Assessment of risk compensation following use of the dapivirine vaginal ring in southwestern Uganda.

OBJECTIVES: Participation in HIV prevention trials could trigger risk compensation among participants. We evaluated potential risk compensation following use of a vaginal ring microbicide by women in a phase III trial in southwestern Uganda. METHODS: We used markers of sexual risk behaviour documented on standardised questionnaires, tested for STIs at baseline and quarterly for 2 years. Risk compensation was defined as a significant increase (trend p<0.05) in the proportion of women reporting risky sexual behaviour or a diagnosed STI between baseline and end of follow-up. RESULTS: Between September 2013 and December 2016, 197 women (active arm: n=132 and placebo: n=65) were enrolled at the Masaka site. There were decreases in all markers of sexual risk behaviour with statistically significant decreases in only the proportion of women reporting ≥2 sexual partners, p=0.026 and those diagnosed with Trichomonas vaginalis p<0.001 and or Neisseria gonorrhoeae p<0.001 CONCLUSIONS: No evidence of risk compensation was observed in this trial. TRIAL REGISTRATION NUMBER: NCT01539226

Contraceptive Preference Among Women at Risk of HIV Acquisition in a Preparatory Screening Study for a Phase III Microbicide Trial in South Western Uganda.

Contraceptive preferences of women at risk for HIV acquisition are not well documented. We report on contraceptive choices among women residing in small townships in southwestern Uganda. This was part of preparatory efforts for recruitment into the Ring Study, a phase 3 microbicide trial, between July 2013 and October 2014. Clinicians provided contraceptives per a woman's choice. HIV testing and screening for other sexually transmitted infections were done at first contact and at screening for the trial. Contraceptive choice was summarized by demographics and regression analysis to show factors associated with use of the injectable method. Of 6725 women contacted, 489 were prescreened. Of these 489 women, most (306, 63%) were already using contraception. Injectables were most preferred (58.7%), followed by implants (23.9%). Women living with a regular sexual partner preferred the injectable method (61.0%, P = 0.06), compared with other methods. Women at risk for HIV infection are willing to initiate use of modern contraceptives, which may reduce study dropout during intervention trials due to unintended pregnancy. Registration no: NCT01539226

The effects of HIV on fertility by infection duration: evidence from African population cohorts before antiretroviral treatment availability.

OBJECTIVES: To estimate the relationship between HIV natural history and fertility by duration of infection in east and southern Africa before the availability of antiretroviral therapy and assess potential biases in estimates of age-specific subfertility when using retrospective birth histories in cross-sectional studies. DESIGN: Pooled analysis of prospective population-based HIV cohort studies in Masaka (Uganda), Kisesa (Tanzania) and Manicaland (Zimbabwe). METHODS: Women aged 15-49 years who had ever tested for HIV were included. Analyses were censored at antiretroviral treatment roll-out. Fertility rate ratios were calculated to see the relationship of duration of HIV infection on fertility, adjusting for background characteristics. Survivorship and misclassification biases on age-specific subfertility estimates from cross-sectional surveys were estimated by reclassifying person-time from the cohort data to simulate cross-sectional surveys and comparing fertility rate ratios with true cohort results. RESULTS: HIV-negative and HIV-positive women contributed 15 440 births and 86 320 person-years; and 1236 births and 11 240 000 person-years, respectively, to the final dataset. Adjusting for age, study site and calendar year, each additional year since HIV seroconversion was associated with a 0.02 (95% confidence interval 0.01-0.03) relative decrease in fertility for HIV-positive women. Survivorship and misclassification biases in simulated retrospective birth histories resulted in modest underestimates of subfertility by 2-5% for age groups 20-39 years. CONCLUSION: Longer duration of infection is associated with greater relative fertility reduction for HIV-positive women. This should be considered when creating estimates for HIV prevalence among pregnant women and prevention of mother-to-child transmission need over the course of the HIV epidemic and antiretroviral treatment scale up

Relationship between Anaemia, Malaria Co-infection and Kaposi Sarcoma-associated Herpesvirus (KSHV) Seropositivity in a Population-based Study in Rural Uganda

We examined anaemia and malaria as risk factors for KSHV seropositivity and antibody levels in a long-standing rural Ugandan cohort, in which KSHV is prevalent. Samples from 4134 children, aged 1-17 years, with a sex ratio of 1:1 and 3149 adults aged 18-103 years, 41% of whom were males, were analysed. Among children, malaria infection was associated with higher KSHV prevalence (61% versus 41% prevalence among malaria infected and uninfected respectively); malaria was not assessed in adults. Additionally, lower haemoglobin level was associated with an increased prevalence of KSHV seropositivity, both in children and in adults

Impaired renal function in a rural Ugandan population cohort

Background: Kidney disease is an important cause of morbidity and mortality globally. However, there are limited data on the prevalence of impaired kidney function in sub-Saharan Africa. We aimed to determine the prevalence of reduced kidney function and associated factors in a rural Ugandan population. Methods: We undertook a study of a representative sample of the General Population Cohort in South-western Uganda. We systematically collected data on cardiovascular disease risk factors, anthropometric measurements and blood tests including haemoglobin, HIV, HbA1c and serum creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi formula, without the race component of the equation. Results: A total of 5,979/6,397 (93.5%) participants had valid creatinine results. The mean age was 39 years (Range: 16-103 years) and 3,627 (60.7%) were female. HIV prevalence was 9.7% and about 40% of the population were pre-hypertensive or hypertensive. The mean serum creatinine level was 0.75 mg/dl (95% CI 0.74–0.75), and the average eGFR was 109.3 ml/min/1.73 m2 (95% CI 108.8–109.9). The overall prevalence of eGFR <60 ml/min/1.73 m2 was 1.64% (98/5,979) (95% CI 1.34–1.99). Additionally, 4,792 (80.2%) were classified as normal eGFR (≥90 ml/min/1.73 m2), 1,089 (18.2%) as low eGFR (60–89 ml/min/1.73 m2), 91 (1.52%) as moderately reduced eGFR (30–59 ml/min/1.73 m2), 4 (0.07%) as severely reduced eGFR (15-29 ml/min/1.73 m2), and 3 (0.05%) classified as having kidney failure (eGFR <15 ml/min/1.73 m2). When age-standardised to the WHO Standard Population the prevalence of eGFR<60 ml/min/1.73 m2 was 1.79%. Age above 35 years and the presence of hypertension (OR 2.86, 95% CI 1.15-7.08) and anaemia (OR 2.14, 95% CI 1.12-4.09) were associated with eGFR<60 ml/min/1.73 m2. Conclusion: In a systematic survey of people in rural Uganda, we found a substantial proportion had eGFR<60 ml/min/1.73 m2, and this was strongly associated with high blood pressure and anaemia

Predictors of oral pre-exposure prophylaxis (PrEP) uptake among individuals in a HIV vaccine preparedness cohort in Masaka, Uganda

Oral pre-exposure prophylaxis (PrEP) significantly reduces human immunodeficiency virus (HIV) acquisition risk. However, data on predictors of PrEP uptake in sub-Saharan Africa are limited. We assessed predictors of PrEP uptake among HIV-uninfected high risk individuals enrolled in a HIV vaccine preparedness study in Masaka, Uganda.Between July 2018 and October 2020, we recruited adults (18-40 years) from sex work hotspots along the trans-African highway and Lake Victoria fishing communities. We collected baseline data on socio-demographics and PrEP awareness, and provided HIV counselling and testing, information on PrEP, and PrEP referrals at quarterly visits. Urine pregnancy tests (women) and data collection on sexual risk behaviour and PrEP uptake were performed every 6 months. We analysed PrEP uptake among participants who had completed 6 months of follow-up.Of the 588 cohort participants, 362 (62%) were included in this analysis. Of these, 176 (49%) were female, 181 (50%) were aged ≤24 years, 104 (29%) worked in sex work hotspots, 74 (20%) were fisher folk. Only 75 (21%) participants initiated PrEP. Predictors of PrEP uptake included having ≥6 sex partners (adjusted odds ratio [aOR] = 2.29; 95% confidence interval [CI] 1.26-4.17), engaging in transactional sex (aOR = 2.23; 95% CI 0.95-5.20), and residence in a nonfishing community (aOR = 2.40; 95% CI 1.14-5.08). The commonest reasons for not starting PrEP were pill burden (38%) and needing more time to decide (27%).PrEP uptake was low and associated with HIV risk indicators in this cohort. Interventions are needed to improve access to PrEP especially in fishing communities

Blood pressure levels among children in rural Uganda: results from 1913 children in a general population survey.

Despite increasing levels of adult hypertension in sub-Saharan Africa (SSA), there is limited information on elevated blood pressure among children in SSA. We described the distribution of blood pressure among children in rural Uganda and estimated hypertension prevalence. We conducted a cross-sectional study in south-western Uganda, collecting demographic, anthropometric and blood pressure measurements from children aged 6-12 years. Children with elevated blood pressure (systolic and/or diastolic blood pressure greater or equal to the 95th percentile for age, height and sex) were invited for two further assessments 6-18 months later. We described blood pressure distribution at first assessment, assessed associations with demographic and anthropometric characteristics and estimated prevalence of hypertension as defined by having elevated blood pressure on three separate occasions months apart. Blood pressure (BP) was measured in 1913 children (50% male, 3% overweight or obese, 22% stunted) at the first assessment. Mean (SD) systolic and diastolic BP at first assessment was 113.4 mmHg (±10.8) and 69.5 mmHg (±8.3), respectively, and 44.2% had elevated BP. Older age, higher BMI, and being female were associated with higher BP, and stunted height was associated with lower BP. An estimated 7.8% [95% CI:(6.6-9.1)], (males: 6.8%, females: 9.0%), had elevated BP on three separate occasions, and were considered hypertensive. High blood pressure levels among adults in SSA may be set early in life. In this study, obesity (a common lifestyle modifiable risk factor in other settings) was largely irrelevant. More research is needed to understand the main drivers for elevated blood pressure in SSA further

Cross-sectional study of IgG antibody levels to invasive nontyphoidal Salmonella LPS O-antigen with age in Uganda.

Invasive nontyphoidal Salmonella (iNTS) disease is a major cause of deaths among children and HIV-infected individuals in sub-Saharan Africa. Acquisition of IgG to iNTS lipopolysaccharide (LPS) O-antigen in Malawi in early childhood corresponds with a fall in cases of iNTS disease suggesting that vaccines able to induce such antibodies could confer protection. To better understand the acquisition of IgG to iNTS in other African settings, we performed a cross-sectional seroepidemiological study using sera from 1090 Ugandan individuals aged from infancy to old age. Sera were analysed for IgG to LPS O-antigen of S. Typhimurium and S. Enteritidis using an in-house ELISA. Below 18 months of age, most children lacked IgG to both serovars. Thereafter, specific IgG levels increased with age, peaking in adulthood, and did not wane noticeably in old age. There was no clear difference in antibody levels between the sexes and the few HIV-infected individuals in the study did not have obviously different levels from uninfected subjects. While IgG to iNTS is acquired at a younger age in Malawian compared with Ugandan children, it is not clear whether this is due to differences in the populations themselves, their exposure to iNTS, or variations between assays used. In conclusion, there is a need to develop a harmonised method and standards for measuring antibodies to iNTS across studies and to investigate acquisition of such antibodies with age across different sites in sub-Saharan Africa

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women.

BACKGROUND: The incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTS: A total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P=0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P=0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONS: Among women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226 .)

Pharmacokinetics of Ganaplacide and Lumefantrine in Adults, Adolescents, and Children with Plasmodium falciparum Malaria Treated with Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Analysis of Data from a Multinational Phase 2 Study.

The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here. The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUCinf, AUClast, AUC0-t, Cmax, and tmax were reported where possible, using non-compartmental analysis. In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (Cmax and AUC0-24 h) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions