Rates of Hepatocellular Carcinoma After Start of Treatment for Chronic Hepatitis C Remain High with Direct Acting Antivirals: Analysis from a Swiss Liver Transplant Center

Abstract

Background Direct-acting antivirals (DAA) have revolutionized the therapy of chronic hepatitis C (CHC) and have replaced previous PEG-interferon/ribavirin (PEG-IFN/RBV) treatment. Patients with CHC and advanced liver disease are at increased risk for hepatocellular carcinoma (HCC). However, the effects of DAA-based CHC treatment on subsequent HCC incidence remain poorly understood. Patients and Methods This retrospective single-institution cohort study included 243 consecutive patients after PEG-IFN/RBV and 263 patients after DAA treatment. Multivariable cause-specific Cox proportional hazards models were used to compare time to HCC between treatment types, censoring patients who died or had an orthotopic liver transplantation (OLT) at the time of the competing event. Age, gender, BMI, viral load, cirrhosis, fibrosis stage, diabetes, virus genotype and previous PEG-IFN/RBV (before DAA) were used as covariates. In addition, we performed a propensity score-matched analysis. Results Nineteen HCC cases were observed after DAA therapy compared to 18 cases after PEG-IFN/RBV treatment. Patients were followed for a median of 4.1 years (IQR: 3.5–4.7) for DAA and 9.3 years (IQR: 6.6–12.4) for the PEG-IFN/RBV group. In an unadjusted Cox model, a hazard ratio (HR) of 6.40 (CI: 2.20–18.61, p=0.006) for HCC following DAA vs PEG-IFN/RBV was estimated. In multivariable Cox proportional hazard models, age and liver cirrhosis were identified as further HCC risk factors but the HR estimates for DAA vs PEG-IFN/RBV still indicate a considerably increased hazard associated with DAA treatment (HR between 7.23 and 11.52, p≤0.001, depending on covariates). A HR of 6.62 (CI: 2.01–21.84, p=0.002) for DAA vs PEG-IFN/RBV was estimated in the propensity score-matched analysis. The secondary outcomes death and OLT did not differ between treatment groups. Conclusion In a cohort study from a tertiary care hospital rates of HCC after the start of DAA treatment were higher compared to PEG-IFN/RBV treatment. Our data reinforce the recommendation that surveillance should be continued after successful CHC treatment.

Hepatocellular carcinoma after treatment of hepatitis C with direct-acting antivirals: a critical re-appraisal

“…Controlled studies showed similar results. Higher recurrence or occurrence rates were reported in patients treated with DAAs compared with IFN treatment [40][41][42] .…”

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

“…A retrospective cohort study was carried out on 243 consecutive HCV patients who received PEG-IFN/RBV and were followed for a median of 9.3 years, and 263 HCV patients who received DAA treatment and were followed for a median of 4.1 years. It revealed that a considerably increased hazard was associated with DAA treatment[ 60 ]. A French study conducted on 1270 HCV patients revealed that, the differences of the occurrence of HCC after IFN and DAA regimens could be explained by the higher prevalence of Child-Pugh class B, portal hypertension, and diabetes among DAA-treated patients vs IFN-induced SVR patients.…”

“…The higher rate of HCC after DAA therapy may be because they are the drugs of choice for treating old patients and those with liver cirrhosis and end-stage liver disease as IFN was not indicated to treat such patients[ 62 ]. The possible clarification of the elevated incidence of HCC after the start of DAA therapy, might be the change in the growth of pre-existing subclinical and undetectable HCC upon DAA treatment[ 60 ]. A high HCC risk after DAA treatment was also reported, especially in individuals with uncharacterized liver nodules[ 63 ].…”