{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T19:31:41Z","timestamp":1780515101356,"version":"3.54.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T00:00:00Z","timestamp":1710115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AI40970"],"award-info":[{"award-number":["R01-AI40970"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HD080485"],"award-info":[{"award-number":["R01-HD080485"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30-AI050410"],"award-info":[{"award-number":["P30-AI050410"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008615","name":"UNC Lineberger Comprehensive Cancer Center","doi-asserted-by":"publisher","award":["P30-CA016086"],"award-info":[{"award-number":["P30-CA016086"]}],"id":[{"id":"10.13039\/100008615","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,7,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The association between low-frequency human immunodeficiency virus type 1 (HIV-1) drug resistance mutations (DRMs) and treatment failure (TF) is controversial. We explore this association using next-generation sequencing (NGS) methods that accurately sample low-frequency DRMs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We enrolled women with HIV-1 in Malawi who were either antiretroviral therapy (ART) naive (cohort A), had ART failure (cohort B), or had discontinued ART (cohort C). At entry, cohorts A and C began a nonnucleoside reverse transcriptase inhibitor\u2013based regimen and cohort B started a protease inhibitor\u2013based regimen. We used Primer ID MiSeq to identify regimen-relevant DRMs in entry and TF plasma samples, and a Cox proportional hazards model to calculate hazard ratios (HRs) for entry DRMs. Low-frequency DRMs were defined as \u226420%.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We sequenced 360 participants. Cohort B and C participants were more likely to have TF than cohort A participants. The presence of K103N at entry significantly increased TF risk among A and C participants at both high and low frequency, with HRs of 3.12 (95% confidence interval [CI], 1.58\u20136.18) and 2.38 (95% CI, 1.00\u20135.67), respectively. At TF, 45% of participants showed selection of DRMs while in the remaining participants there was an apparent lack of selective pressure from ART.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/infdis\/jiae131","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T04:13:25Z","timestamp":1710130405000},"page":"86-94","source":"Crossref","is-referenced-by-count":3,"title":["Impact of Low-Frequency Human Immunodeficiency Virus Type 1 Drug Resistance Mutations on Antiretroviral Therapy Outcomes"],"prefix":"10.1093","volume":"230","author":[{"given":"Rachel M","family":"Burdorf","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8353-386X","authenticated-orcid":false,"given":"Shuntai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Amon","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Long","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin S","family":"Hill","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Adams","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"Tegha","sequence":"additional","affiliation":[{"name":"UNC Project\u2013Malawi , Lilongwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maganizo B","family":"Chagomerana","sequence":"additional","affiliation":[{"name":"UNC Project\u2013Malawi , Lilongwe"},{"name":"Department of Medicine, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Jumbe","sequence":"additional","affiliation":[{"name":"UNC Project\u2013Malawi , Lilongwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalitso","family":"Maliwichi","sequence":"additional","affiliation":[{"name":"UNC Project\u2013Malawi , Lilongwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaphil","family":"Wallie","sequence":"additional","affiliation":[{"name":"UNC Project\u2013Malawi , Lilongwe"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-0571","authenticated-orcid":false,"given":"Yijia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Pittsburgh Medical Center , Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Swanstrom","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center"},{"name":"Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina C","family":"Hosseinipour","sequence":"additional","affiliation":[{"name":"UNC Project\u2013Malawi , Lilongwe"},{"name":"Department of Medicine, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,3,11]]},"reference":[{"key":"2024072520130598900_jiae131-B1","doi-asserted-by":"crossref","first-page":"e588","DOI":"10.1016\/S2352-3018(18)30173-5","article-title":"HIV drug resistance in low-income and middle-income countries","volume":"5","author":"Hamers","year":"2018","journal-title":"Lancet HIV"},{"key":"2024072520130598900_jiae131-B2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1093\/jac\/dkx366","article-title":"No impact of HIV-1 protease minority resistant variants on the virological response to a first-line PI-based regimen containing darunavir or atazanavir","volume":"73","author":"Perrier","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B3","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1001\/jama.2011.375","article-title":"Low-frequency HIV-1 drug resistance mutations and risk of NNRTI-based antiretroviral treatment failure: a systematic review and pooled analysis","volume":"305","author":"Li","year":"2011","journal-title":"JAMA"},{"key":"2024072520130598900_jiae131-B4","doi-asserted-by":"crossref","first-page":"e579","DOI":"10.1016\/S2352-3018(16)30119-9","article-title":"Pretreatment HIV-drug resistance in Mexico and its impact on the effectiveness of first-line antiretroviral therapy: a nationally representative 2015 WHO survey","volume":"3","author":"\u00c1vila-R\u00edos","year":"2016","journal-title":"Lancet HIV"},{"key":"2024072520130598900_jiae131-B5","doi-asserted-by":"crossref","first-page":"100239","DOI":"10.1016\/j.eclinm.2019.100239","article-title":"Pre-treatment HIV-drug resistance associated with virologic outcome of first-line NNRTI-antiretroviral therapy: a cohort study in Kenya","volume":"18","author":"Beck","year":"2020","journal-title":"EClinicalMedicine"},{"key":"2024072520130598900_jiae131-B6","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1093\/infdis\/jis925","article-title":"Impact of minority nonnucleoside reverse transcriptase inhibitor resistance mutations on resistance genotype after virologic failure","volume":"207","author":"Li","year":"2013","journal-title":"J Infect Dis"},{"key":"2024072520130598900_jiae131-B7","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/QAD.0b013e32834e9d7d","article-title":"Relationship between minority nonnucleoside reverse transcriptase inhibitor resistance mutations, adherence, and the risk of virologic failure","volume":"26","author":"Li","year":"2012","journal-title":"AIDS"},{"key":"2024072520130598900_jiae131-B8","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1097\/QAD.0000000000002134","article-title":"Minority and majority pretreatment HIV-1 drug resistance associated with failure of first-line nonnucleoside reverse-transcriptase inhibitor antiretroviral therapy in Kenyan women","volume":"33","author":"Milne","year":"2019","journal-title":"AIDS"},{"key":"2024072520130598900_jiae131-B9","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1086\/596736","article-title":"Low-abundance drug-resistant viral variants in chronically HIV-infected, antiretroviral treatment\u2013naive patients significantly impact treatment outcomes","volume":"199","author":"Simen","year":"2009","journal-title":"J Infect Dis"},{"key":"2024072520130598900_jiae131-B10","doi-asserted-by":"crossref","first-page":"e0210559","DOI":"10.1371\/journal.pone.0210559","article-title":"Presence, persistence and effects of pre-treatment HIV-1 drug resistance variants detected using next generation sequencing: a retrospective longitudinal study from rural coastal Kenya","volume":"14","author":"Hassan","year":"2019","journal-title":"PLoS One"},{"key":"2024072520130598900_jiae131-B11","doi-asserted-by":"crossref","first-page":"3319","DOI":"10.1093\/jac\/dkaa343","article-title":"Impact of pretreatment low-abundance HIV-1 drug-resistant variants on virological failure among HIV-1\/TB-co-infected individuals","volume":"75","author":"Chimukangara","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.virol.2012.01.002","article-title":"Ultra-deep sequencing of HIV-1 reverse transcriptase before start of an NNRTI-based regimen in treatment-naive patients","volume":"426","author":"Messiaen","year":"2012","journal-title":"Virology"},{"key":"2024072520130598900_jiae131-B13","doi-asserted-by":"crossref","first-page":"6360","DOI":"10.3390\/v7122943","article-title":"Emergent HIV-1 drug resistance mutations were not present at low-frequency at baseline in non-nucleoside reverse transcriptase inhibitor-treated subjects in the STaR study","volume":"7","author":"Porter","year":"2015","journal-title":"Viruses"},{"key":"2024072520130598900_jiae131-B14","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1093\/cid\/cix1070","article-title":"Impact of human immunodeficiency virus type 1 minority variants on the virus response to a rilpivirine-based first-line regimen","volume":"66","author":"Raymond","year":"2018","journal-title":"Clin Infect Dis"},{"key":"2024072520130598900_jiae131-B15","doi-asserted-by":"crossref","first-page":"5922","DOI":"10.1038\/s41467-020-19801-x","article-title":"Reduced efficacy of HIV-1 integrase inhibitors in patients with drug resistance mutations in reverse transcriptase","volume":"11","author":"Siedner","year":"2020","journal-title":"Nat Commun"},{"key":"2024072520130598900_jiae131-B16","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/jac\/dky561","article-title":"Detection of pretreatment minority HIV-1 reverse transcriptase inhibitor-resistant variants by ultra-deep sequencing has a limited impact on virological outcomes","volume":"74","author":"Su","year":"2019","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B17","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1093\/jac\/dku470","article-title":"Virological failure after 1 year of first-line ART is not associated with HIV minority drug resistance in rural Cameroon","volume":"70","author":"Zoufaly","year":"2015","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B18","doi-asserted-by":"crossref","first-page":"8540","DOI":"10.1128\/JVI.00522-15","article-title":"Primer ID validates template sampling depth and greatly reduces the error rate of next-generation sequencing of HIV-1 genomic RNA populations","volume":"89","author":"Zhou","year":"2015","journal-title":"J Virol"},{"key":"2024072520130598900_jiae131-B19","doi-asserted-by":"crossref","first-page":"2505","DOI":"10.1021\/acsinfecdis.2c00319","article-title":"Unique molecular identifiers and multiplexing amplicons maximize the utility of deep sequencing to critically assess population diversity in RNA viruses","volume":"8","author":"Zhou","year":"2022","journal-title":"ACS Infect Dis"},{"key":"2024072520130598900_jiae131-B20","doi-asserted-by":"crossref","first-page":"321","DOI":"10.3851\/IMP3309","article-title":"Very high pre-therapy viral load is a predictor of virological rebound in HIV-1-infected patients starting a modern first-line regimen","volume":"24","author":"Armenia","year":"2019","journal-title":"Antivir Ther"},{"key":"2024072520130598900_jiae131-B21","doi-asserted-by":"crossref","first-page":"e77691","DOI":"10.1371\/journal.pone.0077691","article-title":"Adherence as a predictor of the development of class-specific resistance mutations: the Swiss HIV Cohort Study","volume":"8","author":"von Wyl","year":"2013","journal-title":"PLoS One"},{"key":"2024072520130598900_jiae131-B22","doi-asserted-by":"crossref","first-page":"e0196451","DOI":"10.1371\/journal.pone.0196451","article-title":"HIV drug resistance patterns in pregnant women using next generation sequence in Mozambique","volume":"13","author":"Rup\u00e9rez","year":"2018","journal-title":"PLoS One"},{"key":"2024072520130598900_jiae131-B23","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1093\/infdis\/jiz650","article-title":"Low-abundance drug-resistant HIV-1 variants in antiretroviral drug-naive individuals: a systematic review of detection methods, prevalence, and clinical impact","volume":"221","author":"Mbunkah","year":"2020","journal-title":"J Infect Dis"},{"key":"2024072520130598900_jiae131-B24","first-page":"12:694","article-title":"Multi-laboratory comparison of next-generation to sanger-based sequencing for HIV-1 drug resistance genotyping","author":"Parkin","year":"2020","journal-title":"Viruses"},{"key":"2024072520130598900_jiae131-B25","first-page":"e00829","article-title":"Application of next generation sequencing in HIV drug resistance studies in Africa, 2005\u20132019: a systematic review","volume":"12","author":"Mathobo","year":"2021","journal-title":"Sci Afr"},{"key":"2024072520130598900_jiae131-B26","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1093\/jac\/dkab385","article-title":"Deep sequencing of HIV-1 reveals extensive subtype variation and drug resistance after failure of first-line antiretroviral regimens in Nigeria","volume":"77","author":"El Bouzidi","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B27","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.jcv.2014.10.020","article-title":"Minority resistant HIV-1 variants and the response to first-line NNRTI therapy","volume":"62","author":"Nicot","year":"2015","journal-title":"J Clin Virol"},{"key":"2024072520130598900_jiae131-B28","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1093\/jac\/dky198","article-title":"Prevalence and clinical impact of minority resistant variants in patients failing an integrase inhibitor-based regimen by ultra-deep sequencing","volume":"73","author":"Nguyen","year":"2018","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/jac\/dkt316","article-title":"Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing","volume":"69","author":"Melikian","year":"2014","journal-title":"J Antimicrob Chemother"},{"key":"2024072520130598900_jiae131-B30","doi-asserted-by":"crossref","first-page":"7540587","DOI":"10.1155\/2018\/7540587","article-title":"Loss to follow-up among HIV positive pregnant and lactating mothers on lifelong antiretroviral therapy for PMTCT in rural Uganda","volume":"2018","author":"Kweyamba","year":"2018","journal-title":"Adv Public Health"},{"key":"2024072520130598900_jiae131-B31","first-page":"1227","article-title":"Adherence to antiretroviral therapy during and after pregnancy: cohort study on women receiving care in Malawi's option B+ program","volume":"63","author":"Haas","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2024072520130598900_jiae131-B32","doi-asserted-by":"crossref","first-page":"e3361","DOI":"10.1097\/MD.0000000000003361","article-title":"Adherence to antiretroviral therapy and virologic failure: a meta-analysis","volume":"95","author":"Bezabhe","year":"2016","journal-title":"Medicine (Baltimore)"},{"key":"2024072520130598900_jiae131-B33","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1097\/QAI.0000000000002142","article-title":"Antiretroviral adherence level necessary for HIV viral suppression using real-world data","volume":"82","author":"Byrd","year":"2019","journal-title":"J Acquir Immune Defic Syndr"},{"key":"2024072520130598900_jiae131-B34","first-page":"e01443","article-title":"Limited marginal utility of deep sequencing for HIV drug resistance testing in the age of integrase inhibitors","volume":"56","author":"Dalmat Ronit","year":"2018","journal-title":"J Clin Microbiol"}],"container-title":["The Journal of Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jid\/advance-article-pdf\/doi\/10.1093\/infdis\/jiae131\/57100544\/jiae131.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/230\/1\/86\/58649659\/jiae131.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jid\/article-pdf\/230\/1\/86\/58649659\/jiae131.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T20:17:43Z","timestamp":1721938663000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jid\/article\/230\/1\/86\/7625231"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,11]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,3,11]]},"published-print":{"date-parts":[[2024,7,25]]}},"URL":"https:\/\/doi.org\/10.1093\/infdis\/jiae131","relation":{},"ISSN":["0022-1899","1537-6613"],"issn-type":[{"value":"0022-1899","type":"print"},{"value":"1537-6613","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,7,15]]},"published":{"date-parts":[[2024,3,11]]}}}