{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:14:53Z","timestamp":1785428093504,"version":"3.56.0"},"reference-count":84,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NIAID","award":["R24AI13661806"],"award-info":[{"award-number":["R24AI13661806"]}]},{"award":["R24AI13661806"],"award-info":[{"award-number":["R24AI13661806"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"WHO","award":["203682283"],"award-info":[{"award-number":["203682283"]}]},{"award":["203682283"],"award-info":[{"award-number":["203682283"]}],"id":[{"id":"https:\/\/ror.org\/03y0ep822","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Introduction: Drug resistance testing may improve the management of people living with HIV (PLWH) in several scenarios in low- and middle-income countries (LMICs). To guide assay development, the WHO published a target product profile (TPP) outlining two priority use cases (scenarios) for genotypic resistance testing: (1) PLWH with confirmed virological failure (VF) on an integrase strand transfer inhibitor (INSTI)-based regimen, such as tenofovir (TFV) disoproxil fumarate, lamivudine (3TC), and dolutegravir (DTG) and (2) heavily treated PLWH, including infants and young children, with confirmed VF after receiving multiple regimens including a boosted protease inhibitor (PI). An additional potential scenario includes PLWH testing positive for HIV-1 while on pre-exposure prophylaxis (PrEP). Methods: To identify drug-resistance mutations (DRMs) most likely to influence clinical management of PLWH in each WHO TPP scenarios and to inform development of assays that detect individual DRMs and the interpretation of sequence-based assays, we reviewed prevalence and in vitro susceptibility data on HIV-1 DRMs in the Stanford HIV Drug Resistance Database associated with the nucleoside RT inhibitor (NRTI), nonnucleoside RT inhibitor (NNRTI), PI, and INSTI classes and the capsid inhibitor lenacapavir. Results: In the first scenario, the most informative NRTI DRMs were K65R and M184V\/I; and the most informative INSTI DRMs were G118R, N155H, Q148H\/K\/R, and R263K. In the second scenario, a broader spectrum of DRMs is likely to be clinically relevant, including additional NRTI DRMs, the PI DRMs associated with reduced susceptibility to darunavir, and the NNRTI DRMs associated with reduced susceptibility to etravirine and doravirine. In PLWH testing positive for HIV-1 despite PrEP, the most informative NRTI and INSTI DRMs overlap with those in the first scenario, together with the capsid DRMs reported in persons experiencing VF while receiving lenacapavir. Conclusions: As global ART programs increasingly rely on INSTI-based regimens, and as the number of heavily treated individuals and difficult-to-treat pediatric cases grows, many LMICs have begun introducing HIV drug resistance testing for patient management. Although sequence-based assays provide the most comprehensive information for managing individual PLWH, assays that detect individual DRMs are also likely to be highly useful in the three WHO TPP scenarios.<\/jats:p>","DOI":"10.3390\/v18060588","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T12:14:52Z","timestamp":1779452092000},"page":"588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing HIV-1 Genotypic Resistance Testing for Low- and Middle-Income Countries: High-Impact HIV-1 Mutations Across WHO-Defined Scenarios"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2513-2643","authenticated-orcid":false,"given":"Robert W.","family":"Shafer","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Stanford University Stanford, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8731-1271","authenticated-orcid":false,"given":"Kaiming","family":"Tao","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Stanford University Stanford, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2049-3562","authenticated-orcid":false,"given":"Tom","family":"Loosli","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3903-5265","authenticated-orcid":false,"given":"Ana","family":"Abecasis","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Armenia","sequence":"additional","affiliation":[{"name":"Department Faculty, Saint Camillus International University of Health Sciences, 00131 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4867-7200","authenticated-orcid":false,"given":"George","family":"Bwire","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Microbiology, Muhimbili University of Health and Allied Sciences, Dar es Salaam P.O. Box 65001, Tanzania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8395-7304","authenticated-orcid":false,"given":"Ricardo Sobhie","family":"Diaz","sequence":"additional","affiliation":[{"name":"Infectious Diseases Division, Department of Medicine, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04023-062, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1501-2763","authenticated-orcid":false,"given":"Joseph","family":"Fokam","sequence":"additional","affiliation":[{"name":"Chantal BIYA International Reference Centre for Research on HIV\/AIDS Prevention and Management (CIRCB), Yaounde P.O. Box 3077, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8242-0436","authenticated-orcid":false,"given":"Amalia","family":"Giron","sequence":"additional","affiliation":[{"name":"Independent Consultant, Guatemala City 01010, Guatemala"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth","family":"Inzaule","sequence":"additional","affiliation":[{"name":"Department of Global Health, Amsterdam Institute for Global Health and Development, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3659-1108","authenticated-orcid":false,"given":"Rami","family":"Kantor","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine, Brown University, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cissy","family":"Kityo","sequence":"additional","affiliation":[{"name":"Joint Clinical Research Centre, Kampala P.O. Box 10005, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger D.","family":"Kouyos","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, 8091 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-4823","authenticated-orcid":false,"given":"Swarali","family":"Kurle","sequence":"additional","affiliation":[{"name":"HIV Drug Resistance Laboratory, Indian Council of Medical Research\u2014National Institute of Translational Virology and AIDS Research, Pune 411026, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4808-8999","authenticated-orcid":false,"given":"Anne-Genevieve","family":"Marcelin","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, INSERM, Institut Pierre Louis d\u2019Epid\u00e9miologie et de Sant\u00e9 Publique, AP-HP, H\u00f4pitaux Universitaires Piti\u00e9-Salp\u00eatri\u00e8re-Charles Foix, Laboratoire de Virologie, 75013 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Paredes","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases and irsiCaixa, Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Peeters","sequence":"additional","affiliation":[{"name":"Recherches Translationnelles sur le VIH et Maladies Infectieuses, Universit\u00e9 de Montpellier\/INSERM U1175, Institut de Recherche pour le D\u00e9veloppement, 34394 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6390-4128","authenticated-orcid":false,"given":"Victor F.","family":"Pimentel","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Schapiro","sequence":"additional","affiliation":[{"name":"National Hemophilia Center, Sheba Medical Center, Ramat Gan 5265601, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3226-7685","authenticated-orcid":false,"given":"Kim","family":"Steegen","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1687-6723","authenticated-orcid":false,"given":"Marco","family":"Vitoria","sequence":"additional","affiliation":[{"name":"Department for HIV, Tuberculosis, Hepatitis, and Sexually Transmitted Infections, World Health Organization, 1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemarie M.","family":"Wensing","sequence":"additional","affiliation":[{"name":"Department of Global Health and Bio-Ethics, Julius Center for Health Sciences and Primary Care, University Medical Center, 3584 CX Utrecht, The Netherlands"},{"name":"Ezintsha, Wits RHI, University of the Witwatersrand, Johannesburg 2193, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5824-3388","authenticated-orcid":false,"given":"Neil","family":"Parkin","sequence":"additional","affiliation":[{"name":"Independent Researcher, Sebastopol, CA 95473, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Global Health and Tropical Medicine, Associate Laboratory in Translation and Innovation Towards Global Health, LA-REAL, Instituto de Higiene e Medicina Tropical, IHMT, Universidade NOVA de Lisboa, UNL, 1349-008 Lisbon, Portugal"},{"name":"Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1097\/COH.0000000000000743","article-title":"Epidemiology of HIV drug resistance in low- and middle-income countries and WHO global strategy to monitor its emergence","volume":"17","author":"Bertagnolio","year":"2022","journal-title":"Curr. 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