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ObjectiveVoluntary medical male circumcision (MC) is a critical tool in combination HIV prevention programmes in Africa. Self-reported MC (SrMC) status is used in HIV epidemiological surveys to assess MC coverage but is subject to response bias with limited validation. This study evaluated the utility of SrMC status as a marker of MC as well as self-reported genital lesions for genital ulcer disease (GUD) among Ugandan men.MethodsMale participants aged 18–49 years in the cross-sectional Sexually Transmitted Infection Prevalence study, conducted between May and October 2019, responded to a questionnaire capturing SrMC status and current genital ulcer symptoms followed by clinical assessment to verify MC and presence of GUD.Sensitivity, specificity, positive predictive value, negative predictive value and corresponding CIs (95% CI) for SrMC status and GUD were estimated.ResultsThere were 853 male participants, of whom 470 (55.1%) self-reported being circumcised and 23 (2.7%) self-reported GUD (SrGUD). MC was clinically confirmed in 50.2% (n=428) of participants with sensitivity of SrMC status at 99% (95% CI: 98% to 100%) and specificity 89% (95% CI: 86% to 92%). Specificity of SrMC was lowest among persons living with HIV and viremic (>1000 copies/mL) at 72% (95% CI: 46% to 90%). 18 participants had clinically confirmed GUD, but only 12 SrGUD symptoms, corresponding to a sensitivity and specificity of 67% (95% CI: 41% to 87%) and 99% (95% CI: 98% to 99%), respectively.ConclusionsSrMC status is a robust proxy for clinically confirmed MC status and may reliably be used to assess MC coverage in this setting. Conversely, GUD symptoms were under-reported, which may impact effective syndromic management of sexually transmitted infections and warrants further examination.

RECENT randomised clinical trials on the efficacy of male circumcision show that medically performed adult male circumcision can be safe and efficacious in reducing the sexual transmission of HIV from [...]

Treating HIV-infected pregnant women for a sexually transmitted disease can reduce the rate of neonatal death, premature birth, and low birth weight but does not reduce the risk of transmitting the virus to the baby. This was the conclusion of a study of 2,070 pregnant women in Uganda.

International and global organisations advocate targeting interventions to areas of high HIV prevalence (ie, hotspots). To better understand the potential benefits of geo-targeted control, we assessed the extent to which HIV hotspots along Lake Victoria sustain transmission in neighbouring populations in south-central Uganda.

Targeting combination HIV interventions to locations and populations with high HIV burden is a global priority, but the impact of these strategies on HIV incidence is unclear. We assessed the impact of combination HIV interventions on HIV incidence in four HIV-hyperendemic communities in Uganda.

In sub-Saharan Africa, migrants typically have higher HIV prevalence than non-migrants; however, whether HIV acquisition typically precedes or follows migration is unknown. We aimed to investigate the risk of HIV after migration in Rakai District, Uganda.

Understanding the extent to which HIV burden differs across communities and the drivers of local disparities is crucial for an effective and targeted HIV response. We assessed community-level variations in HIV prevalence, risk factors, and treatment and prevention service uptake in Rakai, Uganda.

We assessed medical male circumcision (MMC) scale-up in Rakai, Uganda using population-based surveys during 2007–2014. MMC coverage increased from 28.5 to 52.0%. Coverage was initially lower in 15–19-year-olds but increased in 2014, was higher in married men and in trading communities, and lowest in the sexually inactive. Coverage did not vary by self-perceived risk of HIV or HIV serostatus. Increasing generalized coverage suggested that MMC became normative, but coverage falls short of WHO/Joint United Nations Programme on HIV and AIDS (UNAIDS) 80% targets, indicating the need for demand generation.

The risk of HIV associated with hormonal contraceptives is controversial. We assessed hormonal contraceptive use and HIV incidence in HIV-discordant couples in Rakai, Uganda.

To quantify the association between intimate partner violence (IPV) and incident HIV infection in women in the Rakai Community Cohort Study between 2000 and 2009.

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.

Herpes simplex virus type 2 (HSV-2) increases the risk of HIV acquisition in men and overall CD4T cell density in the foreskin. Using tissues obtained during routine male circumcision, we examined the impact of HSV-2 on the function and phenotype of foreskin T cells in Ugandan men. HSV-2 infection was predominantly associated with a compartmentalized increase in CCR5 expression by foreskin CD4T cells, which may contribute to HIV susceptibility.

The efficacy of male circumcision for HIV prevention over 2 years has been demonstrated in three randomized trials, but the longer-term effectiveness of male circumcision is unknown.

Randomised trials show that male circumcision reduces the prevalence and incidence of high-risk human papillomavirus (HPV) infection in men. We assessed the efficacy of male circumcision to reduce prevalence and incidence of high-risk HPV in female partners of circumcised men.

Observational studies have reported an association between male circumcision and reduced risk of HIV infection in female partners. We assessed whether circumcision in HIV-infected men would reduce transmission of the virus to female sexual partners.

Background: Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men. Methods: 4996 uncircumcised, HIV-negative men aged 15-49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicalTrials.gov, with the number NCT00425984. Findings: Baseline characteristics of the men in the intervention and control groups were much the same at enrolment. Retention rates were much the same in the two groups, with 90-92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% CI 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3.6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up. Interpretation: Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men.

ABSTRACTWe report the development and evaluation of a human immunodeficiency virus type 1 testing algorithm consisting of three rapid antibody detection tests. Stored serum samples from Uganda were utilized with a final algorithm sensitivity of 100% and a specificity of 98.9% (95% confidence interval, 98.6% to 99.3%).

The impact of HIV-1 genetic diversity on candidate vaccines is uncertain. To minimize genetic diversity in the evaluation of HIV-1 vaccines, vaccine products must be matched to the predominant subtype in a vaccine cohort. To that end, full genome sequencing was used to detect and characterize HIV-1 subtypes and recombinant strains from individuals in Rakai District, Uganda. DNA extracted from peripheral blood mononuclear cells (PMBC) was PCR amplified using primers in the long terminal repeats (LTRs) to generate nearly full length genomes. Amplicons were directly sequenced with dye terminators and automated sequencers. Sequences were phylogenetically analyzed and recombinants were detected and mapped with distance scan and bootscan. Among 46 sequences, 54% were subtype D, 15% were subtype A, and 30% were recombinant. All recombinants were individually unique, and most combined subtypes A and D. Subtype D comprised more than 70% of all the HIV-1 genomes in Rakai when both pure subtypes and recombinants were considered. Candidate vaccines based on HIV-1 subtype D would be appropriate for evaluation in Rakai District, Uganda.

We assessed whether women had accurate knowledge of their partners’ male circumcision status using survey data (2010–2011) from Rakai, Uganda, and examined characteristics of women who misreported male circumcision status. Among couples in which men were uncircumcised (n=1744), 8.2 women misreported; and among couples in which men were confirmed circumcised (n=759), 1.2 women misreported. Younger women were 2.2 times more likely to misreport compared with older women. Misreporting was not associated with other sociodemographics or behavioural characteristics. If women are to act as advocates for male circumcision acceptance, there is a need to educate women, particularly younger women about the nature and recognition of male circumcision.

ABSTRACTSexual transmission of HIV requires exposure to the virus and infection of activated mucosal immune cells, specifically CD4+T cells or dendritic cells. The foreskin is a major site of viral entry in heterosexual transmission of HIV. Although the probability of acquiring HIV from a sexual encounter is low, the risk varies even after adjusting for known HIV risk factors. The genital microbiome may account for some of the variability in risk by interacting with the host immune system to trigger inflammatory responses that mediate the infection of mucosal immune cells. We conducted a case-control study of uncircumcised participants nested within a randomized-controlled trial of male circumcision in Rakai, Uganda. Using penile (coronal sulcus) swabs collected by study personnel at trial enrollment, we characterized the penile microbiome by sequencing and real-time PCR and cytokine levels by electrochemiluminescence assays. The absolute abundances of penile anaerobes at enrollment were associated with later risk of HIV seroconversion, with a 10-fold increase in Prevotella, Dialister, Finegoldia, and Peptoniphilusincreasing the odds of HIV acquisition by 54 to 63%, after controlling for other known HIV risk factors. Increased abundances of anaerobic bacteria were also correlated with increased cytokines, including interleukin-8, which can trigger an inflammatory response that recruits susceptible immune cells, suggesting a mechanism underlying the increased risk. These same anaerobic genera can be shared between heterosexual partners and are associated with increased HIV acquisition in women, pointing to anaerobic dysbiosis in the genital microbiome and an accompanying inflammatory response as a novel, independent, and transmissible risk factor for HIV infection.IMPORTANCEWe found that uncircumcised men who became infected by HIV during a 2-year clinical trial had higher levels of penile anaerobes than uncircumcised men who remained HIV negative. We also found that having higher levels of penile anaerobes was also associated with higher production of immune factors that recruit HIV target cells to the foreskin, suggesting that anaerobes may modify HIV risk by triggering inflammation. These anaerobes are known to be shared by heterosexual partners and are associated with HIV risk in women. Therefore, penile anaerobes may be a sexually transmissible risk factor for HIV, and modifying the penile microbiome could potentially reduce HIV acquisition in both men and women.

ABSTRACTBacterial vaginosis (BV) is a common vaginal bacterial imbalance associated with risk for HIV and poor gynecologic and obstetric outcomes. Male circumcision reduces BV-associated bacteria on the penis and decreases BV in female partners, but the link between penile microbiota and female partner BV is not well understood. We tested the hypothesis that having a female partner with BV increases BV-associated bacteria in uncircumcised men. We characterized penile microbiota composition and density (i.e., the quantity of bacteria per swab) by broad-coverage 16S rRNA gene-based sequencing and quantitative PCR (qPCR) in 165 uncircumcised men from Rakai, Uganda. Associations between penile community state types (CSTs) and female partner's Nugent score were assessed. We found seven distinct penile CSTs of increasing density (CST1 to 7). CST1 to 3 and CST4 to 7 were the two major CST groups. CST4 to 7 had higher prevalence and abundance of BV-associated bacteria, such as Mobiluncusand Dialister, than CST1 to 3. Men with CST4 to 7 were significantly more likely to have a female partner with a high Nugent score (P= 0.03). Men with two or more extramarital partners were significantly more likely to have CST4 to 7 than men with only marital partners (CST4 to 7 prevalence ratio, 1.84; 95% confidence interval [CI], 1.16 to 2.92). Female partner Nugent BV is significantly associated with penile microbiota. Our data support the exchange of BV-associated bacteria through intercourse, which may explain BV recurrence and persistence.IMPORTANCEBacterial vaginosis (BV) is sexually associated but not considered a sexually transmitted disease. Our findings suggest that the uncircumcised penis is an important niche for BV-associated genital anaerobes. In addition, we found a link between extramarital sexual relationships and BV-associated bacteria in men, which parallels earlier findings of the association between sexual activity and BV in women. This suggests the sexual transmissibility of BV-associated bacteria. Reducing bacterial exchange by barrier methods and managing carriage of BV-associated bacteria in men may decrease BV persistence and recurrence in women.

Background. Data on the incidence of Trichomonas vaginalis and use of hormonal contraception (HC) are limited. Methods. 2,374 sexually active women aged 15–49 years from cohort surveys in Rakai, Uganda, were included. Incidence of T. vaginalis was estimated per 100 person years (py) and association between HC (DMPA, Norplant, and oral contraceptives) and T. vaginalis infection was assessed by incidence rate ratios (IRR), using Poisson regression models. Results. At baseline, 34.9% had used HC in the last 12 months, 12.8% HIV+, 39.7% with high BV-scores (7–10), and 3.1% syphilis positive. The 12-month incidence of T. vaginalis was 2.4/100 py; CI (1.90, 3.25). When stratified by type of HC used, compared to women who did not use HC or condoms, incidence of T. vaginalis was significantly higher among users of Norplant (adj.IRR = 3.01, CI: 1.07–8.49) and significantly lower among DMPA users (adj.IRR = 0.55, CI: 0.30, 0.98) and women who discontinued HC use at follow-up (adj.IRR = 0.30, CI: 0.09, 0.99). HIV infection was associated with an increase in incidence of T. vaginalis (adj.IRR = 2.34, CI: 1.44, 3.78). Conclusions. Use of Norplant and being HIV+ significantly increased the risk of T. vaginalis, while use of DMPA and discontinuation of overall HC use were associated with a decreased incidence of T. vaginalis.

ABSTRACTMale circumcision reduces female-to-male HIV transmission. Hypothesized mechanisms for this protective effect include decreased HIV target cell recruitment and activation due to changes in the penis microbiome. We compared the coronal sulcus microbiota of men from a group of uncircumcised controls (n= 77) and from a circumcised intervention group (n= 79) at enrollment and year 1 follow-up in a randomized circumcision trial in Rakai, Uganda. We characterized microbiota using16S rRNA gene-based quantitative PCR (qPCR) and pyrosequencing, log response ratio (LRR), Bayesian classification, nonmetric multidimensional scaling (nMDS), and permutational multivariate analysis of variance (PerMANOVA). At baseline, men in both study arms had comparable coronal sulcus microbiota; however, by year 1, circumcision decreased the total bacterial load and reduced microbiota biodiversity. Specifically, the prevalence and absolute abundance of 12 anaerobic bacterial taxa decreased significantly in the circumcised men. While aerobic bacterial taxa also increased postcircumcision, these gains were minor. The reduction in anaerobes may partly account for the effects of circumcision on reduced HIV acquisition.IMPORTANCEThe bacterial changes identified in this study may play an important role in the HIV risk reduction conferred by male circumcision. Decreasing the load of specific anaerobes could reduce HIV target cell recruitment to the foreskin. Understanding the mechanisms that underlie the benefits of male circumcision could help to identify new intervention strategies for decreasing HIV transmission, applicable to populations with high HIV prevalence where male circumcision is culturally less acceptable.

OBJECTIVE: To evaluate the limitations of rapid tests for HIV-1. Design Diagnostic test accuracy study. Setting Rural Rakai, Uganda. Participants 1517 males aged 15-49 screened for trials of circumcision for HIV prevention. MAIN OUTCOME MEASURES: Sensitivity, specificity, negative predictive values, and positive predictive values of an algorithm using three rapid tests for HIV, compared with the results of enzyme immunoassay and western blotting as the optimal methods. RESULTS: Rapid test results were evaluated by enzyme immunoassay and western blotting. Sensitivity was 97.7%. Among 639 samples where the strength of positive bands was coded if the sample showed positivity for HIV, the algorithm had low specificity (94.1%) and a low positive predictive value (74.0%). Exclusion of 37 samples (5.8%) with a weak positive band improved the specificity (99.6%) and positive predictive value (97.7%). CONCLUSION: Weak positive bands on rapid tests for HIV should be confirmed by enzyme immunoassay and western blotting before disclosing the diagnosis. Programmes using rapid tests routinely should use standard serological assays for quality control. Trial registration Clinical Trials NCT00425984.