Advertisement

Post-operative recurrence of liver cancer according to antiviral therapy for detectable hepatitis B viremia: A nationwide study

  • Byungyoon Yun
    Affiliations
    Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Sang Hoon Ahn
    Affiliations
    Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

    Yonsei Liver Centre, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
    Search for articles by this author
  • Juyeon Oh
    Affiliations
    Department of Public Health, Graduate School, Yonsei University College of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and are co-corresponding authors.
    Jin-Ha Yoon
    Correspondence
    Corresponding author at: Department of Occupational Health, Department of Preventive Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun–gu, Seoul 03722, Republic of Korea.
    Footnotes
    1 These authors contributed equally to this work and are co-corresponding authors.
    Affiliations
    Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    The Institute for Occupational Health, Yonsei University College of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and are co-corresponding authors.
    Beom Kyung Kim
    Correspondence
    Corresponding author at: Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun–gu, Seoul 03722, Republic of Korea.
    Footnotes
    1 These authors contributed equally to this work and are co-corresponding authors.
    Affiliations
    Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

    Yonsei Liver Centre, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work and are co-corresponding authors.
Published:November 05, 2022DOI:https://doi.org/10.1016/j.ejim.2022.10.026

      Highlights

      • Postoperative recurrence of hepatitis B virus-infected liver cancer is notably high.
      • The risk of post-op recurrence in antiviral therapy users was similar to non-users.
      • All subgroup and sensitivity analyses reproduced the similar results.
      • The risk of post-op recurrence was also similar in highly active antiviral therapy.

      Abstract

      Background

      High postoperative recurrence of hepatitis B virus (HBV)-infected hepatocellular carcinoma (HCC) remains a significant challenge. Here, we aimed to compare the postoperative HCC recurrence between patients with AVT for detectable serum HBV-DNA vs. those without.

      Methods

      Data of patients undergoing curative resection of HBV-infected HCC as an initial therapy from 2015 to 2017 were obtained from the National Health Insurance Service database in South Korea. AVT was initiated when serum HBV-DNA was detectable. The primary outcome was HCC recurrence. The cumulative risk of HCC recurrence between AVT users and non-users was estimated using the Kaplan–Meier method.

      Results

      During follow-up (median 2.7 years) with 3034 patients, 25.7% and 23.6% of AVT users and non-users experienced HCC recurrence, respectively. The 1-, 2-, and 3-year cumulative recurrence rates were similar (p = 0.57): 15.6%, 23.3%, and 26.4% in AVT users versus 15.3%, 22.0%, and 24.9% in non-users, respectively. After adjusting for covariates, multivariable Cox regression analysis showed comparable outcomes between the two groups with adjusted hazard ratios (aHR 1.08, 95% confidence interval [CI] 0.89–1.31; p = 0.439). Similar outcomes between the two groups were reproduced after stratification of liver cirrhosis. Inverse probability treatment weighting analysis also showed comparable outcomes between the two groups in the subgroups with liver cirrhosis (aHR 1.01, 95% CI 0.80–1.29; p = 0.92) and non-cirrhosis (aHR 1.08, 95% CI 0.87–1.34; p = 0.472).

      Conclusions

      Initiating AVT based on detectable serum HBV-DNA provided the similar risk of postoperative HCC recurrence in HBV-infected HCC patients with and without detectable serum HBV-DNA.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • WHO
        Global progress report on HIV, viral hepatitis and sexually transmitted infections.
        World Health Organization, 2021
        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • Laversanne M.
        • Soerjomataram I.
        • Jemal A.
        • et al.
        Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2021; 71: 209-249
        • EASL
        2017 clinical practice guidelines on the management of hepatitis B virus infection.
        J Hepatol. 2017; 67: 370-398
        • Marcellin P.
        • Gane E.
        • Buti M.
        • Afdhal N.
        • Sievert W.
        • Jacobson I.M.
        • et al.
        Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
        Lancet. 2013; 381: 468-475
        • Iloeje U.H.
        • Yang H.I.
        • Su J.
        • Jen C.L.
        • You S.L.
        • Chen C.J.
        Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
        Gastroenterology. 2006; 130: 678-686
        • Chen C.J.
        • Yang H.I.
        • Su J.
        • Jen C.L.
        • You S.L.
        • Lu S.N.
        • 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.
        • Chang K.M.
        • Hwang J.P.
        • Jonas M.M.
        • et al.
        Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
        Hepatology. 2018; 67: 1560-1599
        • Terrault N.A.
        • Bzowej N.H.
        • Chang K.M.
        • Hwang J.P.
        • Jonas M.M.
        • Murad M.H.
        AASLD guidelines for treatment of chronic hepatitis B.
        Hepatology. 2016; 63: 261-283
        • Sarin S.K.
        • Kumar M.
        • Lau G.K.
        • Abbas Z.
        • Chan H.L.
        • Chen C.J.
        • et al.
        Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
        Hepatol Int. 2016; 10: 1-98
        • Tamai H.
        • Okamura J.
        New next-generation microwave thermosphere ablation for small hepatocellular carcinoma.
        Clin Mol Hepatol. 2021; 27: 564-574
        • Roayaie S.
        • Obeidat K.
        • Sposito C.
        • Mariani L.
        • Bhoori S.
        • Pellegrinelli A.
        • et al.
        Resection of hepatocellular cancer ≤2 cm: results from two Western centers.
        Hepatology. 2013; 57: 1426-1435
        • Kim J.
        • Kang W.
        • Sinn D.H.
        • Gwak G.Y.
        • Paik Y.H.
        • Choi M.S.
        • et al.
        Substantial risk of recurrence even after 5 recurrence-free years in early-stage hepatocellular carcinoma patients.
        Clin Mol Hepatol. 2020; 26: 516-528
        • Kim B.K.
        • Park J.Y.
        • Kim D.Y.
        • Kim J.K.
        • Kim K.S.
        • Choi J.S.
        • et al.
        Persistent hepatitis B viral replication affects recurrence of hepatocellular carcinoma after curative resection.
        Liver Int. 2008; 28: 393-401
        • Wong G.L.
        • Tse Y.K.
        • Chan H.L.
        • Yip T.C.
        • Tsoi K.K.
        • Wong V.W.
        Oral nucleos(t)ide analogues reduce recurrence and death in chronic hepatitis B-related hepatocellular carcinoma.
        Aliment Pharmacol Ther. 2016; 43: 802-813
        • Wu C.Y.
        • Chen Y.J.
        • Ho H.J.
        • Hsu Y.C.
        • Kuo K.N.
        • Wu M.S.
        • et al.
        Association between nucleoside analogues and risk of hepatitis B virus–related hepatocellular carcinoma recurrence following liver resection.
        JAMA. 2012; 308: 1906-1914
        • Lee S.W.
        • Choi J.
        • Kim S.U.
        • Lim Y.S.
        Entecavir versus tenofovir in patients with chronic hepatitis B: enemies or partners in the prevention of hepatocellular carcinoma.
        Clin Mol Hepatol. 2021; 27: 402-412
        • Lee J.H.
        • Kim B.K.
        • Park S.Y.
        • Tak W.Y.
        • Park J.Y.
        • Kim D.Y.
        • et al.
        The efficacies of entecavir and tenofovir in terms of enhancing prognosis after curative treatment of hepatitis B virus-related hepatocellular carcinoma.
        Eur J Intern Med. 2021; 89: 48-55
        • Choi J.
        • Jo C.
        • Lim Y.S.
        Tenofovir versus entecavir on recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection.
        Hepatology. 2021; 73: 661-673
        • Yim H.J.
        • Kim J.H.
        • Park J.Y.
        • Yoon E.L.
        • Park H.
        • Kwon J.H.
        • et al.
        Comparison of clinical practice guidelines for the management of chronic hepatitis B: when to start, when to change, and when to stop.
        Clin Mol Hepatol. 2020; 26: 411-429
        • Torimura T.
        • Iwamoto H.
        Optimizing the management of intermediate-stage hepatocellular carcinoma: current trends and prospects.
        Clin Mol Hepatol. 2021; 27: 236-245
        • Kim J.M.
        • Kim D.G.
        • Kim J.
        • Lee K.
        • Lee K.W.
        • Ryu J.H.
        • et al.
        Outcomes after liver transplantation in Korea: incidence and risk factors from Korean transplantation registry.
        Clin Mol Hepatol. 2021; 27: 451-462
        • Yoon S.M.
        • Kim S.Y.
        • Lim Y.S.
        • Kim K.M.
        • Shim J.H.
        • Lee D.
        • et al.
        Stereotactic body radiation therapy for small (≤5 cm) hepatocellular carcinoma not amenable to curative treatment: results of a single-arm, phase II clinical trial.
        Clin Mol Hepatol. 2020; 26: 506-515
        • van Diepen M.
        • Ramspek C.L.
        • Jager K.J.
        • Zoccali C.
        • Dekker F.W.
        Prediction versus aetiology: common pitfalls and how to avoid them.
        Nephrol Dial Transplant. 2017; 32: ii1-ii5
        • Ramspek C.L.
        • Steyerberg E.W.
        • Riley R.D.
        • Rosendaal F.R.
        • Dekkers O.M.
        • Dekker F.W.
        • et al.
        Prediction or causality? A scoping review of their conflation within current observational research.
        Eur J Epidemiol. 2021; 36: 889-898
        • Simon T.G.
        • Duberg A.S.
        • Aleman S.
        • Hagstrom H.
        • Nguyen L.H.
        • Khalili H.
        • et al.
        Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population.
        Ann Intern Med. 2019; 171: 318-327
        • Kim G.
        • Jang S.Y.
        • Nam C.M.
        • Kangjama E.S.
        Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study.
        J Hepatol. 2018; 68: 476-484
        • Collier J.
        • Sherman M.
        Screening for hepatocellular carcinoma.
        Hepatology. 1998; 27: 273-278
        • Dhanasekaran R.
        • Bandoh S.
        • Roberts L.R.
        Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances.
        F1000Res. 2016; 5https://doi.org/10.12688/f1000research.6946.1
        • Song S.O.
        • Jung C.H.
        • Song Y.D.
        • Park C.Y.
        • Kwon H.S.
        • Cha B.S.
        • et al.
        Background and data configuration process of a nationwide population-based study using the korean national health insurance system.
        Diabetes Metab J. 2014; 38: 395-403
        • Kim D.
        • Yang P.S.
        • Sung J.H.
        • Jang E.
        • Yu H.T.
        • Kim T.H.
        • et al.
        Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study.
        Eur Heart J. 2020; 41: 4483-4493
        • Shin H.
        • Jung Y.W.
        • Kim B.K.
        • Park J.Y.
        • Kim D.Y.
        • Ahn S.H.
        • et al.
        Risk assessment of hepatocellular carcinoma development for indeterminate hepatic nodules in patients with chronic hepatitis B.
        Clin Mol Hepatol. 2019; 25: 390-399
        • Zhou Y.
        • Zhang Z.
        • Zhao Y.
        • Wu L.
        • Li B.
        Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis.
        World J Surg. 2014; 38: 2395-2402
        • Wong J.S.
        • Wong G.L.
        • Tsoi K.K.
        • Wong V.W.
        • Cheung S.Y.
        • Chong C.N.
        • et al.
        Meta-analysis: the efficacy of anti-viral therapy in prevention of recurrence after curative treatment of chronic hepatitis B-related hepatocellular carcinoma.
        Aliment Pharmacol Ther. 2011; 33: 1104-1112
        • Kim H.S.
        • Kim S.U.
        • Kim B.K.
        • Park J.Y.
        • Kim D.Y.
        • Ahn S.H.
        • et al.
        Serum wisteria floribunda agglutinin-positive human Mac-2 binding protein level predicts recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection.
        Clin Mol Hepatol. 2020; 26: 33-44
        • Jang J.W.
        • Kim J.S.
        • Kim H.S.
        • Tak K.Y.
        • Nam H.
        • Sung P.S.
        • et al.
        Persistence of intrahepatic hepatitis B virus DNA integration in patients developing hepatocellular carcinoma after hepatitis B surface antigen seroclearance.
        Clin Mol Hepatol. 2021; 27: 207-218
        • Liang L.Y.
        • Lee H.W.
        • Wong V.W.
        • Yip T.C.
        • Tse Y.K.
        • Hui V.W.
        • et al.
        Serum fibrosis index-based risk score predicts hepatocellular carcinoma in untreated patients with chronic hepatitis B.
        Clin Mol Hepatol. 2021; 27: 499-509
        • Wu J.W.
        • Kao J.H.
        • Tseng T.C.
        Three heads are better than two: hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma.
        Clin Mol Hepatol. 2021; 27: 524-534
        • Luo M.
        • Zhou B.
        • Hou J.
        • Jiang D.
        Biomarkers for predicting nucleos(t)ide analogs discontinuation and hepatitis B virus recurrence after drug withdrawal in chronic hepatitis B patients.
        Hepatol Res. 2022; 52: 337-351
        • Wong D.K.
        • Cheng S.C.Y.
        • Mak L.L.
        • To E.W.
        • Lo R.C.
        • Cheung T.T.
        • et al.
        Among patients with undetectable hepatitis B surface antigen and hepatocellular carcinoma, a high proportion has integration of HBV DNA into hepatocyte DNA and no cirrhosis.
        Clin Gastroenterol Hepatol. 2020; 18: 449-456
        • Péneau C.
        • Imbeaud S.
        • La Bella T.
        • Hirsch T.Z.
        • Caruso S.
        • Calderaro J.
        • et al.
        Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma.
        Gut. 2022; 71: 616-626
        • Kumar R.
        • Pérez-Del-Pulgar S.
        • Testoni B.
        • Lebossé F.
        • Zoulim F.
        Clinical relevance of the study of hepatitis B virus covalently closed circular DNA.
        Liver Int. 2016; 36: 72-77
        • Tabrizian P.
        • Jibara G.
        • Shrager B.
        • Schwartz M.
        • Roayaie S.
        Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis.
        Ann Surg. 2015; 261: 947-955
        • Lee J.
        • Cho E.H.
        • Kim S.B.
        • Kim R.
        Prognosis after intrahepatic recurrence in the patients who underwent curative resection for hepatocellular carcinoma.
        Ann Hepatobiliary Pancreat Surg. 2020; 24: 431-436
        • Seo C.G.
        • Yim S.Y.
        • Um S.H.
        • Lee Y.R.
        • Lee Y.J.
        • Kim T.H.
        • et al.
        Survival according to recurrence patterns after resection for transplantable hepatocellular carcinoma in HBV endemic area: appraisal of liver transplantation strategy.
        Clin Res Hepatol Gastroenterol. 2020; 44: 532-542