Treatment with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) appears to be associated with an early high incidence of hepatocellular carcinoma (HCC) in patients with undefined or nonmalignant nodules, as well as in those with a history of complete response to HCC treatment, according to a study published in the Journal of Hepatology.

Previous data have demonstrated an unexpected early increased incidence, recurrence, and clinical aggressiveness of HCC in patients with HCV cirrhosis after treatment with DAAs; however, other studies have not corroborated this. Therefore, researchers performed a prospective study in 1161 patients without HCC (group 1) and 124 patients with cirrhosis who had received a curative treatment for HCC (group 2) who were receiving DAA treatment for HCV-related cirrhosis.

During a median study time of 17 months among participants in group 1 and 15 months in group 2, de novo HCC developed in 48 patients and recurred in 40 patients. A peak of HCC incidence was observed at 4.2 months in group 1 patients with undefined/nonmalignant liver nodules and at 7.7 months in group 2. The presence of undefined/nonmalignant liver nodules, ascites detected any time before enrollment, and alpha-fetoprotein log-value were independently associated with the incidence of de novo HCC, while history of alcohol abuse and history of recurrence of HCC were associated with HCC recurrence. A two-year cumulative incidence of 5.4% (95% CI, 3.8-7.7) was estimated among 1048 patients with no nodules, 3.1% (95% CI, 0.4-20.2) among 40 patients with hemangioma and 13.6% (95% CI 7.3-24.7) among 73 patients with undefined/nonmalignant liver nodules.

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No evidence of increased clinical tumor aggressiveness was reported in de novo or recurrent HCC. Researchers did highlight that their findings that the highest value of HCC incidence occurred within the first year after starting antiviral treatment is in line with other studies could suggest that DAA treatment promotes progression of premalignant nodules or clinically undetected clones of liver cell cancer to clinically overt HCC.

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“In conclusion, this study suggests a time dependent relationship between de novo appearance of HCC and the presence of [undefined/nonmalignant liver nodules] detected before the beginning of DAA treatment,” stated the study authors. They added that, “Whether the group of patients with [undefined/nonmalignant liver nodules] includes patients with a clinically undetectable nests of cancer cells or with precancerous lesions progressing to HCC upon DAA treatment remains unanswered, since no direct relationship was demonstrated between DAA treatment and HCC development.”


Sangiovanni A, Alimenti E, Gattai R, et al. Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis [published online March 31, 2020]. J Hepatol. doi:10.1016/j.jhep.2020.03.030