Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance

• Published in: Journal of antimicrobial chemotherapy Vol. 75; no. 1; pp. 170 - 182
• Main Authors: 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-Geneviève, Shafer, Robert W
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2020; Oxford University Press (OUP)
• Subjects: Drug Resistance, Viral; Drug Resistance, Viral - genetics; Epidemiological Monitoring; Gene Regulatory Networks; Genotype; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 3-Ring - pharmacology; Heterocyclic Compounds, 3-Ring - therapeutic use; HIV Infections; HIV Infections - drug therapy; HIV Infections - epidemiology; HIV Integrase; HIV Integrase - genetics; HIV Integrase Inhibitors; HIV Integrase Inhibitors - pharmacology; HIV Integrase Inhibitors - therapeutic use; HIV-1; HIV-1 - drug effects; Humans; Life Sciences; Mutation; Original Research; Oxazines; Oxazines - pharmacology; Oxazines - therapeutic use; Phenotype; Piperazines; Piperazines - pharmacology; Piperazines - therapeutic use; Prevalence; Pyridones; Pyridones - pharmacology; Pyridones - therapeutic use
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkz417

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.