Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma

BACKGROUND & AIMS There is controversy over benefits of direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection for patients with a history of hepatocellular carcinoma (HCC). We performed a multicenter cohort study to compare overall survival between patients with HCV infection treated with DAAs vs patients who did not receive DAA treatment for their HCV infection after complete response to prior HCC therapy. METHODS We conducted a retrospective cohort study of patients with HCV-related HCC who achieved a complete response to resection, local ablation, trans-arterial chemo- or radioembolization, or radiation therapy, from January 2013 through December 2017 at 31 healthcare systems throughout the United States and Canada. We used Cox proportional hazards regression to determine the association between receipt of DAA therapy, modeled as a time-varying covariate, and all-cause mortality, accounting for informative censoring and confounding using inverse probability weighting. RESULTS Of 797 patients with HCV-related HCC, 383 patients (48.1%) received DAA therapy and 414 patients (51.9%) did not receive treatment for their HCV infection after complete response to prior HCC therapy. Among DAA-treated patients, 43 deaths occurred during 941 person-years of follow up, compared with 103 deaths during 526.6 person-years of follow up among patients who did not receive DAA therapy (crude rate ratio, 0.23; 95% CI, 0.16-0.33). In inverse probability-weighted analyses, DAA therapy was associated with a significant reduction in risk of death (hazard ratio [HR], 0.54; 95% CI, 0.33-0.90). This association differed by sustained virologic response (SVR) to DAA therapy; risk of death was reduced in patients with SVR to DAA therapy (HR, 0.29; 95% CI, 0.18-0.47) but not in patients without an SVR (HR, 1.13; 95% CI, 0.55-2.33). CONCLUSIONS In an analysis of nearly 800 patients with complete response to HCC treatment, DAA therapy was associated with a significant reduction in risk of death.

[1]  A. Singal,et al.  AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review. , 2019, Gastroenterology.

[2]  J. Bruix,et al.  Time association between hepatitis C therapy and hepatocellular carcinoma emergence in cirrhosis: Relevance of non-characterized nodules. , 2019, Journal of hepatology.

[3]  A. Branch,et al.  Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. , 2019, Gastroenterology.

[4]  Yu Shen,et al.  Hepatocellular Carcinoma Screening Is Associated With Increased Survival of Patients With Cirrhosis , 2019, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[5]  H. El‐Serag,et al.  Epidemiology and Management of Hepatocellular Carcinoma. , 2019, Gastroenterology.

[6]  Giovanni Raimondo,et al.  Incidence of Hepatocellular Carcinoma in Patients With HCV-Associated Cirrhosis Treated With Direct-Acting Antiviral Agents. , 2018, Gastroenterology.

[7]  M. Abecassis,et al.  Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases , 2018, Hepatology.

[8]  G. Cabibbo,et al.  Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer? , 2018, Liver international : official journal of the International Association for the Study of the Liver.

[9]  A. Singal,et al.  Systematic review with meta‐analysis: recurrence of hepatocellular carcinoma following direct‐acting antiviral therapy , 2018, Alimentary pharmacology & therapeutics.

[10]  Kathleen A Cronin,et al.  Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics , 2018, Cancer.

[11]  G. Heinze,et al.  An unjustified benefit: immortal time bias in the analysis of time‐dependent events , 2018, Transplant international : official journal of the European Society for Organ Transplantation.

[12]  G. Dore,et al.  Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. , 2017, Journal of hepatology.

[13]  X. Forns,et al.  Effects of All-Oral Anti-Viral Therapy on HVPG and Systemic Hemodynamics in Patients With Hepatitis C Virus-Associated Cirrhosis. , 2017, Gastroenterology.

[14]  P. Maisonneuve,et al.  Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virus‐related cirrhosis who attained sustained virological response , 2017, Liver international : official journal of the International Association for the Study of the Liver.

[15]  C. Nam,et al.  Statistical methods for elimination of guarantee-time bias in cohort studies: a simulation study , 2017, BMC Medical Research Methodology.

[16]  G. Cabibbo,et al.  Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct‐acting antivirals? A prospective multicentre study , 2017, Alimentary pharmacology & therapeutics.

[17]  G. Ioannou,et al.  Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma. , 2017, Journal of hepatology.

[18]  A. Gasbarrini,et al.  Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma. , 2017, Journal of hepatology.

[19]  D. Goldberg,et al.  Association of Provider Specialty and Multidisciplinary Care With Hepatocellular Carcinoma Treatment and Mortality. , 2017, Gastroenterology.

[20]  R. Salem,et al.  Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals. , 2017, Journal of hepatology.

[21]  J. Bruix,et al.  Liver Cancer Emergence Associated with Antiviral Treatment: An Immune Surveillance Failure? , 2017, Seminars in Liver Disease.

[22]  M. Ziol,et al.  Eradication of Hepatitis C Virus Infection in Patients With Cirrhosis Reduces Risk of Liver and Non-Liver Complications. , 2017, Gastroenterology.

[23]  G. Ioannou,et al.  HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. , 2017, Journal of hepatology.

[24]  Rafael Stern,et al.  Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension. , 2016, Journal of hepatology.

[25]  S. Pol Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. , 2016, Journal of hepatology.

[26]  M. Makuuchi,et al.  Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. , 2015, The Lancet. Oncology.

[27]  M. Schwartz,et al.  Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. , 2015, Annals of surgery.

[28]  Ashley L. Buchanan,et al.  Worth the weight: using inverse probability weighted Cox models in AIDS research. , 2014, AIDS research and human retroviruses.

[29]  Amit G. Singal,et al.  Early Detection, Curative Treatment, and Survival Rates for Hepatocellular Carcinoma Surveillance in Patients with Cirrhosis: A Meta-analysis , 2014, PLoS medicine.

[30]  L. Bolondi,et al.  Hepatocellular carcinoma responding to superselective transarterial chemoembolization: an issue of nodule dimension? , 2013, Journal of vascular and interventional radiology : JVIR.

[31]  J. Marrero,et al.  Establishment of a Multidisciplinary Hepatocellular Carcinoma Clinic is Associated with Improved Clinical Outcome , 2013, Annals of Surgical Oncology.

[32]  S. Altekruse,et al.  Hepatocellular Carcinoma Confirmation, Treatment, and Survival in Surveillance, Epidemiology, and End Results Registries, 1992‐2008 , 2012, Hepatology.

[33]  Ryosuke Tateishi,et al.  nature publishing group ORIGINAL CONTRIBUTIONS 569 CME Radiofrequency Ablation for Hepatocellular Carcinoma: 10-Year Outcome and Prognostic Factors LIVER , 2022 .

[34]  M. Puhan,et al.  Systematic review and meta‐analysis of interferon after curative treatment of hepatocellular carcinoma in patients with viral hepatitis , 2009, The British journal of surgery.

[35]  Stephen R Cole,et al.  Constructing inverse probability weights for marginal structural models. , 2008, American journal of epidemiology.