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Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan

  • Author Footnotes
    † Equal contribution
    Pei-Chien Tsai
    Footnotes
    † Equal contribution
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan

    Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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  • Author Footnotes
    † Equal contribution
    Hsing-Tao Kuo
    Footnotes
    † Equal contribution
    Affiliations
    Division of Hepatogastroenterology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan

    School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan
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  • Chao-Hung Hung
    Affiliations
    Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
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  • Kuo-Chih Tseng
    Affiliations
    Department of Gastroenterology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chiayi, Taiwan
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  • Hsueh-Chou Lai
    Affiliations
    Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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  • Cheng-Yuan Peng
    Affiliations
    Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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  • Jing-Houng Wang
    Affiliations
    Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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  • Jyh-Jou Chen
    Affiliations
    Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
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  • Pei-Lun Lee
    Affiliations
    Division of Gastroenterology and Hepatology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan
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  • Rong-Nan Chien
    Affiliations
    Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Keelung, Taiwan
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  • Chi-Chieh Yang
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan
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  • Gin-Ho Lo
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
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  • Jia-Horng Kao
    Affiliations
    Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
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  • Chun-Jen Liu
    Affiliations
    Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
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  • Chen-Hua Liu
    Affiliations
    Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Division of Gastroenterology and Hepatology, National Taiwan University Hospital, Taipei, Taiwan
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  • Sheng-Lei Yan
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show-Chwan Memorial Hospital, Changhua, Taiwan
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  • Ming-Jong Bair
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, Taitung Mackay Memorial Hospital, Taitung, Taiwan
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  • Chun-Yen Lin
    Affiliations
    Division of Hepatology, Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Keelung, Taiwan
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  • Wei-Wen Su
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
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  • Cheng-Hsin Chu
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
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  • Chih-Jen Chen
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei, Taiwan
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  • Shui-Yi Tung
    Affiliations
    Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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  • Chi-Ming Tai
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
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  • Chih-Wen Lin
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
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  • Ching-Chu Lo
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Martin De Porres Hospital-Daya, Chiayi, Taiwan
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  • Pin-Nan Cheng
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Yen-Cheng Chiu
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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  • Chia-Chi Wang
    Affiliations
    Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, New Taipei, Taiwan
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  • Jin-Shiung Cheng
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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  • Wei-Lun Tsai
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
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  • Han-Chieh Lin
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Yi-Hsiang Huang
    Affiliations
    Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

    Institute of Clinical Medicine, Faculty of Medicine, National Yang Ming, Chiao Tung University, Taipei, Taiwan
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  • Ming-Lun Yeh
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Chung-Feng Huang
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Meng-Hsuan Hsieh
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan

    Health Management Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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  • Jee-Fu Huang
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Chia-Yen Dai
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Wan-Long Chung
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Chi-Yi Chen
    Correspondence
    Department of Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan.
    Affiliations
    Department of Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan
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  • Ming-Lung Yu
    Correspondence
    Corresponding authors. Address: Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung 807, Taiwan; School of Medicine, College of Medicine, National Sun Yat-sen University, No.70 Lien-hai Rd., Kaohsiung 804, Taiwan.
    Affiliations
    Hepatobiliary Section, Department of Internal Medicine, and Hepatitis Center, Kaohsiung Medical University Hospital; Hepatitis Research Center, School of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan

    School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan

    School of Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
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  • T-COACH Study Group
  • Author Footnotes
    † Equal contribution
Published:October 05, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.019

      Highlights

      • Diabetes mellitus is associated with an increased risk of HCC in individuals with CHC.
      • Diabetes mellitus still increases the risk of HCC after successful antiviral therapy.
      • Use of metformin for DM greatly reduces HCC risk after successful antiviral therapy.
      • A simple risk stratification model could predict the risk of HCC and other major liver-related complications.

      Background & Aims

      Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy.

      Methods

      Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases.

      Results

      Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications.

      Conclusions

      Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR.

      Impact and implications

      The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.

      Graphical abstract

      Keywords

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      References

        • EASL Clinical Practice Guidelines
        Management of hepatocellular carcinoma.
        J Hepatol. 2018; 69: 182-236
        • Akinyemiju T.
        • Abera S.
        • Ahmed M.
        • Alam N.
        • Alemayohu M.A.
        • et al.
        • Global Burden of Disease Liver Cancer C
        The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015.
        JAMA Oncol. 2017; 3: 1683-1691
        • Chen V.L.
        • Yeh M.L.
        • Yang J.D.
        • Leong J.
        • Huang D.Q.
        • Toyoda H.
        • et al.
        Effects of cirrhosis and diagnosis scenario in metabolic-associated fatty liver disease-related hepatocellular carcinoma.
        Hepatol Commun. 2021; 5: 122-132
        • Lin C.W.
        • Lin C.C.
        • Mo L.R.
        • Chang C.Y.
        • Perng D.S.
        • Hsu C.C.
        • et al.
        Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis.
        J Hepatol. 2013; 58: 730-735
        • Liu M.
        • Tseng T.C.
        • Jun D.W.
        • Yeh M.L.
        • Trinh H.
        • Wong G.L.H.
        • et al.
        Transition rates to cirrhosis and liver cancer by age, gender, disease and treatment status in Asian chronic hepatitis B patients.
        Hepatol Int. 2021; 15: 71-81
        • Huang J.F.
        • Yu M.L.
        • Dai C.Y.
        • Hsieh M.Y.
        • Hwang S.J.
        • Hsiao P.J.
        • et al.
        Reappraisal of the characteristics of glucose abnormalities in patients with chronic hepatitis C infection.
        Am J Gastroenterol. 2008; 103: 1933-1940
        • Davila J.A.
        • Morgan R.O.
        • Shaib Y.
        • McGlynn K.A.
        • El-Serag H.B.
        Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study.
        Gut. 2005; 54: 533-539
        • Cunha V.
        • Cotrim H.P.
        • Rocha R.
        • Carvalho K.
        • Lins-Kusterer L.
        Metformin in the prevention of hepatocellular carcinoma in diabetic patients: a systematic review.
        Ann Hepatol. 2020; 19: 232-237
        • Zhou J.
        • Ke Y.
        • Lei X.
        • Wu T.
        • Li Y.
        • Bao T.
        • et al.
        Meta-analysis: the efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes.
        Ann Hepatol. 2020; 19: 320-328
        • Nkontchou G.
        • Cosson E.
        • Aout M.
        • Mahmoudi A.
        • Bourcier V.
        • Charif I.
        • et al.
        Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients.
        J Clin Endocrinol Metab. 2011; 96: 2601-2608
        • Hassan M.M.
        • Curley S.A.
        • Li D.
        • Kaseb A.
        • Davila M.
        • Abdalla E.K.
        • et al.
        Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.
        Cancer. 2010; 116: 1938-1946
        • Chen H.P.
        • Shieh J.J.
        • Chang C.C.
        • Chen T.T.
        • Lin J.T.
        • Wu M.S.
        • et al.
        Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies.
        Gut. 2013; 62: 606-615
        • Hsu W.F.
        • Tsai P.C.
        • Chen C.Y.
        • Tseng K.C.
        • Lai H.C.
        • Kuo H.T.
        • et al.
        Hepatitis C virus eradication decreases the risks of liver cirrhosis and cirrhosis-related complications (Taiwanese chronic hepatitis C cohort).
        J Gastroenterol Hepatol. 2021; 36: 2884-2892
        • Perez S.
        • Kaspi A.
        • Domovitz T.
        • Davidovich A.
        • Lavi-Itzkovitz A.
        • Meirson T.
        • et al.
        Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals.
        Plos Genet. 2019; 15e1008181
        • Ciancio A.
        • Ribaldone D.G.
        • Dotta A.
        • Giordanino C.
        • Sacco M.
        • Fagoonee S.
        • et al.
        Long-term follow-up of diabetic and non-diabetic patients with chronic hepatitis C successfully treated with direct-acting antiviral agents.
        Liver Int. 2021; 41: 276-287
        • Huang C.F.
        • Yeh M.L.
        • Huang C.I.
        • Liang P.C.
        • Lin Y.H.
        • Lin Z.Y.
        • et al.
        Post-treatment fibrotic modifications overwhelm pretreatment liver fibrosis in predicting HCC in CHC patients with curative antivirals.
        Hepatol Int. 2018; 12: 544-551
        • Huang C.F.
        • Yeh M.L.
        • Huang C.Y.
        • Tsai P.C.
        • Ko Y.M.
        • Chen K.Y.
        • et al.
        Pretreatment glucose status determines HCC development in HCV patients with mild liver disease after curative antiviral therapy.
        Medicine (Baltimore). 2016; 95: e4157
        • Ioannou G.N.
        • Splan M.F.
        • Weiss N.S.
        • McDonald G.B.
        • Beretta L.
        • Lee S.P.
        Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis.
        Clin Gastroenterol Hepatol. 2007; 5 (945 e931-934): 938-945
        • Hsieh M.H.
        • Bair M.J.
        • Tsai P.C.
        • Tseng K.C.
        • Lo C.C.
        • Chen C.Y.
        • et al.
        Long-term risk of end stage renal diseases with maintenance dialysis among chronic hepatitis C patients after antiviral therapy in Taiwan.
        J Gastroenterol Hepatol. 2021; 36: 2247-2254
        • Tsai P.C.
        • Chen C.Y.
        • Kuo H.T.
        • Hung C.H.
        • Tseng K.C.
        • Lai H.C.
        • et al.
        Successful antiviral therapy reduces risk of schizophrenia among chronic hepatitis C patients: a nationwide real-world Taiwanese cohort (T-COACH).
        Open Forum Infect Dis. 2020; 7: ofaa397
        • Huang C.F.
        • Lai H.C.
        • Chen C.Y.
        • Tseng K.C.
        • Kuo H.T.
        • Hung C.H.
        • et al.
        Extrahepatic malignancy among patients with chronic hepatitis C after antiviral therapy: a real-world nationwide study on Taiwanese chronic hepatitis C cohort (T-COACH).
        Am J Gastroenterol. 2020; 115: 1226-1235
        • Hsu W.F.
        • Chen C.Y.
        • Tseng K.C.
        • Lai H.C.
        • Kuo H.T.
        • Hung C.H.
        • et al.
        Sustained virological response to hepatitis C therapy does not decrease the incidence of systemic lupus erythematosus or rheumatoid arthritis.
        Sci Rep. 2020; 10: 5372
        • Sterling R.K.
        • Lissen E.
        • Clumeck N.
        • Sola R.
        • Correa M.C.
        • Montaner J.
        • et al.
        Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
        Hepatology. 2006; 43: 1317-1325
        • Scheuer P.J.
        Classification of chronic viral hepatitis: a need for reassessment.
        J Hepatol. 1991; 13 ([In eng)]): 372-374
        • Castera L.
        • Vergniol J.
        • Foucher J.
        • Le Bail B.
        • Chanteloup E.
        • Haaser M.
        • et al.
        Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.
        Gastroenterology. 2005; 128: 343-350
        • Lin Y.H.
        • Yeh M.L.
        • Huang C.I.
        • Yang J.F.
        • Liang P.C.
        • Huang C.F.
        • et al.
        The performance of acoustic radiation force impulse imaging in predicting liver fibrosis in chronic liver diseases.
        Kaohsiung J Med Sci. 2016; 32: 362-366
        • Wang C.C.
        • Liu C.H.
        • Lin C.L.
        • Wang P.C.
        • Tseng T.C.
        • Lin H.H.
        • et al.
        Fibrosis index based on four factors better predicts advanced fibrosis or cirrhosis than aspartate aminotransferase/platelet ratio index in chronic hepatitis C patients.
        J Formos Med Assoc. 2015; 114: 923-928
        • Yang Q.
        • Fung W.K.
        • Li G.
        Sample size determination for jointly testing a cause-specific hazard and the all-cause hazard in the presence of competing risks.
        Stat Med. 2018; 37: 1389-1401
        • Gray R.J.
        A class of K-sample tests for comparing the cumulative incidence of a competing risk.
        Ann Stat. 1988; 16: 1141-1154
        • Fine JPG R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Austin P.C.
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Huang C.F.
        • Yeh M.L.
        • Tsai P.C.
        • Hsieh M.H.
        • Yang H.L.
        • Hsieh M.Y.
        • et al.
        Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication.
        J Hepatol. 2014; 61: 67-74
        • Siphepho P.Y.
        • Liu Y.T.
        • Shabangu C.S.
        • Huang J.F.
        • Huang C.F.
        • Yeh M.L.
        • et al.
        The impact of steatosis on chronic hepatitis C progression and response to antiviral treatments.
        Biomedicines. 2021; 9
        • Anstee Q.M.
        • Reeves H.L.
        • Kotsiliti E.
        • Govaere O.
        • Heikenwalder M.
        From NASH to HCC: current concepts and future challenges.
        Nat Rev Gastroenterol Hepatol. 2019; 16: 411-428
        • Benhammou J.N.
        • Lin J.
        • Aby E.S.
        • Markovic D.
        • Raman S.S.
        • Lu D.S.
        • et al.
        Nonalcoholic fatty liver disease-related hepatocellular carcinoma growth rates and their clinical outcomes.
        Hepatoma Res. 2021; 7
        • Matsuura K.
        • Sawai H.
        • Ikeo K.
        • Ogawa S.
        • Iio E.
        • Isogawa M.
        • et al.
        Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection.
        Gastroenterology. 2017; 152: 1383-1394
        • Wang C.P.
        • Kuhn J.
        • Shah D.P.
        • Schmidt S.
        • Lam Y.F.
        • MacCarthy D.
        • et al.
        Metformin modifies disparity in hepatocellular carcinoma incidence in men with type 2 diabetes but without chronic liver diseases.
        Cancer Med. 2019; 8: 3206-3215
        • Kramer J.R.
        • Natarajan Y.
        • Dai J.
        • Yu X.
        • Li L.
        • El-Serag H.B.
        • et al.
        Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease.
        Hepatology. 2022; 75: 1420-1428
        • Chen C.Y.
        • Huang C.F.
        • Cheng P.N.
        • Tseng K.C.
        • Lo C.C.
        • Kuo H.T.
        • et al.
        Factors associated with treatment failure of direct-acting antivirals for chronic hepatitis C: a real-world nationwide hepatitis C virus registry programme in Taiwan.
        Liver Int. 2021; 41: 1265-1277
        • Kanwal F.
        • Kramer J.R.
        • Asch S.M.
        • Cao Y.
        • Li L.
        • El-Serag H.B.
        Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents.
        Hepatology. 2020; 71: 44-55
        • Huang J.F.
        • Huang C.F.
        • Yeh M.L.
        • Dai C.Y.
        • Hsieh M.H.
        • Yang J.F.
        • et al.
        The outcomes of glucose abnormalities in chronic hepatitis C patients receiving interferon-free direct antiviral agents.
        Kaohsiung J Med Sci. 2017; 33: 567-571
        • Chen C.I.
        • Kuan C.F.
        • Fang Y.A.
        • Liu S.H.
        • Liu J.C.
        • Wu L.L.
        • et al.
        Cancer risk in HBV patients with statin and metformin use: a population-based cohort study.
        Medicine (Baltimore). 2015; 94: e462
        • Lin D.
        • Reddy V.
        • Osman H.
        • Lopez A.
        • Koksal A.R.
        • Rhadhi S.M.
        • et al.
        Additional inhibition of wnt/beta-catenin signaling by metformin in DAA treatments as a novel therapeutic strategy for HCV-infected patients.
        Cells. 2021; : 10
        • Simon T.G.
        • Bonilla H.
        • Yan P.
        • Chung R.T.
        • Butt A.A.
        Atorvastatin and fluvastatin are associated with dose-dependent reductions in cirrhosis and hepatocellular carcinoma, among patients with hepatitis C virus: results from ERCHIVES.
        Hepatology. 2016; 64: 47-57
        • Tsan Y.T.
        • Lee C.H.
        • Ho W.C.
        • Lin M.H.
        • Wang J.D.
        • Chen P.C.
        Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.
        J Clin Oncol. 2013; 31: 1514-1521
        • Huang C.F.
        • Dai C.Y.
        • Yeh M.L.
        • Huang C.I.
        • Lee H.C.
        • Lai W.T.
        • et al.
        Cure or curd: modification of lipid profiles and cardio-cerebrovascular events after hepatitis C virus eradication.
        Kaohsiung J Med Sci. 2020; 36: 920-928
        • Simon T.G.
        • Ludvigsson J.F.
        Association between aspirin and hepatocellular carcinoma.
        Reply N Engl J Med. 2020; 382: 2481-2482
        • Liao Y.H.
        • Hsu R.J.
        • Wang T.H.
        • Wu C.T.
        • Huang S.Y.
        • Hsu C.Y.
        • et al.
        Aspirin decreases hepatocellular carcinoma risk in hepatitis C virus carriers: a nationwide cohort study.
        BMC Gastroenterol. 2020; 20: 6