Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study

for the INSIGHT START Study Group

doi:10.1111/hiv.13038

Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study

for the INSIGHT START Study Group

Biostatistics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Objectives: The aim of this analysis was to characterize transmitted drug resistance (TDR) in Strategic Timing of Antiretroviral Treatment (START) study participants by next-generation sequencing (NGS), a sensitive assay capable of detecting low-frequency variants. Methods: Stored plasma from participants with entry HIV RNA > 1000 copies/mL were analysed by NGS (Illumina MiSeq). TDR was based on the WHO 2009 surveillance definition with the addition of reverse transcriptase (RT) mutations T215N and E138K, and integrase strand transfer inhibitor (INSTI) surveillance mutations (Stanford HIVdb). Drug resistance mutations (DRMs) detected at three thresholds are reported: > 2%, 5% and 20% of the viral population. Results: Between 2009 and 2013, START enrolled 4684 antiretroviral therapy (ART)-naïve individuals in 35 countries. Baseline NGS data at study entry were available for 2902 participants. Overall prevalence rates of TDR using a detection threshold of 2%/5%/20% were 9.2%/5.6%/3.2% for nucleoside reverse transcriptase inhibitors (NRTIs), 9.2%/6.6%/4.9% for non-NRTIs, 11.4%/5.5%/2.4% for protease inhibitors (PIs) and 3.5%/1.6%/0.1% for INSTI DRMs and varied by geographic region. Using the 2% detection threshold, individual DRMs with the highest prevalence were: PI M46IL (5.5%), RT K103NS (3.5%), RT G190ASE (3.1%), T215ISCDVEN (2.5%), RT M41L (2.2%), RT K219QENR (1.7%) and PI D30N (1.6%). INSTI DRMs were detected almost exclusively below the 20% detection threshold, most commonly Y143H (0.4%), Q148R (0.4%) and T66I (0.4%). Conclusions: Use of NGS in this study population resulted in the detection of a large proportion of low-level variants which would not have been detected by traditional Sanger sequencing. Global surveillance studies utilizing NGS should provide a more comprehensive assessment of TDR prevalence in different regions of the world.

Original language	English (US)
Pages (from-to)	360-371
Number of pages	12
Journal	HIV Medicine
Volume	22
Issue number	5
DOIs	https://doi.org/10.1111/hiv.13038
State	Published - May 2021

Bibliographical note

Funding Information:
We wish to thank the study participants and clinical staff of the START trial (see Initiation of antiretroviral therapy in early asymptomatic individuals, New England Journal of Medicine 2015:373:794-807 for a complete list of START investigators [14]). Conflict of interest: JDB serves as a consultant for Quest Diagnostics. Yale University receives grants from Gilead and ViiV for which MJK serves as the Principal Investigator. Financial disclosure: The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH, grants UM1-AI068641, UM1-AI120197 and 1U01-AI36780), National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les H?patites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium f?r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (UK), National Institute for Health Research, National Health Service (UK), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Author contributions JDB drafted the first version of the manuscript with support from DD, AT and RLM. DD and AT were primarily responsible for performing the statistical analyses. All authors reviewed the study data and provided comments and approval prior to manuscript submission.

Funding Information:
The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH, grants UM1‐AI068641, UM1‐AI120197 and 1U01‐AI36780), National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (UK), National Institute for Health Research, National Health Service (UK), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol‐Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Financial disclosure:

Publisher Copyright:
© 2020 British HIV Association

Keywords

HIV
HIV drug resistance
antiretroviral therapy
next-generation sequencing

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/hiv.13038

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@article{0e5133eb0b5a40ecb80b219b5a2a3f13,

title = "Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study",

abstract = "Objectives: The aim of this analysis was to characterize transmitted drug resistance (TDR) in Strategic Timing of Antiretroviral Treatment (START) study participants by next-generation sequencing (NGS), a sensitive assay capable of detecting low-frequency variants. Methods: Stored plasma from participants with entry HIV RNA > 1000 copies/mL were analysed by NGS (Illumina MiSeq). TDR was based on the WHO 2009 surveillance definition with the addition of reverse transcriptase (RT) mutations T215N and E138K, and integrase strand transfer inhibitor (INSTI) surveillance mutations (Stanford HIVdb). Drug resistance mutations (DRMs) detected at three thresholds are reported: > 2%, 5% and 20% of the viral population. Results: Between 2009 and 2013, START enrolled 4684 antiretroviral therapy (ART)-na{\"i}ve individuals in 35 countries. Baseline NGS data at study entry were available for 2902 participants. Overall prevalence rates of TDR using a detection threshold of 2%/5%/20% were 9.2%/5.6%/3.2% for nucleoside reverse transcriptase inhibitors (NRTIs), 9.2%/6.6%/4.9% for non-NRTIs, 11.4%/5.5%/2.4% for protease inhibitors (PIs) and 3.5%/1.6%/0.1% for INSTI DRMs and varied by geographic region. Using the 2% detection threshold, individual DRMs with the highest prevalence were: PI M46IL (5.5%), RT K103NS (3.5%), RT G190ASE (3.1%), T215ISCDVEN (2.5%), RT M41L (2.2%), RT K219QENR (1.7%) and PI D30N (1.6%). INSTI DRMs were detected almost exclusively below the 20% detection threshold, most commonly Y143H (0.4%), Q148R (0.4%) and T66I (0.4%). Conclusions: Use of NGS in this study population resulted in the detection of a large proportion of low-level variants which would not have been detected by traditional Sanger sequencing. Global surveillance studies utilizing NGS should provide a more comprehensive assessment of TDR prevalence in different regions of the world.",

keywords = "HIV, HIV drug resistance, antiretroviral therapy, next-generation sequencing",

author = "{for the INSIGHT START Study Group} and Baxter, {J. D.} and D. Dunn and A. Tostevin and Marvig, {R. L.} and M. Bennedb{\ae}k and A. Cozzi-Lepri and S. Sharma and Kozal, {M. J.} and M. Gompels and Pinto, {A. N.} and J. Lundgren",

note = "Funding Information: We wish to thank the study participants and clinical staff of the START trial (see Initiation of antiretroviral therapy in early asymptomatic individuals, New England Journal of Medicine 2015:373:794-807 for a complete list of START investigators [14]). Conflict of interest: JDB serves as a consultant for Quest Diagnostics. Yale University receives grants from Gilead and ViiV for which MJK serves as the Principal Investigator. Financial disclosure: The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH, grants UM1-AI068641, UM1-AI120197 and 1U01-AI36780), National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les H?patites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium f?r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (UK), National Institute for Health Research, National Health Service (UK), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Author contributions JDB drafted the first version of the manuscript with support from DD, AT and RLM. DD and AT were primarily responsible for performing the statistical analyses. All authors reviewed the study data and provided comments and approval prior to manuscript submission. Funding Information: The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH, grants UM1‐AI068641, UM1‐AI120197 and 1U01‐AI36780), National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les H{\'e}patites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium f{\"u}r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (UK), National Institute for Health Research, National Health Service (UK), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol‐Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Financial disclosure: Publisher Copyright: {\textcopyright} 2020 British HIV Association",

year = "2021",

month = may,

doi = "10.1111/hiv.13038",

language = "English (US)",

volume = "22",

pages = "360--371",

journal = "HIV Medicine",

issn = "1464-2662",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "5",

}

TY - JOUR

T1 - Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing

T2 - results from the Strategic Timing of Antiretroviral Treatment (START) study

AU - for the INSIGHT START Study Group

AU - Baxter, J. D.

AU - Dunn, D.

AU - Tostevin, A.

AU - Marvig, R. L.

AU - Bennedbæk, M.

AU - Cozzi-Lepri, A.

AU - Sharma, S.

AU - Kozal, M. J.

AU - Gompels, M.

AU - Pinto, A. N.

AU - Lundgren, J.

N1 - Funding Information: We wish to thank the study participants and clinical staff of the START trial (see Initiation of antiretroviral therapy in early asymptomatic individuals, New England Journal of Medicine 2015:373:794-807 for a complete list of START investigators [14]). Conflict of interest: JDB serves as a consultant for Quest Diagnostics. Yale University receives grants from Gilead and ViiV for which MJK serves as the Principal Investigator. Financial disclosure: The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH, grants UM1-AI068641, UM1-AI120197 and 1U01-AI36780), National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les H?patites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium f?r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (UK), National Institute for Health Research, National Health Service (UK), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Author contributions JDB drafted the first version of the manuscript with support from DD, AT and RLM. DD and AT were primarily responsible for performing the statistical analyses. All authors reviewed the study data and provided comments and approval prior to manuscript submission. Funding Information: The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Health (NIH, grants UM1‐AI068641, UM1‐AI120197 and 1U01‐AI36780), National Institutes of Health Clinical Center, National Cancer Institute, National Heart, Lung, and Blood Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Agence Nationale de Recherches sur le SIDA et les Hépatites Virales (France), National Health and Medical Research Council (Australia), National Research Foundation (Denmark), Bundes ministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (UK), National Institute for Health Research, National Health Service (UK), and University of Minnesota. Antiretroviral drugs were donated to the central drug repository by AbbVie, Bristol‐Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Financial disclosure: Publisher Copyright: © 2020 British HIV Association

PY - 2021/5

Y1 - 2021/5

N2 - Objectives: The aim of this analysis was to characterize transmitted drug resistance (TDR) in Strategic Timing of Antiretroviral Treatment (START) study participants by next-generation sequencing (NGS), a sensitive assay capable of detecting low-frequency variants. Methods: Stored plasma from participants with entry HIV RNA > 1000 copies/mL were analysed by NGS (Illumina MiSeq). TDR was based on the WHO 2009 surveillance definition with the addition of reverse transcriptase (RT) mutations T215N and E138K, and integrase strand transfer inhibitor (INSTI) surveillance mutations (Stanford HIVdb). Drug resistance mutations (DRMs) detected at three thresholds are reported: > 2%, 5% and 20% of the viral population. Results: Between 2009 and 2013, START enrolled 4684 antiretroviral therapy (ART)-naïve individuals in 35 countries. Baseline NGS data at study entry were available for 2902 participants. Overall prevalence rates of TDR using a detection threshold of 2%/5%/20% were 9.2%/5.6%/3.2% for nucleoside reverse transcriptase inhibitors (NRTIs), 9.2%/6.6%/4.9% for non-NRTIs, 11.4%/5.5%/2.4% for protease inhibitors (PIs) and 3.5%/1.6%/0.1% for INSTI DRMs and varied by geographic region. Using the 2% detection threshold, individual DRMs with the highest prevalence were: PI M46IL (5.5%), RT K103NS (3.5%), RT G190ASE (3.1%), T215ISCDVEN (2.5%), RT M41L (2.2%), RT K219QENR (1.7%) and PI D30N (1.6%). INSTI DRMs were detected almost exclusively below the 20% detection threshold, most commonly Y143H (0.4%), Q148R (0.4%) and T66I (0.4%). Conclusions: Use of NGS in this study population resulted in the detection of a large proportion of low-level variants which would not have been detected by traditional Sanger sequencing. Global surveillance studies utilizing NGS should provide a more comprehensive assessment of TDR prevalence in different regions of the world.

AB - Objectives: The aim of this analysis was to characterize transmitted drug resistance (TDR) in Strategic Timing of Antiretroviral Treatment (START) study participants by next-generation sequencing (NGS), a sensitive assay capable of detecting low-frequency variants. Methods: Stored plasma from participants with entry HIV RNA > 1000 copies/mL were analysed by NGS (Illumina MiSeq). TDR was based on the WHO 2009 surveillance definition with the addition of reverse transcriptase (RT) mutations T215N and E138K, and integrase strand transfer inhibitor (INSTI) surveillance mutations (Stanford HIVdb). Drug resistance mutations (DRMs) detected at three thresholds are reported: > 2%, 5% and 20% of the viral population. Results: Between 2009 and 2013, START enrolled 4684 antiretroviral therapy (ART)-naïve individuals in 35 countries. Baseline NGS data at study entry were available for 2902 participants. Overall prevalence rates of TDR using a detection threshold of 2%/5%/20% were 9.2%/5.6%/3.2% for nucleoside reverse transcriptase inhibitors (NRTIs), 9.2%/6.6%/4.9% for non-NRTIs, 11.4%/5.5%/2.4% for protease inhibitors (PIs) and 3.5%/1.6%/0.1% for INSTI DRMs and varied by geographic region. Using the 2% detection threshold, individual DRMs with the highest prevalence were: PI M46IL (5.5%), RT K103NS (3.5%), RT G190ASE (3.1%), T215ISCDVEN (2.5%), RT M41L (2.2%), RT K219QENR (1.7%) and PI D30N (1.6%). INSTI DRMs were detected almost exclusively below the 20% detection threshold, most commonly Y143H (0.4%), Q148R (0.4%) and T66I (0.4%). Conclusions: Use of NGS in this study population resulted in the detection of a large proportion of low-level variants which would not have been detected by traditional Sanger sequencing. Global surveillance studies utilizing NGS should provide a more comprehensive assessment of TDR prevalence in different regions of the world.

KW - HIV

KW - HIV drug resistance

KW - antiretroviral therapy

KW - next-generation sequencing

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Transmitted HIV-1 drug resistance in a large international cohort using next-generation sequencing: results from the Strategic Timing of Antiretroviral Treatment (START) study

Abstract

Bibliographical note

Keywords

UN SDGs

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