Rachel M Burdorf, Shuntai Zhou, Claire Amon, Nathan Long, Collin S Hill, Lily Adams, Gerald Tegha, Maganizo B Chagomerana, Allan Jumbe, Madalitso Maliwichi, Shaphil Wallie, Yijia Li, Ronald Swanstrom, Mina C Hosseinipour
{"title":"低频人类免疫缺陷病毒 1 型耐药性突变对抗逆转录病毒疗法结果的影响。","authors":"Rachel M Burdorf, Shuntai Zhou, Claire Amon, Nathan Long, Collin S Hill, Lily Adams, Gerald Tegha, Maganizo B Chagomerana, Allan Jumbe, Madalitso Maliwichi, Shaphil Wallie, Yijia Li, Ronald Swanstrom, Mina C Hosseinipour","doi":"10.1093/infdis/jiae131","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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-based regimen and cohort B started a protease inhibitor-based 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 ≤20%.</p><p><strong>Results: </strong>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], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), 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.</p><p><strong>Conclusions: </strong>Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.</p>","PeriodicalId":50179,"journal":{"name":"Journal of Infectious Diseases","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11272071/pdf/","citationCount":"0","resultStr":"{\"title\":\"Impact of Low-Frequency Human Immunodeficiency Virus Type 1 Drug Resistance Mutations on Antiretroviral Therapy Outcomes.\",\"authors\":\"Rachel M Burdorf, Shuntai Zhou, Claire Amon, Nathan Long, Collin S Hill, Lily Adams, Gerald Tegha, Maganizo B Chagomerana, Allan Jumbe, Madalitso Maliwichi, Shaphil Wallie, Yijia Li, Ronald Swanstrom, Mina C Hosseinipour\",\"doi\":\"10.1093/infdis/jiae131\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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-based regimen and cohort B started a protease inhibitor-based 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 ≤20%.</p><p><strong>Results: </strong>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], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), 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.</p><p><strong>Conclusions: </strong>Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.</p>\",\"PeriodicalId\":50179,\"journal\":{\"name\":\"Journal of Infectious Diseases\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2024-07-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11272071/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Infectious Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1093/infdis/jiae131\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Infectious Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/infdis/jiae131","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:低频人类免疫缺陷病毒 1 型(HIV-1)耐药突变(DRMs)与治疗失败(TF)之间的关联存在争议。我们使用能准确采样低频 DRMs 的下一代测序(NGS)方法探讨了这种关联:我们在马拉维招募了感染 HIV-1 的女性患者,她们要么是抗逆转录病毒疗法 (ART) 天真者(队列 A),要么是抗逆转录病毒疗法失败者(队列 B),要么是中断抗逆转录病毒疗法者(队列 C)。入组时,A 组和 C 组开始采用非核苷类逆转录酶抑制剂治疗方案,B 组开始采用蛋白酶抑制剂治疗方案。我们使用 Primer ID MiSeq 在入组样本和 TF 血浆样本中识别与治疗方案相关的 DRMs,并使用 Cox 比例危险模型计算入组 DRMs 的危险比 (HRs)。低频DRM定义为≤20%:我们对 360 名参与者进行了测序。与队列 A 的参与者相比,队列 B 和队列 C 的参与者更有可能患有 TF。在 A 组和 C 组参与者中,K103N 的高频和低频出现会显著增加 TF 风险,HR 分别为 3.12(95% 置信区间 [CI],1.58-6.18)和 2.38(95% 置信区间,1.00-5.67)。在TF时,45%的参与者表现出DRMs的选择性,而在其余参与者中,明显缺乏ART的选择性压力:结论:使用准确的 NGS 检测 DRM 可通过识别低频 K103N 突变使另外 10% 的患者受益。
Impact of Low-Frequency Human Immunodeficiency Virus Type 1 Drug Resistance Mutations on Antiretroviral Therapy Outcomes.
Background: 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.
Methods: 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-based regimen and cohort B started a protease inhibitor-based 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 ≤20%.
Results: 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], 1.58-6.18) and 2.38 (95% CI, 1.00-5.67), 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.
Conclusions: Using accurate NGS for DRM detection may benefit an additional 10% of patients by identifying low-frequency K103N mutations.
期刊介绍:
Published continuously since 1904, The Journal of Infectious Diseases (JID) is the premier global journal for original research on infectious diseases. The editors welcome Major Articles and Brief Reports describing research results on microbiology, immunology, epidemiology, and related disciplines, on the pathogenesis, diagnosis, and treatment of infectious diseases; on the microbes that cause them; and on disorders of host immune responses. JID is an official publication of the Infectious Diseases Society of America.