Chemokine Levels in the Penile Coronal Sulcus Correlate with HIV-1 Acquisition and Are Reduced by Male Circumcision in Rakai, Uganda.

Individual susceptibility to HIV is heterogeneous, but the biological mechanisms explaining differences are incompletely understood. We hypothesized that penile inflammation may increase HIV susceptibility in men by recruiting permissive CD4 T cells, and that male circumcision may decrease HIV susceptibility in part by reducing genital inflammation. We used multi-array technology to measure levels of seven cytokines in coronal sulcus (penile) swabs collected longitudinally from initially uncircumcised men enrolled in a randomized trial of circumcision in Rakai, Uganda. Coronal sulcus cytokine levels were compared between men who acquired HIV and controls who remained seronegative. Cytokines were also compared within men before and after circumcision, and correlated with CD4 T cells subsets in foreskin tissue. HIV acquisition was associated with detectable coronal sulcus Interleukin-8 (IL-8 aOR 2.26, 95%CI 1.04-6.40) and Monokine Induced by γ-interferon (MIG aOR 2.72, 95%CI 1.15-8.06) at the visit prior to seroconversion, and the odds of seroconversion increased with detection of multiple cytokines. Coronal sulcus chemokine levels were not correlated with those in the vagina of a man's female sex partner. The detection of IL-8 in swabs was significantly reduced 6 months after circumcision (PRR 0.59, 95%CI 0.44-0.87), and continued to decline for at least two years (PRR 0.29, 95%CI 0.16-0.54). Finally, prepuce IL-8 correlated with increased HIV target cell density in foreskin tissues, including highly susceptible CD4 T cells subsets, as well as with tissue neutrophil density. Together, these data suggest that penile inflammation increases HIV susceptibility and is reduced by circumcision.

Dynamics of Pre-Exposure (PrEP) Eligibility Because of Waxing and Waning of HIV Risk in Rakai, Uganda.

BACKGROUND: We conducted a retrospective population-based study to describe longitudinal patterns of prevalence, incidence, discontinuation, resumption, and durability of substantial HIV risk behaviors (SHR) for pre-exposure prophylaxis (PrEP) eligibility. METHODS: The study was conducted among HIV-negative study participants aged 15-49 years who participated in survey rounds of the Rakai Community Cohort Study between August 2011 and June 2018. Substantial HIV risk was defined based on the Uganda national PrEP eligibility as reporting sexual intercourse with >1 partner of unknown HIV status, nonmarital sex without a condom, having genital ulcers, or having transactional sex. Resumption of SHR meant resuming of SHR after stopping SHR, whereas persistence of SHR meant SHR on >1 consecutive visit. We used generalized estimation equations with log-binomial regression models and robust variance to estimate survey-specific prevalence ratios; Generalized estimation equations with modified Poisson regression models and robust variance to estimate incidence ratios for incidence, discontinuation, and resumption of PrEP eligibility. FINDINGS: Incidence of PrEP eligibility increased from 11.4/100 person-years (pys) in the first intersurvey period to 13.9/100 pys (adjusted incidence rate ratios = 1.28; 95%CI = 1.10-1.30) and declined to 12.6/100 pys (adjusted incidence rate ratios = 1.06; 95%CI = 0.98-1.15) in the second and third intersurvey periods, respectively. Discontinuation rates of SHR for PrEP eligibility were stable (ranging 34.9/100 pys-37.3/100 pys; P = 0.207), whereas resumption reduced from 25.0/100 pys to 14.5/100 pys ( P < 0.001). PrEP eligibility episodes lasted a median time of 20 months (IQR = 10-51). INTERPRETATION: Pre-exposure prophylaxis use should be tailored to the dynamic nature of PrEP eligibility. Preventive-effective adherence should be adopted for assessment of attrition in PrEP programs.

Smoker characteristics and trends in tobacco smoking in Rakai, Uganda, 2010-2018.

INTRODUCTION: Tobacco use is a major public health concern, particularly in low- and middle-income countries where 80% of the world's smokers reside. There is limited population-based data from rural Africa on patterns of tobacco smoking and smoker characteristics. We assessed trends in rates of smoking, characteristics of smokers, and factors associated with smoking using repeat population-based cross-sectional surveys in south-central Uganda. METHODS: Data accrued over five survey rounds (2010-2018) of the Rakai Community Cohort Study (RCCS) from consenting individuals aged 15-49 years including sociodemographic and behavioral characteristics and smoking status. Proportions of smokers per survey were compared using χ2 test for trends, and factors associated with smoking were assessed by multivariable logistic regression. RESULTS: The prevalence of tobacco smoking in the general population declined from 7.3% in 2010-2011 to 5.1% in 2016-2018, p<0.001. Smoking rates declined among males (13.9-9.2%) and females (2.2-1.8%) from 2010-2011 to 2016-2018. Smoking prevalence was higher among previously married (11.8-11.7%) compared to currently (8.4-5.3%) and never married persons (3.1-1.8%) from 2010-2011 to 2016-2018. Older age (≥35 years) was associated with higher odds of smoking (AOR=8.72; 95% CI: 5.68-13.39 in 2010-2011 and AOR=9.03; 95% CI: 5.42-15.06 in 2016-2018) compared to those aged <35 years (AOR=4.73; 95% CI: 3.15-7.12 in 2010-2011 and AOR=4.83; 95% CI: 2.95-7.91 in 2016-2018). Primary and secondary/higher education level was significantly associated with lower odds of smoking (AOR=0.20; 95% CI: 0.14-0.29 in 2010-2011 and AOR=0.26; 95% CI: 0.18-0.39 in 2016-2018) compared to no education (AOR=0.43; 95% CI: 0.31-0.59 in 2010-2011 and AOR=0.48; 95% CI: 0.34-0.68 in 2016-2018). Number of sexual partners and HIV status were not associated with smoking. CONCLUSIONS: We observed declining trends in tobacco smoking in the Rakai region of rural Uganda. Smoking was more prevalent in men, older individuals, individuals who were previously married, and individuals with lower education. The decline in smoking may be due to tobacco control efforts, but there is a continued need to target sub-populations with higher smoking prevalence.

High Rates of Pre-exposure Prophylaxis Eligibility and Associated HIV Incidence in a Population With a Generalized HIV Epidemic in Rakai, Uganda.

BACKGROUND: The utility of using pre-exposure prophylaxis (PrEP) eligibility assessments to identify eligibility in general populations has not been well studied in sub-Saharan Africa. We used the Rakai Community Cohort Study to conduct a cross-sectional analysis to estimate PrEP eligibility and a cohort analysis to estimate HIV incidence associated with PrEP eligibility. METHODS: Based on Uganda's national PrEP eligibility tool, we defined eligibility as reporting at least one of the following HIV risks in the past 12 months: sexual intercourse with more than one partner of unknown HIV status; nonmarital sex act without a condom; sex engagement in exchange for money, goods, or services; or experiencing genital ulcers. We used log-binomial and modified Poisson models to estimate prevalence ratios for PrEP eligibility and HIV incidence, respectively. FINDINGS: We identified 12,764 participants among whom to estimate PrEP eligibility prevalence and 11,363 participants with 17,381 follow-up visits and 30,721 person-years (pys) of observation to estimate HIV incidence. Overall, 29% met at least one of the eligibility criteria. HIV incidence was significantly higher in PrEP-eligible versus non-PrEP-eligible participants (0.91/100 pys versus 0.41/100 pys; P < 0.001) and independently higher in PrEP-eligible versus non-PrEP-eligible female participants (1.18/100 pys versus 0.50/100 pys; P < 0.001). Among uncircumcised male participants, HIV incidence was significantly higher in PrEP-eligible versus non-PrEP-eligible participants (1.07/100 pys versus 0.27/100 pys; P = 0.001), but there was no significant difference for circumcised male participants. INTERPRETATION: Implementing PrEP as a standard HIV prevention tool in generalized HIV epidemics beyond currently recognized high-risk key populations could further reduce HIV acquisition and aid epidemic control efforts.

Alcohol use and alcohol-related consequences are associated with not being virally suppressed among persons living with HIV in the Rakai region of Uganda.

BACKGROUND: Alcohol use is common among persons living with HIV (PWH) in Uganda and associated with poor HIV care outcomes; findings regarding the relationship between alcohol use and viral suppression (VS) have been inconclusive. METHODS: Data from two rounds (2017-2020) of the Rakai Community Cohort Study, an open population-based cohort study in the Rakai region, Uganda, were analyzed. Two alcohol exposures were explored: past year alcohol use and alcohol-related consequences. Multivariable models (GEE) were used to estimate associations between alcohol exposures and VS for the overall sample and stratified by sex, adjusting for repeated measurement. Causal mediation by ART use was explored. RESULTS: Over half (55 %) of participants (n = 3823 PWH) reported alcohol use at baseline; 37.8 % of those reporting alcohol use reported alcohol-related consequences. ART use and VS at baseline significantly differed by alcohol use with person reporting alcohol use being less likely to be on ART or VS. Alcohol use was significantly associated with decreased odds of VS among women but not men (adj. OR 0.72 95 % CI 0.58-0.89, p = 0.0031). However, among males who use alcohol, experiencing alcohol-related consequences was significantly associated with decreased odds of VS (adj. OR 0.69 95 % CI 0.54-0.88, p = 0.0034). The relationships between both alcohol exposures and VS were not significant in models restricted to persons on ART. CONCLUSIONS: We provide sex-stratified estimates of associations between two alcohol measures and VS in the context of current HIV treatment guidelines. This study confirms that alcohol use is adversely associated with VS but ART use mediates this pathway, suggesting that initiation and retention on ART are critical steps to addressing alcohol-related disparities in VS.