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

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 17 302 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.

Genetic Features of HIV-1 Integrase Sub-Subtype A6 Predominant in Russia and Predicted Susceptibility to INSTIs

“…A total of 108 mutations were detected, including 16 highly polymorphic mutations. Five of them (R20K, I72V, L74I, S119P, and V201I) were described as INSTI resistant [7,9,11,[23][24][25][26]33,36,[49][50][51][52].…”

“…Thus, according to interpretation-predicted DR from the HIVdb Program, the first patient had high-level EVG and low-level RAL resistance, the second patient had high-level EVG resistance, and the third patient had low-level resistance to EVG and RAL. No patients in this group had mutations on the list of DRMs used for surveillance of transmitted HIV-1 DR (SDRM) [49].…”

Temporal Trends in HIV-1 Mutations Used for the Surveillance of Transmitted Drug Resistance

“…Antiretroviral therapy (ART) guidelines and treatment practices have changed, and several new antiretroviral drugs have been introduced. In a recent study, we and others reported the prevalence of integrase strand transfer inhibitor (INSTI)-resistance associated mutations in INSTI-naïve and INSTI-experienced persons and developed a list of nonpolymorphic INSTI-selected DRMs that could be useful for the surveillance of INSTI-TDR [ 3 ]. Therefore, we sought to determine how well the original SDRM list met the original selection criteria and whether any additional DRMs might be useful as part of an expanded list to monitor TDR.…”

Characterizing HIV-1 Genetic Subtypes and Drug Resistance Mutations among Children, Adolescents and Pregnant Women in Sierra Leone

“…Another point of caution that has been raised in relation to the roll-out of DTG in SSA is that, due to insufficient studies on the subject, it is uncertain what impact, if any, circulating HIV non-B subtypes in SSA will have on the efficacy of DTG. Several studies have observed a higher frequency of INSTI-associated polymorphisms among non-B subtypes [ 28 , 29 , 30 , 31 ]. However, current experience with DTG and other INSTIs have shown high rates of virologic suppression (>90%) in non-B subtypes, including CRF02_AG, the dominant HIV subtype circulating in Sierra Leone and in West and Central Africa [ 32 , 33 , 34 , 35 ].…”