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

Crane, Heidi M. MD, MPHa; Nance, Robin M. MPHa; Heckbert, Susan R. MD, PhDa; Ritchings, Corey PhDb; Rosenblatt, Lisa PhDb; Budoff, Matthew MDc; Wood, Brian R. MDa; Tirschwell, David L. MDa; Kim, H. Nina MDa; Mathews, William C. MDd; Geng, Elvin MDe; Moore, Richard D. MDf; Hunt, Peter W. MDe; Eron, Joseph J. MDg; Burkholder, Greer A. MDh; Drozd, Daniel R. MDa; Chow, Felicia C. MDe; Becker, Kyra J. MDa; Zunt, Joseph R. MDa; Ho, Emily L. MDa; Kalani, Rizwan MDa; Huffer, Andrew MDa; Whitney, Bridget M. MSa; Saag, Michael S. MDh; Kitahata, Mari M. MDa; Delaney, Joseph A. C. PhDi

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2019 - Volume 81 - Issue 5 - p e141–e147
doi: 10.1097/QAI.0000000000002071

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.

aDepartment of Medicine, University of Washington, Seattle, WA;

bBristol Myers Squibb, Princeton, NJ;

cDepartment of Medicine, University of California Los Angeles, Los Angeles, CA;

dDepartment of Medicine, University of California San Diego, San Diego, CA;

eDepartment of Medicine, University of California San Francisco, San Francisco, CA;

fDepartment of Medicine, Johns Hopkins University, Baltimore, MD;

gDepartment of Medicine, University of North Carolina, Chapel Hill, NC;

hDepartment of Medicine, University of Alabama, Birmingham, AL; and

iDepartment of Epidemiology, University of Washington, Seattle, WA.

Correspondence to: Heidi M. Crane, MD, MPH, University of Washington, Seattle, WA 98104 (e‐mail:

Supported by Bristol-Myers Squibb. Additional support came from the National Institute of Allergy and Infectious Diseases (CNICS R24 AI067039, UW CFAR NIAID Grant P30 AI027757; UNC CFAR Grant P30 AI50410, JHU CFAR Grant P30 AI094189, and UAB CFAR Grant P30 AI027767), the National Institute of Drug Abuse (U01DA036935) and the National Heart, Lung, and Blood Institute (R01HL126538) at the National Institutes of Health, and from the American Heart Association (13GRNT14560022). The following have received grant support or served as consultants or advisors: P.W.H. with Merck and Gilead, G.A.B. with DefiniCare, M.S.S. with BMS, Gilead, Merck, and ViiV, R.D.M. with Medscape, J.J.E. with Merck, ViiV, BMS, Abbvie, Gilead, and Tibotec/Janssen, D.R.D. with Gilead, H.M.C. with ViiV, and M.B. has consulted for General Electric. The following are affiliated with BMS: C.R. and L.R.

Presented in part at the 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV; September 2016; New York, NY.

The authors have no conflicts of interest to disclose.

Received April 15, 2018

Accepted March 11, 2019

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