Infection with the frequently transmitted HIV-1 M41L variant has no influence on selection of tenofovir resistance

• Published in: Journal of antimicrobial chemotherapy Vol. 70; no. 2; pp. 573 - 580
• Main Authors: Pingen, Marieke, Nijhuis, Monique, Mudrikova, Tania, van Laarhoven, Arjan, Langebeek, Nienke, Richter, Clemens, Boucher, Charles A B, Wensing, Annemarie M J
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01.02.2015
• Subjects: Adenine - analogs & derivatives; Adenine - pharmacology; Adenine - therapeutic use; Adult; Amino Acid Substitution; Antiretroviral drugs; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug resistance; Drug Resistance, Viral; Emtricitabine; Evolution, Molecular; Female; Genotype; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - genetics; HIV-1 - classification; HIV-1 - genetics; Human immunodeficiency virus; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Organophosphonates - pharmacology; Organophosphonates - therapeutic use; Phenotype; Phylogenetics; Phylogeny; Reverse Transcriptase Inhibitors - pharmacology; Reverse Transcriptase Inhibitors - therapeutic use; Tenofovir; Viral Load; Virology; emtricitabine; transmission; drug resistance; Atripla; Truvada
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dku377

In ∼10% of newly diagnosed HIV-1 patients, drug-resistant viral variants are detected. In such transmitted HIV-1 variants, the thymidine analogue mutation (TAM) M41L is frequently observed as a single resistance mutation and these viral variants often belong to phylogenetic transmission clusters. The presence of at least three TAMs, in particular patterns with M41L/L210W, impairs the efficacy of the extensively used drug tenofovir. We investigated whether the presence of a single M41L mutation at baseline influences the selection of resistance to tenofovir and emtricitabine in vitro and in vivo. The impact of M41L on the development of drug resistance to tenofovir and emtricitabine was determined by extensive in vitro selection experiments and investigation of the virological outcome of patients on a first-line regimen. The presence of a single M41L mutation did not influence the selected mutational profile or the genetic barrier to resistance to tenofovir and/or emtricitabine during long-term in vitro selection experiments. In vivo, virological outcome of first-line regimens containing tenofovir and emtricitabine was comparable between patients diagnosed with HIV-1 harbouring M41L (n=17, 16 were part of one transmission cluster) and WT virus (n=248). Detection of a single M41L reverse transcriptase mutation at baseline did not influence the development of resistance in vitro or virological outcome on tenofovir-containing regimens in patients belonging to a large transmission cluster. Our results indicate that a high genetic barrier regimen may not be required when patients are diagnosed with HIV variants containing a single M41L mutation in reverse transcriptase.