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
| Autor: | Soo-Yon Rhee, Ravindra K. Gupta, Carlo Federico Perno, John Gregson, Rawlings Datir, Derache A, R S Shafer, Deenan Pillay |
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| Přispěvatelé: | Datir, Rawlings [0000-0003-0521-2144], Gupta, Ravindra [0000-0001-9751-1808], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Anti-HIV Agents
viruses antiretroviral Context (language use) HIV Infections Emtricitabine Virus Major Articles and Brief Reports immune system diseases Drug Resistance Viral Immunology and Allergy Medicine Humans AcademicSubjects/MED00860 Treatment Failure Tenofovir Randomized Controlled Trials as Topic drug resistance business.industry compensatory mutation Lamivudine virus diseases HIV DNA-Directed RNA Polymerases biochemical phenomena metabolism and nutrition Viral Load Resistance mutation Virology Reverse transcriptase HIV Reverse Transcriptase CD4 Lymphocyte Count Regimen Infectious Diseases AcademicSubjects/MED00290 Mutation HIV-1 Reverse Transcriptase Inhibitors HIV/AIDS Drug Therapy Combination lamivudine business Viral load medicine.drug |
| Zdroj: | The Journal of Infectious Diseases |
| ISSN: | 1537-6613 0022-1899 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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