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Impact of HBeAg on Hepatocellular Carcinoma Risk During Oral Antiviral Treatment in Patients With Chronic Hepatitis B

Published:September 05, 2021DOI:https://doi.org/10.1016/j.cgh.2021.09.001

      Background & Aims

      Antiviral treatment from hepatitis B envelope antigen (HBeAg)-positive status may attenuate the integration of hepatitis B virus DNA into the host genome causing hepatocellular carcinoma (HCC). We investigated the impact of HBeAg status at the onset of antiviral treatment on the risk of HCC.

      Methods

      The incidence of HCC was evaluated in Korean patients with chronic hepatitis B who started entecavir or tenofovir in either HBeAg-positive or HBeAg-negative phase. The results in the Korean cohort were validated in a Caucasian PAGE-B cohort.

      Results

      A total of 9143 Korean patients (mean age, 49.2 years) were included: 49.1% were HBeAg-positive and 49.2% had cirrhosis. During follow-up (median, 5.1 years), 916 patients (10.0%) developed HCC. Baseline HBeAg positivity was not associated with the risk of HCC in the entire cohort or cirrhotic subcohort. However, in the non-cirrhotic subcohort, HBeAg positivity was independently associated with a lower risk of HCC in multivariable (adjusted hazard ratio [aHR], 0.41; 95% confidence interval [CI], 0.26–0.66), propensity score-matching (aHR, 0.46; 95% CI, 0.28–0.76), and inverse probability weighting analyses (aHR, 0.44; 95% CI, 0.28–0.70). In the Caucasian cohort (n = 719; mean age, 51.8 years; HBeAg-positive, 20.3%; cirrhosis, 34.8%), HBeAg-positivity was not associated with the risk of HCC either in the entire cohort or cirrhotic subcohort. In the non-cirrhotic subcohort, none of the HBeAg-positive group developed HCC, although the difference failed to reach statistical significance (aHR, 0.21; 95% CI, 0.00–1.67).

      Conclusions

      This multinational cohort study implies that HBeAg positivity at the onset of antiviral treatment seems to be an independent factor associated with a lower risk of HCC in patients with chronic hepatitis B without cirrhosis, but not in those with cirrhosis.

      Keywords

      Abbreviations used in this paper:

      ALT (alanine aminotransferase), CHB (chronic hepatitis B), CT (computed tomography), FiB-4 (Fibrosis-4), HBeAg (hepatitis B envelope antigen), HBsAg (hepatitis B surface antigen), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), HR (hazard ratio), IPTW (inverse probability of treatment weighting), IQR (interquartile range), LC (liver cirrhosis), NA (nucleos(t)ide analog), PSM (propensity score matching)
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      References

        • Foreman K.J.
        • Marquez N.
        • Dolgert A.
        • et al.
        Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories.
        Lancet. 2018; 392: 2052-2090
        • de Martel C.
        • Maucort-Boulch D.
        • Plummer M.
        • et al.
        World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma.
        Hepatology. 2015; 62: 1190-1200
        • Wu C.Y.
        • Lin J.T.
        • Ho H.J.
        • et al.
        Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study.
        Gastroenterology. 2014; 147: 143-151.e5
        • Wong G.L.
        • Chan H.L.
        • Mak C.W.
        • et al.
        Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis.
        Hepatology. 2013; 58: 1537-1547
        • Marongiu F.
        • Doratiotto S.
        • Montisci S.
        • et al.
        Liver repopulation and carcinogenesis: two sides of the same coin?.
        Am J Pathol. 2008; 172: 857-864
        • Chemin I.
        • Zoulim F.
        Hepatitis B virus induced hepatocellular carcinoma.
        Cancer Lett. 2009; 286: 52-59
        • Mason W.S.
        • Liu C.
        • Aldrich C.E.
        • et al.
        Clonal expansion of normal-appearing human hepatocytes during chronic hepatitis B virus infection.
        J Virol. 2010; 84: 8308-8315
        • Mason W.S.
        • Gill U.S.
        • Litwin S.
        • et al.
        HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant.
        Gastroenterology. 2016; 151: 986-998.e4
        • Wooddell C.I.
        • Yuen M.F.
        • Chan H.L.
        • et al.
        RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg.
        Sci Transl Med. 2017; 9eaan0241
        • Kim J.H.
        • Kim Y.D.
        • Lee M.
        • et al.
        Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy.
        J Hepatol. 2018; 69: 1066-1073
        • Papatheodoridis G.
        • Dalekos G.
        • Sypsa V.
        • et al.
        PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
        J Hepatol. 2016; 64: 800-806
        • Wong G.L.
        • Chan H.L.
        • Wong C.K.
        • et al.
        Liver stiffness-based optimization of hepatocellular carcinoma risk score in patients with chronic hepatitis B.
        J Hepatol. 2014; 60: 339-345
        • Kim D.Y.
        • Song K.J.
        • Kim S.U.
        • et al.
        Transient elastography-based risk estimation of hepatitis B virus-related occurrence of hepatocellular carcinoma: development and validation of a predictive model.
        OncoTargets Ther. 2013; 6: 1463-1469
        • Fujiwara N.
        • Friedman S.L.
        • Goossens N.
        • et al.
        Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine.
        J Hepatol. 2018; 68: 526-549
        • Kim G.A.
        • Han S.
        • Choi G.H.
        • et al.
        Moderate levels of serum hepatitis B virus DNA are associated with the highest risk of hepatocellular carcinoma in chronic hepatitis B patients.
        Alimentary pharmacology & therapeutics. 2020; 51: 1169-1179
        • Chen C.J.
        • Yang H.I.
        • Su J.
        • et al.
        Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
        JAMA. 2006; 295: 65-73
        • Terrault N.A.
        • Lok A.S.F.
        • McMahon B.J.
        • et al.
        Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
        Hepatology. 2018; 67: 1560-1599
        • Papatheodoridis G.V.
        • Sypsa V.
        • Dalekos G.N.
        • et al.
        Hepatocellular carcinoma prediction beyond year 5 of oral therapy in a large cohort of Caucasian patients with chronic hepatitis B.
        J Hepatol. 2020; 72: 1088-1096
        • Sterling R.K.
        • Lissen E.
        • Clumeck N.
        • et al.
        Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
        Hepatology. 2006; 43: 1317-1325
        • Wong V.W.
        • Janssen H.L.
        Can we use HCC risk scores to individualize surveillance in chronic hepatitis B infection?.
        J Hepatol. 2015; 63: 722-732
        • Thiele M.
        • Gluud L.L.
        • Fialla A.D.
        • et al.
        Large variations in risk of hepatocellular carcinoma and mortality in treatment naïve hepatitis B patients: systematic review with meta-analyses.
        PLoS One. 2014; 9e107177
        • Kim H.
        • Jee Y.M.
        • Song B.C.
        • et al.
        Molecular epidemiology of hepatitis B virus (HBV) genotypes and serotypes in patients with chronic HBV infection in Korea.
        Intervirology. 2007; 50: 52-57
        • Tu T.
        • Mason W.S.
        • Clouston A.D.
        • et al.
        Clonal expansion of hepatocytes with a selective advantage occurs during all stages of chronic hepatitis B virus infection.
        J Viral Hepatitis. 2015; 22: 737-753
        • Summers J.
        • Jilbert A.R.
        • Yang W.
        • et al.
        Hepatocyte turnover during resolution of a transient hepadnaviral infection.
        Proceedings of the National Academy of Sciences of the United States of America. 2003; 100: 11652-11659
        • Yang W.
        • Summers J.
        Integration of hepadnavirus DNA in infected liver: evidence for a linear precursor.
        J Virol. 1999; 73: 9710-9717
        • Liao Y.
        • Hu X.
        • Chen J.
        • et al.
        Precore mutation of hepatitis B virus may contribute to hepatocellular carcinoma risk: evidence from an updated meta-analysis.
        PLoS One. 2012; 7e38394
        • Chotiyaputta W.
        • Lok A.S.
        Hepatitis B virus variants.
        Nat Rev Gastroenterol Hepatol. 2009; 6: 453-462
        • Tu T.
        • Budzinska M.A.
        • Vondran F.W.R.
        • et al.
        Hepatitis B virus DNA integration occurs early in the viral life cycle in an in vitro infection model via sodium taurocholate cotransporting polypeptide-dependent uptake of enveloped virus particles.
        J Virol. 2018; 92
        • Lee H.W.
        • Yoo E.J.
        • Kim B.K.
        • et al.
        Prediction of development of liver-related events by transient elastography in hepatitis B patients with complete virological response on antiviral therapy.
        Am J Gastroenterol. 2014; 109: 1241-1249
        • Yang H.I.
        • Yuen M.F.
        • Chan H.L.
        • et al.
        Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.
        Lancet Oncol. 2011; 12: 568-574
        • Yuen M.F.
        • Tanaka Y.
        • Fong D.Y.
        • et al.
        Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B.
        J Hepatol. 2009; 50: 80-88
        • Xiao G.
        • Yang J.
        • Yan L.
        Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis.
        Hepatology. 2015; 61: 292-302