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.

Prevalence of Emergent Dolutegravir Resistance Mutations in People Living with HIV: A Rapid Scoping Review

“…Of the nine participants with emergent INSTI DRMs in the NADIA trial, six were randomized to zidovudine (AZT) plus 3TC while three were randomized to TDF plus 3TC. The three TDF/3TC recipients with emergent INSTI DRMs each acquired R263K, which was associated with approximately two-fold reduced DTG susceptibility [ 3 ]. In contrast, the six AZT/3TC recipients included five who acquired multiple mutations including G118R or Q148R that were predicted to be associated with a high level of reduced DTG susceptibility.…”

“…Therefore, we relied on the reports of integrase mutations in each published study. INSTI-associated DRMs were defined as the following nonpolymorphic 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 [ 3 ].…”

“…We recently published a systematic review that identified 36 publications reporting 99 INSTI-naïve PLWH with emergent VF and INSTI DRMs on a DTG-containing regimen [ 3 ]. However, this review did not estimate the risk of emergent INSTI DRMs in INSTI-naïve PLWH because most individuals with INSTI DRMs were reported in studies for which the total number of PLWH receiving DTG was unknown.…”

Virological Findings and Treatment Outcomes of Cases That Developed Dolutegravir Resistance in Malawi’s National HIV Treatment Program

“…R263K was by far the most common mutation. A recent global review of emergent dolutegravir resistance mutations suggests that four largely non-overlapping dolutegravir resistance pathways exist that are characterized through mutations at four signature positions: R263K, G118R, N155H, and Q148H/R/K [ 21 ]. In our cases, we observed the R263K (15/24) and G118R (5/24) pathways.…”

GPT-4 Performance on Querying Scientific Publications: Reproducibility, Accuracy, and Impact of an Instruction Sheet

“…These studies have been performed using foundational LLMs by providing the text of a study and queries about the study at the LLM interface or prompt, a process referred to as prompt engineering. We have extensive experience reviewing published studies on the topic of human immunode ciency virus (HIV) drug resistance (HIVDR) having maintained the Stanford HIV Drug Resistance Database (HIVDB; https://hivdb.stanford.edu) and having performed multiple systematic literature reviews (12,13). In this study, we evaluated the ability of GPT-4 to correctly answer questions about studies on HIVDR with and without an instruction sheet designed to provide GPT-4 with specialized HIVDR knowledge.…”