{"doi":"10.1093/infdis/jiz631","title":"Human Immunodeficiency Virus-1 Viral Load Is Elevated in Individuals With Reverse-Transcriptase Mutation M184V/I During Virological Failure of First-Line Antiretroviral Therapy and Is Associated With Compensatory Mutation L74I","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance and increased tenofovir disoproxil fumarate (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against human immunodeficiency virus-1 with these mutations possibly as a result of reduced replication capacity. In this study, we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We compared VL in the absence and presence of M184V/I across studies using random effects meta-analysis. The effect of mutations on virus reverse-transcriptase activity and infectiousness was analyzed in vitro.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>M184I/V was present in 817 (56.5%) of 1445 individuals with virologic failure (VF). Virus load was similar in individuals with or without M184I/V (difference in log10 VL, 0.18; 95% confidence interval, .05–.31). CD4 count was lower both at initiation of antiretroviral therapy and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (P &amp;lt; .0001). In vitro, L74I compensated for defective replication of M184V-mutated virus.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. Therefore, we did not find evidence for a benefit of XTC in the context of first-line failure on this combination.</jats:p></jats:sec>","journal":"The Journal of Infectious Diseases","year":2020,"id":631201,"datarank":0.5101796072493234,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"self_citation_contribution":0.5101796072493234,"citation_network_contribution":0.0,"self_endowment_contribution":0.5101796072493234,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1082426,"name":"S Y Rhee","orcid":null,"position":1,"is_corresponding":false},{"id":1635725,"name":"R Datir","orcid":null,"position":2,"is_corresponding":false},{"id":1635726,"name":"D Pillay","orcid":null,"position":3,"is_corresponding":false},{"id":1635728,"name":"C F Perno","orcid":null,"position":4,"is_corresponding":false},{"id":1635729,"name":"A Derache","orcid":null,"position":5,"is_corresponding":false},{"id":1635730,"name":"R S Shafer","orcid":null,"position":6,"is_corresponding":false},{"id":69659,"name":"Ravindra K. Gupta","orcid":"0000-0001-9751-1808","position":7,"is_corresponding":false},{"id":1635720,"name":"J Gregson","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Human Immunodeficiency Virus-1 Viral Load Is Elevated in Individuals With Reverse-Transcriptase Mutation M184V/I During Virological Failure of First-Line Antiretroviral Therapy and Is Associated With Compensatory Mutation L74I","abstract":"<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance and increased tenofovir disoproxil fumarate (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against human immunodeficiency virus-1 with these mutations possibly as a result of reduced replication capacity. In this study, we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing regimen.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We compared VL in the absence and presence of M184V/I across studies using random effects meta-analysis. The effect of mutations on virus reverse-transcriptase activity and infectiousness was analyzed in vitro.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>M184I/V was present in 817 (56.5%) of 1445 individuals with virologic failure (VF). Virus load was similar in individuals with or without M184I/V (difference in log10 VL, 0.18; 95% confidence interval, .05–.31). CD4 count was lower both at initiation of antiretroviral therapy and at VF in participants who went on to develop M184V/I. L74I was present in 10.2% of persons with M184V/I but absent in persons without M184V/I (P &amp;lt; .0001). In vitro, L74I compensated for defective replication of M184V-mutated virus.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. Therefore, we did not find evidence for a benefit of XTC in the context of first-line failure on this combination.</jats:p></jats:sec>","is_dataset_classified":null,"base_score":3.4011973816621555,"endowment":3.4011973816621555,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31774913","pmcid":"PMC7459140","openalex_id":"https://openalex.org/W2989732474","authors":[],"funders":[{"funder_name":"NIAID NIH HHS","grant_id":"R24 AI136618","title":null},{"funder_name":"Wellcome Trust","grant_id":"108082/A/15/Z","title":null},{"funder_name":"Wellcome Trust","grant_id":"unidentified","title":"unidentified"},{"funder_name":"Wellcome Trust","grant_id":"","title":null},{"funder_name":"Wellcome Trust","grant_id":"","title":null}],"total_grants":5,"fwci":2.5759,"citation_percentile":0.90345143,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2020,"count":4},{"year":2021,"count":12},{"year":2022,"count":2},{"year":2023,"count":2},{"year":2024,"count":5},{"year":2026,"count":3}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiz631/31558616/jiz631.pdf","host_type":"journal"},{"url":"https://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiz631/31558616/jiz631.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/jid/advance-article-pdf/doi/10.1093/infdis/jiz631/31558616/jiz631.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/jid/article-pdf/222/7/1108/33702639/jiz631.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/infdis/jiz631","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31774913","host_type":"repository"},{"url":"https://researchonline.lshtm.ac.uk/view/creators/emsujgre.html>;","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/7459140","host_type":"repository"},{"url":"https://www.repository.cam.ac.uk/handle/1810/298027","host_type":"repository"},{"url":"https://doi.org/10.17863/cam.45083","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC7459140","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC7459140?pdf=render","host_type":"Europe_PMC"},{"url":"https://dx.doi.org/10.17863/cam.45083","host_type":""},{"url":"http://dx.doi.org/10.1093/infdis/jiz631","host_type":""},{"url":"https://researchonline.lshtm.ac.uk/id/eprint/4655431/1/jiz631.pdf","host_type":""},{"url":"https://dx.doi.org/10.1093/infdis/jiz631","host_type":""}],"fields_of_study":["HIV/AIDS drug development and treatment","HIV-related health complications and treatments","HIV Research and Treatment","0303 health sciences","03 medical and health sciences","Anti-HIV Agents","CD4 Lymphocyte Count","Drug Resistance, Viral","Drug Therapy, Combination","Emtricitabine","HIV Infections","HIV Reverse Transcriptase","HIV-1","Humans","Lamivudine","Mutation","Randomized Controlled Trials as Topic","Reverse Transcriptase Inhibitors","Tenofovir","Treatment Failure","Viral Load"],"mesh_terms":["Emtricitabine","Tenofovir","Drug Therapy, Combination","Humans","Mutation","HIV-1","HIV Infections","Randomized Controlled Trials as Topic","Treatment Failure","CD4 Lymphocyte Count","Reverse Transcriptase Inhibitors","Lamivudine","Anti-HIV Agents","Viral Load","Drug Resistance, Viral","HIV Reverse Transcriptase"],"keywords":["Resistance mutation","Virology","Reverse transcriptase","Mutation","Viral load","Human immunodeficiency virus (HIV)","Virus","Antiretroviral therapy","Reverse-transcriptase inhibitor","Biology","Lentivirus","Medicine","Viral disease","Polymerase chain reaction","Genetics","Gene","Drug resistance","HIV","Lamivudine","Antiretroviral","Compensatory Mutation","Anti-HIV Agents","HIV Infections","HIV Reverse Transcriptase","CD4 Lymphocyte Count","Major Articles and Brief Reports","Drug Resistance, Viral","HIV-1","Emtricitabine","Humans","Reverse Transcriptase Inhibitors","Drug Therapy, Combination","Treatment Failure","Tenofovir","Randomized Controlled Trials as Topic"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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