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

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 (D...

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Autores principales: Tao, Kaiming, Rhee, Soo-Yon, Chu, Carolyn, Avalos, Ava, Ahluwalia, Amrit K., Gupta, Ravindra K., Jordan, Michael R., Shafer, Robert W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10536831/
https://www.ncbi.nlm.nih.gov/pubmed/37766338
http://dx.doi.org/10.3390/v15091932
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author Tao, Kaiming
Rhee, Soo-Yon
Chu, Carolyn
Avalos, Ava
Ahluwalia, Amrit K.
Gupta, Ravindra K.
Jordan, Michael R.
Shafer, Robert W.
author_facet Tao, Kaiming
Rhee, Soo-Yon
Chu, Carolyn
Avalos, Ava
Ahluwalia, Amrit K.
Gupta, Ravindra K.
Jordan, Michael R.
Shafer, Robert W.
author_sort Tao, Kaiming
collection PubMed
description 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.
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spelling pubmed-105368312023-09-29 Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review Tao, Kaiming Rhee, Soo-Yon Chu, Carolyn Avalos, Ava Ahluwalia, Amrit K. Gupta, Ravindra K. Jordan, Michael R. Shafer, Robert W. Viruses Review 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. MDPI 2023-09-15 /pmc/articles/PMC10536831/ /pubmed/37766338 http://dx.doi.org/10.3390/v15091932 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Tao, Kaiming
Rhee, Soo-Yon
Chu, Carolyn
Avalos, Ava
Ahluwalia, Amrit K.
Gupta, Ravindra K.
Jordan, Michael R.
Shafer, Robert W.
Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review
title Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review
title_full Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review
title_fullStr Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review
title_full_unstemmed Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review
title_short Treatment Emergent Dolutegravir Resistance Mutations in Individuals Naïve to HIV-1 Integrase Inhibitors: A Rapid Scoping Review
title_sort treatment emergent dolutegravir resistance mutations in individuals naïve to hiv-1 integrase inhibitors: a rapid scoping review
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10536831/
https://www.ncbi.nlm.nih.gov/pubmed/37766338
http://dx.doi.org/10.3390/v15091932
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