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Abstract Background Illicit drug and high-risk alcohol use among adolescents leads to poor health outcomes. We enrolled adolescents from urban slums in Kampala, Uganda, to assess baseline prevalence and factors associated with illicit drug and high-risk alcohol consumption. Methods We conducted a cross-sectional study using data collected in a cohort that enrolled 14-19-year-old male and female participants from 25 March 2019 to 30 March 2020. Data was collected on social demographics, sexual behavior, and reproductive health using interviewer-administered questionnaires. The main outcomes were illicit drug use and high-risk alcohol use. Data on alcohol use was collected using the Alcohol Use Disorder Identification Test (AUDIT); results were dichotomized. Factors associated with each outcome were analyzed using multivariable logistic regression. Results We enrolled 490 participants (60.6% female) with a median age of 18 (IQR 17–18) years, 84.9% had less than secondary education, 48.4% had their sexual debut before 15 years, 47.1% reported paid sex in the past 3 months and 22.8% had a sexually transmitted infection (chlamydia, gonorrhea, and active syphilis) baseline characteristics associated with illicit drug use in the past 3 months were male gender (aOR 12.45; 95% CI 7.21–21.50) being married (aOR 2.26; 95%CI 1.03–4.94) 10 or more paying sexual partners (aOR 2.45; 95%CI 1.05–5.69) and high-risk alcohol use (aOR 3.94; 95%CI 2.10–7.40), baseline characteristics associated with high-risk alcohol use were male gender (aOR 0.29; 95% CI 0.13–0.63) emotional violence from sexual partners (aOR 2.35; 95%CI 1.32–418) illicit drug users com (aOR 3.94; 95% CI 2.10–7.40). Conclusion Illicit drug and high-risk alcohol use are prevalent among male adolescents and adolescents involved in high-risk sexual behavior living in the urban slums of Kampala.

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

Objectives: We assessed the prevalence of immunoglobulin G (IgG) and IgM against four endemic human coronaviruses and two SARS-CoV-2 antigens among vaccinated and unvaccinated staff at health care centers in Uganda, Sierra Leone, and the Democratic Republic of Congo. Methods: The government health facility staff who had patient contact in Goma (Democratic Republic of Congo), Kambia District (Sierra Leone), and Masaka District (Uganda) were enrolled. Questionnaires and blood samples were collected at three time points over 4 months. Blood samples were analyzed with the Luminex MAGPIXⓇ. Results: Among unvaccinated participants, the prevalence of IgG/IgM antibodies against SARS-CoV-2 receptor-binding domain or nucleocapsid protein at enrollment was 70% in Goma (138 of 196), 89% in Kambia (112 of 126), and 89% in Masaka (190 of 213). The IgG responses against endemic human coronaviruses at baseline were not associated with SARS-CoV-2 sero-acquisition during follow-up. Among the vaccinated participants, those who had evidence of SARS-CoV-2 IgG/IgM at baseline tended to have higher IgG responses to vaccination than those who were SARS-CoV-2 seronegative at baseline, controlling for the time of sample collection since vaccination. Conclusion: The high levels of natural immunity and hybrid immunity should be incorporated into both vaccination policies and prediction models of the impact of subsequent waves of infection in these settings.

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.

Objectives: To document the changes in HIV incidence over thirty years in Kalungu district, Uganda. Methods: Since 1989, residents aged ≥15 years old have been tested for HIV, and data were collected on HIV risk factors annually and later, biennially in the Kyamulibwa open cohort. In the 2019-2021 survey, people living with HIV self-reported on knowledge of their HIV status, antiretroviral therapy (ART) use, and their most recent viral load data were obtained from health facilities. The HIV seroconversion dates were randomly imputed between the last negative and first positive test dates using a uniform distribution. Results: Among 20,959 residents who were HIV-negative, 669 seroconverted within 176,659 person-years. Data showed a downward trend in age-adjusted HIV incidence over 30 years (P

Abstract Background PrEP literacy is influenced by many factors including the types of information available and how it is interpreted. The level of PrEP literacy may influence acceptability and uptake. Methods We conducted 25 in-depth interviews in a HIV vaccine trial preparedness cohort study. We explored what participants knew about PrEP, sources of PrEP knowledge and how much they know about PrEP. We used the framework approach to generate themes for analysis guided by the Social Ecological Model and examined levels of PrEP literacy using the individual and interpersonal constructs of the SEM. Results We found that PrEP awareness is strongly influenced by external factors such as social media and how much participants know about HIV treatment and prevention in the local community. However, while participants highlighted the importance of the internet/social media as a source of information about PrEP they talked of low PrEP literacy in their communities. Participants indicated that their own knowledge came as a result of joining the HIV vaccine trial preparedness study. However, some expressed doubts about the effectiveness of the drug and worried about side effects. Participants commented that at the community level PrEP was associated with being sexually active, because it was used to prevent the sexual transmission of HIV. As a result, some participants commented that one could feel judged by the health workers for asking for PrEP at health facilities in the community. Conclusion The information collected in this study provided an understanding of the different layers of influence around individuals that are important to address to improve PrEP acceptability and uptake. Our findings can inform strategies to address the barriers to PrEP uptake, particularly at structural and community levels. Trial registration https://clinicaltrials.gov/ct2/show/NCT04066881

We report the screening and enrollment process for a phase I vaccine trial in Masaka, Uganda that investigated the safety and immunogenicity of a self-amplifying SARS-CoV-2 RNA vaccine amongst individuals with and without antibodies to SARS-CoV-2. Participant screening and enrollment were conducted between December 2021 and April 2022. Individuals were eligible if they were aged between 18 and 45 years, healthy, and never vaccinated against COVID-19. SARS-CoV-2 antibody status was determined using two point-of-care rapid tests, i.e. Multi G (MGFT3) and Standard Q (Standard Q COVID-19 IgM/IgG Plus). Data were entered and managed in OpenClinica. Analyses were performed and presented descriptively. A total of 212 individuals were screened and 43(20.3%) enrolled. The most common reasons for exclusion were ≥ grade 1 laboratory abnormalities (39, 18.4%), followed by discordant SARS-CoV-2 antibody results (23, 10.9%). While the first 38 participants were quickly enrolled over a period of 9 weeks, it took another 9 weeks to enroll the remaining five, as antibody negative participants became scarce during the surge of the Omicron variant. The SARS-CoV-2 antibody positivity rate was determined to be 60.8% and 84.4% in each half of the 18 months of screening respectively. The mean age (±Standard Deviation, SD) of screened and enrolled participants was 27.7 (±8.1) and 30.2 (±8.3) years respectively. We demonstrated that it is feasible to successfully screen and enroll participants for COVID-19 vaccine trials in Uganda in the time of a pandemic. Our experiences may be useful for investigators planning to undertake similar work in Africa.

Summary: Background: The efficacy of on-demand HIV pre-exposure prophylaxis (PrEP) for men in sub-Saharan Africa has not been evaluated, and the on-demand PrEP dosing requirement for insertive sex remains unknown. Methods: HIV-negative males 13–24 years, requesting voluntary medical male circumcision (VMMC), were enrolled into an open-label randomised controlled trial (NCT03986970), and randomised 1:1:1:1:1:1:1:1:1 to control arm or one of eight arms receiving emtricitabine-tenofovir disoproxil fumarate (F/TDF) or emtricitabine-tenofovir alafenamide (F/TAF) over one or two days, and circumcised 5 or 21 h thereafter. The primary outcome was foreskin p24 concentrations following ex vivo HIV-1BaL challenge. Secondary outcomes included peripheral blood mononuclear cell (PBMC) p24 concentration, and drug concentrations in foreskin tissue, PBMCs, plasma and foreskin CD4+/CD4-cells. In the control arm, post-exposure prophylaxis (PEP) activity of non-formulated tenofovir-emtricitabine (TFV-FTC) or TAF-FTC was assessed with ex vivo dosing 1, 24, 48 or 72 h post-HIV-1 challenge. Findings: 144 participants were analysed. PrEP with F/TDF or F/TAF prevented ex vivo infection of foreskins and PBMCs both 5 and 21 h after PrEP dosing. There was no difference between F/TDF and F/TAF (p24day15 geometric mean ratio 1.06, 95% confidence interval: 0.65–1.74). Additional ex vivo dosing did not further increase inhibition. In the control arm, PEP ex vivo dosing was effective up to 48 post-exposure diminishing thereafter, with TAF-FTC showing prolonged protection compared to TFV-FTC. Participants receiving F/TAF had higher TFV-DP concentrations in foreskin tissue and PBMCs compared with F/TDF, irrespective of dose and sampling interval; but F/TAF did not confer preferential TFV-DP distribution into foreskin HIV target cells. FTC-TP concentrations with both drug regimens were equivalent and ∼1 log higher than TFV-DP in foreskin. Interpretation: A double dose of either F/TDF or F/TAF given once either 5 or 21 h before ex vivo HIV-challenge provided protection across foreskin tissue. Further clinical evaluation of pre-coital PrEP for insertive sex is warranted. Funding: EDCTP2, Gilead Sciences, Vetenskapsrådet.

We examined the effect of the Universal Test and Treat (UTT) policy on the characteristics of people living with HIV (PLHIV) at enrolment in HIV care and initiation of antiretroviral therapy (ART) in Uganda using data from 11 nationally representative clinics of The AIDS Support Organisation (TASO). We created two retrospective PLHIV cohorts: pre-UTT (2004–2016), where ART initiation was conditional on CD4 cell count and UTT (2017–2022), where ART was initiated regardless of World Health Organisation (WHO) clinical stage or CD4 cell count. We used a two-sample test of proportions and Wilcoxon rank-sum test to compare proportions and medians, respectively, between the cohorts. A total of 244,693 PLHIV were enrolled at the clinics [pre-UTT, 210,251 (85.9%); UTT, 34,442 (14.1%)]. Compared to the pre-UTT cohort, the UTT cohort had higher proportions of PLHIV that were male (p 69 years, never married (p 500 cells/μL (47.3% vs. 13.2%, p

BackgroundIn sub-Saharan Africa, one in every five young women becomes pregnant, and 50% of these are unintended. Pregnancies in adolescent girls and young women (AGYW) are associated with poorer maternal and neonatal outcomes and a high abortion rate, yet data are still limited on incident pregnancies among AGYW in vulnerable situations. We studied the incidence and factors associated with unintended pregnancy among AGYW who were frequently engaged in transactional sex in Kampala, Uganda.MethodsWe analyzed data from a study that investigated the uptake of oral pre-exposure prophylaxis among AGYW from January 2019 to December 2020. Volunteers attended 3-monthly study visits for 12 months each. Contraceptive services were provided to interested volunteers free of charge. Interviewers collected data on sociodemographics, sexual behavior, reproductive health outcomes, and substance use. Pregnancy was determined by testing for beta-human chorionic gonadotropin hormone in urine. The pregnancy incidence rate was estimated using the Kaplan–Meier technique, and logistic regression was used to determine the correlates of pregnancy.ResultsWe included 285 volunteers with a mean age of 19.9 [standard deviation (SD), ± 2.24] years; 54.7% had attained secondary school education or higher, 57.2% were single (never married), 92.6% reported engaging in transactional sex, 21.0% reported sex work as their main job, 51.9% consumed alcohol in the month prior to the interview, of whom 12.8% consumed alcohol daily, and 25.3% had Chlamydia trachomatis/Neisseria gonorrhoeae. The mean age at first sexual intercourse was 15.7 (SD, ±2.1) years. We recorded 44 pregnancies over 187.2 person-years of follow-up, an incidence of 23.5 per 100 person-years [95% confidence interval (CI), 17.5–31.6]. Incident pregnancies were more likely among volunteers who had ≥10 sexual partners in the past 3 months [adjusted risk ratio (aRR) 1.97; 95% CI, 1.05–3.70] and those who reported not using contraception (aRR 5.89; 95% CI, 2.74–12.66). Incident pregnancies were less likely among those who reported alcohol consumption in the past month (aRR 0.52; 95% CI, 0.30–0.90).ConclusionThe incidence of unintended pregnancy was high despite the availability of free contraceptive services. We recommend sociobehavioral studies to explore this further. Sexual and reproductive health campaigns should strengthen demand creation and motivation to use contraception among young women with multiple sexual partners.

Objectives: This cross-sectional survey explored COVID-19 vaccine acceptability among public healthcare facility workers in Kambia (Sierra Leone), Goma (Democratic Republic of Congo) and Masaka (Uganda).Methods: Questionnaire-based interviews conducted between April–October 2021 explored participants’ knowledge and perceptions of, and attitudes towards, the COVID-19 pandemic and COVID-19 vaccines, as well as COVID-19 vaccine acceptability (defined as uptake of ≥1 dose or intent to get vaccinated).Results: Whilst most (n = 444; 81.8%) of the 543 participants had one or more concerns about COVID-19 vaccines, 487 (89.7%) nonetheless perceived that they were important for pandemic control. Most participants from Kambia or Masaka either were vaccinated (n = 137/355; 38.6%) or intended to get vaccinated (n = 211/355; 59.4%) against COVID-19. In Goma, all 188 participants were unvaccinated; only 81 (43.1%) participants intended to get vaccinated, and this was associated with positive perceptions about COVID-19 vaccines. In Goma, the most common reasons for not wanting a COVID-19 vaccine were concerns that the vaccines were new (n = 75/107; 70.1%) and fear of side effects (n = 74/107; 69.2%).Conclusion: Reported COVID-19 vaccine acceptability was high among healthcare facility workers in Kambia and Masaka. The lower vaccine acceptability in Goma may highlight the importance of social mobilisation and accurate, accessible information that addresses specific concerns.

Abstract The design of HIV prevention trials in the context of effective HIV preventive methods is a challenge. Alternate designs, including using non-randomised ‘observational control arms’ have been proposed. We used HIV simulated vaccine efficacy trials (SiVETs) to show pitfalls that may arise from using such observational controls and suggest how to conduct the analysis in the face of the pitfalls. Two SiVETs were nested within previously established observational cohorts of fisherfolk (FF) and female sex workers (FSW) in Uganda. SiVET participants received a licensed Hepatitis B vaccine in a schedule (0, 1 and 6 months) similar to that for a possible HIV vaccine efficacy trial. All participants received HIV counselling and testing every quarter for one year to assess HIV incidence rate ratio (IRR) between SiVET and non-SiVET (observational data). Propensity scores, conditional on baseline characteristics were calculated for SiVET participation and matched between SiVET and non-SiVET in the period before and during the SiVET study. We compared IRR before and after propensity score matching (PSM). In total, 3989 participants were enrolled into observational cohorts prior to SiVET, (1575 FF prior to Jul 2012 and 2414 FSW prior to Aug 2014). SiVET enrolled 572 participants (Jul 2012 to Apr 2014 in FF and Aug 2014 to Apr 2017 in FSW), with 953 non-SiVET participants observed in the SiVET concurrent period and 2928 from the pre-SiVET period (before Jul 2012 in FF or before Apr 2014 in FSW). Imbalances in baseline characteristics were observed between SiVET and non-SiVET participants in both periods before PSM. Similarly, HIV incidence was lower in SiVET than non-SiVET; SiVET-concurrent period, IRR = 0.59, 95% CI 0.31–0.68, p = 0.033 and pre-SiVET period, IRR = 0.77, 95% CI 0.43–1.29, p = 0.161. After PSM, participants baseline characteristics were comparable and there were minimal differences in HIV incidence between SiVET and non-SiVET participants. The process of screening for eligibility for efficacy trial selects participants with baseline characteristics different from the source population, confounding any observed differences in HIV incidence. Propensity score matching can be a useful tool to adjust the imbalance in the measured participants’ baseline characteristics creating a counterfactual group to estimate the effect of interventions on HIV incidence.

BackgroundDaily 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.MethodsFrom 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.ResultsParticipants 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.ConclusionWe 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.

BackgroundHealthcare workers (HCWs) are at high risk of acquiring SARS-CoV-2 and COVID-19 and may therefore be a suitable population for COVID-19 vaccine trials. We conducted a survey to evaluate willingness-to-participate in COVID-19 vaccine trials in a population of HCWs at three hospitals in Uganda.MethodsThe survey was conducted between September and November 2020. Using a standardised questionnaire, data were collected on socio-demographics, previous participation in health research, COVID-19 information sources, underlying health conditions, and willingness-to-participate in COVID-19 vaccine trials. Data were analysed descriptively and a binomial generalised linear model with a log link function used to investigate factors associated with unwillingness to participate.Results657 HCWs (female, 63%) were enrolled with a mean age of 33 years (Standard Deviation, 10). Overall willingness-to-participate was 70.2%. Key motivating factors for participation were: hope of being protected against COVID-19 (81.1%), altruism (73.3%), and the opportunity to get health care (26.0%). Selected hypothetical trial attributes reduced willingness-to-participate as follows: weekly-quarterly study visits over a 12-month period (70.2%-63.2%, P = 0.026); provision of approximately 50ml of blood at each study visit (70.2%-63.2%, P = 0.026); risk of mild-moderate local adverse reactions (70.2%-60.3%, PConclusionsWillingness-to-participate in COVID-19 vaccine trials among HCWs in Uganda is high but may be affected by vaccine trial requirements and concerns about the safety of candidate vaccines.

We investigated how follow-up counselling had increased linkage to HIV care in a trial of referral to care and follow-up counseling, compared to referral to care only, for participants diagnosed as HIV-positive through home-based HIV counseling and testing. We carried out a cross-sectional qualitative study. Using random stratified sampling, we selected 43 trial participants (26 [60%] in the intervention arm). Sample stratification was by sex, distance to an ART facility, linkage, and nonlinkage to HIV care. Twenty-six in-depth interviews were conducted with participants in the intervention arm: 17 people who had linked to HIV care and 9 who had not linked after 6 months of follow-up. Home-based follow-up counseling helped to overcome worries resulting from an HIV-positive test result. In addition, the counseling offered an opportunity to address questions on HIV treatment side effects, share experiences of intimate partner violence or threats, and general problems linking to care. The counselling encouraged early linkage to HIV care and use of biomedical medicines, discouraging alternative medicine usage. Home-based follow-up counseling also helped to promote HIV sero-status disclosure, facilitating linkage to, retention in and adherence to HIV care and treatment. This study successfully demonstrated that home-based follow-up counselling increased linkage to care through encouragement to seek care, provision of accurate information about HIV care services and supporting the person living with HIV to disclose and manage stigma.

Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5′ and 3′ half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the gag/pol region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses (n = 3) and inter-subtype mosaic recombinants (n = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies.

Introduction: Home-based HIV counselling & testing (HBHCT) is highly acceptable and has the potential to increase HIV testing uptake in sub-Saharan Africa. However, data are lacking on strategies that can effectively link HIV-positive individuals identified through HBHCT to care. This trial was designed to assess the effectiveness of two brief home-based counselling sessions on linkage to care, provided subsequent to referral for care among HIV-positive patients identified through HBHCT in a rural community in Masaka district, Uganda. Methods: 28 communities (clusters) were randomly allocated to control (referral only) and intervention (referral and follow-up counselling) arms (n = 14 clusters/arm). Randomisation was stratified on distance from the district capital (≤10 km vs > 10 km) and cluster size (larger single village vs combined small villages), and restricted to ensure balance on selected cluster characteristics. A list of possible allocations was generated and one randomly selected at a public ceremony. HBHCT is being offered to all adults (≥18 years), and HIV-positive individuals not yet in care are eligible for enrolment. The intervention is provided at one and two months post-enrolment. Primary outcomes, assessed 6 months after enrolment, are: the proportion of individuals linking to HIV care within 6 months of HIV diagnosis and time to linkage. The primary analysis will be based on individual-level data. Discussion: This study will provide evidence on the impact of a counselling intervention on linkage to care among adults identified with HIV infection through HBHCT. Interpretation of the trial outcomes will be aided by results from an on-going qualitative sub-study.

IntroductionPeople living in fishing communities around Lake Victoria may be suitable for enrolment in HIV prevention trials because of high HIV incidence. We assessed the ability to recruit and retain individuals from fishing communities into an HIV vaccine preparedness cohort study in Masaka, Uganda.MethodsHIV high risk, sero-negative adults (18-49 years) were identified from four fishing villages bordering Lake Victoria through door-to-door HIV counselling and testing (HCT). Interested persons were referred for screening, enrolment, and quarterly follow-up visits at a study clinic located approximately 30-40 kilometres away. Repeat HCT, HIV risk assessment, and evaluation and treatment for sexually transmitted infections were provided. Rates of and factors associated with study dropout were assessed using Poisson regression models.ResultsA total of 940 participants were screened between January 2012 and February 2015, of whom 654 were considered for the analysis. Over a two-year follow-up period, 197 (30.1%) participants dropped out of the study over 778.9 person-years, a dropout rate of 25.3 / 100 person-years of observation. Dropout was associated with being female (aRR = 1.56, 95% confidence interval [CI] 1.12-2.18), being 18-24 years (aRR = 1.64; 95% CI 1.03-2.60) or being 25-34 years (aRR = 1.63; 95% CI 1.04-2.55) compared to being 35+ years; having no education (aRR = 2.02; 95% CI: 1.23-3.31); living in the community for less than one year (aRR = 2.22; 95% CI: 1.46-3.38), or 1-5 years (aRR = 1.68; 95% CI: 1.16-2.45), compared to more than five years.ConclusionsOur results suggest that individuals from fishing communities can be recruited and retained in longitudinal studies; however, intensified participant tracing may be necessary for women, younger volunteers, those who are less educated and new residents.

The ability to efficiently establish a new infection is a critical property for human immunodeficiency virus type 1 (HIV-1). Although the envelope protein of the virus plays an essential role in receptor binding and internalization of the infecting virus, the structural proteins, the polymerase and the assembly of new virions may also play a role in establishing and spreading viral infection in a new host. We examined Ugandan viruses from newly infected patients and focused on the contribution of the Gag-Pol genes to replication capacity. A panel of Gag-Pol sequences generated using single genome amplification from incident HIV-1 infections were cloned into a common HIV-1 NL4.3 pol/env backbone and the influence of Gag-Pol changes on replication capacity was monitored. Using a novel protein domain approach, we then documented diversity in the functional protein domains across the Gag-Pol region and identified differences in the Gag-p6 domain that were frequently associated with higher in vitro replication.

HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.

Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses.In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured.The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration.Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses.ClinicalTrials.gov NCT01264445.

2013 WHO guidelines recommend starting ART at CD4+ T-cell counts ≤500 cells/μL. We present the T-cell counts from adult Africans with HIV shortly following transmission to their sexual partners.HIV-discordant couples in Zambia, Uganda and Rwanda were followed prospectively and received couples counseling and condoms. HIV uninfected partners were tested for HIV at least quarterly and HIV-infected partners received HIV care and referral for ART per national guidelines. Upon diagnosis of incident HIV infection in the previously HIV-uninfected partner, a blood sample was collected from both partners to measure CD4+ T-cells and perform viral linkage. The estimated date of infection (EDI) of the incident case was calculated based on testing history. EDI was unknown for suspected transmitting partners.From 2006-2011, 4,705 HIV-discordant couples were enrolled in this cohort, and 443 cases of incident HIV infection were documented. Virus linkage analysis was performed in 374 transmission pairs, and 273 (73%) transmissions were linked genetically. CD4 counts in the transmitting partner were measured a median of 56 days after EDI (mean:90.5, min:10, max:396). The median CD4 count was 339 cells/μl (mean:386.4, min:15, max:1,434), and the proportion of partners with a CD4+ T-cell count above 500/μl was 25% (95% CI:21, 31).In our cohort of discordant couples, 73% of HIV transmissions occurred within the relationship, and the transmitter CD4+ T cell count shortly after the transmission event was frequently higher than the WHO 2013 ART-initiation guidelines.

ObjectivesTo investigate the effect of seasonal variation on adult clinical laboratory parameters in Rwanda, Zambia, and Uganda and determine its implications for HIV prevention and other clinical trials.MethodsVolunteers in a cross-sectional study to establish laboratory reference intervals were asked to return for a seasonal visit after the local season had changed from dry to rainy or vice versa. Volunteers had to be clinically healthy, not pregnant and negative for HIV, Hepatitis B and C, and syphilis infection at both visits. At each visit, blood was taken for measurement of hemoglobin, haematocrit, mean corpuscular volume, red blood cells, platelets, total white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, CD4/CD8 T cells, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, direct bilirubin, total bilirubin, total immunoglobulin gamma, total protein, creatinine, total amylase, creatine phosphokinase and lactate dehydrogenase (LDH). Consensus dry season reference intervals were applied to rainy season values (and vice versa) and the proportion of 'out-of-range' values determined. Percentage differences between dry and rainy season parameter mean values were estimated.ResultsIn this cohort of 903 volunteers, less than 10.0% of consensus parameter (except LDH) values in one season were "out-of-range" in the other. Twenty-two (22) percent of rainy season LDH values fell outside of the consensus dry season interval with the higher values observed in the rainy season. Variability between consensus seasonal means ranged from 0.0% (total WBC, neutrophils, monocytes, basophils, and direct bilirubin) to 40.0% (eosinophils). Within sites, the largest seasonal variations were observed for monocytes (Masaka, 11.5%), LDH (Lusaka, 21.7%), and basophils (Kigali, 22.2%).ConclusionsSeasonality had minimal impact on adult clinical laboratory parameter values in Rwanda, Zambia, and Uganda. Seasonal variation may not be an important factor in the evaluation of adult clinical laboratory parameters in HIV prevention and other clinical trials in these countries.

BACKGROUND:Early initiation of antiretroviral therapy reduces risk of transmission to the uninfected partner in HIV discordant couples, but there are relatively little observational data on HIV transmission within couples from non-trial settings. The aims of this paper are to estimate HIV incidence among HIV discordant couples using longstanding observational data from a rural Ugandan population and to identify factors associated with HIV transmission within couples, including the role of HSV-2 infection. METHODS:Using existing data collected at population-wide annual serological and behavioural surveys in a rural district in southwest Uganda between 1989 and 2007, HIV discordant partners were identified. Stored serum samples were tested for HSV-2 serostatus using the Kalon ELISA test. HIV seroconversion rates and factors association with HIV seroconversion were analysed using Poisson regression. RESULTS:HIV status of both partners was known in 2465 couples and of these 259 (10.5%) were HIV serodiscordant. At enrollment, HSV-2 prevalence was 87.3% in HIV positive partners and 71.5% in HIV negative partners. Of the 259 discordant couples, 62 converted to HIV (seroconversion rate 7.11/100 PYAR, 95%CI; 5.54, 9.11) with the rate decreasing from 10.89 in 1990-1994 to 4.32 in 2005-2007. Factors independently associated with HIV seroconversion were female sex, non-Muslim religion, greater age difference (man older than woman by more than 15 years), higher viral load in the positive partner and earlier calendar period. HSV-2 was not independently associated with HIV acquisition (HR 1.62, 95%CI; 0.57, 4.55) or transmission (HR 0.61, 95%CI; 0.24, 1.57). No transmissions occurred in the 29 couples where the index partner was on ART during follow up (872 person-years on ART). DISCUSSION:HIV negative partners in serodiscordant couples have a high incidence of HIV if the index partner is not on antiretroviral therapy and should be provided with interventions such as couple counselling, condoms and antiretroviral treatment.

Efficacy of oral pre-exposure prophylaxis (PrEP) in prevention of HIV acquisition has been evaluated using a daily regimen. However, adherence to long term daily medication is rarely perfect. Intermittent regimen may be a feasible alternative. Preclinical studies have demonstrated effectiveness of intermittent PrEP in SHIV prevention among animals. However, little is known about intermittent PrEP regimens.Seventy two HIV-uninfected volunteers in HIV serodiscordant couple relationships in Uganda were randomly assigned to receive daily oral Tenofovir/Emtricitabine (TDF/FTC-Truvada) or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral TDF/FTC or placebo in a 2:1:2:1 ratio. Volunteers and study staff were blinded to drug assignment, but not to regimen assignment.Volunteers were followed for 4 months after randomization, with monthly clinical and laboratory safety assessments and comprehensive HIV risk reduction services. Adherence was monitored using medication event monitoring system (MEMS) and self-report. Sexual activity data were collected via daily short text message (SMS) and self-report. HIV-specific immune responses were assessed by IFN-γ ELISPOT.Both daily and intermittent oral TDF/FTC regimens were well tolerated. Median MEMS adherence rates were 98% (IQR: 93-100) for daily PrEP regimen, 91% (IQR: 73-97) for fixed intermittent dosing and 45% (IQR: 20-63) for post-coital dosing. SMS response rate was 74%, but increased to 80% after excluding server outages; results may have been affected by the novelty of this measure. The majority of volunteers expressed willingness with no particular preference for either regimen.Both daily and intermittent oral PrEP dosing regimens were safe. Adherence was high for daily and fixed intermittent dosing; post-coital dosing was associated with poor adherence. Fixed intermittent PrEP regimens may be feasible especially if a minimum effective drug concentration correlating with HIV prevention can be achieved with this dosing.Clinicaltrials.gov number NCT00931346.

BackgroundLocal HIV epidemiology data are critical in determining the suitability of a population for HIV vaccine efficacy trials. The objective of this study was to estimate the prevalence and incidence of, and determine risk factors for HIV transmission in a rural community-based HIV vaccine preparedness cohort in Masaka, Uganda.MethodsBetween February and July 2004, we conducted a house-to-house HIV sero-prevalence survey among consenting individuals aged 18-60 years. Participants were interviewed, counseled and asked to provide blood for HIV testing. We then enrolled the HIV uninfected participants in a 2-year HIV sero-incidence study. Medical evaluations, HIV counseling and testing, and sample collection for laboratory analysis were done quarterly. Sexual risk behaviour data was collected every 6 months.ResultsThe HIV point prevalence was 11.2%, and was higher among women than men (12.9% vs. 8.6%, P = 0.007). Risk factors associated with prevalent HIV infection for men were age ConclusionsWe found a high prevalence but low incidence of HIV in this cohort. HIV vaccine efficacy trials in this population may not be feasible due to the large sample sizes that would be required. HIV vaccine preparatory efforts in this setting should include identification of higher risk populations.

To determine the incidence of and risk factors for HIV acquisition in a cohort of HIV-uninfected partners from HIV discordant couples in Masaka, Uganda, and to establish its suitability for HIV vaccine trials.HIV-uninfected adults living in HIV discordant couple relationships were enrolled and followed for 2 years. Interviews, medical investigations, HIV counseling and testing, syphilis and urine pregnancy (women) tests were performed at quarterly visits. Sexual risk behaviour data were collected every 6 months.495 participants were enrolled, of whom 34 seroconverted during 786.6 person-years of observation (PYO). The overall HIV incidence rate [95% confidence interval (CI)] was 4.3 [3.1-6]; and 4.3 [2.8-6.4] and 4.4 [2.5-8] per 100 PYO in men and women respectively. Independent baseline predictors for HIV acquisition were young age [18-24 (aRR = 4.1, 95% CI 1.6-10.8) and 25-34 (aRR = 2.7, 95% CI 1.2-5.8) years]; alcohol use (aRR = 2.6, 95% CI 1.1-6); and reported genital discharge (aRR = 3.4, 95% CI 1.6-7.2) in the past year. Condom use frequency in the year preceding enrolment was predictive of a reduced risk of HIV acquisition [sometimes (aRR = 0.4, 95% CI 0.2-0.8); always (aRR = 0.1, 95% CI 0.02-0.9)]. In the follow-up risk analysis, young age [18-24 (aRR = 6.2, 95% CI 2.2-17.3) and 25-34 (aRR = 2.3, 95% CI 1.1-5.0) years], reported genital discharge (aRR = 2.5, 95% CI 1.1-5.5), serological syphilis (aRR 3.2, 95% CI 1.3-7.7) and the partner being ART naïve (aRR = 4.8, 95% CI 1.4-16.0) were independently associated with HIV acquisition. There were no seroconversions among participants who reported consistent condom use during the study.The study has identified important risk factors for HIV acquisition among HIV discordant couples. HIV-uninfected partners in discordant couples may be a suitable population for HIV vaccine efficacy trials. However, recent confirmation that ART reduces heterosexual HIV transmission may make it unfeasible to conduct HIV prevention trials in this population.

Clinical laboratory reference intervals have not been established in many African countries, and non-local intervals are commonly used in clinical trials to screen and monitor adverse events (AEs) among African participants. Using laboratory reference intervals derived from other populations excludes potential trial volunteers in Africa and makes AE assessment challenging. The objective of this study was to establish clinical laboratory reference intervals for 25 hematology, immunology and biochemistry values among healthy African adults typical of those who might join a clinical trial.Equal proportions of men and women were invited to participate in a cross sectional study at seven clinical centers (Kigali, Rwanda; Masaka and Entebbe, Uganda; two in Nairobi and one in Kilifi, Kenya; and Lusaka, Zambia). All laboratories used hematology, immunology and biochemistry analyzers validated by an independent clinical laboratory. Clinical and Laboratory Standards Institute guidelines were followed to create study consensus intervals. For comparison, AE grading criteria published by the U.S. National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) and other U.S. reference intervals were used. 2,990 potential volunteers were screened, and 2,105 (1,083 men and 1,022 women) were included in the analysis. While some significant gender and regional differences were observed, creating consensus African study intervals from the complete data was possible for 18 of the 25 analytes. Compared to reference intervals from the U.S., we found lower hematocrit and hemoglobin levels, particularly among women, lower white blood cell and neutrophil counts, and lower amylase. Both genders had elevated eosinophil counts, immunoglobulin G, total and direct bilirubin, lactate dehydrogenase and creatine phosphokinase, the latter being more pronounced among women. When graded against U.S. -derived DAIDS AE grading criteria, we observed 774 (35.3%) volunteers with grade one or higher results; 314 (14.9%) had elevated total bilirubin, and 201 (9.6%) had low neutrophil counts. These otherwise healthy volunteers would be excluded or would require special exemption to participate in many clinical trials.To accelerate clinical trials in Africa, and to improve their scientific validity, locally appropriate reference ranges should be used. This study provides ranges that will inform inclusion criteria and evaluation of adverse events for studies in these regions of Africa.