Association Between Bilirubin, Atazanavir, and Cardiovascular Disease Events Among People Living With HIV Across the United States

Heidi M. Crane, Robin M. Nance, Susan R. Heckbert, Corey Ritchings, Lisa Rosenblatt, Matthew Budoff, Brian R. Wood, David L. Tirschwell, H. Nina Kim, William C. Mathews, Elvin Geng, Richard D. Moore, Peter W. Hunt, Joseph J. Eron, Greer A. Burkholder, Daniel R. Drozd, Felicia C. Chow, Kyra J. Becker, Joseph R. Zunt, Emily L. HoRizwan Kalani, Andrew Huffer, Bridget M. Whitney, Michael S. Saag, Mari M. Kitahata, Joseph A.C. Delaney

Research output: Contribution to journalArticle

Abstract

Objective: Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is associated with decreased cardiovascular events in HIV-uninfected populations. We examined these associations in people living with HIV (PLWH). Methods: Potential myocardial infarctions (MIs) and strokes were centrally adjudicated. We examined MI types: type 1 MI (T1MI) from atherosclerotic plaque instability and type 2 MI (T2MI) in the setting of oxygen demand/supply mismatch such as sepsis. We used multivariable Cox regression analyses to determine associations between total bilirubin levels and outcomes adjusting for traditional and HIV-specific risk factors. To minimize confounding by hepatobiliary disease, we conducted analyses limited to bilirubin values <2.1 mg/dL; among those with fibrosis-4 values <3.25; and among everyone. We repeated analyses stratified by hepatitis C status and time-updated atazanavir use. Results: Among 25,816 PLWH, there were 392 T1MI and 356 T2MI during follow-up. Adjusted hazard ratios for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. By contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (hazard ratio 0.56:0.33-1.00). Higher bilirubin levels among those on atazanavir were associated with fewer T1MI combined with ischemic stroke. Limitations: Analyses were conducted with total rather than unconjugated bilirubin. Conclusions: Among PLWH, higher bilirubin levels were associated with T2MI among some subgroups. However, among those on atazanavir, there was a protective association between bilirubin and T2MI. These findings demonstrate different associations between outcomes and elevated bilirubin due to diverse causes and the importance of distinguishing MI types.

Original languageEnglish (US)
Pages (from-to)E141-E147
JournalJournal of Acquired Immune Deficiency Syndromes
Volume81
Issue number5
DOIs
StatePublished - Aug 15 2019

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Bilirubin
Cardiovascular Diseases
HIV
Myocardial Infarction
Atazanavir Sulfate
Stroke
Atherosclerotic Plaques
Hepatitis C
Sepsis
Fibrosis
Antioxidants
Regression Analysis
Oxygen
Lipids

Keywords

  • atazanavir
  • bilirubin
  • cardiovascular disease
  • HIV
  • myocardial infarction
  • stroke

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Association Between Bilirubin, Atazanavir, and Cardiovascular Disease Events Among People Living With HIV Across the United States. / Crane, Heidi M.; Nance, Robin M.; Heckbert, Susan R.; Ritchings, Corey; Rosenblatt, Lisa; Budoff, Matthew; Wood, Brian R.; Tirschwell, David L.; Kim, H. Nina; Mathews, William C.; Geng, Elvin; Moore, Richard D.; Hunt, Peter W.; Eron, Joseph J.; Burkholder, Greer A.; Drozd, Daniel R.; Chow, Felicia C.; Becker, Kyra J.; Zunt, Joseph R.; Ho, Emily L.; Kalani, Rizwan; Huffer, Andrew; Whitney, Bridget M.; Saag, Michael S.; Kitahata, Mari M.; Delaney, Joseph A.C.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 81, No. 5, 15.08.2019, p. E141-E147.

Research output: Contribution to journalArticle

Crane, HM, Nance, RM, Heckbert, SR, Ritchings, C, Rosenblatt, L, Budoff, M, Wood, BR, Tirschwell, DL, Kim, HN, Mathews, WC, Geng, E, Moore, RD, Hunt, PW, Eron, JJ, Burkholder, GA, Drozd, DR, Chow, FC, Becker, KJ, Zunt, JR, Ho, EL, Kalani, R, Huffer, A, Whitney, BM, Saag, MS, Kitahata, MM & Delaney, JAC 2019, 'Association Between Bilirubin, Atazanavir, and Cardiovascular Disease Events Among People Living With HIV Across the United States', Journal of Acquired Immune Deficiency Syndromes, vol. 81, no. 5, pp. E141-E147. https://doi.org/10.1097/QAI.0000000000002071
Crane, Heidi M. ; Nance, Robin M. ; Heckbert, Susan R. ; Ritchings, Corey ; Rosenblatt, Lisa ; Budoff, Matthew ; Wood, Brian R. ; Tirschwell, David L. ; Kim, H. Nina ; Mathews, William C. ; Geng, Elvin ; Moore, Richard D. ; Hunt, Peter W. ; Eron, Joseph J. ; Burkholder, Greer A. ; Drozd, Daniel R. ; Chow, Felicia C. ; Becker, Kyra J. ; Zunt, Joseph R. ; Ho, Emily L. ; Kalani, Rizwan ; Huffer, Andrew ; Whitney, Bridget M. ; Saag, Michael S. ; Kitahata, Mari M. ; Delaney, Joseph A.C. / Association Between Bilirubin, Atazanavir, and Cardiovascular Disease Events Among People Living With HIV Across the United States. In: Journal of Acquired Immune Deficiency Syndromes. 2019 ; Vol. 81, No. 5. pp. E141-E147.
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T1 - Association Between Bilirubin, Atazanavir, and Cardiovascular Disease Events Among People Living With HIV Across the United States

AU - Crane, Heidi M.

AU - Nance, Robin M.

AU - Heckbert, Susan R.

AU - Ritchings, Corey

AU - Rosenblatt, Lisa

AU - Budoff, Matthew

AU - Wood, Brian R.

AU - Tirschwell, David L.

AU - Kim, H. Nina

AU - Mathews, William C.

AU - Geng, Elvin

AU - Moore, Richard D.

AU - Hunt, Peter W.

AU - Eron, Joseph J.

AU - Burkholder, Greer A.

AU - Drozd, Daniel R.

AU - Chow, Felicia C.

AU - Becker, Kyra J.

AU - Zunt, Joseph R.

AU - Ho, Emily L.

AU - Kalani, Rizwan

AU - Huffer, Andrew

AU - Whitney, Bridget M.

AU - Saag, Michael S.

AU - Kitahata, Mari M.

AU - Delaney, Joseph A.C.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - Objective: Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is associated with decreased cardiovascular events in HIV-uninfected populations. We examined these associations in people living with HIV (PLWH). Methods: Potential myocardial infarctions (MIs) and strokes were centrally adjudicated. We examined MI types: type 1 MI (T1MI) from atherosclerotic plaque instability and type 2 MI (T2MI) in the setting of oxygen demand/supply mismatch such as sepsis. We used multivariable Cox regression analyses to determine associations between total bilirubin levels and outcomes adjusting for traditional and HIV-specific risk factors. To minimize confounding by hepatobiliary disease, we conducted analyses limited to bilirubin values <2.1 mg/dL; among those with fibrosis-4 values <3.25; and among everyone. We repeated analyses stratified by hepatitis C status and time-updated atazanavir use. Results: Among 25,816 PLWH, there were 392 T1MI and 356 T2MI during follow-up. Adjusted hazard ratios for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. By contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (hazard ratio 0.56:0.33-1.00). Higher bilirubin levels among those on atazanavir were associated with fewer T1MI combined with ischemic stroke. Limitations: Analyses were conducted with total rather than unconjugated bilirubin. Conclusions: Among PLWH, higher bilirubin levels were associated with T2MI among some subgroups. However, among those on atazanavir, there was a protective association between bilirubin and T2MI. These findings demonstrate different associations between outcomes and elevated bilirubin due to diverse causes and the importance of distinguishing MI types.

AB - Objective: Bilirubin is an antioxidant that may suppress lipid oxidation. Elevated bilirubin is associated with decreased cardiovascular events in HIV-uninfected populations. We examined these associations in people living with HIV (PLWH). Methods: Potential myocardial infarctions (MIs) and strokes were centrally adjudicated. We examined MI types: type 1 MI (T1MI) from atherosclerotic plaque instability and type 2 MI (T2MI) in the setting of oxygen demand/supply mismatch such as sepsis. We used multivariable Cox regression analyses to determine associations between total bilirubin levels and outcomes adjusting for traditional and HIV-specific risk factors. To minimize confounding by hepatobiliary disease, we conducted analyses limited to bilirubin values <2.1 mg/dL; among those with fibrosis-4 values <3.25; and among everyone. We repeated analyses stratified by hepatitis C status and time-updated atazanavir use. Results: Among 25,816 PLWH, there were 392 T1MI and 356 T2MI during follow-up. Adjusted hazard ratios for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. By contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (hazard ratio 0.56:0.33-1.00). Higher bilirubin levels among those on atazanavir were associated with fewer T1MI combined with ischemic stroke. Limitations: Analyses were conducted with total rather than unconjugated bilirubin. Conclusions: Among PLWH, higher bilirubin levels were associated with T2MI among some subgroups. However, among those on atazanavir, there was a protective association between bilirubin and T2MI. These findings demonstrate different associations between outcomes and elevated bilirubin due to diverse causes and the importance of distinguishing MI types.

KW - atazanavir

KW - bilirubin

KW - cardiovascular disease

KW - HIV

KW - myocardial infarction

KW - stroke

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