Larry William Chang

Summary: Background: As HIV incidence declines in African settings with high treatment coverage, it remains unclear how transmission is structured within populations and whether new infections arise from external introductions or local transmission. We characterized the molecular epidemiology of ongoing transmission in a mature multi-subtype epidemic in Uganda. Methods: We analyzed HIV genome sequences and survey data from the Rakai Community Cohort Study collected between 1994 and 2019. We identified phylogenetic clusters at 5·3% and 2·5% genetic distance thresholds and inferred long-horizon transmission chains with phylogeographic models. Newly diagnosed infections identified between 2016 and 2019 were mapped onto subtype- specific phylogenies to assess their origins and transmission context. A Bayesian negative binomial branching process model estimated undersampled chain sizes and case reproduction numbers. Findings: Among 4215 participants living with HIV between December 2016 and May 2019, 474 were newly diagnosed, of whom 269 had at least one pure-subtype sequence available. We identified 649 phylogenetic clusters at 5·3% genetic distance and 673 phylogeographic chains including ≥2 individuals. Most clusters and chains were small (median sizes 2 [IQR 2–3] and 3 [2–4], respectively), with new diagnoses rarely clustered together. Only 46/269 (17·1%) new diagnoses had phylogeographic external origins, while the remaining 82·9% were partially or fully linked to local chains. Mixed-subtypes/recombinant chains were larger and had higher case reproduction numbers (A1/D: 0.84 [95% CrI: 0.79-0.93]; mixed: 0.84 [0.73-0.97]) than single- subtype chains (A1: 0.56 [0.51-0.60]; D: 0.63 [0.59-0.66]; C: 0.55 [0.41-0.71]), yet all estimates were less than one. Interpretation: HIV transmission was fragmented across numerous, slowly propagating lineages, maintained by local clusters with occasional introduction. Continued transmission across many chains suggests that further reductions in HIV incidence will require maintaining high levels of population-wide treatment and prevention coverage. Funding: The National Institute of Allergy and Infectious Diseases, the Gates Foundation, and the HIV Prevention Trials Network Laboratory Center

SUMMARY: Background: Novel HIV prevention interventions such as long-acting pre-exposure prophylaxis (PrEP) could substantially reduce HIV transmission in Africa. However, efficient implementation in high-prevalence settings where incidence has declined requires an understanding of the contemporary dynamics driving new infections. Methods: We identified incident HIV cases from a longitudinal, population-based cohort in Uganda. We individually matched cases to HIV-negative controls; traced and enrolled reported sexual partners; and enrolled female sex workers (FSWs) from reported venues. Conditional logistic regression, transmission modeling, and phylogenetics were used to characterize transmission networks. Findings: From 2021-2024, 38,899 HIV tests among 22,255 people identified 187 people with incident infections (47.6% male); 164 (88%) were enrolled and matched to 164 HIV-negative controls. Overall, 593 non-sex-worker partners (371 enrolled,62.6%), 146 FSW partners (21 enrolled,14.4%), and 28 venues (208 FSWs enrolled) were reported. Incident infection was most strongly predicted by partnership with a FSW (odds ratio:15.5; 95%CI:3.7-64.8), identified in 43.0% of male cases versus 6.3% of controls. Men with FSW partners had larger sexual networks than men without (median:6 vs 2 partners), and 91.2% of men with FSW partners also had non-sex-worker partners. Transmission modeling attributed 34.4% (95%CI:31.5-36.8%) of all male infections and 80.0% (95%CI:73.2-84.4%) of infections among male clients to sex with FSWs. Oral PrEP use among HIV-negative partners of incident cases was low (8.9% in women; 2.1% in men). Interpretation: Men with FSW partners accounted for a substantial share of incident HIV infections and had markedly higher odds of infection than men without such partnerships. Together with the high potential for onward transmission within male client networks, these findings suggest that inclusion of male clients in long-acting HIV prevention strategies could be highly efficient and impactful. Funding: National Institutes of Health, United States; Gates Foundation; National Health and Medical Research Council, Australia

BACKGROUND There is limited analysis into text messaging-based data in mHealth intervention apps. Natural language processing (NLP), through topic modeling, can be used to achieve this, grouping textually and semantically similar texts into coherent topics in large datasets. OBJECTIVE To explore using BERTopic, an NLP tool, in combination with qualitative methods to identify representative topics and analyze trends through topic modeling messages exchanged between patients and patient navigators in NextStep, an HIV patient support app designed to facilitate HIV linkage and retention (LAR) in care. METHODS We analyzed messages exchanged between English-speaking patients and patient navigators in the NextStep app between February 2020 and August 2022. The messages were preprocessed and de-identified before topic modeling using two BERTopic models, one for patient messages and one for navigator messages. Then, two coders condensed the generated topics into distinct thematic categories. Messages not sorted into topics by the model were qualitatively coded for analysis. Data validation was performed by calculating the CV coherence score for each model and Cohen Kappa coefficient for inter-rater agreement between the models and the qualitative coders. The proportion of patient and navigator-initiated topics per patient were compared generally, by patient use-time tertiles, and by endline HIV virologic suppression. RESULTS A total of 2,337 patient messages and 3,264 patient navigator messages were analyzed. Per patient, the most prevalent topics found in patient messages was App Set-Up (33.1%, 95% CI 28.2%-38.0%). Additionally, Appointment Help Request (11.9%, 95% CI 9.3%-14.4%) was distinctly prevalent when compared to other topics implicated in direct HIV care. The most frequent topics for patient navigator messages per patient were Appointment Assistance (21.0%, 95% CI 18.4%-23.7%) and Conversation (16.9%, 95% CI 14.4%-19.5%). Across patient messages stratified by use-time tertiles, the App Set-Up topic decreased in prevalence with increasing use-time, while the Help Request topic increased in prevalence. Within navigator messages, the Introduction topic similarly decreased in prevalence by patients’ use-time tertiles, and the Medication Assistance topic increased in prevalence from the short-term use tertile to mid-term or long-term use tertiles. When stratified by patient study endline HIV viral load, no differences in prevalence were found for either patient or patient navigator message topics. CONCLUSIONS BERTopic is a highly promising tool for integrating user-generated content into the design and evaluation process for messaging mHealth interventions. The high prevalence of the App Set-Up topic reflects a high drop off patient usage after first use, and the prevalence of appointment-related topics in relation to other care topics suggest that the NextStep messaging feature was used primarily to set up appointments for HIV care-related tasks. These use patterns suggest that future LAR messaging interventions should emphasize focus on appointment scheduling features and initial app retention in their design process.

We analyzed perinatal transmission in a pre–antiretroviral therapy Ugandan cohort by maternal human immunodeficiency virus type 1 subtype and infant sex in 131 mother-child pairs. Among all children, if the mother was infected with subtype A there was a nearly 3-fold increased risk of perinatal transmission compared with subtype D (risk ratio [RR], 2.96 [95% confidence interval (CI), 1.46–6.01]; P = .008). When stratifying infants by both sex and maternal subtype, significantly more female (56.3% [9 of 16]) than male (9.1% [1 of 11]) infants born to mothers with subtype A were infected (RR, 6.19 [95% CI, .91–42.12]; P = .02). In contrast, among infants born to mothers with subtype D, transmission rates were comparable across sex (RR, 1.59 [95% CI, .57–4.41]; P = .39).

Background: HIV incidence among adolescent girls and young women (AGYW) in eastern and southern Africa has declined substantially over the past two decades. These declines are often attributed to biomedical HIV prevention strategies, though concurrent changes in sexual behavior may also contribute. We evaluated the contributions of biomedical and behavioral drivers to historical incidence decline in AGYW and projected their impact on incidence trajectories over the next 30 years. Methods and findings: We conducted a mathematical modeling study using data from the Rakai Community Cohort Study (RCCS), an open, population-based cohort of adults aged 15–49 years in 30 communities in Rakai, Uganda. We used an agent-based HIV-1 transmission model calibrated to cohort data to estimate HIV incidence trends among AGYW, aged 15–24, and to quantify the independent and combined effects of antiretroviral therapy (ART), voluntary medical male circumcision (VMMC), and changes in age at first sex (AFS). HIV incidence among women aged 15–24 declined by 71% between 2000 and 2019, from 1.57 to 0.45 per 100 person-years, representing the largest decline across female age groups in the cohort. Increasing AFS over the study period (by approximately 3 years in women and 2 years in men) was the largest contributor to incidence declines among adolescent women aged 15–19, averting 17% of cumulative infections between 2000 and 2020 and 37% between 2000 and 2050. Among women aged 20–24, ART scale-up had the greatest impact, averting 13% of infections by 2020 and 43% by 2050. VMMC contributed modestly to historical declines but had larger projected effects over longer time horizons. ART, VMMC, and delays in AFS acted additively to reduce HIV incidence among AGYW. Study limitations include reliance on self-reported sexual behavior and the use of a mathematical model that cannot capture all real-world sexual network dynamics. Conclusions: Both biomedical HIV interventions and broader behavioral changes contributed to declines in HIV incidence among AGYW. Sustaining continued incidence declines in young women will require maintaining both the protective changes in sexual behaviors and effective biomedical interventions.

BACKGROUND Disparities in HIV care persist and there is a need to evaluate scalable approaches to improving HIV care engagement and viral suppression in real-world settings. OBJECTIVE To compare standard of care HIV linkage, adherence, and retention (LAR) clinic-based support services to a mobile health (mHealth)-enhanced linkage, adherence, and retention (mLAR) intervention and assess mLAR implementation. METHODS Participants were enrolled from six Baltimore HIV clinics in an individual-level randomized controlled trial. Eligibility criteria included adults living with HIV who had a new HIV diagnosis, were out of care, or were deemed by clinic staff as someone who could benefit from LAR services. Participants in the control group received the referring clinic’s standard LAR services. Participants randomized to the intervention additionally received mHealth-supported patient navigation including an app platform that integrated HIV surveillance data from throughout Maryland. The primary outcome was HIV virologic suppression at 12 months. Participants with non-suppressed viral load or missing viral loads at 12 months (inclusive of a +/- 3-month window) were considered virologic failures. Secondary outcomes included loss to follow-up and mortality at 12 months. Implementation outcomes were assessed via in-depth interviews with participants and patient support staff. This study was implemented in collaboration with patients and stakeholders, including members of the Baltimore City Health Department, the Maryland Department of Health, patient navigators, HIV healthcare providers, and people living with HIV. Members of the Steering Committee provided guidance on the study design and implementation, app development, interpretation of results, and dissemination of findings. RESULTS A total of 451 participants (226 LAR control group and 225 mLAR intervention group) were randomized and 3 (1 LAR and 2 mLAR) withdrew consent before the study endpoint. Virologic suppression was 56.9% (95% CI 50.4%-63.4%, LAR) and 50.3% (95% CI 44.%-57.7%, mLAR) in the two arms [difference 5.8% (-3.4%-14.9%), p-value=0.22]. Sixty-six participants (29.3%) in the LAR arm and 71 (31.8%) in the mLAR arm were missing a viral load test at 12 months and were assumed to be not virologically suppressed. These results were similar when stratified by race, ethnicity and clinic site. In the LAR and mLAR arms, respectively, 28.9% (95% CI 22.9%-34.8%) and 31.8% (95% CI 25.7%-37.9%) of participants were lost to follow-up [difference -2.9% (-11.5%-5.6%), p-value=0.49] while all-cause mortality was 4.9% versus 4.0% [Pearson's chi-squared p<0.662]. In-depth interviews revealed mixed perceptions of the app; some participants and patient navigators valued its usability, while others found it redundant with existing tools like electronic medical record portals and phone communication. CONCLUSIONS An app-based mobile health intervention for patients and patient supporters had no impact on virologic suppression, engagement in care, or mortality. In populations with complex socio-structural determinants of health, additional strategies are needed to improve HIV care outcomes. CLINICALTRIAL ClinicalTrials.gov NCT03934437

Background: Preventing HIV infections among adolescents and young adults (AYAs) is crucial for curtailing the epidemic. Oral pre-exposure prophylaxis (PrEP) is a highly effective prevention method increasingly available to this age group in sub-Saharan Africa but population-based data on awareness and use of PrEP among AYAs remains limited. Methods: Analyzing survey data from 2 rounds of the Rakai Community Cohort Study, an open, population-based cohort, we estimated prevalence ratios associating various sociodemographic characteristics with PrEP awareness and ever-use among 15- to 24-year-olds in south-central Uganda between 2018 and 2023. Results: Most (62.4%, N = 3308/5301) participants were aware of PrEP as an HIV prevention method but only 1.7% (N = 133/7999) of AYAs had ever used it. Among the 35.5% (N = 2838/7999) of participants meeting PrEP eligibility criteria, ever-use was similarly rare (2.6%, N = 75/2838). Compared with 20 to 24-year-olds, 15 to 19-year-olds were less likely to report awareness [fullyadjPR (prevalence ratio) = 0.82, 95%CI (confidence interval): 0.78, 0.86] or ever-use (fullyadjPR = 0.35, 95%CI: 0.21, 0.58). Participants from fishing communities were more likely to be PrEP-aware (fullyadjPR = 1.22, 95%CI: 1.16, 1.29) or have ever used the prevention method (fullyadjPR = 6.07, 95%CI: 4.10, 8.98) than those from non-fishing communities. Conclusions: In this cross-sectional study of AYAs in Uganda, awareness of PrEP was common but ever-use was rare, even among the third of respondents who were likely PrEP-eligible. This suggests that prevention policies and barriers besides unawareness of the method impede PrEP initiation. Efforts that target those barriers, particularly for adolescents, are critical for reducing HIV incidence among this priority population.

During the COVID-19 pandemic lockdown, we deployed a rapid, mobile phone-based survey to assess access and participation rates when using mobile phones to collect data on COVID-19 in Rakai, south-central Uganda. We sampled prior Rakai Community Cohort Study (RCCS) participants based on HIV status using mobile phone contacts. We administered a 30-minute phone-based interview to consenting participants to assess their knowledge about different aspects of COVID-19 and their access to care. Our analysis compares the mobile phone survey participation rates with historic participation rates in regular RCCS face-to-face interviews. We supplemented phone survey data with demographic, behavioral, and HIV status data from prior face-to-face RCCS surveys. Phone access in Round 19 of the RCCS was found to be 90.2%, with lower access among older people, and people living with HIV. When including only individuals who participated in the previous RCCS survey round, participation in the face-to-face survey (81.9%) was higher than participation in our phone survey (74.8%, p < .001). Survey participation was higher among people living with HIV compared to HIV-negative individuals (84.0% vs 81.4%, p < .001) in the face-to-face survey, but in the phone survey the reverse was found, with participation rates being higher among HIV-negative individuals compared to people living with HIV (78.0% vs 71.6%, p < .001). It was possible to collect data from an existing population cohort during the lockdown using phones. Phone access was high. Overall participation rates were somewhat lower in the phone survey, notably in people living with HIV, compared to the face-to-face survey.

Background: The geographical environments within which individuals conduct their daily activities may influence health behaviors, yet little is known about individual-level geographic mobility and specific, linked behaviors in rural low- and middle-income settings. Objective: Nested in a 3-month ecological momentary assessment intervention pilot trial, this study aims to leverage mobile health app user GPS data to examine activity space through individual spatial mobility and locations of reported health behaviors in relation to their homes. Methods: Pilot trial participants were recruited from the Rakai Community Cohort Study—an ongoing population-based cohort study in rural south-central Uganda. Participants used a smartphone app that logged their GPS coordinates every 1-2 hours for approximately 90 days. They also reported specific health behaviors (alcohol use, cigarette smoking, and having condomless sex with a non–long-term partner) via the app that were both location and time stamped. In this substudy, we characterized participant mobility using 3 measures: average distance (kilometers) traveled per week, number of unique locations visited (deduplicated points within 25 m of one another), and the percentage of GPS points recorded away from home. The latter measure was calculated using home buffer regions of 100 m, 400 m, and 800 m. We also evaluated the number of unique locations visited for each specific health behavior, and whether those locations were within or outside the home buffer regions. Sociodemographic information, mobility measures, and locations of health behaviors were summarized across the sample using descriptive statistics. Results: Of the 46 participants with complete GPS data, 24 (52%) participants were men, 30 (65%) participants were younger than 35 years, and 33 (72%) participants were in the top 2 socioeconomic status quartiles. On median, participants traveled 303 (IQR 152-585) km per week. Over the study period, participants on median recorded 1292 (IQR 963-2137) GPS points—76% (IQR 58%-86%) of which were outside their 400-m home buffer regions. Of the participants reporting drinking alcohol, cigarette smoking, and engaging in condomless sex, respectively, 19 (83%), 8 (89%), and 12 (86%) reported that behavior at least once outside their 400-m home neighborhood and across a median of 3.0 (IQR 1.5-5.5), 3.0 (IQR 1.0-3.0), and 3.5 (IQR 1.0-7.0) unique locations, respectively. Conclusions: Among residents in rural Uganda, an ecological momentary assessment app successfully captured high mobility and health-related behaviors across multiple locations. Our findings suggest that future mobile health interventions in similar settings can benefit from integrating spatial data collection using the GPS technology in mobile phones. Leveraging such individual-level GPS data can inform place-based strategies within these interventions for promoting healthy behavior change.