Prevalence and Predictors of Persistent Human Immunodeficiency Virus Viremia and Viral Rebound After Universal Test and Treat: A Population-Based Study.

BACKGROUND: There are limited data on individual human immunodeficiency virus (HIV) viral load (VL) trajectories at the population-level after the introduction of universal test and treat (UTT) in sub-Saharan Africa. METHODS: Human immunodeficiency virus VLs were assessed among HIV-positive participants through 3 population-based surveys in 4 Ugandan fishing communities surveyed between November 2011 and August 2017. The unit of analysis was a visit-pair (2 consecutive person-visits), which were categorized as exhibiting durable VL suppression, new/renewed VL suppression, viral rebound, or persistent viremia. Adjusted relative risks (adjRRs) and 95% confidence intervals (CIs) of persistent viremia were estimated using multivariate Poisson regression. RESULTS: There were 1346 HIV-positive participants (n = 1883 visit-pairs). The population-level prevalence of durable VL suppression increased from 29.7% to 67.9% during UTT rollout, viral rebound declined from 4.4% to 2.7%, and persistent viremia declined from 20.8% to 13.3%. Younger age (15-29 vs 40-49 years; adjRR = 1.80; 95% CI = 1.19-2.71), male sex (adjRR = 2.09, 95% CI = 1.47-2.95), never being married (vs currently married; adjRR = 1.88, 95% CI = 1.34-2.62), and recent migration to the community (vs long-term resident; adjRR = 1.91, 95% CI = 1.34-2.73) were factors associated with persistent viremia. CONCLUSIONS: Despite increases in durable VL suppression during roll out of UTT in hyperendemic communities, a substantial fraction of the population, whose risk profile tended to be younger, male, and mobile, remained persistently viremic.

Adaptive Viral Load Monitoring Frequency to Facilitate Differentiated Care: A Modeling Study From Rakai, Uganda.

BACKGROUND: After scale-up of antiretroviral therapy (ART), routine annual viral load monitoring has been adopted by most countries, but reduced frequency of viral load monitoring may offer cost savings in resource-limited settings. We investigated if viral load monitoring frequency could be reduced while maintaining detection of treatment failure. METHODS: The Rakai Health Sciences Program performed routine, biannual viral load monitoring on 2489 people living with human immunodeficiency virus (age ≥15 years). On the basis of these data, we built a 2-stage simulation model to compare different viral load monitoring schemes. We fit Weibull regression models for time to viral load >1000 copies/mL (treatment failure), and simulated data for 10 000 individuals over 5 years to compare 5 monitoring schemes to the current viral load testing every 6 months and every 12 months. RESULTS: Among 7 monitoring schemes tested, monitoring every 6 months for all subjects had the fewest months of undetected failure but also had the highest number of viral load tests. Adaptive schemes using previous viral load measurements to inform future monitoring significantly decreased the number of viral load tests without markedly increasing the number of months of undetected failure. The best adaptive monitoring scheme resulted in a 67% reduction in viral load measurements, while increasing the months of undetected failure by <20%. CONCLUSIONS: Adaptive viral load monitoring based on previous viral load measurements may be optimal for maintaining patient care while reducing costs, allowing more patients to be treated and monitored. Future empirical studies to evaluate differentiated monitoring are warranted.

Elevated liver stiffness without histological evidence of liver fibrosis in rural Ugandans.

Liver fibrosis may be assessed noninvasively with transient electrography (TE). Data on the performance of TE for detecting liver fibrosis in sub-Saharan Africa are limited. We evaluated the diagnostic accuracy of TE by performing liver biopsies on persons with liver fibrosis indicated by TE. We enrolled HIV-infected and HIV-uninfected participants with TE scores consistent with at least minimal disease (liver stiffness measurement [LSM]≥7.1 kPa). Biopsies were performed and staged using the Ishak scoring system. A concordant result was defined using accepted thresholds for significant fibrosis by TE (LSM ≥ 9.3 kPa) and liver biopsy (Ishak score ≥ 2). We used modified Poisson regression methods to quantify the univariate and adjusted prevalence risk ratios (PRR) of the association between covariates and the concordance status of TE and liver biopsy in defining the presence of liver fibrosis. Of 131 participants with valid liver biopsy and TE data, only 5 participants (3.8%) had Ishak score ≥ 2 of whom 4 had LSM ≥ 9.3 kPa (sensitivity = 80%); of the 126 (96.2%) with Ishak score < 2, 76 had LSM < 9.3 kPa (specificity = 61%). In multivariable analysis, discordance was associated with female gender (adjPRR = 1.80, 95%CI 1.1-2.9; P = .019), herbal medicine use (adjPRR 1.64, 95% CI = 1.0-2.5; P = .022), exposure to lake or river water (adjPRR 2.05, 95% CI = 1.1-3.7; P = .016), and current smoking (adjPRR 1.72, 95%CI 1.0-2.9; P = .045). These data suggest that TE among rural Ugandans has low specificity for detection of histologically confirmed liver fibrosis. Caution should be exercised when using this tool to confirm significant liver fibrosis.

Rates of switching to second-line antiretroviral therapy and impact of delayed switching on immunologic, virologic, and mortality outcomes among HIV-infected adults with virologic failure in Rakai, Uganda.

BACKGROUND: Switch from first to second-line ART is recommended by WHO for patients with virologic failure. Delays in switching may contribute to accumulated drug resistance, advanced immunosuppression, increased morbidity and mortality. The 3rd 90' of UNAIDS 90:90:90 targets 90% viral suppression for persons on ART. We evaluated the rate of switching to second-line antiretroviral therapy (ART), and the impact of delayed switching on immunologic, virologic, and mortality outcomes in the Rakai Health Sciences Program (RHSP) Clinical Cohort Study which started providing ART in 2004 and implemented 6 monthly routine virologic monitoring beginning in 2005. METHODS: Retrospective cohort study of HIV-infected adults on first-line ART who had two consecutive viral loads (VLs) >1000 copies/ml after 6 months on ART between June 2004 and June 2011 was studied for switching to second-line ART. Immunologic decline after virologic failure was defined as decrease in CD4 count of ≥50 cells/ul and virologic increase was defined as increase of 0.5 log 10 copies/ml. Competing risk models were used to summarize rates of switching to second-line ART while cox proportional hazard marginal structural models were used to assess the risk of virologic increase or immunologic decline associated with delay to switch first line ART failing patients. RESULTS: The cumulative incidence of switching at 6, 12, and 24 months following virologic failure were 30.2%, 44.6%, and 65.0%, respectively. The switching rate was increased with higher VL at the time of virologic failure; compared to those with VLs ≤ 5000 copies/ml, patients with VLs = 5001-10,000 copies/ml had an aHR = 1.81 (95% CI = 0.9-3.6), and patients with VLs > 10,000 copies/ml had an aHR = 3.38 (95%CI = 1.9-6.2). The switching rate was also increased with CD4 < 100 cells/ul at ART initiation, compared to those with CD4 ≥ 100 cells/ul (aHR = 2.30, 95% CI = 1.5-3.6). Mortality in patients not switched to second-line ART was 11.9%, compared to 1.2% for those who switched (p = 0.009). Patients switched after 12 months of of virologic failure were more likely to experience CD4 decline and/or further VL increases. CONCLUSIONS: Intervention strategies that aid clinicians to promptly switch patients to second-line ART as soon as virologic failure on 1st line ART is confirmed should be prioritized.

Pre-exposure prophylaxis (PrEP) knowledge, use, and discontinuation among Lake Victoria fisherfolk in Uganda: a cross-sectional population-based study.

Background: There are limited population-level data on the pre-exposure prophylaxis (PrEP) care continuum in eastern Africa. Here, we assessed the PrEP care continuum following PrEP rollout in a Ugandan community with ~40% HIV seroprevalence. Methods: We used cross-sectional population-based data collected between September 3 and December 19, 2018 from a Lake Victoria fishing community in southern Uganda to measure levels of self-reported PrEP knowledge, ever use, and discontinuation following 2017 PrEP rollout via a U.S. President's Emergency Plan for AIDS Relief (PEPFAR)-supported phased implementation program. Our analysis included HIV-seronegative persons reporting having ever received an HIV test result. We examined associations between demographic, behavioral, and health utilization factors with each outcome using age-adjusted modified Poisson regression. Results: There were 1,401 HIV-seronegative participants, of whom 1,363 (97.3%) reported ever receiving an HIV test result. Median age was 29 years (IQR: 23-36), and 42.3% (n=577) were women. Most (85.5%; n=1,166) participants reported PrEP knowledge, but few (14.5%; n=197) reported ever using PrEP. Among 375 (47.7%) men and 169 (29.3%) women PrEP-eligible at time of survey, 18.9% (n=71) and 27.8% (n=47) reported ever using PrEP, respectively. Over half (52.3%, n=103) of those who had ever used PrEP, self-reported current use. Conclusion: In this Lake Victoria fishing community, there were low levels of PrEP use despite high levels of PrEP awareness and eligibility, particularly among men. Efforts that enhance awareness of HIV risk and increase PrEP accessibility may help increase PrEP use among HIV-seronegative persons in African settings with high HIV burden.

Temporal dynamics and drivers of durable HIV viral load suppression and persistent high- and low-level viraemia during Universal Test and Treat scale-up in Uganda: a population-based study.

INTRODUCTION: Population-level data on durable HIV viral load suppression (VLS) following the implementation of Universal Test and Treat (UTT) in Africa are limited. We assessed trends in durable VLS and viraemia among persons living with HIV in 40 Ugandan communities during the UTT scale-up. METHODS: In 2015-2020, we measured VLS (<200 RNA copies/ml) among participants in the Rakai Community Cohort Study, a longitudinal population-based HIV surveillance cohort in southern Uganda. Persons with unsuppressed viral loads were characterized as having low-level (200-999 copies/ml) or high-level (≥1000 copies/ml) viraemia. Individual virologic outcomes were assessed over two consecutive RCCS survey visits (i.e. visit-pairs; ∼18-month visit intervals) and classified as durable VLS (<200 copies/ml at both visits), new/renewed VLS (<200 copies/ml at follow-up only), viral rebound (<200 copies/ml at initial visit only) or persistent viraemia (≥200 copies/ml at both visits). Population prevalence of each outcome was assessed over calendar time. Community-level prevalence and individual-level predictors of persistent high-level viraemia were also assessed using multivariable Poisson regression with generalized estimating equations. RESULTS: Overall, 3080 participants contributed 4604 visit-pairs over three survey rounds. Most visit-pairs (72.4%) exhibited durable VLS, with few (2.5%) experiencing viral rebound. Among those with any viraemia at the initial visit (23.5%, n = 1083), 46.9% remained viraemic through follow-up, 91.3% of which was high-level viraemia. One-fifth (20.8%) of visit-pairs exhibiting persistent high-level viraemia self-reported antiretroviral therapy (ART) use for ≥12 months. Prevalence of persistent high-level viraemia varied substantially across communities and was significantly elevated among young persons aged 15-29 years (vs. 40- to 49-year-olds; adjusted risk ratio [adjRR] = 2.96; 95% confidence interval [95% CI]: 2.21-3.96), males (vs. females; adjRR = 2.40, 95% CI: 1.87-3.07), persons reporting inconsistent condom use with non-marital/casual partners (vs. persons with marital/permanent partners only; adjRR = 1.38, 95% CI: 1.10-1.74) and persons reporting hazardous alcohol use (adjRR = 1.09, 95% CI: 1.03-1.16). The prevalence of persistent high-level viraemia was highest among males <30 years (32.0%). CONCLUSIONS: Following universal ART provision, most persons living with HIV in south-central Uganda are durably suppressed. Among persons exhibiting any viraemia, nearly half exhibited high-level viraemia for ≥12 months and reported higher-risk behaviours associated with onward HIV transmission. Intensified efforts linking individuals to HIV treatment services could accelerate momentum towards HIV epidemic control.

Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda.

HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep-sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted: whereas HIV transmission to girls and women (aged 15-24 years) from older men declined by about one-third, transmission to women (aged 25-34 years) from men that were 0-6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programmes to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa.

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.

Temporal dynamics and drivers of durable HIV viral load suppression and persistent high- and low-level viremia during Universal Test and Treat scale-up in Uganda: a population-based study.

Introduction: Population-level data on durable HIV viral load suppression (VLS) following implementation of Universal Test and Treat (UTT) in Africa are limited. We assessed trends in durable VLS and viremia among persons living with HIV in 40 Ugandan communities during UTT scale-up. Methods: In 2015-2020, we measured VLS (defined as <200 RNA copies/mL) among participants in the Rakai Community Cohort Study, a longitudinal population-based HIV surveillance cohort in southern Uganda. Persons with unsuppressed viral loads were characterized as having low-level (200-999 copies/mL) or high-level (≥1,000 copies/mL) viremia. Individual virologic outcomes were assessed over two consecutive RCCS survey visits (i.e., visit-pairs; ∼18 month visit intervals) and classified as durable VLS (<200 copies/mL at both visits), new/renewed VLS (<200 copies/mL at follow-up only), viral rebound (<200 copies/mL at initial visit only), or persistent viremia (<200 copies/mL at neither visit). Population prevalence of each outcome was assessed over calendar time. Community-level prevalence and individual-level predictors of persistent high-level viremia were also assessed using multivariable Poisson regression with generalized estimating equations. Results: Overall, 3,080 participants contributed 4,604 visit-pairs over three survey rounds. Most visit-pairs (72.4%) exhibited durable VLS, with few (2.5%) experiencing viral rebound. Among those with viremia at the initial visit ( n =1,083), 46.9% maintained viremia through follow-up, 91.3% of which was high-level viremia. One-fifth (20.8%) of visit-pairs exhibiting persistent high-level viremia self-reported antiretroviral therapy (ART) use for ≥12 months. Prevalence of persistent high-level viremia varied substantially across communities and was significantly elevated among young persons aged 15-29 years (versus 40-49-year-olds; adjusted risk ratio [adjRR]=2.96; 95% confidence interval [95%CI]:2.21-3.96), men (versus women; adjRR=2.40, 95%CI:1.87-3.07), persons reporting inconsistent condom use with non-marital/casual partners (versus persons with marital/permanent partners only; adjRR=1.38, 95%CI:1.10-1.74), and persons exhibiting hazardous alcohol use (adjRR=1.09, 95%CI:1.03-1.16). The prevalence of persistent high-level viremia was highest among men <30 years (32.0%). Conclusions: Following universal ART provision, most persons living with HIV in south-central Uganda are durably suppressed. Among persons exhibiting viremia, nearly half maintain high-level viremia for ≥12 months and report higher-risk behaviors associated with onward HIV transmission. Enhanced linkage to HIV care and optimized treatment retention could accelerate momentum towards HIV epidemic control.

Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda.

HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years. As new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance of 38,749 participants in the Rakai Community Cohort Study and longitudinal deep sequence viral phylogenetics to assess how HIV incidence and population groups driving transmission have changed from 2003 to 2018 in Uganda. We observed 1,117 individuals in the incidence cohort and 1,978 individuals in the transmission cohort. HIV viral suppression increased more rapidly in women than men, however incidence declined more slowly in women than men. We found that age-specific transmission flows shifted, while HIV transmission to girls and women (aged 15-24 years) from older men declined by about one third, transmission to women (aged 25-34 years) from men that were 0-6 years older increased by half in 2003 to 2018. Based on changes in transmission flows, we estimated that closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018. This study suggests that HIV programs to increase HIV suppression in men are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa.

Male circumcision for the prevention of HSV-2 and HPV infections and syphilis.

BACKGROUND: Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. METHODS: We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2-seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. RESULTS: At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P=0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P=0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P=0.44). CONCLUSIONS: In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure. (ClinicalTrials.gov numbers, NCT00425984 and NCT00124878.)

HIV-1 transmitting couples have similar viral load set-points in Rakai, Uganda.

It has been hypothesized that HIV-1 viral load set-point is a surrogate measure of HIV-1 viral virulence, and that it may be subject to natural selection in the human host population. A key test of this hypothesis is whether viral load set-points are correlated between transmitting individuals and those acquiring infection. We retrospectively identified 112 heterosexual HIV-discordant couples enrolled in a cohort in Rakai, Uganda, in which HIV transmission was suspected and viral load set-point was established. In addition, sequence data was available to establish transmission by genetic linkage for 57 of these couples. Sex, age, viral subtype, index partner, and self-reported genital ulcer disease status (GUD) were known. Using ANOVA, we estimated the proportion of variance in viral load set-points which was explained by the similarity within couples (the 'couple effect'). Individuals with suspected intra-couple transmission (97 couples) had similar viral load set-points (p = 0.054 single factor model, p = 0.0057 adjusted) and the couple effect explained 16% of variance in viral loads (23% adjusted). The analysis was repeated for a subset of 29 couples with strong genetic support for transmission. The couple effect was the major determinant of viral load set-point (p = 0.067 single factor, and p = 0.036 adjusted) and the size of the effect was 27% (37% adjusted). Individuals within epidemiologically linked couples with genetic support for transmission had similar viral load set-points. The most parsimonious explanation is that this is due to shared characteristics of the transmitted virus, a finding which sheds light on both the role of viral factors in HIV-1 pathogenesis and on the evolution of the virus.

Evaluation of the safety and efficiency of the dorsal slit and sleeve methods of male circumcision provided by physicians and clinical officers in Rakai, Uganda.

OBJECTIVE: To assess the safety and efficiency of the dorsal slit and sleeve male circumcision (MC) procedures performed by physicians and clinical officers (COs). PATIENTS AND METHODS: We evaluated the time required for the MC procedure (efficiency) and moderate/severe adverse events (AEs) for MC (safety) by trained physicians and COs using the sleeve and dorsal slit MC methods in a service programme. Univariate and multiple regressions with robust variance estimation were used to assess factors associated with operative duration (linear) and AEs (logistic). RESULTS: Six physicians and eight COs conducted 1934 and 3218 MCs, respectively; there were 2471 dorsal slit and 2681 sleeve MC procedures. The overall mean operative duration was 33 min for newly trained providers, which decreased to ≈20 min after ≈100 MCs. The adjusted mean operative duration for dorsal slit MC was significantly shorter than that for the sleeve MC method (Δ - 2.7 min, P < 0.001). The operative duration was longer for COs than physicians for the sleeve procedure, but not the dorsal slit procedure; however this difference reduced with increasing numbers of MCs completed. The unadjusted AE rates were 0.6% for dorsal slit MC and 1.4% for the sleeve method (P = 0.006) and 1.5% for physicians and 0.68% for COs (P = 0.003); however, there were no significant differences after multivariate adjustment. Use of bipolar cautery significantly reduced operative duration (Δ - 4.0 min, P = 0.008), but was associated with higher AE rates (adjusted odds ratio 2.13, 95% confidence interval 1.26-3.61, P = 0.005). CONCLUSION: The dorsal slit MC method is faster than sleeve resection, and can be safely performed by non-physicians; however, use of bipolar cautery may be inadvisable in this setting.

Hepatitis B virus infection and factors associated with its acquisition among adults in a Lake Victoria HIV hyperendemic fishing community in Kyotera district, Uganda: a cross-sectional observation.

OBJECTIVE: To investigate hepatitis B virus (HBV) prevalence and factors associated with viral acquisition in a HIV-hyperendemic fishing community, we tested sera for anti-hepatitis B core (HBc) and hepatitis B surface antigen (HBsAg). DESIGN: Observational cross-sectional study. SETTING: Large fishing village on Lake Victoria, one of the HIV-hyperendemic Rakai Community Cohort Study (RCCS) sites (HIV prevalence ~40%). PARTICIPANTS: Sample of 460 RCCS participants aged 15-49 years from survey conducted from 5 December 2016 to 13 February 2017. These proportionately included HIV-negative, HIV-positive antiretroviral therapy (ART)-naïve and HIV positive on ART participants. RESULTS: Of the 460 participants, 49.6% (95% CI 45.0% to 54.1%) had evidence of prior HBV infection and 3.7% (95% CI 2.3% to 5.9%) were either acutely or chronically infected. HBV risk increased with age, number of lifetime sex partners and HIV seropositivity. HBV risk decreased with HIV ART use among HIV-positive participants. Prevalence of prior HBV infection was 17.1% in participants aged 15-19 years, 43.2%, 55.3% and 70.1% in participants aged 20-39, 30-39 and 40-49 years, respectively (p<0.001). Additionally, the prevalence of prior HBV infection was 23.8% in participants with 0-1 lifetime sex partners, 43.2% and 54.8% in participants with 2-3 lifetime sex partners and 4+ lifetime sex partners, respectively (p<0.001). CONCLUSIONS: Findings from this fishing community suggest the need to provide HBV vaccination to adults at risk of sexual transmission who have not been previously immunised.

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.

Impact of a mHealth intervention for peer health workers on AIDS care in rural Uganda: a mixed methods evaluation of a cluster-randomized trial.

Mobile phone access in low and middle-income countries is rapidly expanding and offers an opportunity to leverage limited human resources for health. We conducted a mixed methods evaluation of a cluster-randomized trial exploratory substudy on the impact of a mHealth (mobile phone) support intervention used by community-based peer health workers (PHW) on AIDS care in rural Uganda. 29 PHWs at 10 clinics were randomized by clinic to receive the intervention or not. PHWs used phones to call and text higher level providers with patient-specific clinical information. 970 patients cared for by the PHWs were followed over a 26 month period. No significant differences were found in patients' risk of virologic failure. Qualitative analyses found improvements in patient care and logistics and broad support for the mHealth intervention among patients, clinic staff, and PHWs. Key challenges identified included variable patient phone access, privacy concerns, and phone maintenance.

Circumcision of HIV-infected men: effects on high-risk human papillomavirus infections in a randomized trial in Rakai, Uganda.

UNLABELLED: In Rakai, Uganda, human immunodeficiency virus (HIV)-positive men were randomized to undergo either immediate circumcision (intervention arm) or delayed circumcision (control arm). Penile swab samples were assayed for high-risk human papillomavirus (HR-HPV) by Roche HPV Linear Array at enrollment and at 24 months (intervention arm, 103 subjects; control arm, 107 subjects). Rate ratios (RRs) of HR-HPV were estimated by Poisson regression. At 24 months, HR-HPV prevalence was found in 57 (55.3%) of 103 subjects in the intervention arm and in 77 (71.7%) of 107 subjects in the control arm (RR, 0.77; 95% confidence interval [CI], 0.62-0.97). Multiple HR-HPV infections were found in 19 (22.4%) of 85 subjects in the intervention arm and in 45 (42.5%) of 106 subjects in the control arm (RR, 0.53; 95% CI, 0.33-0.83). New HR-HPV genotypes were acquired by 34 (42.0%) of 81 subjects in the intervention arm and by 53 (57.0%) 85 subjects in the control arm (RR, 0.74; 95% CI, 0.54-1.01; P = .06). Multiple new HR-HPV genotypes were acquired by 8 (9.9%) of 81 subjects in the intervention arm and by 23 (24.7%) of 93 subjects in the control arm (RR, 0.40; 95% CI, 0.19-0.84; P = .01). Circumcision did not affect the acquisition of single HR-HPV infections (RR, 1.00; 95% CI 0.65-1.53) or clearance of HR-HPV infections (RR, 1.09; 95% CI 0.94-1.27). Circumcision of HIV-positive men reduced the prevalence and incidence of multiple HR-HPV infections. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00124878 .

Male circumcision decreases acquisition and increases clearance of high-risk human papillomavirus in HIV-negative men: a randomized trial in Rakai, Uganda.

METHODS: Uncircumcised human immunodeficiency virus (HIV)-negative men aged 15-49 years were randomized to immediate circumcision (intervention arm, 441 subjects) or delayed circumcision (control arm, 399 subjects). Human papillomavirus (HPV) was detected by Roche HPV Linear Array at enrollment, and at 6, 12, and 24 months. Incident high-risk HPV (HR-HPV) was estimated in men who acquired a new HR-HPV genotype. HR-HPV clearance was determined in men with prior genotype-specific HR-HPV infections. Rate ratios (RRs) and 95% confidence intervals (CIs) of HR-HPV acquisition were estimated by Poisson multiple regression. RESULTS: Enrollment characteristics were comparable between study groups. HR-HPV incidence was 19.7 cases per 100 person-years (PYs) in the intervention arm (70 cases per 355.8 PYs) and 29.4 cases per 100 PYs (125 cases per 424.8 PYs) in the control arm (RR, 0.67; 95% CI, 0.51-0.89; P = .006). The incidence of multiple HR-HPV infections was 6.7 cases per 100 PYs in the intervention arm and 14.8 cases per 100 PYs in the control arm (RR, 0.45; 95% CI, 0.28-0.73), but there was no significant effect on single infections (RR, 0.89; 95% CI, 0.60-1.30). HR-HPV incidence was lower in the intervention arm for all genotypes and demographic/behavioral subgroups. The clearance of preexisting HR-HPV infections was 215.8 cases per 100 PYs (205 cases per 95 PYs) in the intervention arm and 159.1 cases per 100 PYs (255 cases per 160.25 PYs) in the control arm (adjusted RR, 1.39; 95% CI, 1.17-1.64). CONCLUSIONS: Male circumcision reduces the incidence of multiple HR-HPV infections and increases clearance of HR-HPV infections in HIV-uninfected men. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00425984 .

Circumcision in HIV-infected men and its effect on HIV transmission to female partners in Rakai, Uganda: a randomised controlled trial.

BACKGROUND: 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. METHODS: 922 uncircumcised, HIV-infected, asymptomatic men aged 15-49 years with CD4-cell counts 350 cells per microL or more were enrolled in this unblinded, randomised controlled trial in Rakai District, Uganda. Men were randomly assigned by computer-generated randomisation sequence to receive immediate circumcision (intervention; n=474) or circumcision delayed for 24 months (control; n=448). HIV-uninfected female partners of the randomised men were concurrently enrolled (intervention, n=93; control, n=70) and followed up at 6, 12, and 24 months, to assess HIV acquisition by male treatment assignment (primary outcome). A modified intention-to-treat (ITT) analysis, which included all concurrently enrolled couples in which the female partner had at least one follow-up visit over 24 months, assessed female HIV acquisition by use of survival analysis and Cox proportional hazards modelling. This trial is registered with ClinicalTrials.gov, number NCT00124878. FINDINGS: The trial was stopped early because of futility. 92 couples in the intervention group and 67 couples in the control group were included in the modified ITT analysis. 17 (18%) women in the intervention group and eight (12%) women in the control group acquired HIV during follow-up (p=0.36). Cumulative probabilities of female HIV infection at 24 months were 21.7% (95% CI 12.7-33.4) in the intervention group and 13.4% (6.7-25.8) in the control group (adjusted hazard ratio 1.49, 95% CI 0.62-3.57; p=0.368). INTERPRETATION: Circumcision of HIV-infected men did not reduce HIV transmission to female partners over 24 months; longer-term effects could not be assessed. Condom use after male circumcision is essential for HIV prevention. FUNDING: Bill & Melinda Gates Foundation with additional laboratory and training support from the National Institutes of Health and the Fogarty International Center.

Temporal trends of early mortality and its risk factors in HIV-infected adults initiating antiretroviral therapy in Uganda.

BACKGROUND: A decline in mortality rates during the first 12 months of antiretroviral therapy (ART) has been mainly linked to increased ART initiation at higher CD4 counts and at less advanced World Health Organization (WHO) clinical stages of HIV infection; however, the role of improved patient care has not been well studied. We estimated improvements in early mortality due to improved patient care. METHODS: We conducted a retrospective cohort study of HIV-infected individuals ages 18 and older who initiated ART at the Mengo HIV Counseling and Home Care Clinic between 2006 and 2016. We conducted a mediation analysis using generalized structural equation models with inverse odds ratio weighting to estimate the natural direct and indirect effects of ART initiation time on early mortality. FINDINGS: Among 6,847 patients, most were female (69%), with a median age of 32 (interquartile range [IQR] = 28-38), versus a median age of 38 (IQR = 32-45) for males. The median CD4 count at ART initiation increased from 142 cells/ul (95% confidence interval [CI] = 135-150) in 2006-2010 to 302 cells/ul (95% CI = 283-323) in 2015-2016 (p < 0·001). The number of patients at WHO clinical stages I/II increased from 52% in 2006-2010 to 78% in 2015-2016 (p < 0·001). Annual early mortality decreased from 8·8 deaths/100 person years (PYS) in 2006 to 2.5 deaths/100 pys in 2016 (p < 0·001). Mediation by CD4 counts and WHO clinical stages accounted for 54% of the total effect of ART initiation timing on early mortality. In comparison, 46% remained as the direct effect, reflecting the contribution of improved patient care. INTERPRETATION: Improved patient care practices should be promoted as a strategy for reducing early mortality after ART initiation, above and beyond the effects from ART initiation at higher CD4 counts and less advanced WHO clinical stage alone. FUNDING: This research was supported by the President's Emergency Plan for AIDS Relief (PEPFAR), the National Institute of Allergy and Infectious Diseases Division of Intramural Research, and the National Cancer Institute.