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Association between bilirubin, atazanavir, and cardiovascular disease events among people living with HIV across the US.

Crane, Heidi M1; Nance, Robin M1; Heckbert, Susan R1; Ritchings, Corey2; Rosenblatt, Lisa2; Budoff, Matthew3; Wood, Brian R.1; Tirschwell, David L.1; Kim, H Nina1; Mathews, William C4; Geng, Elvin5; Moore, Richard D6; Hunt, Peter W5; Eron, Joseph J7; Burkholder, Greer A8; Drozd, Daniel R1; Chow, Felicia C.5; Becker, Kyra J.1; Zunt, Joseph R.1; Ho, Emily L.1; Kalani, Rizwan1; Huffer, Andrew1; Whitney, Bridget M.1; Saag, Michael S8; Kitahata, Mari M1; Delaney, Joseph AC1

JAIDS Journal of Acquired Immune Deficiency Syndromes: May 16, 2019 - Volume Publish Ahead of Print - Issue - p
doi: 10.1097/QAI.0000000000002071
Original Article: PDF Only

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 (MI) 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 (HR) for the association of higher bilirubin levels with T1MI were not significant. Higher bilirubin levels were associated with T2MI. In contrast, among PLWH on atazanavir, higher bilirubin levels were associated with fewer T2MI (HR 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.

Conclusion: 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.

1University of Washington, Seattle, WA, USA

2Bristol Myers Squibb, Princeton, NJ, USA

3University of California Los Angeles, Los Angeles, CA, USA

4University of California San Diego, San Diego, CA, USA

5University of California San Francisco, San Francisco, CA, USA

6Johns Hopkins University, Baltimore, MD, USA

7University of North Carolina, Chapel Hill, NC, USA

8University of Alabama, Birmingham, AL, USA

Presented in part at the 18th International Workshop on Comorbidities and Adverse Drug Reactions in HIV, New York

Conflicts of Interest and Source of Funding: This work was supported by Brystol-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: Dr. Hunt with Merck and Gilead, Dr. Burkholder with DefiniCare, Dr. Saag with BMS, Gilead, Merck, and ViiV, Dr. Moore with Medscape, Dr. Eron with Merck, ViiV, BMS, Abbvie, Gilead, Tibotec/Janssen, Dr. Drozd with Gilead, Dr. Crane with ViiV, and Dr. Budoff has consulted for General Electric. The following are affiliated with BMS: C Ritchings, L Rosenblatt.

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