Faculty Bibliography

INTRODUCTION/BACKGROUND:Long-acting injectable cabotegravir (CAB-LA) demonstrated superiority to daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) in two clinical trials. This analysis projects the impact of expanding PrEP coverage with CAB-LA in South Africa between 2022 and 2042. METHODS:Three independently calibrated models of HIV transmission in South Africa (Synthesis, EMOD-HIV, Thembisa) projected HIV acquisitions and effective coverage (average PrEP coverage across exposure groups, weighted by HIV incidence in the absence of PrEP in each group) over 20 years under multiple scenarios of PrEP expansion compared to no PrEP expansion. PrEP expansion scenarios differed in targeted overall coverage, speed of expansion, coverage of high-exposure groups, and relative coverage of women and men. RESULTS:Achieving 5% PrEP coverage with CAB-LA by 2032 prioritizing high-exposure groups resulted in 49% (Synthesis), 18% (EMOD-HIV), and 8% (Thembisa) effective coverage and averted a median of 43%, 29% and 10% of new HIV acquisitions, respectively. Similar expansion with TDF/FTC resulted in lower impact by 19 percentage points (pp), 18pp and 3pp, respectively. Increasing CAB-LA coverage to 15% led to an additional 7pp, 12pp and 16pp, respectively, of HIV acquisitions averted. Achieving 5% CAB-LA coverage expanding to women only resulted in a lower impact by 16pp (Synthesis) and 13pp (EMOD-HIV), and a higher impact by 2pp (Thembisa). Scenarios with similar effective coverage resulted in comparable impact estimates across models. CONCLUSIONS:Offering CAB-LA in South Africa may substantially impact the HIV epidemic based on these projections. Effective coverage proved to be a good predictor of intervention effectiveness.

BACKGROUND:HIV hotspots, regions with higher prevalence than surrounding areas, are observed across Africa, yet their formation and persistence mechanisms remain poorly understood. We hypothesized that random fluctuations during the early stages of the HIV epidemic (1978-1982), amplified by positive feedback between HIV incidence and prevalence, play a critical role in hotspot formation and persistence. To explore this, we applied a network-based HIV transmission model, focusing on randomness in the spatial structure of the epidemic. METHODS:We adapted a previously validated agent-based network HIV transmission model, EMOD-HIV, to simulate HIV spread in western Kenya communities. The model includes demographics, age-structured social networks, and HIV transmission, prevention, and treatment. We simulated 250 identical communities, introducing stochastic fluctuations in network structure and case importation. Outliers were defined as communities with prevalence > 1.5x the median, and persistence as meeting these criteria for >70% of 1980-2050. We systematically varied community size (1,000-10,000), importation timing (1978-1982), and importation patterns (spread over 1, 3, or 5 years), and calculated the proportion of outliers and persistent outliers. RESULTS:HIV prevalence outliers were more common in smaller communities: in 1990, 25.3% (uncertainty interval: 22.3%-28.2%) of 1,000-person communities vs. 9.1% (uncertainty interval: 6.9%-11.4%) of 10,000-person communities. By 2050, 21.6% of 1,000-person communities were persistent outliers, compared to none in larger communities. Autocorrelation of HIV prevalence was high (Pearson's correlation coefficient 0.801 [95% CI: 0.796-0.806] for 1,000-person communities), reflecting feedback that amplified early fluctuations. CONCLUSIONS:Early random fluctuations contribute to the emergence and persistence of prevalence outliers, especially in smaller communities. Recognizing the role of randomness in prevalence outlier formation in these settings is crucial for refining HIV control strategies, as traditional methods may overlook these areas. Adaptive surveillance systems can enhance detection and intervention efforts for HIV and future pandemics.

BACKGROUND:Although HIV incidence has considerably decreased in eastern, central, and southern Africa, new HIV infections continue to be a major public health challenge in the region. We aimed to investigate where in the HIV treatment cascade new transmissions are occurring in Malawi, Zimbabwe, and South Africa (the three countries involved in the Modelling to Inform HIV Programmes in Sub-Saharan Africa project). METHODS:In this model comparison study, we used six well described and independently calibrated HIV transmission dynamics models that have been used to inform HIV policy in Africa (Optima HIV, EMOD, Goals, Thembisa, PopART-IBM, and HIV Synthesis) to estimate and predict the proportion of annual new HIV transmissions attributable to people living with HIV who are undiagnosed, have been diagnosed but have not yet started antiretroviral therapy (ART), are receiving ART, and have interrupted ART in Malawi, Zimbabwe, and South Africa from 2010 to 2040 stratified by the age and sex of the individual acquiring HIV. FINDINGS/RESULTS:Despite the different model structures and underlying assumptions, the six models were well aligned in relation to key HIV epidemic characteristics (including population estimates and HIV prevalence) in each of the three settings. There was, however, considerable variation in the predicted number of new infections, particularly in Malawi and Zimbabwe where this number ranged from fewer than 10 000 new infections to over 30 000 new infections in 2024. Most model results suggested that the mean age of HIV acquisition has been increasing since 2000, with men acquiring HIV at an older age than women in all three settings. All models attributed fewer than 5% of transmissions to individuals who had been diagnosed but had not yet started ART. In Malawi, the proportion of transmissions attributable to undiagnosed people with HIV in 2024 ranged from 33·3% to 75·3% across the models, and transmissions attributable to individuals who had experienced interrupted treatment ranged from 8·4% to 20·1%. In Zimbabwe, the proportion of transmissions attributable to undiagnosed individuals in 2024 ranged from 29·8% to 64·6% across the models and the proportion of transmissions attributable to individuals who had interrupted treatment ranged from 4·7% to 21·5%. In South Africa, 21·8-46·4% of transmissions in 2024 were attributable to undiagnosed individuals and 27·6-58·9% of transmissions were attributable to individuals who had interrupted treatment. INTERPRETATION/CONCLUSIONS:Across the three study settings, a substantial proportion of new HIV transmissions were attributable to undiagnosed individuals and people who have received interrupted ART, reinforcing the importance of continuing HIV testing and ART re-engagement and retention interventions. FUNDING/BACKGROUND:The Bill & Melinda Gates Foundation.

BACKGROUND:The HIV/AIDS epidemic remains critical in sub-Saharan Africa, with UNAIDS establishing "95-95-95" targets to optimize HIV care. Using the 2020 Zimbabwe Population-based HIV Impact Assessment (ZIMPHIA) geospatial data, this study aimed to identify patterns in these targets and determinants impacting the HIV care continuum in underserved Zimbabwean communities. METHODS:Analysis techniques, including Gaussian kernel interpolation, optimized hotspot, and multivariate geospatial k-means clustering, were utilized to establish spatial patterns and cluster regional HIV care continuum needs. Further, we investigated healthcare availability, access, and social determinants and scrutinized the association between socio-demographic and behavioral covariates with HIV care outcomes. RESULTS:Disparities in progress toward the "95-95-95" targets were noted across different regions, with each target demonstrating unique geographic patterns, resulting in four distinct clusters with specific HIV care needs. Key factors associated with gaps in achieving targets included younger age, male gender, employment, and minority or no religious affiliation. CONCLUSIONS:Our study uncovers significant spatial heterogeneity in the HIV care continuum in Zimbabwe, with unique regional patterns in "95-95-95" targets. The spatial analysis of the UNAIDS targets presented here could prove instrumental in designing effective control strategies by identifying vulnerable communities that are falling short of these targets and require intensified efforts. We provide insights for designing region-specific interventions and enhancing community-level factors, emphasizing the need to address regional gaps and improve HIV care outcomes in vulnerable communities that lag behind.

IMPORTANCE/UNASSIGNED:Depression is a prevalent mental health condition contributing to morbidity worldwide. The World Health Organization (WHO) recommends group-based interpersonal psychotherapy (IPT-G) for first-line depression treatment in resource-constrained settings. Standard of care in the study context is 8 to 12 weekly sessions in groups with a mix of depression problem areas (eg, grief, life changes, loneliness, conflict). OBJECTIVE/UNASSIGNED:To investigate whether grouping participants with a common depression problem area (problem area-concordant) using shortened IPT-G (6 sessions) is noninferior to grouping participants with a mix of problem areas (problem area-discordant) using standard IPT-G (8 sessions) in Uganda. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This noninferiority randomized clinical trial included adults 18 years or older in central Uganda with 9-item Patient Health Questionnaire (PHQ-9) scores of 10 or greater, indicating symptoms consistent with probable depression. Assessors were masked to treatment arm. Data were accrued from October 31, 2022, to March 24, 2023. INTERVENTIONS/UNASSIGNED:Participants were randomized 1:1 to 6-session problem area-concordant or 8-session problem area-discordant IPT-G. MAIN OUTCOME AND MEASURES/UNASSIGNED:The primary outcome was PHQ-9 score reduction at 3 months. Secondary outcomes were treatment response (PHQ-9 5-point, 10-point, and 50% score reduction), reduction in disability (WHO Disability Assessment Schedule 2.0), and improvement in subjective quality of life (WHO Quality of Life tool). RESULTS/UNASSIGNED:Among 328 enrolled participants (303 [92.4%] female; mean [SD] age, 42.3 [15.2] years), retention was high, with 321 [97.9%] undergoing assessment at the end of therapy and 292 [89.0%] at 3-month follow-up. From baseline to the end of therapy, PHQ-9 scores dropped a mean (SD) of 15.2 (5.1) points in the problem area-concordant arm and 13.3 (5.3) points in the problem area-discordant arm. Problem area-concordant 6-week IPT-G was noninferior (P < .001) at end of therapy and 3 months post therapy. Compared with the 8-week problem area-discordant arm, posttherapy PHQ-9 scores in the 6-week problem area-concordant arm were 1.86 (95% CI, 0.74-3.00) points lower (P = .001). At 3 months, PHQ-9 scores were 1.98 (95% CI, 0.60-3.36) points lower (P = .005). Disability score reduction was significantly larger post therapy in the 6-week arm compared with the 8-week arm (2.70 [95% CI, 0.95-4.44] points) but not significantly different between arms after 3 months. Quality of life scores across all domains were not significantly different between arms at end of therapy and 3 months post therapy. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this randomized clinical trial, 6-week problem area-concordant IPT-G was noninferior to 8-week problem area-discordant IPT-G for reducing depression symptoms, with similar to larger improvements in disability and quality of life. Problem area-concordant group therapy appears to be a promising approach to increase efficiency and scalability of depression treatment. TRIAL REGISTRATION/UNASSIGNED:Pan African Clinical Trials Registry Identifier: PACTR202306771120632.

BACKGROUND:A disco matanga, or "disco funeral," is a celebration of a decedent's life that is culturally important in parts Africa, often involving overnight travel and alcohol consumption. These are known risk factors for HIV, which is prevalent in many areas where disco matanga is practiced. However, the contribution of disco matanga to HIV transmission is not well-understood. We used agent-based network modeling to estimate how disco matanga impacted HIV transmission, and to explore the impact of relevant biomedical, biobehavioral, and structural interventions to reduce HIV risk. METHODS:We adapted EMOD-HIV, a previously validated network-based model of HIV in the Nyanza region of Kenya, to incorporate disco matanga assumptions informed by literature review. Occurrence of disco matanga was modeled to occur following any death in the population. We compared past HIV incidence (1980-2024) with and without incorporating disco matanga, and future HIV incidence (2025-2050) with different interventions for disco matanga attendees: (1) biomedical (HIV prophylaxis), (2) biobehavioral (reduction in condomless sex partners), (3) structural (female empowerment to avoid unwanted sex). We estimated HIV infections and deaths averted in the overall population, with sensitivity analysis around intervention uptake. RESULTS:Over 1980-2024, disco matanga contributed 7.8% (95% CI: 5.5-9.3%) of all HIV infections, an effect that peaked at 9.9% (95% CI: 6.4-12.0%) in the year 2004, coinciding with a peak in all-cause mortality due to HIV/AIDS. Biomedical prevention at disco matanga could avert up to 9.7% (95% CI: 8.9-10.5%) of adult HIV infections and 2.3% (95% CI: 1.9-2.6%) of deaths; biobehavioral 2.9% (95% CI: 2.1-3.6%) of infections and 0.9% (95% CI: 0.6-1.2%) of deaths; and structural 1.2% (95% CI: 0.5-1.8%) of infections and 0.5% (95% CI: 0.2-0.7%) of deaths. Results were highly sensitive to intervention uptake. CONCLUSIONS:We conducted the first modeling study, to our knowledge, simulating the interactions between disco matanga, HIV/AIDS, and intervention options. We found that biomedical, biobehavioral, or structural interventions implemented during disco matanga could substantially reduce HIV transmission and mortality in the Nyanza region. Research is needed to understand the feasibility and acceptability of HIV interventions tailored to local cultural practices.

BACKGROUND:In parts of Africa, women who become widowed lose housing, bank accounts, and other property and must re-marry to avoid extreme poverty. To re-marry, some women are required to undergo widow "cleansing"-condomless sex with a man who removes "impurities" ascribed to her from her husband's death-and are "inherited" as a wife of a brother-in-law. This study explores how HIV biomedical and structural interventions could reduce HIV-related harms associated with these practices. METHODS:We adapted EMOD-HIV, an HIV agent-based network transmission model previously calibrated and validated for the Nyanza region of western Kenya. Building on the model's pre-existing configuration of marriages, mortality, and widowhood, we added widow cleansing and wife inheritance with assumptions based on literature. Modeled HIV prevalence among inherited widows was validated to match observed data. We modeled the effect of widowed women, cleansers, and inheritors receiving biomedical HIV interventions (testing, treatment for those tested positive, and 1 year of pre-exposure prophylaxis (PrEP) initiated at cleansing for those tested negative) with or without structural interventions (female empowerment). We modeled low (30%) and high (70%) intervention uptake and reported HIV outcomes including cumulative infections over 2025-2050. RESULTS:Modeled HIV prevalence among inherited widowed women was 59.8% (95% CI: 59.5-60.2%), comparable to observed prevalence of 64.1% (95% CI: 63.2-65.4%). Among all widowed women, biomedical interventions averted 2.0% (95% CI: 1.3-2.6%) of HIV infections with low uptake and 2.6% (95% CI: 2.0-3.2%) with high uptake. Combined biomedical and structural interventions averted 7.8% (95% CI: 7.2-8.4%) of HIV infections with low uptake and 16.1% (95% CI: 15.5-16.6%) with high uptake. Impacts were smaller for men, e.g., high-uptake structural and biomedical interventions averted 1.8% (95% CI: 1.5-2.2%) of infections among cleansers and 2.7% (95% CI: 2.4-3.0%) among inheritors. CONCLUSIONS:Widowed women are a vulnerable population with extremely high HIV prevalence. Combined biomedical and structural interventions focused on the practice of widow cleansing and wife inheritance have the potential to avert up to one-quarter of HIV infections among widowed women, and a smaller proportion among men participating in these practices.

INTRODUCTION/BACKGROUND:Affordable HIV prevention tools are needed in Eastern and Southern Africa (ESA). Several promising long-acting pre-exposure prophylaxis (LA-PrEP) products are available or in development. However, ESA settings face severe healthcare resource constraints. We aimed to estimate the threshold price at which LA-PrEP products could be cost-effective in three ESA settings. METHODS:We adapted an agent-based model, EMOD-HIV, to simulate LA-PrEP (monthly oral, 2- and 6-monthly injectable) rollout in South Africa, Zimbabwe and Kenya. Due to uncertainties about LA-PrEP use, we examined a range of coverages (5%-20% of HIV-negative sexually active adults) and extents to which LA-PrEP use will be concentrated among those most at risk (prioritized rollout from higher- to lower-risk groups vs. uniform rollout among sexually active adults). To evaluate a 20-year commitment to LA-PrEP delivery, we assumed LA-PrEP was scaled up to target coverage from 2025 to 2030 and maintained at target levels before ending in 2045. We estimated maximum per-dose and per-year LA-PrEP costs that achieve cost-effectiveness (<US$500 per disability-adjusted life-year averted) over 35 years (until 2060), compared to a scenario of daily oral PrEP only. Sensitivity analyses varied PrEP scale-up speeds and eligible populations. RESULTS:Risk-prioritized LA-PrEP for 5% of adults was projected to avert 11-21% of HIV acquisitions across settings, with 3-5 times more HIV acquisitions averted and 3-5 times higher maximum cost compared to non-prioritized rollout. Six-monthly injectable PrEP supported the highest per-dose cost: in the scenario with the most cost-effective LA-PrEP use (5% risk-prioritized rollout), the maximum per-dose price in South Africa was $52.99 (95% CI: $48.82-$57.21), in Zimbabwe $14.64 (95% CI: $12.04-$17.38) and in western Kenya $7.50 (95% CI: $6.73-$8.27). For monthly oral PrEP, corresponding per-dose costs were $5.02 (95% CI: $4.67-$5.37), $1.45 (95% CI: $1.10-$1.79) and $0.87 (95% CI: $0.80-$0.93). Results were sensitive to eligible population and prioritization, and moderately sensitive to scale-up speed and product effectiveness. CONCLUSIONS:LA-PrEP is likely to require reduced pricing and/or risk-prioritized rollout to be cost-effective in ESA.

Greenhouse gas (GHG) emissions are creating unprecedented climate-driven extreme weather, with levels of heat and humidity surpassing human physiological tolerance for heat stress. These conditions create a risk of mass casualties, with some populations particularly vulnerable due to physiological, behavioural and socioeconomic conditions (eg, lack of adequate shelter, limited healthcare infrastructure, sparse air conditioning access and electrical grid vulnerabilities). Children, especially young children, are uniquely vulnerable to extreme heat-related morbidity and mortality due to factors including low body mass, high metabolism, suboptimal thermoregulatory mechanisms and behavioural vulnerabilities. Children are also uniquely vulnerable to non-fatal heat-related morbidities, including malnutrition due to agricultural disruptions and cardiometabolic, respiratory and mental illnesses from heat exposure and/or confinement during heat avoidance. Climate mitigation through GHG reductions is central to reducing harms to children and preventing the loss of a generation to climate change. In regions most predisposed to extreme heat-driven mass casualties under various GHG emission scenarios-particularly South Asian and Southwest Asian and North African regions-adaptation tools specific to children's needs are the most urgently needed. Existing public health interventions (eg, cooling infrastructure and preventative educational campaigns) to reduce acute heat mortality, and medical infrastructure capacity to treat heat-related illnesses are currently inadequate to meet children's growing heat resiliency needs. Paediatricians and other clinical and community child healthcare providers in these regions lack education about children's heat risks and adaptation tools. Paediatricians and other child healthcare providers have a crucial role in research, education, clinical practice and advocacy to protect children during extreme heat events. Paediatricians, other child healthcare providers and stakeholders of children's well-being are urged to act on young children's behalf and to elevate youth leadership in GHG mitigation and extreme heat adaptation policy-making.

BACKGROUND:Injectable lenacapavir administered every 6 months is a promising product for HIV pre-exposure prophylaxis (PrEP). We aimed to estimate the health and budget impacts and threshold price at which lenacapavir could be cost-effective in eastern and southern Africa. METHODS:We adapted an agent-based network model, EMOD-HIV, to simulate lenacapavir scale-up in Zimbabwe, South Africa, and western Kenya from 2026 to 2035. Uptake assumptions were informed by a literature review of PrEP product preferences. In the main analysis, we varied lenacapavir coverage by subgroup: female sex workers (40% coverage); male clients of female sex workers (40%); adolescent girls and young women aged 15-24 years with more than one sexual partner (32%); women aged 25 years and older with more than one sexual partner (36%); and males with more than one sexual partner (32%). We also assessed a higher coverage scenario (64-76% across subgroups) and scenarios of expanding lenacapavir use, varying from concentrated among those at highest HIV risk to broader coverage including those at medium HIV risk. We estimated the maximum per-dose lenacapavir price that achieved cost-effectiveness (<US$500 per disability-adjusted life-year averted), infections averted, and 5-year budget impact, compared with daily oral PrEP only. FINDINGS/RESULTS:In the main analysis, lenacapavir was projected to achieve from 1·6% (95% uncertainty interval [UI] 1·5-1·8) to 4·0% (3·4-5·1) population coverage across settings and to avert from 12·3% (5·4-19·5) to 18·0% (11·0-22·9) of infections over 10 years. The maximum price per dose was highest in South Africa ($106·28 [95% UI 95·72-115·87]), followed by Zimbabwe ($21·15 [17·70-24·89]), and lowest in western Kenya ($16·58 [15·44-17·70]). The 5-year budget impact was US$507·25 million (95% UI 436·14-585·42) in South Africa, $16·80 million (13·95-22·64) in Zimbabwe, and $4·09 million (3·86-4·30) in western Kenya. In the higher coverage scenario, lenacapavir distribution was projected to reach from 3·2% (95% UI 2·9-3·6) to 8·1% (6·8-10·5) population coverage and to avert from 21·2% (95% UI 14·7-18·5) to 33·3% (28·5-36·9) of HIV infections across settings over 10 years. Price thresholds were lower than in the main analysis: $88·34 (95% UI 83·02-94·19) in South Africa, $17·71 (15·61-20·05) in Zimbabwe, and $14·78 (14·33-15·30) in western Kenya. The 5-year budget impact was higher than the main analysis: $835·29 million (95% UI 736·98-962·98) in South Africa, $29·50 million (24·62-39·52) in Zimbabwe, and $7·45 million (7·11-7·85) in western Kenya. Expanding lenacapavir coverage resulted in higher HIV infections averted but lower price thresholds than scenarios of concentrated use among those with highest HIV risk. INTERPRETATION/CONCLUSIONS:Our findings suggest that lenacapavir could avert substantial HIV incidence and that price thresholds and budget impacts vary by setting and coverage. These results could inform policy deliberations regarding lenacapavir pricing and resource planning. FUNDING/BACKGROUND:The Bill & Melinda Gates Foundation.