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.

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.

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.

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.

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.

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.

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.

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.

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.

Impact of combination HIV interventions on HIV incidence in hyperendemic fishing communities in Uganda: a prospective cohort study.

BACKGROUND: 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. METHODS: We did an open population-based cohort study of people aged 15-49 years residing in four fishing communities on Lake Victoria. The communities were surveyed five times to collect self-reported demographic, behavioural, and service-uptake data. Free HIV testing was provided at each interview, with referral to combination HIV intervention services as appropriate. From November, 2011, combination HIV intervention services were rapidly expanded in these geographical areas. We evaluated trends in HIV testing coverage among all participants, circumcision coverage among male participants, antiretroviral therapy (ART) coverage and HIV viral load among HIV-positive participants, and sexual behaviours and HIV incidence among HIV-negative participants. FINDINGS: From Nov 4, 2011, to Aug 16, 2017, data were collected from five surveys. Overall, 8942 participants contributed 20 721 person-visits; 4619 (52%) of 8942 participants were male. HIV prevalence was 41% (1598 of 3870) in the 2011-12 baseline survey and declined to 37% (1740 of 4738) at the final survey (p<0·0001). 3222 participants who were HIV-negative at baseline, and who had at least one repeat visit, contributed 9477 person-years of follow-up, and 230 incident HIV infections occurred. From the first survey in 2011-12 to the last survey in 2016-17, HIV testing coverage increased from 68% (2613 of 3870) to 96% (4526 of 4738; p<0·0001); male circumcision coverage increased from 35% (698 of 2011) to 65% (1630 of 2525; p<0·0001); ART coverage increased from 16% (254 of 1598) to 82% (1420 of 1740; p<0·0001); and population HIV viral load suppression in all HIV-positive participants increased from 34% (546 of 1596) to 80% (1383 of 1734; p<0·0001). Risky sexual behaviours did not decrease over this period. HIV incidence decreased from 3·43 per 100 person-years (95% CI 2·45-4·67) in 2011-12 to 1·59 per 100 person-years (95% CI 1·19-2·07) in 2016-17; adjusted incidence rate ratio (IRR) 0·52 (95% CI 0·34-0·79). Declines in HIV incidence were similar among men (adjusted IRR 0·53, 95% CI 0·30-0·93) and women (0·51, 0·27-0·96). The risk of incident HIV infection was lower in circumcised men than in uncircumcised men (0·46, 0·32-0·67). INTERPRETATION: Rapid expansion of combination HIV interventions in HIV-hyperendemic fishing communities is feasible and could have a substantial impact on HIV incidence. However, incidence remains higher than HIV epidemic control targets, and additional efforts will be needed to achieve this global health priority. FUNDING: The National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, the National Cancer Institute, the National Institute for Allergy and Infectious Diseases Division of Intramural Research, Centers for Disease Control and Prevention Uganda, Karolinska Institutet, and the Johns Hopkins University Center for AIDS Research.

Results of Early Virologic Monitoring May Facilitate Differentiated Care Monitoring Strategies for Clients on ART, Rakai, Uganda.

BACKGROUND: Viral load (VL) monitoring is standard of care in HIV-infected persons initiated on antiretroviral therapy (ART). We evaluated the predictive value of VL measurements at 6 and 12 months after initiation of firstline ART to estimate the future risk of virologic failure (VF). METHODS: HIV-infected persons with VL measurements at 6 and 12 months post-ART initiation and at least 2 additional VL measurements thereafter were assessed for risk of future VF, defined per World Health Organization guidelines. VL at 6 or 12 months post-ART was categorized into <400, 400-1000, 1001-2000, and >2000 copies/mL. Cox proportional hazard models were used to compare VF incidence associated with 6-month, 12-month, and a composite of 6- and 12-month VL prediction indicators. RESULTS: Overall, 1863 HIV-infected adults had a 6- and 12-month VL measurement, and 1588 had at least 2 additional VLs thereafter for predicting future VF. The majority (67%) were female (median age: females 33 years and males 37 years). At 12 months post-ART, 90% had VL<400 copies/mL (cumulative incidence of VF at 1.5%), 3% had 400-1000 copies/mL (VF 12%), 2% had 1001-2000 copies/mL (VF 22%), and 5% had >2000 copies/mL (VF 71%). The predictive value of the 12-month VL measurement was comparable to the composite of both the 6- and 12-month VL measurements and better than the 6-month VL measurement. CONCLUSIONS: At 12 months after ART initiation, 90% of patients were virally suppressed with a low likelihood of future VF. VL measurement at 12 months post-ART initiation predicts risk of VF and could inform differentiated virologic monitoring strategies.

Opportunistic diseases diminish the clinical benefit of immediate antiretroviral therapy in HIV-tuberculosis co-infected adults with low CD4+ cell counts.

INTRODUCTION: HIV-tuberculosis (TB) co-infection remains an important cause of mortality in sub-Saharan Africa. Clinical trials have reported early (within 2 weeks of TB therapy) antiretroviral therapy (ART) reduces mortality among HIV-TB co-infected research participants with low CD4 cell counts, but this has not been consistently observed. We aimed to evaluate the current WHO recommendations for ART in HIV-TB co-infected patients on mortality in routine clinical settings. METHODS: We compared two cohorts before (2008-2010) and after (2012-2013) policy change on ART timing after TB and examined the effectiveness of early versus delayed ART on mortality in HIV-TB co-infected participants with CD4 cell count 100 cells/µl or less. We used inverse probability censoring-weighted Cox models on baseline characteristics to balance the study arms and generated hazard ratios for mortality. RESULTS: Of 356 participants with CD4 cell counts 100 cells/µl or less, 180 were in the delayed ART cohorts whereas 176 were in the early ART cohorts. Their median age (32.5 versus 32 years) and baseline CD4 cell counts (26.5 versus 26 cells/µl) respectively were similar. There was no difference in mortality rates of both cohorts. The risk of death increased in participants with a positive Cryptococcal antigen (CrAg) test in both the early ART cohort (aHR = 2.6, 95% CI 1.0-6.8; P = 0.045) and the delayed ART cohort (aHR = 4.2, 95% CI 1.9-9.0; P < 0.001 CONCLUSION:: Early ART in patients with HIV-TB co-infection was not associated with reduced risk of mortality in routine care. Asymptomatic Cryptococcal antigenaemia increased the risk of mortality in both cohorts.

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.

Impact of HIV and Atiretroviral Therapy on Neurocognitive Outcomes Among School-Aged Children.

INTRODUCTION: The impact of HIV infection and antiretroviral therapy (ART) on neurocognitive outcomes among children aged 7-14 years was assessed. We hypothesized that ART would ameliorate neurocognitive sequelae of HIV infection. METHODS: HIV-positive and HIV-negative mother-child pairs from the Rakai Community Cohort Study and ART clinics in Rakai, Uganda, were followed prospectively for 4 years. Exposures were stratified as: perinatally HIV infected, perinatally HIV exposed but uninfected, and HIV unexposed and uninfected. The Kaufman Assessment Battery for Children assessed sequential and simultaneous processing, learning, planning, knowledge, and fluid crystalized index for overall functioning. Multivariable generalized linear models estimated adjusted prevalence rate ratios by age. RESULTS: Of the 370 mother-child pairs, 55% were HIV unexposed and uninfected, 7% were perinatally HIV exposed but uninfected, and 37.9% were perinatally HIV infected. Among HIV-infected children, longer duration of ART was associated with a significant improvement of sequential processing skills (adjusted prevalence rate ratios 25-36 months: 0.55, 95% confidence interval [CI]: 0.34 to 0.9; 37-48 months: 0.39, 95% CI: 0.2 to 0.76; 49+ months: 0.23, 95% CI: 0.1 to 0.54). Each additional year of schooling was associated with a 30%-40% decrease of impairment for all neurocognitive measures assessed. Healthier children (higher age-standardized height and weight) had improved sequential and simultaneous processing and overall fluid crystalized index. CONCLUSIONS: Sequential processing skills of working memory improved with prolonged ART, and increased duration of schooling was associated with a reduction of neurocognitive impairment. Early initiation and sustained use of ARTs and longer schooling are needed to reduce neurocognitive impairment among HIV-infected school-aged children.

Hepatitis B incidence and prevention with antiretroviral therapy among HIV-positive individuals in Uganda.

OBJECTIVE: Antiretroviral therapy (ART) may interfere with replication of hepatitis B virus (HBV), raising the hypothesis that HBV infection might be prevented by ART. We investigated the incidence and risk factors associated with HBV among HIV-infected adults in Rakai, Uganda. METHODS: We screened stored sera from 944 HIV-infected adults enrolled in the Rakai Community Cohort Study between September 2003 and March 2015 for evidence of HBV exposure. Serum from participants who tested anti-hepatitis B core-negative (497) at baseline were tested over 3-7 consecutive survey rounds for incident HBV. Poisson incidence methods were used to estimate incidence of HBV with 95% confidence intervals (CIs), whereas Cox proportional regression methods were used to estimate hazard ratios (HRs). RESULTS: Thirty-nine HBV infections occurred over 3342 person-years, incidence 1.17/100 person-years. HBV incidence was significantly lower with ART use: 0.49/100 person-years with ART and 2.3/100 person-years without ART [adjusted HR (aHR) 0.25, 95% CI 0.1-0.5, P < 0.001], and with lamivudine (3TC) use: 0.58/100 person-years) with 3TC and 2.25/100 person-years without 3TC (aHR 0.32, 95% CI 0.1-0.7, P =  < 0.007). No new HBV infections occurred among those on tenofovir-based ART. HBV incidence also decreased with HIV RNA suppression: 0.6/100 person-years with 400 copies/ml or less and 4.0/100 person-years with more than 400 copies/ml (aHR, 6.4, 95% CI 2.2-19.0, P < 0.001); and with age: 15-29 years versus 40-50 years (aHR 3.2, 95% CI 1.2-9.0); 30-39 years versus 40-50 years (aHR 2.1, 95% CI 0.9-5.3). CONCLUSION: HBV continues to be acquired in adulthood among HIV-positive Ugandans and HBV incidence is dramatically reduced with HBV-active ART. In addition to widespread vaccination, initiation of ART may prevent HBV acquisition among HIV-positive adults in sub-Saharan Africa.

Low Rates of Transmitted Drug Resistance Among Newly Identified HIV-1 Seroconverters in Rural Rakai, Uganda.

We investigated the rate of transmitted drug resistance (TDR) among HIV-1 seroconverters identified from the Rakai Community Cohort Study (RCCS) survey, a population-based cohort in Rakai District, Uganda. Participants aged 15-49 are interviewed at study visits approximately every 12-18 months and provided a serological sample. Antiretroviral therapy (ART) has been provided free of charge since 2004. RCCS participants with documented negative HIV-1 serology between January 2011 and August 2012 and confirmed seroconversion between November 2012 and October 2013 were included in this analysis. Serum was genotyped for HIV drug resistance mutations in reverse transcriptase and protease genes. Mutations were classified according to the 2009 World Health Organization surveillance of transmitted HIV-1 drug resistance update. Seventy-five (75) seroconverters were identified and genotyped. The mean age was 28 years (range 18-49) and the majority were male, n = 44 (58%). The HIV-1 subtype frequencies were A = 19 (25%), D = 44 (59%), C = 4 (5%), A/D recombinant = 5 (7%), and C/D recombinant = 3 (4%). The majority (72/75, 96%) of individuals were infected with wild-type virus with no evidence of TDR. Two individuals had a single non-nucleoside reverse transcriptase inhibitor mutation each, K101E and K103N, and one had a single protease inhibitor mutation, M46I. No mutations were identified involving nucleoside reverse transcriptase inhibitors. In conclusion, almost 10 years after the introduction of ART in rural Uganda, rates of TDR remain low. Ongoing surveillance for TDR remains an important public health priority and should be conducted among known seroconverters to estimate TDR.

Postcoital penile washing and the risk of HIV acquisition in uncircumcised men.

BACKGROUND: Postcoital genital washing by uncircumcised men may affect the risk of male HIV acquisition. METHOD: We assessed the association between self-reported washing after sex in 2976 initially HIV-negative, uncircumcised men enrolled in a prospective cohort study in Rakai, Uganda. RESULTS: Data from the 2976 participants who reported sexual intercourse in the past 12 months contributed 4290 visits, with 7316.6 person-years of observation during the 2-year follow-up. The overall HIV-incidence was 1.28/100 person-years 95%CI (1.04-1.57). About 91.0% of men reported washing their penis after sex, and their HIV incidence was 1.34/100 person-years (95%CI 1.08-1.66), compared with an incidence of 0.62/100 person-years (95%CI 0.17-1.60) in men who did not wash their penis after intercourse. Using Poisson multivariable regression, the adjusted incidence rate ratio of HIV acquisition associated with postcoital washing was 1.94 (95%CI 0.71-5.29). CONCLUSION: Postcoital penile washing, as practiced in this rural African population does not afford protection from HIV acquisition among uncircumcised men, and may increase risk.