1. Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance
- Author
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Tzou, Philip L, Rhee, Soo-Yon, Descamps, Diane, Clutter, Dana S, Hare, Bradley, Mor, Orna, Grude, Maxime, Parkin, Neil, Jordan, Michael R, Bertagnolio, Silvia, Schapiro, Jonathan M, Harrigan, P Richard, Geretti, Anna Maria, Marcelin, Anne-Genevieve, Shafer, Robert W, and Grp, WHO HIVResNet Working
- Subjects
0301 basic medicine ,Microbiology (medical) ,Genotype ,Pyridones ,030106 microbiology ,Human immunodeficiency virus (HIV) ,Integrase inhibitor ,HIV Infections ,HIV Integrase ,Drug resistance ,medicine.disease_cause ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Resistance, Viral ,Oxazines ,Prevalence ,medicine ,Humans ,Gene Regulatory Networks ,Pharmacology (medical) ,HIV Integrase Inhibitors ,Original Research ,Pharmacology ,Mutation ,biology ,Transmission (medicine) ,Virology ,Integrase ,Integrase strand transfer inhibitor ,Phenotype ,030104 developmental biology ,Infectious Diseases ,chemistry ,Epidemiological Monitoring ,Dolutegravir ,HIV-1 ,biology.protein ,Heterocyclic Compounds, 3-Ring - Abstract
Background Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. Objectives We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. Methods To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. Results Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. Conclusions A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.
- Published
- 2019