Treating chronic hepatitis C virus (HCV) with direct-acting antivirals (DAAs) in patients with cirrhosis doesn’t increase the risk of hepatocellular carcinoma (HCC), according to a recent article in Hepatology.
The authors of this retrospective study used data from the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database to investigate whether DAA use is associated with higher incidence of HCC compared with interferon-based (IFN) treatment.
They determined that DAA treatment is, in fact, not associated with a higher risk of HCC in cirrhotics with chronic HCV infection, as previously reported in other studies. The investigators explained that the higher rates of HCC seen in other studies were likely due to selection bias, as well as inclusion of fewer baseline HCC risk factors in those treated with IFN.
Until recently, the standard of care for treating HCV was IFNs, which typically achieved a sustained virologic response (SVR) in 50%-60% of eligible patients. INF-induced SVR reduced HCC by about four-fold, regardless of stage of liver disease.
However, introduction of DAAs dramatically improved treatment, as over 90% of HCV patients treated with these new medications achieved SVR.
DAAs were expected to further reduce the incidence of HCC; however, some studies suggested that the risk of HCC increased after DAA treatment. The authors of this study aimed to determine the cause of this paradox.
All HCV-infected veterans in Department of Veterans Affairs medical facilities in the US were identified (17,836) using ERCHIVES. Demographic, clinical, laboratory, and pharmacy information were obtained from similar databases and integrated for analysis.
Patients were divided into three groups:
- INF group: 3,534 received pegylated interferon (PEG) and ribavirin (RBV) for 28 days or more
- DAA group: 5,834 received one of the following for 28 days or more: Sofosbuvir + simeprevir ± RBV; sofosbuvir + ledipasvir ± RBV; sofosbuvir + daclatasvir ± RBV; paritaprevir/ritonavir/ombitasvir + dasabuvir ± RBV
- Control group: 8,468 participants who never received any HCV treatment for more than 28 days.
All groups were predominantly male with similar median HCV RNA levels.
In the IFN group, 66.6% attained SVR compared with 96.2% of patients in the DAA group. The mean follow-up time was 2,719 days for the IFN-treated group and 396 days for DAA-treated group.
DAAs and HCC
In a sub-analysis of the entire cohort that achieved SVR, the group treated with DAAs had a significantly higher incidence of HCC than the IFN-treated group. However, patients in the DAA group also had significantly more risk factors for HCC, including cirrhosis, older age, and higher baseline alpha-fetoprotein (AFP) level.
Cirrhosis due to chronic infection is one of the most common risk factors for HCC. Overall, 13.3% of IFN-treated participants were classified as cirrhotic compared to 20% in the DAA group.
“When we performed our primary analysis in cirrhotics alone, we found no difference in HCC-free survival between the DAA and IFN groups,” the authors wrote. “This finding strongly suggests that the pretreatment risk of HCC is what drives the post-treatment risk of HCC. Observed differences in the incidence of HCC between DAA and IFN-treated groups are therefore very unlikely to be related to the treatment itself.”
In an analysis of HCC incidence in those treated with specific DAA treatment regimens, the most recently introduced regimens had the highest risk of HCC. The authors hypothesize that the earliest DAA regimens, such as sofosbuvir/simeprevir, were used to treat those who had previously failed treatment with IFN.
The investigators reported that risk factors for the development of HCC include older age and an AFP ≥20. Statin use was associated with a lower risk of HCC; proton-pump inhibitors were associated with a higher risk of HCC.
SVR above all
Some limitations of the study include the short follow-up time in the DAA cohort due to recent introduction of the medications, a primarily male cohort with high rates of smoking and alcohol use, the retrospective design, and the use of FIB-4 score rather than a liver biopsy to identify participants with cirrhosis.
The authors stated that achieving SVR with any antiviral regimen is the most important factor in lowering HCC risk.
“In conclusion, in cirrhotics with chronic HCV infection, we found no association between HCC incidence rates and DAA treatment compared to IFN treatment in this large retrospective cohort study. Further, our secondary analyses suggested that both insufficient controlling for baseline risks for HCC and selection bias likely drove the previously reported associations between DAA treatment and increased HCC risk,” the authors wrote.