Can We Move on From the Discussion of Direct Antiviral Agents and Risk of Hepatocellular Carcinoma Recurrence?

Abstract

See “Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study,” by Singal AG, Rich NE, Mehta N, et al, on page 1683. See “Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study,” by Singal AG, Rich NE, Mehta N, et al, on page 1683. After the breakthrough of direct antiviral agents (DAA) for hepatitis C virus (HCV) treatment, a seminal study from the Barcelona Clinic Liver Cancer team suggested a potential increase of hepatocellular carcinoma (HCC) recurrence (“a note of caution”) after DAA implementation in HCV cirrhotic patients treated for HCC.1Reig M. Marino Z. Perello C. et al.Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution.J Hepatol. 2016; 65: 719-726Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar This report was based on a retrospective analysis of 58 patients who exhibited a higher than expected rate of tumor recurrence after the combination of HCC treatment and DAA therapy.1Reig M. Marino Z. Perello C. et al.Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution.J Hepatol. 2016; 65: 719-726Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar After this report, a wave of reports sought to decipher the potential deleterious role of DAA in cirrhotic patients naïve of HCC and in cirrhotic patients with a previous history of HCC treatment.2Ioannou G.N. Green P.K. Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma.J Hepatol. 2018; 68: 25-32Abstract Full Text Full Text PDF Scopus (263) Google Scholar, 3Virlogeux V. Pradat P. Hartig-Lavie K. et al.Direct-acting antiviral therapy decreases hepatocellular carcinoma recurrence rate in cirrhotic patients with chronic hepatitis C.Liver Int. 2017; 37: 1122-1127Crossref PubMed Scopus (52) Google Scholar, 4Waziry 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: 1204-1212Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar, 5Conti 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: 727-733Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar, 6Nagata H. Nakagawa M. Asahina Y. et al.Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.J Hepatol. 2017; 67: 933-939Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 7Kanwal F. Kramer J. Asch S.M. et al.Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.Gastroenterology. 2017; 153: 996-1005.e1Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar, 8Nishibatake 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: 78-86Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar Mostly based on retrospective single-center reports, these analyses were hampered by various biases in patient selection, data collection, and interpretation of results, which precluded definite conclusions. The analysis of large populations derived from national registries or hospital-based prospective cohorts of patients included in HCC surveillance programs allowed less biased estimates of the incidence of a first liver cancer after the implementation of DAAs, particularly in those with cirrhosis or extensive fibrosis.7Kanwal F. Kramer J. Asch S.M. et al.Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents.Gastroenterology. 2017; 153: 996-1005.e1Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar, 9Romano A. Angeli P. Piovesan S. et al.Newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with DAAs: a prospective population study.J Hepatol. 2018; 69: 345-352Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 10Calvaruso V. Cabibbo G. Cacciola I. et al.Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents.Gastroenterology. 2018; 155: 411-421.e4Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 11Nahon 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.e6Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar In total, all these large-scale data analyses converged toward a comparable HCC incidence to that reported in patients who previously achieved HCV clearance using an interferon-based regimen. Furthermore, dedicated analyses revealed potential confounders, such as impaired liver function or limitations in HCC surveillance programs, which likely biased results from evaluations of the first patients treated, in the setting of early access programs.12Innes H. Barclay S.T. Hayes P.C. et al.The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen.J Hepatol. 2018; 68: 646-654Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 13Li D.K. Ren Y. Fierer D.S. et al.The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: an ERCHIVES study.Hepatology. 2018; 67: 2244-2253Crossref PubMed Scopus (107) Google Scholar Conversely, the potential deleterious association between these drugs and a higher risk of HCC recurrence remains to be accurately assessed.14Ioannou G.N. Feld J.J. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection?.Gastroenterology. 2019; 156: 446-460.e2Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Two reasons might account for this observation: first, the lack of large, prospective, multicenter efforts studying the outcome of HCC patients infected by HCV under DAAs, which are the only reliable source of data for rigorous time-dependent analyses. Second, analyses are complicated by the heterogeneity of patients referred for HCC management, in particular the often imprecise boundaries between curative and palliative therapeutic approaches for this difficult-to-treat cancer. However, despite this controversy and the absence of robust data in the literature, most scientific societies and health care programs considered that the signal was not strong enough to halt the use of DAA after HCC treatment and suggested performing additional studies15Pawlotsky J.-M. Negro F. Aghemo A. et al.EASL Recommendations on treatment of hepatitis C 2018.J Hepatol. 2018; 69: 461-511Abstract Full Text Full Text PDF PubMed Scopus (1241) Google Scholar Given the difficulties of performing a randomized, controlled trial, more robust observational data are required to answer this important clinical question. In this issue of Gastroenterology, Singal et al16Singal A.G. Rich N.E. Mehta N. et al.Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study.Gastroenterology. 2019; 156: 1683-1692Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar report the outcome of 793 patients treated for HCV-related HCC from 31 centers in the United States and Canada.16Singal A.G. Rich N.E. Mehta N. et al.Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study.Gastroenterology. 2019; 156: 1683-1692Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar They analyzed data from 304 patients who received DAA after HCC management and their outcome was compared with 489 patients untreated for hepatitis C (Figure 1). Using a time-dependent landmark approach, DAA-based therapy was not associated with overall HCC recurrence (hazard ratio, 0.90; 95% confidence interval, 0.70–1.16) or early HCC recurrence (tumor recurrence within the first year; hazard ratio, 0.96; 95% confidence interval, 0.70–1.34). The strengths of the study include a protocol-driven collection of data, time-dependent analyses to account for the delay in DAAs initiation after HCC management and sophisticated statistical approaches, including propensity score matching, inverse probability of treatment weighting, and multiple sensitivity analyses, which all supported this result.16Singal A.G. Rich N.E. Mehta N. et al.Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study.Gastroenterology. 2019; 156: 1683-1692Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Is this study sufficient to definitively halt the controversy about the deleterious effect of DAA after HCC treatment? Probably not. Despite its strengths, this study bears some of the drawbacks observed in previous studies. First, this study has a retrospective design, with the associated potential for selection and observational biases. Moreover, Singal et al16Singal A.G. Rich N.E. Mehta N. et al.Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study.Gastroenterology. 2019; 156: 1683-1692Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar analyzed a heterogeneous group of patients treated by curative approaches such as resection and percutaneous ablation (n = 375) and also by less reliably curative treatments such as radioembolization and transarterial chemoembolization (n = 416). Even if the authors only included patients with a complete response to these endovascular noncurative procedures, their presence brings heterogeneity and a background noise. In this line, the high rate of recurrence in the first year after HCC treatment (46%) in patients not treated by DAA is puzzling. However, despite these limitations, Singal et al16Singal A.G. Rich N.E. Mehta N. et al.Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study.Gastroenterology. 2019; 156: 1683-1692Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar bring new data to the literature suggesting an absence of higher rates of tumor recurrence after DAA implementation based on the analysis of a large number of patients. What will be the next step to close (or not) the controversy about DAA prescription after treatment of HCC? Maybe the relevance of this question will decrease, at least in Western countries. It is anticipated that most patients with hepatitis C will be cured in the setting of national and international eradication programs and most future HCC cases will develop in cirrhotic patients already cured for hepatitis C.14Ioannou G.N. Feld J.J. What are the benefits of a sustained virologic response to direct-acting antiviral therapy for hepatitis C virus infection?.Gastroenterology. 2019; 156: 446-460.e2Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 17Kim D. Li A.A. Perumpail B.J. et al.Changing trends in etiology- and ethnicity-based annual mortality rates of cirrhosis and hepatocellular carcinoma in the United States.Hepatology. 2018; 67: 2076-2078Crossref PubMed Scopus (4) Google Scholar Consequently, the rates of patients with HCC developing in the setting of active hepatitis C-related cirrhosis will probably dramatically decrease, at least if efficient programs of screening followed by universal anti-HCV treatment are widely implemented. Thus, until confirmation by other multicenter studies, patients eligible for curative treatment of HCC should be proposed for DAA-based antiviral therapy after assurance that the tumor is fully controlled, for preservation of liver function and to allow sequential retreatment of HCC recurrences and decrease competing risks of death from end-stage liver disease.18Cabibbo G. Petta S. Barbara M. et al.Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma.J Hepatol. 2017; 67: 65-71Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 19Backus L.I. Belperio P.S. Shahoumian T.A. et al.Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease: Backus et al.Hepatology. 2019; 69: 487-497Crossref PubMed Scopus (131) Google Scholar Direct-Acting Antiviral Therapy Not Associated With Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort StudyGastroenterologyVol. 156Issue 6PreviewThere is controversy over the effects of direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) infection on hepatocellular carcinoma (HCC) recurrence and tumor aggressiveness. We compared HCC recurrence patterns between DAA-treated and untreated HCV-infected patients who had achieved a complete response to HCC treatment in a North American cohort. Full-Text PDF