Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study

the INSIGHT START Study Group

doi:10.1002/jia2.25297

Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study

the INSIGHT START Study Group

Biostatistics

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

17 Scopus citations

Abstract

INTRODUCTION: Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study.

METHODS: Plasma levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein, serum amyloid A protein (SAA), IL-27, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, D-dimer and the CD4+/CD8+ T-cell ratio, were analysed at baseline and eight months after ART initiation in treatment-naïve participants with HIV and CD4+ T-cells >500 cells/mm 3 enrolled in the immediate arm of START. Adherence was assessed by seven-day self-report. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eight-month visit in participants who achieved virologic suppression (<50 copies/mL).

RESULTS: We evaluated 1627 participants (422 female) who achieved virologic suppression at the eight-month visit in the period between 2009 and 2013. Median (IQR) CD4+ T-cell count before ART was 651 (585, 769) cells/mm 3 . Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma IL-6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed.

CONCLUSIONS: Incomplete ART adherence was associated with higher IL-6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048.

Original language	English (US)
Article number	e25297
Journal	Journal of the International AIDS Society
Volume	22
Issue number	6
DOIs	https://doi.org/10.1002/jia2.25297
State	Published - Jun 2019

Bibliographical note

Funding Information:
The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium fu€r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck.

Funding Information:
The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. We thank the study participants for volunteering to this study. These data were partially presented at the 22nd International AIDS Conference (AIDS 2018), Amsterdam, Netherlands, 23 to 27 July 2018, Abstract number A-899-0147-05171. See N Engl J Med 2015; 373:795-807 for the complete list of START investigators. The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck.

Publisher Copyright:
© 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.

Keywords

START study
adherence
antiretroviral therapy
inflammation
inteleukin-6
serum amyloid A protein

UN SDGs

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

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10.1002/jia2.25297

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title = "Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study",

abstract = "INTRODUCTION: Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study.METHODS: Plasma levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein, serum amyloid A protein (SAA), IL-27, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, D-dimer and the CD4+/CD8+ T-cell ratio, were analysed at baseline and eight months after ART initiation in treatment-na{\"i}ve participants with HIV and CD4+ T-cells >500 cells/mm 3 enrolled in the immediate arm of START. Adherence was assessed by seven-day self-report. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eight-month visit in participants who achieved virologic suppression (<50 copies/mL). RESULTS: We evaluated 1627 participants (422 female) who achieved virologic suppression at the eight-month visit in the period between 2009 and 2013. Median (IQR) CD4+ T-cell count before ART was 651 (585, 769) cells/mm 3 . Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma IL-6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed. CONCLUSIONS: Incomplete ART adherence was associated with higher IL-6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048.",

keywords = "START study, adherence, antiretroviral therapy, inflammation, inteleukin-6, serum amyloid A protein",

author = "{the INSIGHT START Study Group} and Castillo-Mancilla, {Jose R.} and Phillips, {Andrew N.} and Neaton, {James D.} and Jim Neaton and Nordwall, {Jacqueline A} and Mistry, {Shweta S} and Simon Collins and Sharon Mannheimer and Sarah Pett and Veronique Touzeau-R{\"o}mer and Polizzotto, {Mark N.} and Lundgren, {Jens D.} and Gardner, {Edward M.}",

note = "Funding Information: The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium fu€r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Funding Information: The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium f{\"u}r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. We thank the study participants for volunteering to this study. These data were partially presented at the 22nd International AIDS Conference (AIDS 2018), Amsterdam, Netherlands, 23 to 27 July 2018, Abstract number A-899-0147-05171. See N Engl J Med 2015; 373:795-807 for the complete list of START investigators. The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium f{\"u}r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Publisher Copyright: {\textcopyright} 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.",

year = "2019",

month = jun,

doi = "10.1002/jia2.25297",

language = "English (US)",

volume = "22",

journal = "Journal of the International AIDS Society",

issn = "1758-2652",

publisher = "International AIDS Society",

number = "6",

}

TY - JOUR

T1 - Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study

AU - the INSIGHT START Study Group

AU - Castillo-Mancilla, Jose R.

AU - Phillips, Andrew N.

AU - Neaton, James D.

AU - Neaton, Jim

AU - Nordwall, Jacqueline A

AU - Mistry, Shweta S

AU - Collins, Simon

AU - Mannheimer, Sharon

AU - Pett, Sarah

AU - Touzeau-Römer, Veronique

AU - Polizzotto, Mark N.

AU - Lundgren, Jens D.

AU - Gardner, Edward M.

N1 - Funding Information: The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium fu€r Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Funding Information: The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. We thank the study participants for volunteering to this study. These data were partially presented at the 22nd International AIDS Conference (AIDS 2018), Amsterdam, Netherlands, 23 to 27 July 2018, Abstract number A-899-0147-05171. See N Engl J Med 2015; 373:795-807 for the complete list of START investigators. The START is primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under award numbers UM1-AI068641 and UMN1-AI120197, with additional support from the 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), Bundesministerium für Bildung und Forschung (Germany), European AIDS Treatment Network, Medical Research Council (United Kingdom), National Institute for Health Research, National Health Service (United Kingdom), and University of Minnesota. J.C.M. is supported by NIH/NIAID grants K23AI104315 and R21AI124859. S.L.P. was supported by MRC Core Funding (MC_UU_12023/23). Antiretroviral drugs for the START study were donated to the central drug repository by AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV Healthcare, Janssen Scientific Affairs, and Merck. Publisher Copyright: © 2019 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.

PY - 2019/6

Y1 - 2019/6

N2 - INTRODUCTION: Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study.METHODS: Plasma levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein, serum amyloid A protein (SAA), IL-27, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, D-dimer and the CD4+/CD8+ T-cell ratio, were analysed at baseline and eight months after ART initiation in treatment-naïve participants with HIV and CD4+ T-cells >500 cells/mm 3 enrolled in the immediate arm of START. Adherence was assessed by seven-day self-report. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eight-month visit in participants who achieved virologic suppression (<50 copies/mL). RESULTS: We evaluated 1627 participants (422 female) who achieved virologic suppression at the eight-month visit in the period between 2009 and 2013. Median (IQR) CD4+ T-cell count before ART was 651 (585, 769) cells/mm 3 . Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma IL-6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed. CONCLUSIONS: Incomplete ART adherence was associated with higher IL-6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048.

AB - INTRODUCTION: Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study.METHODS: Plasma levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein, serum amyloid A protein (SAA), IL-27, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, D-dimer and the CD4+/CD8+ T-cell ratio, were analysed at baseline and eight months after ART initiation in treatment-naïve participants with HIV and CD4+ T-cells >500 cells/mm 3 enrolled in the immediate arm of START. Adherence was assessed by seven-day self-report. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eight-month visit in participants who achieved virologic suppression (<50 copies/mL). RESULTS: We evaluated 1627 participants (422 female) who achieved virologic suppression at the eight-month visit in the period between 2009 and 2013. Median (IQR) CD4+ T-cell count before ART was 651 (585, 769) cells/mm 3 . Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma IL-6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed. CONCLUSIONS: Incomplete ART adherence was associated with higher IL-6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048.

KW - START study

KW - adherence

KW - antiretroviral therapy

KW - inflammation

KW - inteleukin-6

KW - serum amyloid A protein

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DO - 10.1002/jia2.25297

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JO - Journal of the International AIDS Society

JF - Journal of the International AIDS Society

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Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study

Abstract

Bibliographical note

Keywords

UN SDGs

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