Sinead Delany-Moretlwe

Effect of aciclovir on HIV-1 acquisition in herpes simplex virus 2 seropositive women and men who have sex with men: a randomised, double-blind, placebo-controlled trial

BACKGROUND Across many observational studies, herpes simplex virus type 2 (HSV-2) infection is associated with two-fold to three-fold increased risk for HIV-1 infection. We investigated whether HSV-2 suppression with aciclovir would reduce the risk of HIV-1 acquisition. METHODS We undertook a double-blind, randomised, placebo-controlled phase III trial in HIV-negative, HSV-2 seropositive women in Africa and men who have sex with men (MSM) from sites in Peru and the USA. Participants were randomly assigned by block randomisation to twice daily aciclovir 400 mg (n=1637) or matching placebo (n=1640) for 12-18 months, and were seen monthly for dispensation of study drug, adherence counselling and measurement by pill count and self-reporting, and risk reduction counselling, and every 3 months for genital examination and HIV testing. The primary outcome was HIV-1 acquisition and secondary was incidence of genital ulcers. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00076232. FINDINGS 3172 participants (1358 women, 1814 MSM) were included in the primary dataset (1581 in aciclovir group, 1591 in control group). The incidence of HIV-1 was 3.9 per 100 person-years in the aciclovir group (75 events in 1935 person-years of follow-up) and 3.3 per 100 person-years in the placebo group (64 events in 1969 person-years of follow-up; hazard ratio 1.16 [95% CI 0.83-1.62]). Incidence of genital ulcers on examination was reduced by 47% (relative risk 0.53 [0.46-0.62]) and HSV-2 positive genital ulcers by 63% (0.37 [0.31-0.45]) in the aciclovir group. Adherence to dispensed study drug was 94% in the aciclovir group and 94% in the placebo group, and 85% of expected doses in the aciclovir group and 86% in the placebo group. Retention was 85% at 18 months in both groups (1028 of 1212 in aciclovir group, 1030 of 1208 in placebo group). We recorded no serious events related to the study drug. INTERPRETATION Our results show that suppressive therapy with standard doses of aciclovir is not effective in reduction of HIV-1 acquisition in HSV-2 seropositive women and MSM. Novel strategies are needed to interrupt interactions between HSV-2 and HIV-1.

Genital HIV-1 RNA Predicts Risk of Heterosexual HIV-1 Transmission

Genital HIV-1 RNA quantity predicts risk of heterosexual HIV-1 transmission independently of plasma HIV-1 concentration. Elucidating the Insidious Transmission of a Deadly Pathogen The deadly HIV-1 retrovirus that causes AIDS has been a scourge of humanity for nearly 30 years. Although combination therapy with antiretroviral drugs has proved successful, the complex drug regimen and great cost have prevented their widespread use in the developing world where they are most needed. The goal of developing a vaccine that would protect individuals from becoming infected with HIV-1 has remained elusive. Given that 90% of all HIV infections worldwide are due to sexual transmission, there has been much interest in developing new strategies that could block HIV infection through the genital mucosa. However, the mechanisms underlying mucosal transmission of HIV are still poorly understood. Higher amounts of HIV-1 in genital secretions are thought to reflect a greater chance of sexual transmission, but testing this correlation is a difficult undertaking. Baeten and colleagues have taken on this challenge with their prospective study in Africa of 2521 heterosexual serodiscordant couples (one partner is HIV-infected and the other partner is not). These investigators evaluated the relationship between the quantity of HIV-1 RNA in the genital secretions of the infected partner and the risk of HIV-1 transmission to the uninfected partner in each couple. They tested the amount of HIV-1 RNA in endocervical swabs from 1805 HIV-1–infected women including 46 women known to have transmitted the virus to their male partners. They also tested the amount of HIV-1 RNA in semen from 716 men, including 32 who had transmitted HIV-1 to their female partners. The authors demonstrate that higher concentrations of HIV-1 RNA in genital secretions are associated with a greater risk of heterosexual transmission of HIV-1, and that these concentrations provide a new biomarker for predicting the infectiousness of HIV-1–infected individuals. The authors propose that HIV-1 RNA concentrations in genital secretions could also be used as a biomarker to monitor the efficacy of new microbicides and other interventions designed to block mucosal transmission of the virus. 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. There was a correlation between genital and plasma HIV-1 RNA concentrations: For endocervical swabs, Spearman’s rank correlation coefficient ρ was 0.56, and for semen, ρ was 0.55. Each 1.0 log10 increase in genital HIV-1 RNA was associated with a 2.20-fold (for endocervical swabs: 95% confidence interval, 1.60 to 3.04) and a 1.79-fold (for semen: 95% confidence interval, 1.30 to 2.47) 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 11 cases, 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.

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.

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.

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.

Pregnancy, Contraceptive Use, and HIV Acquisition in HPTN 039: Relevance for HIV Prevention Trials Among African Women

Background:Biomedical HIV prevention trials enroll sexually active women at risk of HIV and often discontinue study product during pregnancy. We assessed risk factors for pregnancy and HIV acquisition, and the effect of pregnancy on time off study drug in HIV Prevention Trials Network 039. Methods:A total of 1358 HIV negative, herpes simplex virus type 2-seropositive women from South Africa, Zambia, and Zimbabwe were enrolled and followed for up to 18 months. Results:A total of 228 pregnancies occurred; time off study drug due to pregnancy accounted for 4% of woman-years of follow-up among women. Being pregnant was not associated with increased HIV risk (hazard ratio 0.64, 95% confidence interval 0.23-1.80, P = 0.40). However, younger age was associated with increased risk for both pregnancy and HIV. There was no association between condom use as a sole contraceptive and reduced pregnancy incidence; hormonal contraception was not associated with increased HIV risk. Bacterial vaginosis at study entry was associated with increased HIV risk (hazard ratio 2.03, P = 0.02). Conclusions:Pregnancy resulted in only a small amount of woman-time off study drug. Young women are at high risk for HIV and are an appropriate population for HIV prevention trials but also have higher risk of pregnancy. Condom use was not associated with reduced incidence of pregnancy.

HIV testing and counseling leads to immediate consistent condom use among South African stable HIV-discordant couples.

Objective:Effective behavioral HIV prevention is needed for stable HIV-discordant couples at risk for HIV, especially those without access to biomedical prevention. This analysis addressed whether HIV testing and counseling with ongoing counseling and condom distribution lead to reduced unprotected sex in HIV-discordant couples. Methods:Partners in Prevention HSV/HIV Transmission Study was a randomized trial conducted from 2004 to 2008 assessing whether acyclovir reduced HIV transmission from HSV-2/HIV-1–coinfected persons to HIV-uninfected sex partners. This analysis relied on self-reported behavioral data from 508 HIV-infected South African participants. The exposure was timing of first HIV testing and counseling: 0–7, 8–14, 15–30, or >30 days before baseline. In each exposure group, predicted probabilities of unprotected sex in the last month were calculated at baseline, month 1, and month 12 using generalized estimating equations with a logit link and exchangeable correlation matrix. Results:At baseline, participants who knew their HIV status for less time experienced higher predicted probabilities of unprotected sex in the last month: 0–7 days, 0.71; 8–14 days, 0.52; 15–30 days, 0.49; >30 days, 0.26. At month 1, once all participants had been aware of being in HIV-discordant relationships for ≥1 month, predicted probabilities declined: 0–7 days, 0.08; 8–14 days, 0.08; 15–30 days, 0.15; >30 days, 0.14. Lower predicted probabilities were sustained through month 12: 0–7 days, 0.08; 8–14 days, 0.11; 15–30 days, 0.05; >30 days, 0.19. Conclusions:Unprotected sex declined after HIV-positive diagnosis and declined further after awareness of HIV discordance. Identifying HIV-discordant couples for behavioral prevention is important for reducing HIV transmission risk.

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.

Bidirectional links between HIV and intimate partner violence in pregnancy: implications for prevention of mother-to-child transmission

Prevention of mother‐to‐child transmission (PMTCT) has the potential to eliminate new HIV infections among infants. Yet in many parts of sub‐Saharan Africa, PMTCT coverage remains low, leading to unacceptably high rates of morbidity among mothers and new infections among infants. Intimate partner violence (IPV) may be a structural driver of poor PMTCT uptake, but has received little attention in the literature to date.

Preventing HIV among young people: research priorities for the future.

Objective:To review the current state of knowledge on the prevention of sexual transmission of HIV in adolescents and to highlight the existing gaps and priority areas for future research. Background:A disproportionate burden of HIV infections falls on adolescents, a developmental stage marked by unique neural, biological, and social transition. Successful interventions are critical to prevent the spread of HIV in this vulnerable population. Methods:We summarized the current state of research on HIV prevention in adolescents by providing examples of successful interventions and best practices, and highlighting current research gaps. Results:Adolescent interventions fall into 3 main categories: biomedical, behavioral, and structural. The majority of current research has focused on individual behavior change, whereas promising biomedical and structural interventions have been largely understudied in adolescents. Combination prevention interventions may be particularly valuable to this group. Conclusions:Adolescents have unique needs with respect to HIV prevention, and, thus, interventions should be designed to most effectively reach out to this population with information and services that will be relevant to them.