Objective: To analyze antiretroviral drug susceptibility in HIV-infected adults failing first- and second-line antiretroviral treatment (ART) in Rakai, Uganda. Methods: Samples obtained from participants at baseline (pre-treatment), at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Results: Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only 8 (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Conclusions: Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART.

OBJECTIVES:: High-risk human papillomavirus (HR-HPV) infection is the most common sexually transmitted infection. Penile and cervical cancer rates are highest in sub-Saharan Africa. However, little is known about the impact of HIV infection on HR-HPV acquisition and clearance among heterosexual men. DESIGN:: HR-HPV incidence and clearance were evaluated in 999 men (776 HIV-negative and 223 HIV-positive) aged 15-49 who participated in male circumcision trials in Rakai, Uganda. METHODS:: Penile swabs were tested for HR-HPV by Roche HPV Linear Array. A Poisson multivariable model was used to estimate adjusted incidence rate ratios (adjIRR) and clearance risk ratios (adjRR). RESULTS:: HR-HPV incidence was 66.5/100 py in HIV-positive men and 32.9/100 py among HIV-negative men (IRR = 2.02, 95%CI 1.67-2.44). Incidence was higher in the unmarried (adjIRR = 1.73, 95%CI 1.19-2.52), and decreased with age (adjIRR for men >35 years = 0.64, 95%CI 0.43-0.94) and male circumcision (adjIRR = 0.70, 95%CI 0.55-0.89). HR-HPV clearance was 114.7/100 py for HIV-positive men and 170.2/100 py for HIV-negative men (RR = 0.67, 95%I 0.59-0.77). HR-HPV clearance in HIV-negative men was increased with circumcision (adjRR = 1.48, 95%CI 1.26-1.74), HSV-2 infection (adjRR = 1.20, 95%CI 1.01-1.44), and symptoms of urethral discharge (adjRR = 1.35, 95%CI 1.06-1.73). Clearance of HR-HPV was significantly lower for unmarried men (adjRR 0.76, 95% CI 0.59-0.98). CONCLUSIONS:: HR-HPV is common among heterosexual Ugandan men, particularly the HIV-infected. HIV infection increases HR-HPV acquisition and reduces HR-HPV clearance. Promotion of male circumcision and additional prevention measures, such as HPV vaccination, is critical in sub-Saharan Africa.

BACKGROUND: Daily suppression of herpes simplex virus type 2 (HSV-2) reduces plasma HIV-1 concentrations and modestly delayed HIV-1 disease progression in one clinical trial. We investigated the effect of daily suppressive aciclovir on HIV-1 disease progression in Rakai, Uganda. METHODS: We did a single site, parallel, randomised, controlled trial of HIV-1, HSV-2 dually infected adults with CD4 cell counts of 300-400 cells per μL. We excluded individuals who had an AIDS-defining illness or active genital ulcer disease, and those that were taking antiretroviral therapy. Participants were randomly assigned (1:1) with computer-generated random numbers in blocks of four to receive either aciclovir 400 mg orally twice daily or placebo; participants were followed up for 24 months. All study staff and participants were masked to treatment, except for the two statisticians. The primary outcome was CD4 cell count less than 250 cells per μL or initiation of antiretroviral therapy for WHO stage 4 disease. Our intention-to-treat analysis used Cox proportional hazards models, adjusting for baseline log(10) viral load, CD4 cell count, sex, and age to assess the risk of disease progression. We also investigated the effect of suppressive HSV-2 treatment stratified by baseline HIV viral load with a Cox proportional hazards model. This trial is registered with ClinicalTrials.gov, number NCT00405821. FINDINGS: 440 participants were randomly assigned, 220 to each group. 110 participants in the placebo group and 95 participants in the treatment group reached the primary endpoint (adjusted hazard ratio [HR] 0·75, 95% CI 0·58-0·99; p=0·040). 24 participants in the placebo group and 22 in the treatment group were censored, but all contributed data for the final analysis. In a subanalysis stratified by baseline HIV viral load, participants with a baseline viral load of 50 000 copies mL or more in the treatment group had a reduced HIV disease progression compared with those in the placebo group (0·62, 0·43-0·96; p=0·03). No significant difference in HIV disease progression existed between participants in the treatment group and those in the placebo group who had baseline HIV viral loads of less than 50 000 copies per mL (0·90, 0·54-1·5; p=0·688). No safety issues related to aciclovir treatment were identified. INTERPRETATION: Aciclovir reduces the rate of disease progression, with the greatest effect in individuals with a high baseline viral load. Suppressive aciclovir might be warranted for individuals dually infected with HSV-2 and HIV-1 with viral loads of 50 000 copies per mL or more before initiation of antiretroviral treatment. FUNDING: National Institute of Allergy and Infectious Diseases, National Cancer Institute (National Institutes of Health, USA).

Evaluation of: Heffron R, Donnell D, Rees H et al.; for the Partners in Prevention HISV/HIV Transmission Study Team. Use of hormonal contraceptives and risk of HIV-1 transmission: a prospective cohort study. Lancet Infect. Dis. 12(1), 19-26 (2012). Prior observational studies produced inconsistent findings regarding hormonal contraception (HC) and risks of HIV acquisition and transmission. Heffron et al. conducted secondary data analyses on 3790 HIV discordant couples enrolled in two studies (a randomized trial of HSV-2 suppression and a study of immune correlates of HIV-1 protection) to assess HIV-1 acquisition and transmission in relation to HC use in females. HIV incidence among female HC nonusers was 3.8/100 person years (py), compared to 6.9/100 py among injectable users (p = 0.04) and 5.9/100 py in oral contraceptive users (p = 0.33). Among men, HIV incidence was 1.5/100 py in partners of HIV-positive HC nonusers, compared to 2.6/100 py in partners of injectable users (p < 0.05) and 2.5/100 py in men whose HIV-infected partners used oral contraceptives (p = 0.31). Study strengths included frequent follow up, excellent retention, known HIV exposure and viral load in the index infected partner, genetic linkage of virus from both partners and sexual behavior information. However, confounding by factors that cannot be controlled, including misreporting of condom use, is likely, given participants' high pregnancy rates. Clinicians and clients need to balance potential HC risks with the known risks of unwanted pregnancies. Condom use remains essential for HIV prevention regardless of other contraceptive usage.

ABSTRACT: BACKGROUND: Circumcision is a common procedure, but regional and societal attitudes differ on whether there is a need for a male to be circumcised and, if so, at what age. This is an important issue for many parents, but also paediatricians, other doctors, policy makers, public health authorities, medical bodies, and males themselves. DISCUSSION: We show here that infancy is an optimal time for clinical circumcision because an infant's low mobility facilitates the use of local anesthesia, sutures are not required, healing is quick, cosmetic outcome is usually excellent, costs are minimal, and complications are uncommon. The benefits of infant circumcision include prevention of urinary tract infections (a cause of renal scarring), reduction in risk of inflammatory foreskin conditions such as balanoposthitis, foreskin injuries, phimosis and paraphimosis. When the boy later becomes sexually active he has substantial protection against risk of HIV and other viral sexually transmitted infections such as genital herpes and oncogenic human papillomavirus, as well as penile cancer. The risk of cervical cancer in his female partner(s) is also reduced. Circumcision in adolescence or adulthood may evoke a fear of pain, penile damage or reduced sexual pleasure, even though unfounded. Time off work or school will be needed, cost is much greater, as are risks of complications, healing is slower, and stitches or tissue glue must be used. SUMMARY: Infant circumcision is safe, simple, convenient and cost-effective. The available evidence strongly supports infancy as the optimal time for circumcision.

Male circumcision reduces acquisition of herpes simplex virus type 2 (HSV-2) in men. We assessed whether male circumcision reduces HSV-2 infection among female partners. HSV-2-negative, human immunodeficiency virus-negative female partners of 368 males who were and 372 males who were not randomized to receive male circumcision were enrolled. The incidence of HSV-2 infection among females over a period of 2 years was 6.09 cases per 100 person-years in the intervention arm and 6.32 cases per 100 person-years in the control arm (incidence rate ratio [IRR], 0.96 [95% confidence interval {CI},.62-1.49]; P =.87). Among female partners of HSV-2-positive males, the incidence of HSV-2 infection was 9.55 cases per 100 person-years in the intervention arm and 11.17 cases per 100 person-years in the control arm (IRR, 0.85 [95% CI,.44-1.67]; P =.62). Contrary to findings in males, male circumcision did not affect HSV-2 acquisition among female partners.

BACKGROUND:: Large datasets for investigating vaginal flora change at frequent, repeated intervals are limited and graphical methods for exploring such data are inadequate. We report 2-year weekly vaginal flora changes based on Gram stain using lasagna plots. METHODS:: Weekly vaginal flora patterns were evaluated among 211 sexually experienced women with ≥18 months of follow-up in Rakai, Uganda. Vaginal flora swabs were self-collected weekly and categorized by Nugent Gram stain criteria (0-3, normal; 4-6, intermediate; 7-10, bacterial vaginosis [BV]). Vaginal flora patterns were analyzed as the percentage of weekly observations with BV (longitudinal prevalence) and illustrated by lasagna plots. Characteristics of women were compared across tertiles of longitudinal prevalence of BV. RESULTS:: Ninety-five percent of women had at least 1 episode of BV over 2 years, with one-third of women spending more than half (52%-100%) of their time with BV. Vaginal pH >4.5 increased with increasing tertiles of longitudinal prevalence of BV (P < 0.001). Weekly fluctuation in vaginal flora states, as measured by a change in flora states from the before current visit, was highest in the middle (41.9%) compared with the lower (30.1%) and upper tertiles (27.8%, P < 0.001). HIV status and reported vaginal symptoms did not differ significantly across BV tertiles. CONCLUSIONS:: Women exhibited different patterns of vaginal flora changes over time, which could not be described by baseline behaviors. Lasagna plots aided in describing the natural history of BV within and across women and may be applied to future BV natural history studies.