Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose in young women aged 15-20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials.

BACKGROUND: The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE. METHODS: In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50. FINDINGS: Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines. INTERPRETATION: HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination. FUNDING: The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Prevalence of Curable Sexually Transmitted Infections in a Population-Representative Sample of Young Adults in a High HIV Incidence Area in South Africa.

BACKGROUND: Recent population-representative estimates of sexually transmitted infection (STI) prevalence in high HIV burden areas in southern Africa are limited. We estimated the prevalence and associated factors of 3 STIs among adolescents and young adults (AYA) in rural South Africa. METHODS: Between March 2020 and May 2021, a population-representative sample of AYA aged 16 to 29 years were randomly selected from a Health and Demographic Surveillance Site in rural KwaZulu-Natal, South Africa, for a 2 × 2 factorial randomized controlled trial. Participants in 2 intervention arms were offered baseline testing for gonorrhea, chlamydia, and trichomoniasis using GeneXpert. Prevalence estimates were weighted for participation bias, and logistic regression models were used to assess factors associated with STIs. RESULTS: Of 2323 eligible AYA, 1743 (75%) enrolled in the trial. Among 863 eligible for STI testing, 814 (94%) provided specimens (median age of 21.8 years, 52% female, and 71% residing in rural areas). Population-weighted prevalence estimates were 5.0% (95% confidence interval [CI], 4.2%-5.8%) for gonorrhea, 17.9% (16.5%-19.3%) for chlamydia, 5.4% (4.6%-6.3%) for trichomoniasis, and 23.7% (22.2%-25.3%) for any STI. In multivariable models, female sex (adjusted odds ratio [aOR], 2.24; 95% CI, 1.48-3.09) and urban/periurban (vs. rural) residence (aOR, 1.48; 95% CI, 1.02-2.15) were associated with STIs; recent migration was associated with lower odds of STI (aOR, 0.37; 95% CI, 0.15-0.89). Among those with an STI, 53 (31.0%) were treated within 7 days; median time to treatment was 11 days (interquartile range, 6-77 days). CONCLUSIONS: We identified a high prevalence of curable STIs among AYA in rural South Africa. Improved access to STI testing to enable etiologic diagnosis and rapid treatment is needed.

Sustainability capacity and health worker normalisation of a successful non-communicable disease (NCD) health systems intervention within primary care settings in Uganda: a quantitative approach to a qualitative question.

BACKGROUND: Interventions for non-communicable diseases are increasingly implemented and evaluated in sub-Saharan Africa, but little is known about their medium- to long-term sustainability beyond the end of research funding. A cluster randomised trial conducted between 2013 and 2016 in Uganda and Tanzania showed that an intervention package to improve hypertension (HT) and type-2 diabetes mellitus (DM) care was highly effective in increasing service readiness and quality of care. The present study assesses the sustainability of the intervention 4 years after the trial in Uganda. METHODS: The study was conducted in 2020 in 22 primary care health facilities (HFs) (3 referrals and 19 lower-level units) that had received the intervention package until trial end (2016), to assess their current capacity and practice to sustain ongoing intervention activities for HT and DM care. Through a cross-sectional survey, 4 pre-defined domains (i.e., cognitive participation, coherence, collective action, and reflexive monitoring) were examined with regard to health worker (HW) normalization and 8 pre-defined domains for intervention sustainability (i.e., organisational capacity, local environment, funding stability, partnerships, communication, evaluation, adaptation, and strategic planning), using the normalisation tool and the program sustainability tool (PSAT). Summary scores were assessed by domains and facility level. RESULTS: Overall normalization strength was adequate at 4.0 (IQR: 3.8, 4.2) of a possible 5 with no evidence of association with HF level (p = 0.40); cognitive participation (buy-in) and reflexive monitoring (appraisal) were strongest at > 4 across all HF levels. All HF levels were weak (< 4) on collective action (teamwork) and coherence (sense-making). Only collective action differed by level (p < 0.002). Overall intervention sustainability was suboptimal at 3.1 [IQR: 1.9, 4.1] of a possible 7 with weak scores on funding stability (2.0), supportive partnerships (2.2), and strategic planning (2.6). Domain differences by HF level were significant for environmental support (p = 0.02) and capacity in organisation (p = 0.01). Adequate strength at a cut-off mean of ≥5 did not differ by HF level for any domain. CONCLUSIONS: Four years after their introduction, practice-dependent intervention elements e.g., local organisational context, HW knowledge or dedication were sustained, but external elements e.g., new funding support or attracting new partners to sustain intervention efforts were not. Whenever new interventions are introduced into an existing health service, their long-term sustainability including the required financial support should be ensured. The quality of services should be upheld by providing routine in-service training with dedicated support supervision.

Medium-to-long term sustainability of a health systems intervention to improve service readiness and quality of non-communicable disease (NCD) patient care and experience at primary care settings in Uganda.

BACKGROUND: With the double burden of rising chronic non-communicable diseases (NCDs) and persistent infectious diseases facing sub-Saharan Africa, integrated health service delivery strategies among resource-poor countries are needed. Our study explored the post-trial sustainability of a health system intervention to improve NCD care, introduced during a cluster randomised trial between 2013 and 2016 in Uganda, focusing on hypertension (HT) and type-2 diabetes mellitus (DM) services. In 2020, 19 of 38 primary care health facilities (HFs) that constituted the trial's original intervention arm until 2016 and 3 of 6 referral HFs that also received the intervention then, were evaluated on i) their facility performance (FPS) through health worker knowledge, and service availability and readiness (SAR), and ii) the quality-of-patient-care-and-experience (QoCE) received. METHODS: Cross-sectional data from the original trial (2016) and our study (2020) were compared. FPS included a clinical knowledge test with 222 health workers: 131 (2016) and 91 (2020) and a five-element SAR assessment of all 22 HFs. QoCE assessment was performed among 420 patients: 88 (2016) and 332 (2020). Using a pair-matched approach, FPS and QoCE summary scores were compared. Linear and random effects Tobit regression models were also analysed. RESULTS: The mean aggregate facility performance (FPS) in 2020 was lower than in 2016: 70.2 (95%CI = 66.0-74.5) vs. 74.8 (95%CI = 71.3-78.3) respectively, with no significant difference (p = 0.18). Mean scores declined in 4 of 5 SAR elements. Overall FPS was negatively affected by rural or urban HF location relative to peri-urban HFs (p < 0.01). FPS was not independently predicted but patient club functionality showed weak association (p = 0.09). QoCE declined slightly to 8.7 (95%CI = 8.4-91) in 2020 vs 9.5 (95%CI = 9.1-9.9) in 2016 (p = 0.02) while the proportion of patients receiving adequate quality care also declined slightly to 88.2% from 98.5% respectively, with no statistical difference (p = 0.20). Only the parent district weakly predicted QoCE (p = 0.05). CONCLUSIONS: Four years after the end of research-related support, overall facility performance had declined as expected because of the interrupted supplies and a decline in regular supervision. However, both service availability and readiness and quality of HT/DM care were surprisingly well preserved. Sustainability of an NCD intervention in similar settings may remain achievable despite the funding instability following a trial's end but organisational measures to prepare for the post-trial phase should be taken early on in the intervention process.

Thetha Nami ngithethe nawe (Let's Talk): a stepped-wedge cluster randomised trial of social mobilisation by peer navigators into community-based sexual health and HIV care, including pre-exposure prophylaxis (PrEP), to reduce sexually transmissible HIV amongst young people in rural KwaZulu-Natal, South Africa.

BACKGROUND: Antiretroviral therapy (ART) through universal test and treat (UTT) and HIV pre-exposure prophylaxis (PrEP) substantially reduces HIV-related mortality and incidence. Effective ART based prevention has not translated into population-level impact in southern Africa due to sub-optimal coverage among youth. We aim to investigate the effectiveness, implementation and cost effectiveness of peer-led social mobilisation into decentralised integrated HIV and sexual reproductive health (SRH) services amongst adolescents and young adults in KwaZulu-Natal (KZN). METHODS: We are conducting a type 1a hybrid effectiveness/implementation study, with a cluster randomized stepped-wedge trial (SWT) to assess effectiveness and a realist process evaluation to assess implementation outcomes. The SWT will be conducted in 40 clusters in rural KZN over 45 months. Clusters will be randomly allocated to receive the intervention in period 1 (early) or period 2 (delayed). 1) Intervention arm: Resident peer navigators in each cluster will approach young men and women aged 15-30 years living in their cluster to conduct health, social and educational needs assessment and tailor psychosocial support and health promotion, peer mentorship, and facilitate referrals into nurse led mobile clinics that visit each cluster regularly to deliver integrated SRH and differentiated HIV prevention (HIV testing, UTT for those positive, and PrEP for those eligible and negative). Standard of Care is UTT and PrEP delivered to 15-30 year olds from control clusters through primary health clinics. There are 3 co-primary outcomes measured amongst cross sectional surveys of 15-30 year olds: 1) effectiveness of the intervention in reducing the prevalence of sexually transmissible HIV; 2) uptake of universal risk informed HIV prevention intervention; 3) cost of transmissible HIV infection averted. We will use a realist process evaluation to interrogate the extent to which the intervention components support demand, uptake, and retention in risk-differentiated biomedical HIV prevention. DISCUSSION: The findings of this trial will be used by policy makers to optimize delivery of universal differentiated HIV prevention, including HIV pre-exposure prophylaxis through peer-led mobilisation into community-based integrated adolescent and youth friendly HIV and sexual and reproductive health care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier-NCT05405582. Registered: 6th June 2022.

The met and unmet health needs for HIV, hypertension, and diabetes in rural KwaZulu-Natal, South Africa: analysis of a cross-sectional multimorbidity survey.

BACKGROUND: The convergence of infectious diseases and non-communicable diseases in South Africa is challenging to health systems. In this analysis, we assessed the multimorbidity health needs of individuals and communities in rural KwaZulu-Natal and established a framework to quantify met and unmet health needs for individuals living with infectious and non-communicable diseases. METHODS: We analysed data collected between May 25, 2018, and March 13, 2020, from participants of a large, community-based, cross-sectional multimorbidity survey (Vukuzazi) that offered community-based HIV, hypertension, and diabetes screening to all residents aged 15 years or older in a surveillance area in the uMkhanyakude district in KwaZulu-Natal, South Africa. Data from the Vukuzazi survey were linked with data from demographic and health surveillance surveys with a unique identifier common to both studies. Questionnaires were used to assess the diagnosed health conditions, treatment history, general health, and sociodemographic characteristics of an individual. For each condition (ie, HIV, hypertension, and diabetes), individuals were defined as having no health needs (absence of condition), met health needs (condition that is well controlled), or one or more unmet health needs (including diagnosis, engagement in care, or treatment optimisation). We analysed met and unmet health needs for individual and combined conditions and investigated their geospatial distribution. FINDINGS: Of 18 041 participants who completed the survey (12 229 [67·8%] were female and 5812 [32·2%] were male), 9898 (54·9%) had at least one of the three chronic diseases measured. 4942 (49·9%) of these 9898 individuals had at least one unmet health need (1802 [18·2%] of 9898 needed treatment optimisation, 1282 [13·0%] needed engagement in care, and 1858 [18·8%] needed a diagnosis). Unmet health needs varied by disease; 1617 (93·1%) of 1737 people who screened positive for diabetes, 2681 (58·2%) of 4603 people who screened positive for hypertension, and 1321 (21·7%) of 6096 people who screened positive for HIV had unmet health needs. Geospatially, met health needs for HIV were widely distributed and unmet health needs for all three conditions had specific sites of concentration; all three conditions had an overlapping geographical pattern for the need for diagnosis. INTERPRETATION: Although people living with HIV predominantly have a well controlled condition, there is a high burden of unmet health needs for people living with hypertension and diabetes. In South Africa, adapting current, widely available HIV care services to integrate non-communicable disease care is of high priority. FUNDING: Fogarty International Center and the National Institutes of Health, the Bill & Melinda Gates Foundation, the South African Department of Science and Innovation, the South African Medical Research Council, the South African Population Research Infrastructure Network, and the Wellcome Trust. TRANSLATION: For the isiZulu translation of the abstract see Supplementary Materials section.

The Impact of Drought on HIV Care in Rural South Africa: An Interrupted Time Series Analysis.

This analysis investigates the relationship between drought and antiretroviral treatment (ART) adherence and retention in HIV care in the Hlabisa sub-district, KwaZulu-Natal, South Africa. Data on drought and ART adherence and retention were collated for the study period 2010-2019. Drought was quantified using the 3-month Standard Precipitation Evapotranspiration Index (SPEI) and Standard Precipitation Index (SPI) from station data. Adherence, proxied by the Medication Possession Ratio (MPR), and retention data were obtained from the public ART programme database. MPR and retention were calculated from individuals aged 15-59 years who initiated ART between January 2010 and December 2018 and visited clinic through February 2019. Between 01 January 2010 and 31 December 2018, 40,714 individuals started ART in the sub-district and made 1,022,760 ART visits. The SPI showed that 2014-2016 were dry years, with partial recovery after 2016 in the wet years. In the period from 2010 to 2012, mean 6-month MPR increased from 0.85 in July 2010 to a high of 0.92 in December 2012. MPR then decreased steadily through 2013 and 2014 to 0.78 by December 2014. The mean proportion retained in care 6 months after starting ART showed similar trends to MPR, increasing from 86.9% in July 2010 to 91.4% in December 2012. Retention then decreased through 2013, with evidence of a pronounced drop in January 2014 when the odds of retention decreased by 30% (OR = 0.70, CI = 0.53-0.92, P = 0.01) relative to the end of 2013. Adherence and retention in care decreased during the drought years.

Protocol: Implementation evaluation of a combination intervention for sustainable blood pressure control in rural KwaZulu-Natal, South Africa (IMPACT BP): A three-arm, unblinded, parallel group individually randomized clinical trial.

BACKGROUND: Hypertension is the primary risk factor for stroke and heart disease, which are leading causes of death in South Africa. Despite the availability of treatments, there is an implementation gap in how best to deliver hypertension care in this resource-limited region. METHODS: We describe a three-arm parallel group individually randomized control trial to evaluate the effectiveness and implementation of a technology-supported, community-based intervention to improve blood pressure control among people with hypertension in rural KwaZulu-Natal. The study will compare three strategies: 1) standard of care (SOC arm) clinic-based management, 2) home-based blood pressure management supported by community blood pressure monitors (CBPM arm) and a mobile health application to record blood pressure readings and enable clinic-based nurses to remotely manage care, and 3) an identical strategy to the CBPM arm, except that participants will use a cellular blood pressure cuff, which automatically transmits completed readings over cellular networks directly to clinic-based nurses (eCBPM+ arm). The primary effectiveness outcome is change in blood pressure from enrollment to 6 months. The secondary effectiveness outcome is the proportion of participants with blood pressure control at 6 months. Acceptability, fidelity, sustainability, and cost-effectiveness of the interventions will also be assessed. CONCLUSIONS: In this protocol, we report the development of interventions in partnership with the South Africa Department of Health, a description of the technology-enhanced interventions, and details of the study design so that our intervention and evaluation can inform similar efforts in rural, resource-limited settings. PROTOCOL: Version 3 November 9th, 2022. CLINICALTRIALS: gov Trial Registration: NCT05492955 SAHPRA Trial Number: N20211201. SANCTR Number: DOH-27-112,022-4895.

Evaluating use of mass-media communication intervention 'MTV-Shuga' on increased awareness and demand for HIV and sexual health services by adolescent girls and young women in South Africa: an observational study.

OBJECTIVE: To investigate the effect of exposure to MTV Shuga:Down South' (MTVShuga-DS) during the scale-up of combination HIV-prevention interventions on awareness and uptake of sexual reproductive health (SRH) and HIV-prevention services by adolescent girls and young women (AGYW). DESIGN: One longitudinal and three cross-sectional surveys of representative samples of AGYW. SETTING: AGYW in four South African districts with high HIV prevalence (>10%) (May 2017 and September 2019). PARTICIPANTS: 6311 AGYW aged 12-24. MEASURES: Using logistic regression, we measured the relationship between exposure to MTV Shuga-DS and awareness of pre-exposure prophylaxis (PrEP), condom use at last sex, uptake of HIV-testing or contraception, and incident pregnancy or herpes simplex virus 2 (HSV-2) infection. RESULTS: Within the rural cohort 2184 (85.5%) of eligible sampled individuals were enrolled, of whom 92.6% had at least one follow-up visit; the urban cross-sectional surveys enrolled 4127 (22.6%) of eligible sampled individuals. Self-report of watching at least one MTV Shuga-DS episode was 14.1% (cohort) and 35.8% (cross-section), while storyline recall was 5.5% (cohort) and 6.7% (cross-section). In the cohort, after adjustment (for HIV-prevention intervention-exposure, age, education, socioeconomic status), MTVShuga-DS exposure was associated with increased PrEP awareness (adjusted OR (aOR) 2.06, 95% CI 1.57 to 2.70), contraception uptake (aOR 2.08, 95% CI 1.45 to 2.98) and consistent condom use (aOR 1.84, 95% CI 1.24 to 2.93), but not with HIV testing (aOR 1.02, 95% CI 0.77 to 1.21) or acquiring HSV-2 (aOR 0.92, 95% CI 0.61 to 1.38). In the cross-sections, MTVShuga-DS was associated with greater PrEP awareness (aOR 1.7, 95% CI 1.20 to 2.43), but no other outcome. CONCLUSIONS: Among both urban and rural AGYW in South Africa, MTVShuga-DS exposure was associated with increased PrEP awareness and improved demand for some HIV prevention and SRH technologies but not sexual health outcomes. However, exposure to MTVShuga-DS was low. Given these positive indications, supportive programming may be required to raise exposure and allow future evaluation of edu-drama impact in this setting.

Associations between age of menarche, early sexual debut and high-risk sexual behaviour among urban Tanzanian schoolgirls: A cross-sectional study.

OBJECTIVES: This cross-sectional survey aimed to explore associations between age of menarche, early sexual debut and high-risk sexual behaviour among urban Tanzanian schoolgirls. METHODS: Secondary schoolgirls aged 17-18 years from Mwanza, Tanzania, participated in structured face-to-face questionnaire-based interviews, conducted by nurses and clinicians. Age of menarche was evaluated in categories of 11-12, 13-14, 15-16 or ≥17 years. Primary outcome measures were self-reported early sexual debut (first vaginal sex at <16 years) and high-risk sexual behaviour, including non-use of condoms, having sex for gifts/money, having older sexual partners and/or other risky behaviours. RESULTS: Of 401 girls enrolled, 174 (43.4%) reported prior vaginal sex. Prevalence of early sexual debut was 14.2% but pressured/forced sex and risky sexual behaviours were common. Adjusted for potential confounding, younger age at menarche was associated with early sexual debut (adjusted odds ratio for linear trend: 1.88 per category, 95% confidence interval: 1.21-2.92, p = 0.005). This association remained after excluding girls with first sex at <8 years or experiencing pressure or force at first sex. Further, adjusted for potential confounding (including ever experiencing forced sex), early sexual debut was associated with high-risk sexual behaviour (adjusted odds ratio: 2.85, 95% confidence interval: 1.38-5.88, p = 0.004). CONCLUSIONS: Among urban Tanzanian school girls, younger age of menarche was associated with early sexual debut, and early sexual debut was associated with high-risk sexual behaviour. Researchers and public health professionals developing and delivering interventions aimed at preventing adverse sexual health outcomes should consider the impact of these early biological and sexual exposures.

Costs of delivering human papillomavirus vaccination using a one- or two-dose strategy in Tanzania.

OBJECTIVE: As part of the Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls (DoRIS; NCT02834637), the current study is one of the first to evaluate the financial and economic costs of the national rollout of an HPV vaccination program in school-aged girls in sub-Saharan Africa and the potential costs associated with a single dose HPV vaccine program, given recent evidence suggesting that a single dose may be as efficacious as a two-dose regimen. METHODS: The World Health Organization's (WHO) Cervical Cancer Prevention and Control Costing (C4P) micro-costing tool was used to estimate the total financial and economic costs of the national vaccination program from the perspective of the Tanzanian government. Cost data were collected in 2019 via surveys, workshops, and interviews with local stakeholders for vaccines and injection supplies, microplanning, training, sensitization, service delivery, supervision, and cold chain. The cost per two-dose and one-dose fully immunized girl (FIG) was calculated. RESULTS: The total financial and economic costs were US$10,117,455 and US$45,683,204, respectively, at a financial cost of $5.17 per two-dose FIG, and an economic cost of $23.34 per FIG. Vaccine and vaccine-related costs comprised the largest proportion of costs, followed by service delivery. In a one-dose scenario, the cost per FIG reduced to $2.51 (financial) and $12.18 (economic), with the largest reductions in vaccine and injection supply costs, and service delivery. CONCLUSIONS: The overall cost of Tanzania's HPV vaccination program was lower per vaccinee than costs estimated from previous demonstration projects in the region, especially in a single-dose scenario. Given the WHO Strategic Advisory Group of Experts on Immunization's recent recommendation to update dosing schedules to either one or two doses of the HPV vaccine, these data provide important baseline data for Tanzania and may serve as a guide for improving coverage going forward. The findings may also aid in the prioritization of funding for countries that have not yet added HPV vaccines to their routine immunizations.

Where do those data go? Reuse of screening results from clinical trials to estimate population prevalence of HBV infection in adults in Kilifi, Kenya.

Chronic hepatitis B infection (CHB) is a significant problem worldwide with around 300 million people infected. Ambitious goals have been set towards its elimination as a public health threat by 2030. However, accurate seroprevalence estimates in many countries are lacking or fail to provide representative population estimates, particularly in the WHO African Region (AFRO). This means the full extent of HBV infection is not well described, leading to a lack of investment in diagnostics, treatment and disease prevention. Clinical trials in the WHO AFRO region have been increasing over time and many test for infectious diseases including hepatitis B virus (HBV) to determine baseline eligibility for participants, however these screening data are not reported. Here we review data from six clinical trials completed at the KEMRI-Wellcome Trust Research Programme between 2016 and 2023 that screened for HBV using hepatitis B surface antigen (HBsAg) as part of the trial exclusion criteria. 1727 people had HBsAg results available, of which 60 tested positive. We generated a crude period HBV prevalence estimate of 3.5% (95% CI 2.6-4.5%), and after standardisation for sex and age to account for the population structure of the Kilifi Health Demographics Surveillance System (KHDSS), the prevalence estimate increased to 5.0% (95% CI 3.4-6.6%). The underrepresentation of women in these trials was striking with 1263/1641 (77%) of participants being male. Alanine aminotransferase (ALT) was significantly higher in the HBsAg positive group but was not outside the normal range. We argue that routine collation and publishing of data from clinical trials could increase precision and geographical representation of global HBV prevalence estimates, enabling evidence-based provision of clinical care pathways and public health interventions to support progress towards global elimination targets. We do acknowledge when using clinical trials data for seroprevalence estimates, that local population structure data is necessary to allow standardisation of results, and the point of care tests used here are limited in sensitivity and specificity.

Immunogenicity and safety of one-dose human papillomavirus vaccine compared with two or three doses in Tanzanian girls (DoRIS): an open-label, randomised, non-inferiority trial.

BACKGROUND: An estimated 15% of girls aged 9-14 years worldwide have been vaccinated against human papillomavirus (HPV) with the recommended two-dose or three-dose schedules. A one-dose HPV vaccine schedule would be simpler and cheaper to deliver. We report immunogenicity and safety results of different doses of two different HPV vaccines in Tanzanian girls. METHODS: In this open-label, randomised, phase 3, non-inferiority trial, we enrolled healthy schoolgirls aged 9-14 years from Government schools in Mwanza, Tanzania. Eligible participants were randomly assigned to receive one, two, or three doses of either the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart) or the 9-valent vaccine (Gardasil-9, Sanofi Pasteur MSD, Lyon). The primary outcome was HPV 16 specific or HPV 18 specific seropositivity following one dose compared with two or three doses of the same HPV vaccine 24 months after vaccination. Safety was assessed as solicited adverse events up to 30 days after each dose and unsolicited adverse events up to 24 months after vaccination or to last study visit. The primary outcome was done in the per-protocol population, and safety was analysed in the total vaccinated population. This study was registered in ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility. 72 girls were excluded. 930 girls were enrolled and randomly assigned to receive one dose of Cervarix (155 participants), two doses of Cervarix (155 participants), three doses of Cervarix (155 participants), one dose of Gardasil-9 (155 participants), two doses of Gardasil-9 (155 participants), or three doses of Gardasil-9 (155 participants). 922 participants received all scheduled doses within the defined window (three withdrew, one was lost to follow-up, and one died before completion; two received their 6-month doses early, and one received the wrong valent vaccine in error; all 930 participants were included in the total vaccinated cohort). Retention at 24 months was 918 (99%) of 930 participants. In the according-to-protocol cohort, at 24 months, 99% of participants who received one dose of either HPV vaccine were seropositive for HPV 16 IgG antibodies, compared with 100% of participants who received two doses, and 100% of participants who received three doses. This met the prespecified non-inferiority criteria. Anti-HPV 18 seropositivity at 24 months did not meet non-inferiority criteria for one dose compared to two doses or three doses for either vaccine, although more than 98% of girls in all groups had HPV 18 antibodies. 53 serious adverse events (SAEs) were experienced by 42 (4·5%) of 930 girls, the most common of which was hospital admission for malaria. One girl died of malaria. Number of events was similar between groups and no SAEs were considered related to vaccination. INTERPRETATION: A single dose of the 2-valent or 9-valent HPV vaccine in girls aged 9-14 years induced robust immune responses up to 24 months, suggesting that this reduced dose regimen could be suitable for prevention of HPV infection among girls in the target age group for vaccination. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial.

BACKGROUND: Human papillomavirus (HPV) vaccines are given as a two-dose schedule in children aged 9-14 years, or as three doses in older individuals. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), a randomised trial of different HPV vaccine schedules in Tanzania, to those from two observational HPV vaccine trials that found high efficacy of one dose up to 11 years against HPV16 and HPV18 (Costa Rica Vaccine Trial [CVT] and Institutional Agency for Research on Cancer [IARC] India trial). METHODS: In this immunobridging analysis of an open-label randomised controlled trial, girls were recruited from 54 government schools in Mwanza, Tanzania, into the DoRIS trial. Girls were eligible if they were aged 9-14 years, healthy, and HIV negative. Participants were randomly assigned (1:1:1:1:1:1), using permutated block sizes of 12, 18, and 24, to one, two, or three doses of the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart, Belgium) or the 9-valent vaccine (Gardasil 9, Sanofi Pasteur MSD, Lyon, France). For this immunobridging analysis, the primary objective was to compare geometric mean concentrations (GMCs) at 24 months after one dose in the per-protocol population compared with in historical cohorts: the one-dose 2-valent vaccine group in DoRIS was compared with recipients of the 2-valent vaccine Cervarix from CVT and the one-dose 9-valent vaccine group in DoRIS was compared with recipients of the 4-valent vaccine Gardasil (Merck Sharp & Dohme, Whitehouse Station, NJ, USA) from the IARC India trial. Samples were tested together with virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial vs historical cohort) was predefined as when the lower bound of the 95% CI was greater than 0·50. This study is registered with ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility, of whom 930 were enrolled into DoRIS and 155 each were assigned to one dose, two doses, or three doses of 2-valent vaccine, or one dose, two doses, or three doses of 9-valent vaccine. 154 (99%) participants in the one-dose 2-valent vaccine group (median age 10 years [IQR 9-12]) and 152 (98%) in the one-dose 9-valent vaccine group (median age 10 years [IQR 9-12]) were vaccinated and attended the 24 month visit, and so were included in the analysis. 115 one-dose recipients from the CVT (median age 21 years [19-23]) and 139 one-dose recipients from the IARC India trial (median age 14 years [13-16]) were included in the analysis. At 24 months after vaccination, GMCs for HPV16 IgG antibodies were 22·9 international units (IU) per mL (95% CI 19·9-26·4; n=148) for the DoRIS 2-valent vaccine group versus 17·7 IU/mL (13·9-22·5; n=97) for the CVT (GMC ratio 1·30 [95% CI 1·00-1·68]) and 13·7 IU/mL (11·9-15·8; n=145) for the DoRIS 9-valent vaccine group versus 6·7 IU/mL (5·5-8·2; n=131) for the IARC India trial (GMC ratio 2·05 [1·61-2·61]). GMCs for HPV18 IgG antibodies were 9·9 IU/mL (95% CI 8·5-11·5: n=141) for the DoRIS 2-valent vaccine group versus 8·0 IU/mL (6·4-10·0; n=97) for the CVT trial (GMC ratio 1·23 [95% CI 0·95-1·60]) and 5·7 IU/mL (4·9-6·8; n=136) for the DoRIS 9-valent vaccine group versus 2·2 IU/mL (1·9-2·7; n=129) for the IARC India trial (GMC ratio 2·12 [1·59-2·83]). Non-inferiority of antibody GMCs was met for each vaccine for both HPV16 and HPV18. INTERPRETATION: One dose of HPV vaccine in young girls might provide sufficient protection against persistent HPV infection. A one-dose schedule would reduce costs, simplify vaccine delivery, and expand access to the vaccine. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

The association of exposure to DREAMS on sexually acquiring or transmitting HIV amongst adolescent girls and young women living in rural South Africa.

OBJECTIVE: We investigate how risk of sexually acquiring or transmitting HIV in adolescent girls and young women (AGYW) changed following the real-world implementation of DREAMS (Determined, Resilient, Empowered, AIDS free, Mentored and Safe) HIV prevention programme. DESIGN: A representative population-based prospective cohort study of AGYW living in rural KwaZulu-Natal. METHODS: Between 2017 and 2019, we interviewed a random sample of AGYW aged 13-22 years annually. We measured exposure to DREAMS as self-reported receipt of an invitation to participate and/or participation in DREAMS activities that were provided by DREAMS implementing organizations. HIV and herpes simplex virus type 2 (HSV-2) statuses were ascertained through blood tests on Dried Blood Spot (DBS). We used multivariable regression analysis to assess the association between exposure to DREAMS and risk of acquiring HIV: measured as incident HSV-2 (a proxy of sexual risk) and incident HIV;and the risk of sexually transmitting HIV: measured as being HIV positive with a detectable HIV viral load (≥50 copie/ml) on the last available DBS. We adjusted for sociodemographic, sexual relationship, and migration. RESULTS: Two thousand one hundred and eighty-four (86.4%) of those eligible agreed to participate and 2016 (92.3%) provided data for at least one follow-up time-point. One thousand and thirty (54%) were exposed to DREAMS;HIV and HSV-2 incidence were 2.2/100 person-years [95% confidence interval (CI) 1.66-2.86] and 17.3/100 person-years (95% CI 15.5-19.4), respectively. There was no evidence that HSV-2 and HIV incidence were lower in those exposed to DREAMS: adjusted rate ratio (aRR) 0.96 (95% CI 0.76-1.23 and 0.83 (95% CI 0.46-1.52), respectively. HIV viral load was detectable for 169 (8.9%) respondents;there was no evidence this was lower in those exposed to DREAMS with an adjusted risk difference, compared with those not exposed to DREAMS, of 0.99% (95% CI-1.52 to 3.82]. Participants who lived in peri-urban/ urban setting were more likely to have incident HIV and transmissible HIV. Both HSV-2 incidence and the transmissible HIV were associated with older age and ever having sex. Findings did not differ substantively by respondent age group. CONCLUSION: DREAMS exposure was not associated with measurable reductions in risk of sexually acquiring or transmitting HIV amongst a representative cohort of AGYW in rural South Africa.

Hidden heterogeneity: Uncovering patterns of adherence in microbicide trials for HIV prevention.

BACKGROUND: Interpretation of clinical trial results testing vaginal microbicide gels for HIV prevention depends on participant adherence. Prior to the era of antiretrovirals, microbicide trials collected adherence data via self-report, and trials typically reported trial population adherence as overall averages in primary results manuscripts. This study first sought to determine if different patterns of adherence from three trials of vaginal microbicide gels could be identified, using self-reported data and if so, how those patterns compare across trials. The second objective was to explore which individual-level factors were associated with different adherence patterns. METHODS: Data from the following three clinical trials of vaginal microbicides were used for this study: HIV Prevention Trials Network (HPTN) 035 testing PRO 2000 and Buffergel, the Microbicides Development Programme (MDP) 301 testing PRO 2000, and the Population Council's Carraguard study, testing Carraguard gel. Latent Class Analysis (LCA) was used to identify longitudinal patterns of adherence using self-reported data about gel use. Multinomial multivariable logistic regression was used to estimate relative risk-ratios for factors which were independently associated with different latent adherence trajectories within each trial, and compared across trials. RESULTS: Included in this analysis are 2,282 women from HPTN 035 (age 17-56 years), 6238 women from MDP 301 (age 16-75 years), and 6039 women from Carraguard (age 16-73 years). Using LCA, 3-4 different patterns of gel adherence were identified in each trial; these patterns were similar across the trials. Factors associated with adherence patterns were identified in all trials. Older age was associated with the adherence trajectory that consistently reported gel use in three trials. Participant-reported negative reaction of partners to the gel was associated with trajectories that reported less consistent adherence in two trials. A greater number of baseline-reported sex partners or sex acts was associated with trajectories which reported less consistent adherence in some trials. Trial site location was associated with membership of trajectories in all trials. CONCLUSION: LCA was able to identify patterns of microbicide gel adherence in clinical trials that used self-reported data. Key factors associated with patterns of adherence in this study were participant age, clinical trial site location, and partner reaction to the study gel. These findings, in particular, age and perceived partner reaction to the method, are consistent with results from other clinical trials and programmatic rollout of biomedical HIV prevention methods for women in Africa. This study contributes to the body of evidence that women need more support to navigate power dynamics within their relationships with men so that they can successfully use HIV prevention methods.

Estimating the contribution of transmission in primary healthcare clinics to community-wide TB disease incidence, and the impact of infection prevention and control interventions, in KwaZulu-Natal, South Africa.

BACKGROUND: There is a high risk of Mycobacterium tuberculosis (Mtb) transmission in healthcare facilities in high burden settings. WHO guidelines on tuberculosis (TB) infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare settings. These were evaluated primarily based on evidence for their effects on transmission to healthcare workers in hospitals. To estimate the overall impact of IPC interventions, it is necessary to also consider their impact on community-wide TB incidence and mortality. METHODS: We developed an individual-based model of Mtb transmission in households, primary healthcare (PHC) clinics, and all other congregate settings. The model was parameterised using data from a high HIV prevalence community in South Africa, including data on social contact by setting, by sex, age, and HIV/antiretroviral therapy status; and data on TB prevalence in clinic attendees and the general population. We estimated the proportion of disease in adults that resulted from transmission in PHC clinics, and the impact of a range of IPC interventions in clinics on community-wide TB. RESULTS: We estimate that 7.6% (plausible range 3.9%-13.9%) of non-multidrug resistant and multidrug resistant TB in adults resulted directly from transmission in PHC clinics in the community in 2019. The proportion is higher in HIV-positive people, at 9.3% (4.8%-16.8%), compared with 5.3% (2.7%-10.1%) in HIV-negative people. We estimate that IPC interventions could reduce incident TB cases in the community in 2021-2030 by 3.4%-8.0%, and deaths by 3.0%-7.2%. CONCLUSIONS: A non-trivial proportion of TB results from transmission in clinics in the study community, particularly in HIV-positive people. Implementing IPC interventions could lead to moderate reductions in disease burden. We recommend that IPC measures in clinics should be implemented for their benefits to staff and patients, but also for their likely effects on TB incidence and mortality in the surrounding community.

Exploring linkages between drought and HIV treatment adherence in Africa: a systematic review.

Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a systems understanding of the nexus between drought and antiretroviral therapy (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/MEDLINE, and PsycINFO suggests that livelihoods and economic conditions, comorbidities and ART regimens, human mobility, and psychobehavioural dispositions and support systems interact in complex ways in the drought-ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions, and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and developing interventions.