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While various PrEP-delivery models exist in South Africa, little is known about optimizing PrEP-uptake and adherence for AGYW and ABYM. This study explored preferred and feasible PrEP care models to enhance initiation and adherence among at-risk adolescents and young adults (AYAs) in a high-HIV prevalent rural district in South Africa. We conducted a longitudinal, population-based cohort study from August 2021 to July 2022 across 22 service delivery points (SDPs) in KwaZulu-Natal. High-risk, sexually active HIV-negative AGYW (15\u201324 years) and ABYM (15\u201335 years) were recruited from clinics, schools, and community-based youth zones. PrEP-uptake and adherence, based on national guidelines, were assessed using Pearson\u2019s Chi square test and binomial regression. Of 2,772 HIV-negative AYA, 781 (28%) initiated PrEP. Despite 65% being classified as high risk for HIV (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt; 0.001), only 22% initiated PrEP. Initiation was higher in female (82%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt; 0.001) and among the 15\u201319 years (51%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009= 0.11). PrEP uptake varied significantly by SDPs, lowest in clinics (9%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt; 0.001), higher in youth zones (58%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt; 0.001), and highest in schools (73%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt; 0.001). Adherence declined significantly over time, dropping from 12% at one month to 2% at six months (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt; 0.001). These findings highlight the need for targeted interventions in schools and communities, addressing barriers such as awareness, side effects, and accessibility. Expanding PrEP services to non-traditional settings may enhance uptake and adherence, reducing HIV risk among young people.\n                  <\/jats:p>","DOI":"10.1007\/s10461-025-04719-6","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T21:30:03Z","timestamp":1746135003000},"page":"2588-2609","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Assessing PrEP Initiation and Adherence Among High-Risk, Sexually Active Adolescents and Young Adults: A Population-Based Prospective Study Across Diverse Service Delivery Models in a High HIV Prevalent District in South Africa"],"prefix":"10.1007","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6019-9259","authenticated-orcid":false,"given":"Edward","family":"Nicol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wisdom","family":"Basera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice","family":"Turawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl","family":"Lombard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noluntu","family":"Funani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dakalo","family":"Chavhalala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the SHeS\u2019Cap-PrEP group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"4719_CR1","unstructured":"UNAIDS. 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