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.

J Gregson,R Datir,R K Gupta,D Pillay,A Derache,R S Shafer,S Y Rhee,C F Perno

doi:10.1093/infdis/jiz631

Abstract

BackgroundM184V/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.MethodsWe 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.ResultsM184I/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.ConclusionsVirus 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.

Highlights

The global scale up of antiretroviral therapy (ART) using a public health approach with limited viral load monitoring has been accompanied by high prevalence of drug resistance to nonnucleoside RT inhibitor (NNRTI) containing regimens amongst individuals with virological failure in low-middle income countries (LMIC), 1-3 4-6.The cytosine analogues lamivudine (3TC) and emtricitabine (FTC), collectively referred to as XTC, are components of first and second line regimens recommended by WHO
Virus loads were similar in persons with and without M184V/I during virologic failure (VF)
The global scale up of antiretroviral therapy (ART) using a public health approach with limited viral load monitoring has been accompanied by high prevalence of drug resistance to NNRTI containing regimens amongst individuals with virological failure in LMIC, 1-3 4-6

Summary

Results

Amongst 2873 participants included in the initial group, 1445 from 32 study groups across 15 countries had an available failure viral load measurement of which. There was no evidence that relationship between M184I/V and failure viral load was modified by choice of NRTI, choice of NNRTI, or drug resistance to NNRTI or tenofovir We found that removing the L74I mutation significantly decreased the efficiency of reverse transcription (Figure 5B, compare left bar with middle bar) whilst virus abundance was not affected as determined by western blot of viral p24 abundance in supernatants (Figure 5B bottom panel). Infectivity was significantly decreased by reversion of the compensatory mutation (Figure 5C, compare left bar with middle bar). Mutation of M184V back to M, leaving a virus with only L74I, had no impact on reverse transcriptase efficiency and a minor effect on infectivity (Figure 5B, C compare left and right bars)

Conclusion

Introduction

Discussion