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. (27th November 2019)

• Record Type: Journal Article
• Authors: Gregson, J; Rhee, S Y; Datir, R; Pillay, D; Perno, C F; Derache, A; Shafer, R S; Gupta, R K
• Is Part Of: Journal of infectious diseases. Volume 222:Number 7(2020)
• Page Start: 1108
• Page End: 1116
• Publication Date: 2019-11-27
• Subjects: antiretroviral -- compensatory mutation -- drug resistance -- HIV -- lamivudine; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiz631
• Languages: English
• ISSNs: 0022-1899

Abstract

Abstract: Background: 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. Methods: 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. Results: 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 < .0001). In vitro, L74I compensated for defective replication of M184V-mutated virus. Conclusions: 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. Abstract : Lamivudine is a cornerstone antiretroviral whose efficacy has been ascribed to high fitness cost of the lamivudine resistance mutation M184V. However, here we demonstrate elevated viral loads in the context of M184V, likely attributable to compensatory mutations such as L74I.