HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis

Tom O Loosli; Stefanie Hossmann; Suzanne M Ingle; Hajra Okhai; Katharina  Kusejko; Johannes  Mouton; Pantxika  Bellecave; Ard van Sighem; Melanie Stecher; Antonella D'Arminio Monforte; M John Gill; Caroline A Sabin; Gary Maartens; Huldrych F Günthard; Jonathan A C Sterne; Richard Lessells; Matthias E Egger; Roger D Kouyos

doi:10.1016/S2352-3018(23)00228-X

HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis

Tom O Loosli
, Stefanie Hossmann
, Suzanne M Ingle
, Hajra Okhai
, Katharina Kusejko
, Johannes Mouton
, Pantxika Bellecave
, Ard van Sighem
, Melanie Stecher
, Antonella D'Arminio Monforte
, M John Gill
, Caroline A Sabin
, Gary Maartens
, Huldrych F Günthard
, Jonathan A C Sterne
, Richard Lessells
, Matthias E Egger
, Roger D Kouyos

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

Background
The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance.
Methods
We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models.
Findings
We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59%), a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual therapy, and 18 (3%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most (n=563, 94%) were susceptible to dolutegravir, seven (1%) had potential low, six (1%) low, 17 (3%) intermediate, and six (1%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95% CI 9·93–117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20–38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32–20·7) or intermediate or high-level (aOR 13·4, 4·55–39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance.
Interpretation
Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART.
Funding
US National Institutes of Health, Swiss National Science Foundation.

Original language	English
Pages (from-to)	e733-e741
Number of pages	9
Journal	The Lancet HIV
Volume	10
Issue number	11
Early online date	10 Oct 2023
DOIs	https://doi.org/10.1016/S2352-3018(23)00228-X
Publication status	Published - 1 Nov 2023

Bibliographical note

Funding Information:
We thank Anthony Hauser, Suraj Balakrishna, and Marius Zeeb for helpful discussions on data analysis. This study was supported by the NIH National Institute of Allergy and Infectious Diseases under award number R01AI152772 and the Swiss National Science Foundation (32FP30_207285, 324730_207957). The participating cohorts or cohort collaborations were funded by the Swiss National Science Foundation (33CS30_201369) and the Yvonne Jacob Foundation (for the SHCS), the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1; for the UK Collaborative HIV Cohort), the National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Agency for Research on AIDS and Viral Hepatitis | Emerging Infectious Diseases (ANRS|MIE), and the CHU de Bordeaux (for the ANRS CO3 Aquitaine-AquiVIH-NA cohort), the Dutch Ministry of Health (for the ATHENA cohort), and the German Center for Infection Research (8018704707; for the CBC). The ICONA Foundation is supported by unrestricted grants from BMS, Gilead Sciences, Janssen, MSD, and ViiV Healthcare. AfA is supported via IeDEA-SA by the following NIH institutes: the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Fogarty International Center under award number U01AI069924. The ART-CC is funded by the NIH National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Publisher Copyright:
© 2023 Elsevier Ltd

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Loosli, T. O., Hossmann, S., Ingle, S. M., Okhai, H., Kusejko, K., Mouton, J., Bellecave, P., van Sighem, A., Stecher, M., Monforte, A. DA., Gill, M. J., Sabin, C. A., Maartens, G., Günthard, H. F., Sterne, J. A. C., Lessells, R., Egger, M. E., & Kouyos, R. D. (2023). HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis. The Lancet HIV, 10(11), e733-e741. https://doi.org/10.1016/S2352-3018(23)00228-X

@article{66809bc14e01482bbfd5177bd2f5fa28,

title = "HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis",

abstract = "Background The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance. Methods We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models. Findings We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59\%), a third had been exposed to first-generation INSTIs (n=193, 32\%), 70 (12\%) were on dolutegravir dual therapy, and 18 (3\%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14\%) individuals; 20 (3\%) had more than one mutation. Most (n=563, 94\%) were susceptible to dolutegravir, seven (1\%) had potential low, six (1\%) low, 17 (3\%) intermediate, and six (1\%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95\% CI 9·93–117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20–38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32–20·7) or intermediate or high-level (aOR 13·4, 4·55–39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance. Interpretation Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART. Funding US National Institutes of Health, Swiss National Science Foundation.",

author = "Loosli, \{Tom O\} and Stefanie Hossmann and Ingle, \{Suzanne M\} and Hajra Okhai and Katharina Kusejko and Johannes Mouton and Pantxika Bellecave and \{van Sighem\}, Ard and Melanie Stecher and Monforte, \{Antonella D'Arminio\} and Gill, \{M John\} and Sabin, \{Caroline A\} and Gary Maartens and G{\"u}nthard, \{Huldrych F\} and Sterne, \{Jonathan A C\} and Richard Lessells and Egger, \{Matthias E\} and Kouyos, \{Roger D\}",

note = "Funding Information: We thank Anthony Hauser, Suraj Balakrishna, and Marius Zeeb for helpful discussions on data analysis. This study was supported by the NIH National Institute of Allergy and Infectious Diseases under award number R01AI152772 and the Swiss National Science Foundation (32FP30\_207285, 324730\_207957). The participating cohorts or cohort collaborations were funded by the Swiss National Science Foundation (33CS30\_201369) and the Yvonne Jacob Foundation (for the SHCS), the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1; for the UK Collaborative HIV Cohort), the National Agency for AIDS Research (France REcherche Nord\&Sud Sida-hiv H{\'e}patites), the French Agency for Research on AIDS and Viral Hepatitis | Emerging Infectious Diseases (ANRS|MIE), and the CHU de Bordeaux (for the ANRS CO3 Aquitaine-AquiVIH-NA cohort), the Dutch Ministry of Health (for the ATHENA cohort), and the German Center for Infection Research (8018704707; for the CBC). The ICONA Foundation is supported by unrestricted grants from BMS, Gilead Sciences, Janssen, MSD, and ViiV Healthcare. AfA is supported via IeDEA-SA by the following NIH institutes: the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Fogarty International Center under award number U01AI069924. The ART-CC is funded by the NIH National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: {\textcopyright} 2023 Elsevier Ltd",

year = "2023",

month = nov,

day = "1",

doi = "10.1016/S2352-3018(23)00228-X",

language = "English",

volume = "10",

pages = "e733--e741",

journal = "The Lancet HIV",

issn = "2405-4704",

publisher = "Elsevier Limited",

number = "11",

}

Loosli, TO, Hossmann, S, Ingle, SM, Okhai, H, Kusejko, K, Mouton, J, Bellecave, P, van Sighem, A, Stecher, M, Monforte, ADA, Gill, MJ, Sabin, CA, Maartens, G, Günthard, HF, Sterne, JAC, Lessells, R, Egger, ME & Kouyos, RD 2023, 'HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis', The Lancet HIV, vol. 10, no. 11, pp. e733-e741. https://doi.org/10.1016/S2352-3018(23)00228-X

TY - JOUR

T1 - HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy

T2 - a collaborative cohort analysis

AU - Loosli, Tom O

AU - Hossmann, Stefanie

AU - Ingle, Suzanne M

AU - Okhai, Hajra

AU - Kusejko, Katharina

AU - Mouton, Johannes

AU - Bellecave, Pantxika

AU - van Sighem, Ard

AU - Stecher, Melanie

AU - Monforte, Antonella D'Arminio

AU - Gill, M John

AU - Sabin, Caroline A

AU - Maartens, Gary

AU - Günthard, Huldrych F

AU - Sterne, Jonathan A C

AU - Lessells, Richard

AU - Egger, Matthias E

AU - Kouyos, Roger D

N1 - Funding Information: We thank Anthony Hauser, Suraj Balakrishna, and Marius Zeeb for helpful discussions on data analysis. This study was supported by the NIH National Institute of Allergy and Infectious Diseases under award number R01AI152772 and the Swiss National Science Foundation (32FP30_207285, 324730_207957). The participating cohorts or cohort collaborations were funded by the Swiss National Science Foundation (33CS30_201369) and the Yvonne Jacob Foundation (for the SHCS), the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1; for the UK Collaborative HIV Cohort), the National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Agency for Research on AIDS and Viral Hepatitis | Emerging Infectious Diseases (ANRS|MIE), and the CHU de Bordeaux (for the ANRS CO3 Aquitaine-AquiVIH-NA cohort), the Dutch Ministry of Health (for the ATHENA cohort), and the German Center for Infection Research (8018704707; for the CBC). The ICONA Foundation is supported by unrestricted grants from BMS, Gilead Sciences, Janssen, MSD, and ViiV Healthcare. AfA is supported via IeDEA-SA by the following NIH institutes: the National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Fogarty International Center under award number U01AI069924. The ART-CC is funded by the NIH National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Publisher Copyright: © 2023 Elsevier Ltd

PY - 2023/11/1

Y1 - 2023/11/1

N2 - Background The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance. Methods We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models. Findings We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59%), a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual therapy, and 18 (3%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most (n=563, 94%) were susceptible to dolutegravir, seven (1%) had potential low, six (1%) low, 17 (3%) intermediate, and six (1%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95% CI 9·93–117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20–38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32–20·7) or intermediate or high-level (aOR 13·4, 4·55–39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance. Interpretation Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART. Funding US National Institutes of Health, Swiss National Science Foundation.

AB - Background The widespread use of the integrase strand transfer inhibitor (INSTI) dolutegravir in first-line and second-line antiretroviral therapy (ART) might facilitate emerging resistance. The DTG RESIST study combined data from HIV cohorts to examine patterns of drug resistance mutations (DRMs) and identify risk factors for dolutegravir resistance. Methods We included cohorts with INSTI resistance data from two collaborations (ART Cohort Collaboration, International epidemiology Databases to Evaluate AIDS in Southern Africa), and the UK Collaborative HIV Cohort. Eight cohorts from Canada, France, Germany, Italy, the Netherlands, Switzerland, South Africa, and the UK contributed data on individuals who were viraemic on dolutegravir-based ART and underwent genotypic resistance testing. Individuals with unknown dolutegravir initiation date were excluded. Resistance levels were categorised using the Stanford algorithm. We identified risk factors for resistance using mixed-effects ordinal logistic regression models. Findings We included 599 people with genotypic resistance testing on dolutegravir-based ART between May 22, 2013, and Dec 20, 2021. Most had HIV-1 subtype B (n=351, 59%), a third had been exposed to first-generation INSTIs (n=193, 32%), 70 (12%) were on dolutegravir dual therapy, and 18 (3%) were on dolutegravir monotherapy. INSTI DRMs were detected in 86 (14%) individuals; 20 (3%) had more than one mutation. Most (n=563, 94%) were susceptible to dolutegravir, seven (1%) had potential low, six (1%) low, 17 (3%) intermediate, and six (1%) high-level dolutegravir resistance. The risk of dolutegravir resistance was higher on dolutegravir monotherapy (adjusted odds ratio [aOR] 34·1, 95% CI 9·93–117) and dolutegravir plus lamivudine dual therapy (aOR 9·21, 2·20–38·6) compared with combination ART, and in the presence of potential low or low (aOR 5·23, 1·32–20·7) or intermediate or high-level (aOR 13·4, 4·55–39·7) nucleoside reverse transcriptase inhibitor (NRTI) resistance. Interpretation Among people with viraemia on dolutegravir-based ART, INSTI DRMs and dolutegravir resistance were rare. NRTI resistance substantially increased the risk of dolutegravir resistance, which is of concern, notably in resource-limited settings. Monitoring is important to prevent resistance at the individual and population level and ensure the long-term sustainability of ART. Funding US National Institutes of Health, Swiss National Science Foundation.

U2 - 10.1016/S2352-3018(23)00228-X

DO - 10.1016/S2352-3018(23)00228-X

M3 - Article (Academic Journal)

C2 - 37832567

SN - 2405-4704

VL - 10

SP - e733-e741

JO - The Lancet HIV

JF - The Lancet HIV

IS - 11

ER -

HIV-1 drug resistance in people on dolutegravir-based antiretroviral therapy: a collaborative cohort analysis

Abstract

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