The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies

Christina Ekenberg; Joanne Reekie; Adrian G. Zucco; Daniel D. Murray; Shweta Sharma; Cameron R. Macpherson; Abdel Babiker; Virginia Kan; H. Clifford Lane; James D. Neaton; Jens D. Lundgren

doi:10.1097/QAD.0000000000002800

The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies

Christina Ekenberg, Joanne Reekie, Adrian G. Zucco, Daniel D. Murray, Shweta Sharma, Cameron R. Macpherson, Abdel Babiker, Virginia Kan, H. Clifford Lane, James D. Neaton, Jens D. Lundgren

Biostatistics

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

1 Scopus citations

Abstract

Objectives:The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals.Design:Cohort study.Methods:In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4⁺T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini - Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05).Results:Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB106:04 and HLA-DRB113:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B15:17 and HLA-DPB115:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less.Conclusion:This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4⁺T-cell count.

Original language	English (US)
Pages (from-to)	783-789
Number of pages	7
Journal	AIDS
Volume	35
Issue number	5
DOIs	https://doi.org/10.1097/QAD.0000000000002800
State	Published - Apr 1 2021

Bibliographical note

Funding Information:
Source of funding: this work was supported by National Institutes of Health [grant numbers U01AI068641, U01AI042170, and U01AI046362 (SMART); UM1-AI068641 and UM1-AI120197 (START)]. The START trial was supported by the National Institute of Allergy and Infectious Diseases, 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 fur Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and the 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. The present study was also supported by the Danish National Research Foundation (grant number DNRF126).

Publisher Copyright:
© 2021 Lippincott Williams and Wilkins. All rights reserved.

Keywords

HIV-1
disease progression
host genetics
human leukocyte antigen
immune dysfunction

UN SDGs

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Ekenberg, C., Reekie, J., Zucco, A. G., Murray, D. D., Sharma, S., Macpherson, C. R., Babiker, A., Kan, V., Lane, H. C., Neaton, J. D., & Lundgren, J. D. (2021). The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies. AIDS, 35(5), 783-789. https://doi.org/10.1097/QAD.0000000000002800

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abstract = "Objectives:The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals.Design:Cohort study.Methods:In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4+T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini - Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05).Results:Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB106:04 and HLA-DRB113:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B15:17 and HLA-DPB115:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less.Conclusion:This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4+T-cell count.",

keywords = "HIV-1, disease progression, host genetics, human leukocyte antigen, immune dysfunction",

author = "Christina Ekenberg and Joanne Reekie and Zucco, {Adrian G.} and Murray, {Daniel D.} and Shweta Sharma and Macpherson, {Cameron R.} and Abdel Babiker and Virginia Kan and Lane, {H. Clifford} and Neaton, {James D.} and Lundgren, {Jens D.}",

note = "Funding Information: Source of funding: this work was supported by National Institutes of Health [grant numbers U01AI068641, U01AI042170, and U01AI046362 (SMART); UM1-AI068641 and UM1-AI120197 (START)]. The START trial was supported by the National Institute of Allergy and Infectious Diseases, 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 fur Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and the 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. The present study was also supported by the Danish National Research Foundation (grant number DNRF126). Publisher Copyright: {\textcopyright} 2021 Lippincott Williams and Wilkins. All rights reserved.",

year = "2021",

month = apr,

day = "1",

doi = "10.1097/QAD.0000000000002800",

language = "English (US)",

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pages = "783--789",

journal = "AIDS",

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TY - JOUR

T1 - The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies

AU - Ekenberg, Christina

AU - Reekie, Joanne

AU - Zucco, Adrian G.

AU - Murray, Daniel D.

AU - Sharma, Shweta

AU - Macpherson, Cameron R.

AU - Babiker, Abdel

AU - Kan, Virginia

AU - Lane, H. Clifford

AU - Neaton, James D.

AU - Lundgren, Jens D.

N1 - Funding Information: Source of funding: this work was supported by National Institutes of Health [grant numbers U01AI068641, U01AI042170, and U01AI046362 (SMART); UM1-AI068641 and UM1-AI120197 (START)]. The START trial was supported by the National Institute of Allergy and Infectious Diseases, 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 fur Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and the 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. The present study was also supported by the Danish National Research Foundation (grant number DNRF126). Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.

PY - 2021/4/1

Y1 - 2021/4/1

N2 - Objectives:The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals.Design:Cohort study.Methods:In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4+T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini - Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05).Results:Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB106:04 and HLA-DRB113:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B15:17 and HLA-DPB115:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less.Conclusion:This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4+T-cell count.

AB - Objectives:The Strategic Timing of AntiRetroviral Treatment (START) and Strategies for Management of Antiretroviral Therapy (SMART) trials demonstrated that ART can partly reverse clinically defined immune dysfunction induced by HIV replication. As control of HIV replication is influenced by the HLA region, we explored whether HLA alleles independently influence the risk of clinical events in HIV+ individuals.Design:Cohort study.Methods:In START and SMART participants, associations between imputed HLA alleles and AIDS, infection-related cancer, herpes virus-related AIDS events, chronic inflammation-related conditions, and bacterial pneumonia were assessed. Cox regression was used to estimate hazard ratios for the risk of events among allele carriers versus noncarriers. Models were adjusted for sex, age, geography, race, time-updated CD4+T-cell counts and HIV viral load and stratified by treatment group within trials. HLA class I and II alleles were analyzed separately. The Benjamini - Hochberg procedure was used to limit the false discovery rate to less than 5% (i.e. q value <0.05).Results:Among 4829 participants, there were 132 AIDS events, 136 chronic inflammation-related conditions, 167 bacterial pneumonias, 45 infection-related cancers, and 49 herpes virus-related AIDS events. Several associations with q value less than 0.05 were found: HLA-DQB106:04 and HLA-DRB113:02 with AIDS (adjusted HR [95% CI] 2.63 [1.5-4.6] and 2.25 [1.4-3.7], respectively), HLA-B15:17 and HLA-DPB115:01 with bacterial pneumonia (4.93 [2.3-10.7] and 4.33 [2.0-9.3], respectively), and HLA-A69:01 with infection-related cancer (15.26 [3.5-66.7]). The carriage frequencies of these alleles were 10% or less.Conclusion:This hypothesis-generating study suggests that certain HLA alleles may influence the risk of immune dysfunction-related events irrespective of viral load and CD4+T-cell count.

KW - HIV-1

KW - disease progression

KW - host genetics

KW - human leukocyte antigen

KW - immune dysfunction

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The association of human leukocyte antigen alleles with clinical disease progression in HIV-positive cohorts with varied treatment strategies

Abstract

Bibliographical note

Keywords

UN SDGs

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