Interferon-free Therapy of Chronic Hepatitis C With Direct-acting Antivirals Does Not Change the Short-term Risk for De Novo Hepatocellular Carcinoma in Patients With Liver Cirrhosis

F. Mettke; B. Schlevogt; K. Deterding; A. Wranke; A. Smith; K. Port; M. P. Manns; A. Vogel; M. Cornberg; H. Wedemeyer


Aliment Pharmacol Ther. 2018;47(4):516-525. 

In This Article

Abstract and Introduction


Background Hepatitis C virus (HCV) clearance with IFN-based therapies reduces the incidence of hepatocellular carcinoma (HCC). There has been some debate if IFN-free therapy with direct-acting antivirals alters the risk for HCC.

Aim To investigate the HCC incidence in cirrhotic HCV patients who cleared HCV with direct-acting antivirals vs untreated controls.

Methods We prospectively monitored 373 patients with chronic hepatitis C who received IFN-free therapies with direct-acting antiviral after January 2014. A retrospective control cohort of untreated cirrhotic patients was recruited out of 3715 HCV patients who were followed at our centre between 2007 and 2013, with similar HCC screening protocols.

Results 158 direct-acting antiviral-treated and 184 control patients with liver cirrhosis were included in this analysis. The groups did not differ in gender and genotype distribution, severity of liver disease and prevalence of diabetes mellitus. Patients were followed up for a median of 440 (range 91–908) and 592 (range 90–1000) days. HCCs developed in 6 and 14 patients during follow-up, resulting in an incidence of 2.90 vs 4.48 HCCs per 100 person-years. In the direct-acting antiviral-treated group, there was no new case of HCC later than 450 days after treatment initiation. In multivariate analysis, higher MELD-Scores and AFP-levels were independently associated with HCC development. Transplant-free patient survival was similar in both groups.

Conclusions IFN-free direct-acting antiviral therapy of chronic hepatitis C does not alter the short-term risk for HCC in patients with liver cirrhosis. A reduced HCC incidence may become evident after more than 1.5 years of follow-up.


The introduction of direct-acting antivirals (DAA) has revolutionized treatment of chronic hepatitis C in terms of tolerability and sustained virological response (SVR) rates.[1,2] Successful DAA treatment is associated with improved liver function,[3,4] quality of life,[5] as well as reduced risk of decompensated liver disease[6] and portal hypertension.[7] IFN-based treatment regimens have a mode of action that is fundamentally different from DAA therapy. Therefore, our knowledge regarding the improvement of liver function, regression of cirrhosis and portal hypertension, as well as incidence of hepatocellular carcinoma after HCV cure cannot simply be transferred from the IFN-based to the IFN-free era.

After IFN-based SVR there is a decreased but not abrogated risk of HCC.[8–13] The presence of liver cirrhosis, higher age and diabetes mellitus type 2 are well-known risk factors for the development of post-SVR HCC.[14]

Emerging data raised suspicion of an increased risk of recurrence of curatively treated HCC after DAA therapy,[15,16] although both studies lacked an untreated control group. There was an unexpectedly high recurrence rate of almost 30% in a short-term observation period of 6 months. On the contrary the French ANRS study and the Italian RESIST HCV cohort did not show an increased risk regarding HCC recurrence after DAA therapy.[17,18]

The development of de novo HCC after DAA must be examined separately from HCC recurrence because it presents a fundamentally different setting. Incidence of de novo HCC in DAA-treated cirrhotic patients was reported to be 3.2% over 6 months,[16] 5.2% over 48 weeks[19] and 4.7% over 15 months.[6] The latter study showed a significantly decreased rate of HCC in patients with SVR compared to patients with treatment failure. The other studies had no control group.

The aim of this study was to address the yet unanswered question whether DAA-based antiviral treatment of chronic hepatitis C changes the short-term risk for de novo HCC. For reliable risk evaluation, we recruited an untreated historical control cohort treated at the same centre which had similar patient characteristics and was monitored with identical protocols.