Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review

Abstract

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) rarely leads to virological failure (VF) and drug resistance in integrase strand transfer inhibitor (INSTI)-naïve persons living with HIV (PLWH). As a result, limited data are available on INSTI-associated drug resistance mutations (DRMs) selected by DTG-containing ART regimens. Methods: We reviewed studies published through July 2023 to identify those reporting emergent major INSTI-associated DRMs in INSTI-naïve PLWH receiving DTG and those containing in vitro DTG susceptibility results using a standardized assay. Results: We identified 36 publications reporting 99 PLWH in whom major nonpolymorphic INSTI-associated DRMs developed on a DTG-containing regimen and 21 publications containing 269 in vitro DTG susceptibility results. DTG-selected DRMs clustered into four largely non-overlapping mutational pathways characterized by mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K. Eighty-two (82.8%) viruses contained just one signature DRM, including R263K (n = 40), G118R (n = 24), N155H (n = 9), and Q148H/R/K (n = 9). Nine (9.1%) contained ≥1 signature DRM, and eight (8.1%) contained just other DRMs. R263K and G118R were negatively associated with one another and with N155H and Q148H/K/R. R263K alone conferred a median 2.0-fold (IQR: 1.8-2.2) reduction in DTG susceptibility. G118R alone conferred a median 18.8-fold (IQR:14.2-23.4) reduction in DTG susceptibility. N155H alone conferred a median 1.4-fold (IQR: 1.2-1.6) reduction in DTG susceptibility. Q148H/R/K alone conferred a median 0.8-fold (IQR: 0.7-1.1) reduction in DTG susceptibility. Considerably higher levels of reduced susceptibility often occurred when signature DRMs occurred with additional INSTI-associated DRMs. Conclusions: Among INSTI-naïve PLWH with VF and treatment emergent INSTI-associated DRMs, most developed one of four signature DRMs, most commonly R263K or G118R. G118R was associated with a much greater reduction in DTG susceptibility than R263K.

Keywords: Dolutegravir; HIV-1 integrase; antiviral resistance; mutations.

Figure 1

Flow chart summarizing the review process. One of the 36 publications describing emergent INSTI-associated mutations was identified through a routine BLAST search of GenBank as part of the work for maintaining the Stanford HIV Drug Resistance Database and through the review of references in other papers with emergent INSTI-associated DRMs selected by DTG. Of the 21 publications reporting DTG susceptibility testing, 2 were reported only at scientific meetings. These were retrieved from the Stanford HIV Drug Resistance Database (https://hivdb.stanford.edu/cgi-bin/Phenotypes.cgi?Gene=IN; last accessed 18 July 2023) and cited in our earlier review [3]. Abbreviations: VL (virus load); INSTI (integrase strand transfer inhibitor); DRMs (drug-resistance mutations) VF (virological failure); PLWH (people living with HIV-1).

Figure 2

Patterns of INSTI-associated DRMs occurring in 99 previously INSTI-naïve individuals with virological failure on a DTG-containing regimen who developed a major nonpolymorphic INSTI-associated DRM defined as one of the following mutations: H51Y, T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, S153Y/F, N155H, S230R, and R263K. Polymorphic and accessory DRMs were identified only when they occurred in an isolate that also contained a major nonpolymorphic INSTI-associated DRM. Additional patterns of mutations that do not conform to the above categories included one with and eight without signature DRMs. The one with signature DRMs included L74I + G118GR + E138K + Q148QR + R263RK. The eight without signature mutations included S230R (n = 3), T66I, E138K, H51Y + S147G, E138A + G149A, and E138K + D232N.

Figure 3

Regression coefficients of the least-squares regression (LSR) model for predicting fold reductions in DTG susceptibility using genotypic predictors. Integrase mutations scored by the HIVDB drug resistance interpretation system were included as explanatory variables and log fold change in susceptibility was the response variable. Ten repetitions of 5-fold cross-validation were performed to estimate the variance among the fitted coefficients. The mutations shown are those that occurred at least 5 times in isolates that underwent susceptibility testing using the PhenoSense assay. For each mutation, the y axis indicates the magnitude of the mean coefficient of 50 LSR runs (10 × 5-fold cross-validation), and the error bar indicates the standard deviation from the mean. Positive coefficients indicate mutations that reduced DTG susceptibility. Negative coefficients indicate mutations that increased DTG susceptibility. Bars representing coefficients whose cross-validated means were ≥1.5-fold and ≥3 standard deviations from zero are blue; other coefficient bars are white, indicating a lack of statistical significance after cross-validation.

Figure 4

Replication capacities of 60 HIV-1 isolates containing a signature DTG-associated DRM and 82 HIV-1 isolates lacking such a DRM. Each of the signature DRMs were present both alone and in combination with other DRMs. For some isolates, the complete list of accompanying integrase DRMs was not available. Isolates containing more than one signature DRM are not shown.