Study design approaches for future active-controlled HIV prevention trials.

Objectives: Vigorous discussions are ongoing about future efficacy trial designs of candidate human immunodeficiency virus (HIV) prevention interventions. The study design challenges of HIV prevention interventions are considerable given rapid evolution of the prevention landscape and evidence of multiple modalities of highly effective products; future trials will likely be 'active-controlled', i.e., not include a placebo arm. Thus, novel design approaches are needed to accurately assess new interventions against these highly effective active controls. Methods: To discuss active control design challenges and identify solutions, an initial virtual workshop series was hosted and supported by the International AIDS Enterprise (October 2020-March 2021). Subsequent symposia discussions continue to advance these efforts. As the non-inferiority design is an important conceptual reference design for guiding active control trials, we adopt several of its principles in our proposed design approaches. Results: We discuss six potential study design approaches for formally evaluating absolute prevention efficacy given data from an active-controlled HIV prevention trial including using data from: 1) a registrational cohort, 2) recency assays, 3) an external trial placebo arm, 4) a biomarker of HIV incidence/exposure, 5) an anti-retroviral drug concentration as a mediator of prevention efficacy, and 6) immune biomarkers as a mediator of prevention efficacy. Conclusions: Our understanding of these proposed novel approaches to future trial designs remains incomplete and there are many future statistical research needs. Yet, each of these approaches, within the context of an active-controlled trial, have the potential to yield reliable evidence of efficacy for future biomedical interventions.

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.

Developing HIV risk prediction tools in four African settings.

OBJECTIVE: HIV risk prediction tools are a critical component of efforts to end the HIV pandemic. We aimed to create and validate tools for identifying individuals at highest risk of prevalent and incident HIV in an African setting. METHODS: We used Logistic regression and Poisson regression to determine risk factors for HIV prevalence and incidence in a multi-country HIV vaccine trial preparedness cohort study among individuals at high risk of HIV, and used the identified factors to create and validate tools that predict HIV risk. We also assessed the performance of the VOICE risk score in predicting HIV incidence among women in the cohort. RESULTS: The prevalent HIV prediction tool created had good predictive ability [area under the curve (AUC) = 0.70, 95% CI 0.66-0.74]. It included the following participant variables: age, sex, recreational drug use, unprotected male-to-male anal sex, a sexual partner who had other partners, transactional sex and having a partner who was a long-distance truck driver/miner. It was not possible to create a valid HIV incidence prediction tool. Participants with high VOICE risk scores (≥7) had slightly higher HIV incidence but this tool performed poorly within our study (AUC = 0.58, 95% CI 0.51-0.64: Harrell's concordance index = 0.59). CONCLUSION: We created a prevalent HIV prediction tool that could be used to increase efficiency in diagnosis of HIV and linkage to care in sub-Saharan Africa. Existing incident HIV prediction tools may need modification to include context-specific predictors such as calendar period, participant occupation, study site, before adoption in settings different from those in which they were developed.

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.

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.

Quality of life and associated factors among HIV positive patients after completion of treatment for Cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CCM) remains one of the leading causes of mortality among HIV infected patients. Due to factors such as the severity of CCM pathology, the quality of life (QOL) of patients post-treatment is likely to be poor. Few studies have reported on QOL of CCM patients post treatment completion. We used data collected among patients in the CryptoDex trial (ISRCTN59144167) to determine QOL and associated factors at week 10 and six months from treatment initiation. METHODOLOGY: CryptoDex was a double-blind placebo-controlled trial of adjunctive dexamethasone in HIV infected adults with CCM, conducted between 2013 and 2015 in six countries in Asia and Africa. QOL was determined using the descriptive and Visual Analog Scales (VAS) of the EuroQol Five-Dimension-Three-Level (EQ-5D-3L) tool. We derived index scores, and described these and the VAS scores at 10 weeks and 6 months; and used linear regression to determine the relationship between various characteristics and VAS scores at both time points. VAS scores were interpreted as very good (81-100), good (51-80), normal (31-50) and bad/very bad (0-30). RESULTS: Of 451 patients enrolled in the trial, 238 had QOL evaluations at week 10. At baseline, their mean age (SD) was 35.2(8.5) years. The mean index scores (SD) were 0.785(0.2) and 0.619(0.4) among African and Asian patients respectively at week 10, and 0.879(0.2) and 0.731(0.4) among African and Asian patients respectively at month six. The overall mean VAS score (SD) at 10 weeks was 57.2 (29.7), increasing significantly to 72(27.4) at month six (p<0.001). At week 10, higher VAS score was associated with greater weight (p = 0.007) and being African (p<0.001), while lower VAS score was associated with positive yeast culture at day 14 (p = 0.026). At month six, higher VAS score remained associated with African origin (p = 0.006) while lower VAS score was associated with positive yeast culture (p = 0.006). Lower VAS scores were associated with higher number of inpatient days at 10 weeks and 6 months (p = 0.003 and 0.002 respectively). CONCLUSION: QOL was good among patients that had completed therapy for CCM, but below perfect. Strategies to improve QOL among CCM survivors are required.

Prevalence of non-communicable diseases among HIV positive patients on antiretroviral therapy at joint clinical research centre, Lubowa, Uganda.

INTRODUCTION: Antiretroviral therapy (ART) has changed the course of HIV/AIDs by enabling patients to live longer, raising concern of the co- existence of HIV with other chronic illnesses, notably non-communicable diseases (NCDs). NCDs are on the rise in developing countries and evidence shows higher occurrence among people living with HIV (PLHIV). In Uganda, the burden of NCDs among PLHIV remains largely unquantified. OBJECTIVE: To determine the prevalence of hypertension, osteoporosis, diabetes mellitus, renal impairment, asthma, cardiomyopathy and multi-morbidity among HIV positive patients, receiving Anti-Retroviral Therapy at Joint Clinical Research Centre, Lubowa, Uganda. METHODS: This was a cross-sectional study conducted among 387 systematically sampled patients, receiving ART at the Joint Clinical Research Centre, Lubowa, between March and April 2017. The study used data extracted from routine care patient files to identify individuals with non-communicable diseases. Prevalence of the NCDs was estimated and reported with 95% confidence intervals. Prevalence was also reported at various levels of socio- demographic, behavioural and clinical factors. RESULTS: The overall prevalence of having at least one NCD was 20.7% (95% CI: 16.7-24.5). The prevalence of hypertension was 12.4% (95% CI: 9.1-15.7), osteoporosis 6.5% (95% CI: 4.0-8.9), diabetes mellitus 4.7% (95% CI: 2.6-6.8), renal impairment 1.6% (95% CI: 0.3-2.8), asthma 1.6% (95% CI: 0.3-2.8), and cardiomyopathy 1.3% (95% CI: 0.2-2.4). Prevalence of multi-morbidity was 4.7% (95% CI: 2.6-6.8). Prevalence was significantly higher among older participants, widowed participants and individuals with an opportunistic infection. CONCLUSION: Non-communicable diseases are common among people living with HIV. There is need to encourage early diagnosis and treatment of non-communicable diseases in PLHIV in Uganda.