Advertisement

What Comes First: Treatment of Viral Hepatitis or Liver Cancer?

  • Jordan J. FeldEmail author
  • Lisette A. P. Krassenburg
Review

Abstract

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the most important underlying causes for the development of hepatocellular carcinoma (HCC) worldwide. Determining the optimal approach for management of the viral infection and the HCC depends on the virus and the stage of the cancer. In patients with HCV-associated HCC, there are multiple reasons to first treat the HCC. Firstly, in case of a curable HCC, the urgency for HCC treatment is important to avoid progression during HCV treatment. Secondly, the presence of HCC itself appears to reduce the rates of sustained virological response (SVR) achieved with direct-acting antivirals (DAAs). And finally, the evidence does not support the concept of an increase in HCC recurrence due to DAAs, so a patient can safely be treated after HCC cure. For patients with very advanced HCC, the benefits of HCV therapy are questionable. In contrast, those who develop HCC in the setting of chronic HBV infection, treatment with nucleoside analogues (NAs) is recommended prior to treating HCC, to prevent further liver injury and reduce the risk for HCC recurrence. Ultimately, earlier diagnosis and treatment of HBV and HCV will hopefully reduce the incidence of HCC worldwide.

Keywords

Hepatitis C virus (HCV) Sustained virological response (SVR) Hepatocellular carcinoma (HCC) Direct-acting antivirals (DAAs) Hepatitis B virus (HBV) 

Notes

Compliance with ethical standards

Conflict of interest

Dr. Jordan J. Feld reports receiving research funds from Abbvie, Gilead Sciences and Janssen as well as consulting fees from Abbvie, Gilead Sciences, Enanta, Contravir and Roche. Lisette A. P. Krassenburg reports no conflict of interest.

References

  1. 1.
    Golabi P, Fazel S, Otgonsuren M, Sayiner M, Locklear CT, Younossi ZM. Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities. Medicine (Baltimore). 2017;96:e5904.CrossRefGoogle Scholar
  2. 2.
    de Martel C, Maucort-Boulch D, Plummer M, Franceschi S. World-wide relative contribution of hepatitis B and C viruses in hepatocellular carcinoma. Hepatology. 2015;62:1190–1200.CrossRefGoogle Scholar
  3. 3.
    Chiang CJ, Yang YW, You SL, Lai MS, Chen CJ. Thirty-year outcomes of the national hepatitis B immunization program in Taiwan. JAMA. 2013;310:974–976.CrossRefGoogle Scholar
  4. 4.
    Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. Gastroenterology. 2017;153:996–1005.e1001.CrossRefGoogle Scholar
  5. 5.
    El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. Hepatology. 2016;64:130–137.CrossRefGoogle Scholar
  6. 6.
    van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–2593.CrossRefGoogle Scholar
  7. 7.
    Hutin YJ, Bulterys M, Hirnschall GO. How far are we from viral hepatitis elimination service coverage targets? J Int AIDS Soc. 2018;21:e25050.CrossRefGoogle Scholar
  8. 8.
    Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of Hepatocellular Cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology. 2017;153(4):996–1005 e1001.Google Scholar
  9. 9.
    Barua S, Greenwald R, Grebely J, Dore GJ, Swan T, Taylor LE. Restrictions for Medicaid reimbursement of sofosbuvir for the treatment of hepatitis C virus infection in the United States. Ann Intern Med. 2015;163:215–223.CrossRefGoogle Scholar
  10. 10.
    Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67:358–380.CrossRefGoogle Scholar
  11. 11.
    Mahmood S, Gul A, Saif T. Regression of hepatocellular carcinoma after treatment with Sofosbuvir—a case report. J Pak Med Assoc. 2016;66:1507–1509.Google Scholar
  12. 12.
    Beste LA, Green PK, Berry K, Kogut MJ, Allison SK, Ioannou GN. Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma. J Hepatol. 2017;67:32–39.CrossRefGoogle Scholar
  13. 13.
    Prenner SB, VanWagner LB, Flamm SL, Salem R, Lewandowski RJ, Kulik L. Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals. J Hepatol. 2017;66:1173–1181.CrossRefGoogle Scholar
  14. 14.
    Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2019;156:477–491.e1.CrossRefGoogle Scholar
  15. 15.
    Daniel KE, Said A. Considerations when treating hepatitis C in a cirrhotic transplant candidate. Curr Gastroenterol Rep. 2018;20:20.CrossRefGoogle Scholar
  16. 16.
    Panel AIHG. HCV guidance: recommendations for testing, managing and treating hepatitis C. Published 2018. Accessed April 23, 2018, 2018.Google Scholar
  17. 17.
    El-Sherif O, Jiang ZG, Tapper EB, et al. Baseline factors associated with improvements in decompensated cirrhosis after direct-acting antiviral therapy for hepatitis C virus infection. Gastroenterology. 2018;154:2111–2121.e2118.CrossRefGoogle Scholar
  18. 18.
    Reig M, Marino Z, Perello C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65:719–726.CrossRefGoogle Scholar
  19. 19.
    Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol. 2016;65:727–733.CrossRefGoogle Scholar
  20. 20.
    Yang JD, Aqel BA, Pungpapong S, Gores GJ, Roberts LR, Leise MD. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol. 2016;65:859–860.CrossRefGoogle Scholar
  21. 21.
    ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER COCaCCcEaspaf. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol. 2016;65(4):734–740.Google Scholar
  22. 22.
    Cabibbo G, Petta S, Calvaruso V, et al. Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Aliment Pharmacol Ther. 2017;46:688–695.CrossRefGoogle Scholar
  23. 23.
    Nishibatake Kinoshita M, Minami T, Tateishi R, et al. Impact of direct-acting antivirals on early recurrence of HCV-related HCC: comparison with interferon-based therapy. J Hepatol. 2019;70:78–86.CrossRefGoogle Scholar
  24. 24.
    Tsai PC, Huang CF, Yu ML. Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: issue of the interval between HCC treatment and antiviral therapy. J Hepatol. 2017;66:464.CrossRefGoogle Scholar
  25. 25.
    Werner JM, Adenugba A, Protzer U. Immune reconstitution after HCV clearance with direct antiviral agents: potential consequences for patients with HCC? Transplantation. 2017;101:904–909.CrossRefGoogle Scholar
  26. 26.
    Waziry R, Hajarizadeh B, Grebely J, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol. 2017;67:1204–1212.CrossRefGoogle Scholar
  27. 27.
    Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373:2599–2607.CrossRefGoogle Scholar
  28. 28.
    Nahon P, Layese R, Bourcier V, et al. Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs. Gastroenterology. 2018;155:1436–1450.e1436.CrossRefGoogle Scholar
  29. 29.
    Zangneh HF, Wong WW, Sander B, et al. Cost-effectiveness of hepatocellular carcinoma surveillance after a sustained virologic response to therapy in patients with HCV Infection and advanced fibrosis. Clin Gastroenterol Hepatol. 2018.  https://doi.org/10.1016/j.cgh.2018.12.018.Google Scholar
  30. 30.
    Locarnini S, Hatzakis A, Chen DS, Lok A. Strategies to control hepatitis B: public policy, epidemiology, vaccine and drugs. J Hepatol. 2015;62:S76–86.CrossRefGoogle Scholar
  31. 31.
    Feld JJ, Hepatitis B. Reactivation: the controversies continue. Dig Dis. 2017;35:351–358.CrossRefGoogle Scholar
  32. 32.
    Jun BG, Kim YD, Kim SG, et al. Hepatitis B virus reactivation after radiotherapy for hepatocellular carcinoma and efficacy of antiviral treatment: a multicenter study. PLoS ONE. 2018;13:e0201316.CrossRefGoogle Scholar
  33. 33.
    Wang K, Jiang G, Jia Z, Zhu X, Ni C. Effects of transarterial chemoembolization combined with antiviral therapy on HBV reactivation and liver function in HBV-related hepatocellular carcinoma patients with HBV-DNA negative. Medicine (Baltimore). 2018;97:e10940.CrossRefGoogle Scholar
  34. 34.
    Dan JQ, Zhang YJ, Huang JT, et al. Hepatitis B virus reactivation after radiofrequency ablation or hepatic resection for HBV-related small hepatocellular carcinoma: a retrospective study. Eur J Surg Oncol. 2013;39:865–872.CrossRefGoogle Scholar
  35. 35.
    El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–2502.CrossRefGoogle Scholar
  36. 36.
    Brahmania M, Feld J, Arif A, Janssen HL. New therapeutic agents for chronic hepatitis B. Lancet Infect Dis. 2016;16:e10–21.CrossRefGoogle Scholar
  37. 37.
    Bolotin S, Feld JJ, Garber G, Wong WWL, Guerra FM, Mazzulli T. Population-based estimate of hepatitis C virus prevalence in Ontario, Canada. PLoS ONE. 2018;13:e0191184.CrossRefGoogle Scholar
  38. 38.
    Jang JW, Choi JY, Kim YS, et al. Effects of virologic response to treatment on short- and long-term outcomes of patients with chronic hepatitis B virus infection and decompensated cirrhosis. Clin Gastroenterol Hepatol. 2018;16:1954–1963.e1953.CrossRefGoogle Scholar
  39. 39.
    Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009;50:2001–2006.CrossRefGoogle Scholar
  40. 40.
    Kwon SY, Choe WH, Lee CH, Yeon JE, Byun KS. Rapid re-emergence of YMDD mutation of hepatitis B virus with hepatic decompensation after lamivudine retreatment. World J Gastroenterol. 2008;14:4416–4419.CrossRefGoogle Scholar
  41. 41.
    Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599.CrossRefGoogle Scholar
  42. 42.
    Papatheodoridis GV, Idilman R, Dalekos GN, et al. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology. 2017;66:1444–1453.CrossRefGoogle Scholar
  43. 43.
    Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 2008;28:1067–1077.CrossRefGoogle Scholar
  44. 44.
    Cho H, Ahn H, Lee DH, et al. Entecavir and tenofovir reduce hepatitis B virus-related hepatocellular carcinoma recurrence more effectively than other antivirals. J Viral Hepat. 2018;25:707–717.CrossRefGoogle Scholar
  45. 45.
    Zhou HY, Luo Y, Chen WD, Gong GZ. Hepatitis B virus mutation may play a role in hepatocellular carcinoma recurrence: a systematic review and meta-regression analysis. J Gastroenterol Hepatol. 2015;30:977–983.CrossRefGoogle Scholar
  46. 46.
    Wong JS, Wong GL, Tsoi KK, 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.CrossRefGoogle Scholar
  47. 47.
    Pollicino T, Saitta C. Occult hepatitis B virus and hepatocellular carcinoma. World J Gastroenterol. 2014;20:5951–5961.CrossRefGoogle Scholar
  48. 48.
    Huang X, Hollinger FB. Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review. J Viral Hepat. 2014;21:153–162.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Toronto Centre for Liver Disease, Toronto General Hospital, Sandra Rotman Centre for Global HealthUniversity of TorontoTorontoCanada
  2. 2.Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands

Personalised recommendations