Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis C patients with advanced fibrosis

doi:10.1016/j.jhep.2009.12.028

Journal of Hepatology

Volume 52, Issue 5, May 2010, Pages 652-657

https://doi.org/10.1016/j.jhep.2009.12.028 Get rights and content

Background & Aims

Hepatocellular carcinoma (HCC) currently represents the major cause of liver-related death in patients with hepatitis C virus (HCV)-related cirrhosis. We assessed the influence of combination therapy on the risk of HCC, liver-related complications (ascites, variceal bleeding), and liver-related death (or liver transplantation).

Methods

Three hundred seven chronic hepatitis C patients with bridging fibrosis (n = 127) or cirrhosis (n = 180) were evaluated by Cox regression analysis. Sustained virological response (SVR) was defined as undetectable serum HCV RNA at 24 weeks after treatment.

Results

SVR developed in 33% of patients. The SVR rates were not different between patients with bridging fibrosis (37%) and those with cirrhosis (30%), p = 0.186. During a median follow-up of 3.5 years (range 1–18 years) after the last treatment, the incidence rates per 100 person-years of HCC, liver-related complications, and liver-related death, were 1.24, 0.62, and 0.61 among SVR patients, respectively, and 5.85, 4.16, and 3.76 among non-SVR patients, respectively (log-rank test, p <0.001). According to multivariate analysis, non-SVR was an independent predictor of HCC (HR 3.06; 95% CI = 1.12–8.39), liver-related complications (HR 4.73; 95% CI: 1.09–20.57), and liver-related death (HR 3.71; 95% CI = 1.05–13.05).

Conclusions

SVR is achieved in one-third of patients with HCV-related cirrhosis treated with peginterferon and ribavirin. SVR has a strong independent positive influence on the incidence of HCC and on the prognosis of these patients.

Introduction

According to the World Health Organization, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, accounting for 662,000 deaths every year throughout the world [1]. The overwhelming majority of HCC occurs in patients with chronic liver disease, 80–90% having cirrhosis, with most of the remainder having advanced fibrosis. Chronic viral hepatitis accounts for more than 80% of HCC cases worldwide [2]. Among patients with hepatitis C virus (HCV)-related cirrhosis, HCC is the most common complication. In a 17-year cohort study of 214 patients with chronic hepatitis C (CHC), HCC was the main cause of death (44%) and the first complication to develop in 27% of patients [3]. The incidence of HCV-related HCC is increasing in both the United States and Europe [4], [5], [6].

Previous studies have shown that interferon therapy may reduce the incidence of HCV-related HCC [7], [8], [9]. The majority of these studies were retrospective, raising the concern of selection bias (patients who did not receive therapy either had more advanced disease or were more likely to develop cancer) [10]. Indeed, a meta-analysis concluded that, although interferon treatment appeared to reduce the risk of HCC, the effect was slight and most evident among few patients with cirrhosis who achieved a sustained virological response (SVR) [11]. In the last few years, the efficacy of HCV therapy has evolved substantially, with improvement in the SVR rates from 10% with the initially recommended 24-week course of interferon monotherapy [12] to 50–60% with the combination of peginterferon and ribavirin for 48 weeks [13]. Importantly, data on the long-term follow-up and rates of HCC among Caucasian patients who received combination peginterferon and ribavirin therapy, are very limited [14]. Recently, the results from the HALT-C trial suggested that maintenance therapy with peginterferon monotherapy does not reduce the risk of HCC, thus highlighting the importance of achieving SVR in these patients [15]. Finally, SVR has been shown to be associated with eradication of the HCV virus [16], [17].

The aim of this study was to assess the influence of peginterferon and ribavirin combination therapy on the risk of HCC, liver-related complications, and liver-related death in a large cohort of patients with HCV-related bridging fibrosis or cirrhosis.

Section snippets

Study population

All patients in this study had been included in clinical trials and followed up in a single center (Hôpital Beaujon). Subjects were identified through our clinical trial database. Individuals with CHC and biopsy-proven bridging fibrosis or cirrhosis who had been treated with interferon-based therapy in clinical trials between 1987 and 2007, were included in this study [7], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]. CHC was documented by the

Study population

We identified a total of 307 CHC patients with bridging fibrosis (F3) or cirrhosis (F4). The last course of therapy consisted of peginterferon and ribavirin in 252 patients (82%), peginterferon monotherapy in 22 patients (7%), and conventional interferon with or without ribavirin in 33 patients (11%). Patients received a median of two treatment courses (range 1–6), with a median cumulative duration of 14 months (range 3–185 months). Patients were followed for a median period of 3.5 years (range

Discussion

This study provides information on the incidence of HCC, liver-related complications, and live-related death in a large cohort of Caucasian patients with HCV-related bridging fibrosis or cirrhosis who were treated with a combination of peginterferon and ribavirin. Importantly, SVR was assessed using a highly sensitive HCV RNA assay, thus avoiding possible bias due to misclassification of the response category in previous studies.

The overall SVR rate (33%) was lower than that observed in

Financial support

This study was supported by a grant from Schering Plough, but the sponsor had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript.

Disclosures

Patrick Marcellin received fees as a consultant or lecturer for Roche, Schering Plough, Novartis, Gilead Sciences, BMS, MSD, Vertex, Tibotec, Biolex, Zymmogenetics and grants from Gilead Sciences, Roche and Schering Plough. All other co-authors have no conflicts of interest to declare.

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^†: These authors contributed equally to this work.

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Research ArticleImpact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis C patients with advanced fibrosis

Background & Aims

Methods

Results

Conclusions

Introduction

Section snippets

Study population

Study population

Discussion

Financial support

Disclosures

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Gastroenterology

Clin Liver Dis

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Hepatology

Lancet

Gastroenterology

J Hepatol

Gastroenterology

J Hepatol

Gastroenterology

Hepatology

Gastroenterology

Research Article
Impact of peginterferon and ribavirin therapy on hepatocellular carcinoma: Incidence and survival in hepatitis C patients with advanced fibrosis