIV.

HIV Incidence Determination in the United States: A Multiassay Approach

BACKGROUND Accurate testing algorithms are needed for estimating human immunodeficiency virus (HIV) incidence from cross-sectional surveys. METHODS We developed a multiassay algorithm (MAA) for HIV incidence that includes the BED capture enzyme immunoassay (BED-CEIA), an antibody avidity assay, HIV load, and CD4(+) T-cell count. We analyzed 1782 samples from 709 individuals in the United States who had a known duration of HIV infection (range, 0 to >8 years). Logistic regression with cubic splines was used to compare the performance of the MAA to the BED-CEIA and to determine the window period of the MAA. We compared the annual incidence estimated with the MAA to the annual incidence based on HIV seroconversion in a longitudinal cohort. RESULTS The MAA had a window period of 141 days (95% confidence interval [CI], 94-150) and a very low false-recent misclassification rate (only 0.4% of 1474 samples from subjects infected for >1 year were misclassified as indicative of recent infection). In a cohort study, annual incidence based on HIV seroconversion was 1.04% (95% CI, .70%-1.55%). The incidence estimate obtained using the MAA was essentially identical: 0.97% (95% CI, .51%-1.71%). CONCLUSIONS The MAA is as sensitive for detecting recent HIV infection as the BED-CEIA and has a very low rate of false-recent misclassification. It provides a powerful tool for cross-sectional HIV incidence determination.

Increased levels of immune activation in the genital tract of healthy young women from sub-Saharan Africa

Objectives:To determine whether healthy, young women in sub-Saharan Africa have a more activated immune milieu in the genital tract (i.e. activated CD4+ T cells) than a similar population in the United States. Design:A cross-sectional study nested in a phase 1 microbicide trial. Methods:Cervical cytobrushes were collected from 18 to 24-year-old women in San Francisco, California, USA (n = 18) and Kisumu, Kenya (n = 36) at enrollment into a phase 1 microbicide trial. All participants tested negative for HIV, herpes simplex virus 2, gonorrhea, chlamydia, and trichomonas, and had abstained from sex for at least 7 days prior to enrollment. Cryopreserved T-cell populations were assayed by flow cytometry in a central laboratory. Secretory leukocyte protease inhibitor levels were assayed in cervicovaginal lavage samples. The Wilcoxon rank-sum test was used to compare immune parameters between sites. Results:The total number of endocervical CD4+ T cells was slightly higher in participants from San Francisco, but participants from Kisumu had a substantially higher number and proportion of CD4+ T cells expressing the early activation marker CD69, with and without the HIV coreceptor C–C chemokine receptor type 5, and a greater proportion of activated CD8+ T cells. Median (interquartile range) genital levels of secretory leukocyte protease inhibitor were lower in participants from Kisumu compared with those from San Francisco [190 (96–519) vs. 474 (206 817) pg/ml, P < 0.03]. Conclusion:Activated mucosal T cells were increased in the genital tract of young, sexually transmitted infection/HIV-free Kenyan women, independent of common genital coinfections, and secretory leukocyte protease inhibitor levels were reduced. The cause of these mucosal immune differences is not known, but could partly explain the high HIV incidence in young women from sub-Saharan Africa.

A phase I randomized placebo controlled trial of the safety of 3% SPL7013 Gel (VivaGel®) in healthy young women administered twice daily for 14 days.

Objective To assess the safety of VivaGel® used vaginally twice daily for 14 days among healthy, sexually-abstinent women, aged 18–24 years in the USA and Kenya. Design Randomized placebo controlled trial. Methods Participants were randomized 2∶1, VivaGel to placebo. Safety was assessed by comparing genitourinary (GU) adverse events (AEs), colposcopy findings, vaginal lactobacilli and laboratory abnormalities by arm. Results Fifty-four women were enrolled; 35 in the VivaGel arm and 19 in the placebo arm. Twenty-six (74%) and 10 (53%) women reported taking all doses of VivaGel and placebo, respectively. No grade 3 or 4 AEs, or serious AEs occurred. Twenty-five (71%) participants in the VivaGel arm compared to 10 (53%) participants in the placebo arm had at least one grade 1 or 2 GU AE associated with product use (RR = 1.4, 95% CI 0.8-2.2). All seven grade 2 GU AEs associated with product use occurred among four women in the VivaGel arm. Vulvar and cervical erythema, cervical lesions, symptomatic BV, urinary frequency and metrorrhagia were more common in the VivaGel arm than the placebo arm. Twenty-nine (83%) participants in the VivaGel arm had a colposcopic finding compared to 10 (53%) participants in the placebo arm (RR = 1.6, 95%CI = 1.0-2.5). Two women in the VivaGel arm prematurely discontinued product use themselves due to a reported GU AE. Persistence of H2O2-producing and non-producing lactobacilli did not differ by study arm. Conclusions GU AEs and colposcopic findings consistent with mild epithelial irritation and inflammation occurred more commonly among women in the VivaGel arm. Trial Registration ClinicalTrials.gov NCT003311032

Performance of a limiting-antigen avidity enzyme immunoassay for cross-sectional estimation of HIV incidence in the United States

Background A limiting antigen avidity enzyme immunoassay (HIV-1 LAg-Avidity assay) was recently developed for cross-sectional HIV incidence estimation. We evaluated the performance of the LAg-Avidity assay alone and in multi-assay algorithms (MAAs) that included other biomarkers. Methods and Findings Performance of testing algorithms was evaluated using 2,282 samples from individuals in the United States collected 1 month to >8 years after HIV seroconversion. The capacity of selected testing algorithms to accurately estimate incidence was evaluated in three longitudinal cohorts. When used in a single-assay format, the LAg-Avidity assay classified some individuals infected >5 years as assay positive and failed to provide reliable incidence estimates in cohorts that included individuals with long-term infections. We evaluated >500,000 testing algorithms, that included the LAg-Avidity assay alone and MAAs with other biomarkers (BED capture immunoassay [BED-CEIA], BioRad-Avidity assay, HIV viral load, CD4 cell count), varying the assays and assay cutoffs. We identified an optimized 2-assay MAA that included the LAg-Avidity and BioRad-Avidity assays, and an optimized 4-assay MAA that included those assays, as well as HIV viral load and CD4 cell count. The two optimized MAAs classified all 845 samples from individuals infected >5 years as MAA negative and estimated incidence within a year of sample collection. These two MAAs produced incidence estimates that were consistent with those from longitudinal follow-up of cohorts. A comparison of the laboratory assay costs of the MAAs was also performed, and we found that the costs associated with the optimal two assay MAA were substantially less than with the four assay MAA. Conclusions The LAg-Avidity assay did not perform well in a single-assay format, regardless of the assay cutoff. MAAs that include the LAg-Avidity and BioRad-Avidity assays, with or without viral load and CD4 cell count, provide accurate incidence estimates.

Primaquine to reduce transmission of Plasmodium falciparum malaria in Mali: a single-blind, dose-ranging, adaptive randomised phase 2 trial

BACKGROUND Single low doses of primaquine, when added to artemisinin-based combination therapy, might prevent transmission of Plasmodium falciparum malaria to mosquitoes. We aimed to establish the activity and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine in male patients in Mali. METHODS In this phase 2, single-blind, dose-ranging, adaptive randomised trial, we enrolled boys and men with uncomplicated P falciparum malaria at the Malaria Research and Training Centre (MRTC) field site in Ouelessebougou, Mali. All participants were confirmed positive carriers of gametocytes through microscopy and had normal function of glucose-6-phosphate dehydrogenase (G6PD) on colorimetric quantification. In the first phase, participants were randomly assigned (1:1:1) to one of three primaquine doses: 0 mg/kg (control), 0·125 mg/kg, and 0·5 mg/kg. Randomisation was done with a computer-generated randomisation list (in block sizes of six) and concealed with sealed, opaque envelopes. In the second phase, different participants were sequentially assigned (1:1) to 0·25 mg/kg primaquine or 0·0625 mg/kg primaquine. Primaquine tablets were dissolved into a solution and administered orally in a single dose. Participants were also given a 3 day course of dihydroartemisinin-piperaquine, administered by weight (320 mg dihydroartemisinin and 40 mg piperaquine per tablet). Outcome assessors were masked to treatment allocation, but participants were permitted to find out group assignment. Infectivity was assessed through membrane-feeding assays, which were optimised through the beginning part of phase one. The primary efficacy endpoint was the mean within-person percentage change in mosquito infectivity 2 days after primaquine treatment in participants who completed the study after optimisation of the infectivity assay, had both a pre-treatment infectivity measurement and at least one follow-up infectivity measurement, and who were given the correct primaquine dose. The safety endpoint was the mean within-person change in haemoglobin concentration during 28 days of study follow-up in participants with at least one follow-up visit. This study is registered with ClinicalTrials.gov, number NCT01743820. FINDINGS Between Jan 2, 2013, and Nov 27, 2014, we enrolled 81 participants. In the primary analysis sample (n=71), participants in the 0·25 mg/kg primaquine dose group (n=15) and 0·5 mg/kg primaquine dose group (n=14) had significantly lower mean within-person reductions in infectivity at day 2-92·6% (95% CI 78·3-100; p=0·0014) for the 0·25 mg/kg group; and 75·0% (45·7-100; p=0·014) for the 0·5 mg/kg primaquine group-compared with those in the control group (n=14; 11·3% [-27·4 to 50·0]). Reductions were not significantly different from control for participants assigned to the 0·0625 mg/kg dose group (n=16; 41·9% [1·4-82·5]; p=0·16) and the 0·125 mg/kg dose group (n=12; 54·9% [13·4-96·3]; p=0·096). No clinically meaningful or statistically significant drops in haemoglobin were recorded in any individual in the haemoglobin analysis (n=70) during follow-up. No serious adverse events were reported and adverse events did not differ between treatment groups. INTERPRETATION A single dose of 0·25 mg/kg primaquine, given alongside dihydroartemisinin-piperaquine, was safe and efficacious for the prevention of P falciparum malaria transmission in boys and men who are not deficient in G6PD. Future studies should assess the safety of single-dose primaquine in G6PD-deficient individuals to define the therapeutic range of primaquine to enable the safe roll-out of community interventions with primaquine. FUNDING Bill & Melinda Gates Foundation.