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 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.

Figure 1.

Principal components analysis of the 59 INSTI-resistance mutations on one or more expert lists. The original characteristics or variables were related to the number of expert lists containing the mutation, the positional importance of the mutation, the frequency of the mutation in INSTI-naive and INSTI-experienced persons and the statistical association of the mutation with reduced susceptibility to one or more INSTIs. The mutations at the upper right are non-polymorphic mutations significantly associated with INSTI treatment. Those at the lower right are polymorphic mutations significantly associated with therapy. Those on the left are rare non-polymorphic mutations, which nearly always occurred too infrequently to be associated with therapy.

Figure 2.

Correlation network analysis of the 25 INSTI-resistance mutations that most frequently co-occurred with one or more other INSTI-resistance mutations. INSTI-resistance mutations having a non-parametric Spearman correlation coefficient (ρ) of >0.075 and a P value ≤0.00001 are linked with an edge. Edge thickness is proportional to ρ, with the greatest thicknesses for the edge between G140S and Q148H (ρ=0.93), Y143C and S230R (ρ=0.65) and G140A and Q148R (ρ=0.38).