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HIV-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

Gregson, J; Rhee, SY; Datir, R; Pillay, D; Perno, CF; Derache, A; Shafer, RS; (2019) HIV-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. Journal of Infectious Diseases 10.1093/infdis/jiz631. (In press). Green open access

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Abstract

Background: M184V/I cause high-level lamivudine (3TC) and emtricitabine (FTC) resistance, and increased tenofovir (TDF) susceptibility. Nonetheless, 3TC and FTC (collectively referred to as XTC) appear to retain modest activity against HIV-1 with these mutations possibly as a result of reduced replication capacity. Here we determined how M184V/I impacts virus load (VL) in patients failing therapy on a TDF/XTC plus nonnucleoside RT inhibitor (NNRTI)-containing regimen. / Methods: We compared VL in absence and presence M184V/I across studies using random effects meta-analysis. The effect of mutations on virus RT activity and infectiousness was analysed in vitro. / Results: M184I/V was present in 817 (56.5%) of 1445 individuals with VF. VL was similar in individuals with or without M184I/V (difference in log10VL 0.18, 95% CI 0.05-0.31). CD4 count was lower both at initiation of ART 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<0.0001). In vitro, L74I compensated for defective replication of M184V mutated virus. / Conclusion: Virus loads were similar in persons with and without M184V/I during VF on a TDF/XTC/NNRTI-containing regimen. We therefore do not find evidence for a benefit of XTC in the context of first line failure on this combination.

Type: Article
Title: HIV-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
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/infdis/jiz631
Publisher version: https://doi.org/10.1093/infdis/jiz631
Language: English
Additional information: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: antiretroviral, drug resistance, HIV, Lamivudine, fitness cost, compensatory mutation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/10087194
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