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Higher Bilirubin Tied to Lower CVD Risk in Veterans With or Without HIV
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Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle
Mark Mascolini
Higher bilirubin levels appeared to protect HIV-positive and negative veterans from cardiovascular disease (CVD) in a 98,405-person analysis of the Veterans Aging Cohort Study (VACS). The association persisted after statistical adjustment for confounders and in veterans without liver disease.
High bilirubin may protect people from CVD by one or more mechanisms, including lowering lipids, reducing oxidative stress, and inhibiting platelet activation, note VACS investigators who conducted the new study. The HIV protease inhibitor atazanavir causes unconjugated hyperbilirubinemia and has been linked to lower cardiovascular biomarkers and slower carotid artery intima media thickness progression in ACTG protocol 5257/5260.
The researchers conducted this study to see whether higher total bilirubin is associated with lower rates of heart failure, acute myocardial infarction (AMI), ischemic stroke, or all three (labeled CVD) in veterans with and without HIV and to see if identified associations persist in HIV-positive veterans and those without liver disease.
The analysis included veterans free of CVD when they entered VACS and followed from their first visit after April 2003 (baseline) until a CVD event, death, their last study visit, or September 2012. The researchers counted new cases of heart failure, AMI, or stroke in medical records. They recorded total bilirubin closest to baseline, divided levels into quartiles (4 equal parts), and determined CVD incidence by quartile. Cox regression analysis to determine CVD risk adjusted for traditional cardiovascular risk factors, sociodemographic factors, liver fibrosis, and (in an HIV model) CD4 count, viral load, and antiretroviral regimen. A secondary analysis estimated CVD risk by HIV status.
The study group included 31,418 veterans with HIV and 66,987 without HIV. Age averaged 48 years overall, 97% of participants were men, and 48% were black. Through an average follow-up of 6 years, the investigators counted 3843 heart failures, 1931 AMIs, 2112 strokes, and 6603 total cases of CVD.
CVD incidence stood at 10.21 per 1000 person-years in HIV-negative veterans, 11.95 per 1000 in HIV-positive veterans not on ART, 13.02 per 1000 in HIV-positive veterans on ART including atazanavir, and 13.33 per 1000 in HIV-positive veterans on ART without atazanavir. The analysis did not have the power to assess the impact of atazanavir use on CVD incidence.
An adjusted model determined that, compared with CVD incidence in the lowest bilirubin quartile (0.4 mg/dL or lower), incidence was significantly lower in the second quartile (0.5-0.6 mg/dL), hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.81 to 0.92; in the third quartile (0.7-0.8 mg/dL), HR 0.83, 95% CI 0.77 to 0.89; and in the highest quartile (0.9 mg/dL or higher), HR 0.76, 95% CI 0.70 to 0.82 (P < 0.001 for overall significance of total bilirubin categories).
The association of each higher bilirubin level with CVD usually retained statistical significance for each of the individual CVD events--heart failure, AMI, and stroke. The highest bilirubin quartile was always significantly associated with lower CVD incidence compared with the lowest quartile: for heart failure HR 0.76, 95% CI 0.69 to 0.84; for AMI HR 0.80, 95% CI 0.70 to 0.92; and for stroke HR 0.71, 95% CI 0.62 to 0.81 (P < 0.01 for all comparisons).
In the analysis restricted to veterans with HIV, higher bilirubin was associated with lower incidence of CVD (for highest vs lowest quartile HR 0.75, 95% CI 0.66 to 0.86, P < 0.001), of heart failure (for highest vs lowest quartile HR 0.75, 95% CI 0.63 to 0.88, P < 0.01), and of stroke (for highest vs lowest quartile HR 0.68, 95% CI 0.54 to 0.86, P = 0.009). But the association with AMI incidence lacked statistical significance (for highest vs lowest quartile HR 0.84, 95% CI 0.67 to 1.06, P = 0.16).
The analysis for veterans without liver disease excluded those with HCV, alcohol dependence, or FIB4 fibrosis score 1.45 or higher. Each of the three higher bilirubin quartiles protected against CVD in this analysis (for highest vs lowest quartile HR 0.68, 95% CI 0.59 to 0.77, P < 0.001).
The VACS team concluded that higher bilirubin is associated with lower CVD incidence (1) before and after adjusting for confounders, (2) in veterans with and without HIV, and (3) in veterans without liver disease. They caution that the findings may not apply to women, who made up a tiny fraction of the study group.
Reference
1. Marconi VC, So-Armah K, Tate J. Hyperbilirubinemia prevents cardiovascular disease for HIV+ and HIV- individuals. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 127. http://www.croiconference.org/sessions/hyperbilirubinemia-prevents-cardiovascular-disease-hiv-and-hiv-individuals
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