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While antiretroviral therapy effectively suppresses systemic viral replication, drug penetration into the MGT tissues and semen varies considerably between and within drug classes, potentially leading to subtherapeutic concentrations in the MGT. The organs comprising the MGT have anatomical barriers and express several drug-metabolizing enzymes, resulting in immune privilege, active drug efflux, and site-specific metabolism. These factors may collectively limit antiretroviral efficacy in this compartment. This review discusses the evidence of HIV persistence in MGT organs and provides insight into the anatomical, physiological, and pharmacological considerations to target this viral reservoir. Additionally, we synthesize current knowledge on contemporary antiretroviral pharmacokinetics within the MGT, highlighting differences in drug penetration between and within classes. We identify associations between drug properties (e.g., lipophilicity and protein binding) and distribution into the MGT. Finally, we forecast emerging therapeutic approaches that introduce new pharmacological opportunities and challenges, as well as advanced computational techniques to help us better understand the downstream effects of antiretroviral pharmacology at the site of action. Understanding the interplay between antiretroviral penetration, local inflammation, and viral dynamics is essential for optimizing HIV treatment and prevention strategies. Together, these insights set the stage for targeted studies to guide precision dosing based on local therapeutic exposure thresholds. Addressing remaining knowledge gaps in MGT pharmacology will be essential to overcome anatomical and physiological barriers and achieve sustained viral suppression in the MGT.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.01401-25","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T13:00:31Z","timestamp":1774270831000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Contemporary antiretroviral pharmacology in the male genital tract: implications for HIV treatment and prevention"],"prefix":"10.1128","volume":"70","author":[{"given":"Noah C.","family":"Neverette","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Clinical Pharmaceutical Sciences, Department of Pharmacy & Therapeutics, School of Pharmacy, University of Pittsburgh","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1799-098X","authenticated-orcid":true,"given":"Jordan","family":"Winfield","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Clinical Pharmaceutical Sciences, Department of Pharmacy & Therapeutics, School of Pharmacy, University of Pittsburgh","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia","family":"Chaparro-C\u00e1ceres","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042bbge36","id-type":"ROR","asserted-by":"publisher"}],"name":"Barry and Judy Silverman College of Pharmacy, Nova Southeastern University","place":["San Juan, Puerto Rico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ken S.","family":"Ho","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Infectious Diseases, School of Medicine, University of Pittsburgh","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-5819","authenticated-orcid":true,"given":"Julie B.","family":"Dumond","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0130frc33","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina","place":["Chapel Hill, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2778-3725","authenticated-orcid":true,"given":"Aaron S.","family":"Devanathan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Clinical Pharmaceutical Sciences, Department of Pharmacy & Therapeutics, School of Pharmacy, University of Pittsburgh","place":["Pittsburgh, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414926112"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0000000000000230"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqab156"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2011.06.005"},{"key":"e_1_3_2_6_2","unstructured":"HIV.gov. 2024. 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