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.

The dapivirine vaginal ring from the perspective of married men in Uganda.

Background: Men play a key role in influencing uptake of women's health products, such as female condoms and vaginal microbicides used for family planning and HIV prevention.Method: We explored men's perceptions of the dapivirine vaginal ring (DVR), a vaginal microbicide, in Kalungu District, rural south-western Uganda. In June/July 2018, we conducted in-depth interviews with 10 partners of women participating in the DREAM study, a phase 3B open-label extension trial of the DVR. Data were analysed thematically, drawing on the socio-ecological model theoretical framework.Results: Influencing factors such as individual and interpersonal characteristics, perception of HIV risk, lack of knowledge about the DVR, misconceptions, and product characteristics acting at different levels (individual, societal and organisational) affected men's knowledge, attitudes and perceptions towards the DVR, which in turn impacted on their willingness to allow their partners to use it. Above all, men wanted to be involved in the decision- making process about the use of the DVR. All the men were happy that there was a new HIV prevention option in the pipeline and were not concerned about the degree of effectiveness, saying it was better than nothing.Conclusion: The use of the DVR in an environment where men expect to make decisions about sex on behalf of women may affect its usage and success. Given this context, women may not always be able to independently choose to use it. If the DVR is approved and rolled out, increased sensitisation of men about it will be critical to ensure its uptake.

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 .).

Relationship Between Anemia, Malaria Coinfection, and Kaposi Sarcoma-Associated Herpesvirus Seropositivity in a Population-Based Study in Rural Uganda.

We examined anemia and malaria as risk factors for Kaposi sarcoma-associated herpesvirus (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 analyzed. Among children, malaria infection was associated with higher KSHV prevalence (61% vs 41% prevalence among malaria infected and uninfected, respectively); malaria was not assessed in adults. Additionally, lower hemoglobin level was associated with an increased prevalence of KSHV seropositivity, both in children and in adults.

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.

Associations between intravaginal practices and incidence of sexually transmitted infections and bacterial vaginosis among women enrolled in the dapivirine vaginal ring trial (The Ring Study) in southwestern Uganda: a retrospective secondary analysis.

OBJECTIVES: We assessed associations between intravaginal practices (IVPs) and the incidence of sexually transmitted infections (STIs) and bacterial vaginosis (BV) among women using the dapivirine vaginal ring (DVR) or placebo vaginal ring in southwestern Uganda. METHODS: This was a retrospective secondary analysis of data collected from women at risk of HIV infection recruited into the Ring Study. The latter evaluated the safety and efficacy of the DVR between 2013 and 2016. At baseline, a behavioural questionnaire was administered to obtain information on sexual activity and IVP (exposure) defined as; insertion inside the vagina of any items aimed at cleaning the vagina for any reason before, during or after sex other than practices to manage menses. Each participant self-inserted the DVR/placebo and replaced it every 4 weeks for 2 years. Outcomes were diagnosis of STIs, that is, Chlamydia trachomatis, Neisseria gonorrhoea, Trichomonas vaginalis (TV), HIV and BV. The incidence rate of STI/BV was estimated, overall, by IVP and trial arm in single-event-per-participant and multiple-event-per-participant analyses. RESULTS: Of the 197 women enrolled, 66 (33.5%) were <25 years of age. Overall, 93 (47.2%) practised at least one form of IVP. During the follow-up, 172 (87.3%) women were diagnosed with an STI/BV at least once. The majority had TV (73.6%, n=145). Overall rate of STI/BV was 51.9/100 person-years, 95% CI 44.7 to 60.3 (IVP: yes, 51.0 (40.8-63.8) vs no, 52.6 (43.0-64.4)). IVPs were not statistically significantly associated with rate of individual STIs/BV. Similar results were observed when the analyses were conducted separately for each trial arm. CONCLUSIONS: IVP was not associated with risk of STIs/BV in the Ring Study. TRIAL REGISTRATION 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.

Changes in self-reported risky sexual behaviour indicators among adults receiving regular risk reduction counselling and optional initiation of pre-exposure prophylaxis in an HIV vaccine preparedness study in Masaka, Uganda.

BACKGROUND: HIV risk reduction counselling may reduce risk-taking behaviours. Yet, concerns remain about risk compensation among individuals initiating pre-exposure prophylaxis (PrEP). OBJECTIVE: We assessed changes in risky sexual behaviour indicators among HIV vaccine preparedness study participants who received regular risk reduction counselling and referral for PrEP in Masaka, Uganda. METHODS: Adults (18-39 years) at high risk of HIV infection were enrolled in the study between July 2018 and December 2021. Data were collected on socio-demographic factors (baseline) and self-reported sexual risk behaviours (baseline, six monthly). HIV testing and risk-reduction counselling and referral for PrEP were done quarterly. Participants who had completed at least 1 year of follow-up were included in the analysis. Proportional differences and McNemar chi-square tests were used to assess changes in the prevalence of self-reported risky sexual behaviour indicators between baseline and 1 year. Logistic regression was used to assess the predictors of unchanged/increased HIV risk at 1 year. RESULTS: Three hundred participants [132 (44%) females, 152 (51%) aged ≤24 years] were included in this analysis. Eighty-one (27%) participants initiated PrEP at 1 year. Compared to baseline, there were significant reductions in the prevalence of the following self-reported HIV risk indicators at 1 year (overall, among non-PrEP initiators, and among PrEP initiators): transactional sex, ≥6 sexual partners, unprotected sex with ≥3 partners, sex while drunk, and sexually transmitted infection diagnosis/treatment. Percentage differences ranged from 10% for individuals reporting at least six sexual partners to 30% for those reporting unprotected sex with three or fewer sexual partners. There was weak evidence of association between female gender and unchanged/increased HIV risk at 1 year (adjusted OR: 1.35, 95% CI (0.84-2.17)). No other indicators, including PrEP use, were associated with unchanged/increased HIV risk at 1 year. CONCLUSION: Regular risk-reduction counselling may reduce risky sexual behaviour, while PrEP initiation may not lead to risk compensation.

Optimising DTwP-containing vaccine infant immunisation schedules (OptImms) - a protocol for two parallel, open-label, randomised controlled trials.

BACKGROUND: Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. METHODS: The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. DISCUSSION: These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. TRIAL REGISTRATIONS: ISRCTN12240140 (Nepa1, 7th January 2021) and ISRCTN6036654 (Uganda, 17th February 2021).

Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial.

BACKGROUND: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. METHODS: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per µL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242). FINDINGS: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. INTERPRETATION: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). FUNDING: Novartis and Medicines for Malaria Venture.

Predictors of Loss to Follow-Up in an HIV Vaccine Preparedness Study in Masaka, Uganda.

BACKGROUND: High participant retention is essential to achieve adequate statistical power for clinical trials. We assessed participant retention and predictors of loss to follow-up (LTFU) in an HIV vaccine-preparedness study in Masaka, Uganda. METHODS: Between July 2018 and March 2021, HIV sero-negative adults (18-45 years) at high risk of HIV infection were identified through HIV counselling and testing (HCT) from sex-work hotspots along the trans-African highway and fishing communities along the shores of Lake Victoria. Study procedures included collection of baseline socio-demographic data, quarterly HCT, and 6-monthly collection of sexual risk behaviour data. Retention strategies included collection of detailed locator data, short clinic visits (1-2 h), flexible reimbursement for transport costs, immediate (≤7 days) follow-up of missed visits via phone and/or home visits, and community engagement meetings. LTFU was defined as missing ≥2 sequential study visits. Poisson regression models were used to identify baseline factors associated with LTFU. RESULTS: 672 participants were included in this analysis. Of these, 336 (50%) were female and 390 (58%) were ≤24 years. The median follow-up time was 11 months (range: 0-31 months). A total 214 (32%) participants were LTFU over 607.8 person-years of observation (PYO), a rate of 35.2/100 PYO. LTFU was higher in younger participants (18-24 years versus 35-45 years, adjusted rate ratio (aRR) = 1.29, 95% confidence interval (CI) 0.80-2.11), although this difference was not significant. Female sex (aRR = 2.07, 95% CI, 1.51-2.84), and recreational drug use (aRR = 1.61, 95% CI, 1.12-2.34) were significantly associated with increased LTFU. Engagement in transactional sex was associated with increased LTFU (aRR = 1.36, 95% CI, 0.97-1.90) but this difference was not significant. LTFU was higher in 2020-2021 (the period of COVID-19 restrictions) compared to 2018-2019 (aRR = 1.54, 1.17-2.03). Being Muslim or other (aRR = 0.68, 95% CI 0.47-0.97) and self-identification as a sex worker (aRR = 0.47, 95% CI, 0.31-0.72) were associated with reduced LTFU. CONCLUSION: We observed a high LTFU rate in this cohort. LTFU was highest among women, younger persons, recreational drug users, and persons who engage in transactional sex. Efforts to design retention strategies should focus on these subpopulations.

Assessing acceptability of pre-exposure prophylaxis (PrEP) among participants in an HIV vaccine preparedness study in southwestern Uganda.

BACKGROUND: Daily oral pre-exposure prophylaxis (PrEP) use is highly effective against HIV infection. However, the uptake of PrEP among individuals at high-risk of HIV acquisition in sub-Saharan Africa varies because of availability and acceptability. We assessed the acceptability of PrEP among participants in a prospective HIV vaccine preparedness study in Masaka, southwestern Uganda. METHODS: From November 2018 to August 2019, 20 participants (10 female) were purposively selected for in-depth interviews (IDIs) at 3 and 9 months' post-enrolment in the vaccine preparedness study. Four focus group discussions (FGD) (two among men) were conducted with 29 individuals categorized as: younger (18-24 years) men, younger (18-24 years) women, older (≥30 years) men, and older (≥30 years) women. Apart from IDI specific questions on recent life history including work experience, relationship history and places lived, topics for IDIs and FGDs included knowledge of HIV, perceptions of HIV risk (including own risk), knowledge of and use of PrEP. The Theoretical Framework of Acceptability was used to structure a thematic framework approach for data analysis. RESULTS: Participants understood that PrEP was an oral pill taken daily by HIV negative individuals to prevent acquisition of HIV. Overall, interest in and acceptability of PrEP was high, more than half expressed positivity towards PrEP but were not ready to initiate taking it citing the burden of daily oral pill taking, related side effects, stigma and distrust of PrEP. Fourteen participants (from IDI and FGD) initiated PrEP, although some (one FGD and two IDI participants) stopped taking it due to side effects or perceived reduced risk. CONCLUSION: We observed a keen interest in PrEP initiation among our study participants. However, a limited understanding of PrEP and associated concerns impeded uptake and sustained use. Hence, interventions are needed to address end-user challenges to increase uptake and support adherence.

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.

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

ABSTRACT: 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.

Strategies for retention of heterosexual men in HIV care in sub-Saharan Africa: A systematic review.

Expansion of Antiretroviral Therapy (ART) programs in sub-Saharan Africa (SSA) has increased the number of people accessing treatment. However, the number of males accessing and being retained along the human immunodeficiency virus (HIV) care cascade is significantly below the UNAIDS target. Male gender has been associated with poor retention in HIV care programs, and little is known about strategies that reduce attrition of men in ART programs. This review aimed to summarize any studies on strategies to improve retention of heterosexual males in HIV care in SSA. An electronic search was conducted through Ovid® for three databases (MEDLINE®, Embase and Global Health). Studies reporting interventions aimed at improving retention among heterosexual men along the HIV care cascade were reviewed. The inclusion criteria included randomized-controlled trials (RCTs), prospective or retrospective cohort studies that studied adult males (≥15years of age), conducted in SSA and published between January 2005 and April 2019 with an update from 2019 to 2020. The search returned 1958 articles, and 14 studies from eight countries met the inclusion criteria were presented using the PRISMA guidelines. A narrative synthesis was conducted. Six studies explored community-based adherence support groups while three compared use of facility versus community-based delivery models. Three studies measured the effect of national identity cards, disclosure of HIV status, six-monthly clinic visits and distance from the health center. Four studies measured risk of attrition from care using hazard ratios ranging from 1.2-1.8, four studies documented attrition proportions at an average of 40.0% and two studies an average rate of attrition of 43.4/1000PYs. Most (62%) included studies were retrospective cohorts, subject to risk of allocation and outcome assessment bias. A pooled analysis was not performed because of heterogeneity of studies and outcome definitions. No studies have explored heterosexual male- centered interventions in HIV care. However, in included studies that explored retention in both males and females, there were high rates of attrition in males. More male-centered interventions need to be studied preferably in RCTs. Registry number: PROSPERO2020 CRD42020142923 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020142923.

Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study.

BACKGROUND: The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use. METHODS: The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171. FINDINGS: Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65·5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0·6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0·25 mg lower (95% CI 0·03-0·47; p=0·027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1·9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1·8 (95% CI 1·1-2·6) per 100 person-years, 62% lower than the simulated placebo rate. INTERPRETATION: Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. FUNDING: The Ministry of Foreign Affairs (MFA) Denmark, Flanders MFA, Irish Aid, Dutch MFA, UK Aid from the UK Government's Foreign, Commonwealth and Development Office, and the US President's Emergency Plan for AIDS Relief through the US Agency for International Development.

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.

Impaired renal function in a rural Ugandan population cohort.

Background: Chronic kidney disease (CKD) 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 CKD 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 for haemoglobin, HIV, HbA1c, Hepatitis B and C 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 m 2 (95% CI 108.8-109.9). The overall prevalence of CKD (eGFR <60 ml/min/1.73 m 2) 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 m 2), 1,089 (18.2%) as low (eGFR 60-89 ml/min/1.73 m 2), 91 (1.52%) as moderate (eGFR 30-59 ml/min/1.73 m 2), 4 (0.07%) as severe (eGFR 15-29 ml/min/1.73 m 2), and 3 (0.05%) classified as having kidney failure (eGFR <15 ml/min/1.73 m 2).  When age-standardised to the WHO Standard Population the prevalence of CKD was 1.79%. Age above 35 years (OR 78.3, 95% CI 32.3-189), and the presence of hypertension (OR 2.98, 95% CI 1.47-6.02) and anaemia (OR 2.47, 95% CI 1.37-4.42) were associated with CKD. Conclusion: We found a substantial prevalence of CKD in rural Uganda, strongly associated with high blood pressure and anaemia.

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.

Rapid Antiretroviral Therapy Initiation for Women in an HIV-1 Prevention Clinical Trial Experiencing Primary HIV-1 Infection during Pregnancy or Breastfeeding.

During an HIV-1 prevention clinical trial in East Africa, we observed 16 cases of primary HIV-1 infection in women coincident with pregnancy or breastfeeding. Nine of eleven pregnant women initiated rapid combination antiretroviral therapy (ART), despite having CD4 counts exceeding national criteria for ART initiation; breastfeeding women initiated ART or replacement feeding. Rapid ART initiation during primary HIV-1 infection during pregnancy and breastfeeding is feasible in this setting.