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Introduction: Our previous nested-case-control study demonstrated elevated adiponectin increased liver cirrhosis and HCC risk in HBV carriers. We extended the analysis to the whole REVEAL-HBV cohort to prospectively evaluate whether adiponectin directly affected end-stage liver diseases, or through affecting HBV progression. Methods: Baseline plasma adiponectin were determined to investigate the association between adiponectin and subsequent HBeAg, HBsAg and HBV DNA seroclearance, and the development of cirrhosis, HCC and liver-related death. Whether HBV characteristics modify the adiponectin-milestones associations was also examined. Results: Among 3931 HBsAg(+)/anti-HCV(-) REVEAL-HBV participants, 3684 had sufficient biosamples left for adiponectin assay. Elevated adiponectin was associated with higher chance of HBeAg seropositive, high HBV viral load (>2x105 IU/mL) and high HBsAg titers (>1000 IU/mL) in a dose-response manner (OR=2.21, 95% CI: 1.52 – 3.22; OR= 2.08, 95% CI: 1.45 – 3.00 and OR= 1.91, 95% CI: 1.45 – 2.50 for Q5 vs. Q1, respectively). Those with the highest quintile had a lower chance of achieving HBsAg (HR=0.48, 95% CI: 0.27 – 0.85), HBeAg (HR=0.71, 95% CI: 0.50 – 1.00), and HBV DNA seroclearance (HR=0.61, 95% CI: 0.43 – 0.88), and higher chance of developing liver cirrhosis (HR=2.73, 95% CI: 1.87 – 3.98), HCC (HR =2.51, 95% CI: 1.52 – 4.15), and died from liver-related causes (HR=2.40, 95% CI: 1.49 – 3.85). HBV genotype significantly modified the adiponectin-HCC (Pinteraction = 0.005) and adiponectin-liver deaths associations (Pinteraction = 0.0157), with higher risk among genotype C. Conclusions: Elevated adiponectin is consistently associated with all important chronic HBV infection milestones towards progression to liver cancer. The exact mechanism of how adiponectin mediate HBV infection toward carcinogenesis remains unclear and warrant further investigation. Disentangling this may help us in finding new HBV treatment target, biomarker in HBV surveillance to identify high risk patients, or even cancer prevention.

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