Neil Osterweil

November 13, 2016

BOSTON — Direct-acting antiviral agents do not appear to increase risk for liver cancer in patients with hepatitis C infection and cirrhosis, but the drugs could make existing but previously undetected cancers worse and harder to treat, according to results from a large-scale prospective study.

"An unexpected finding in this population is that 50% of the patients who developed a tumor early in the course of treatment or just after stopping treatment developed a more aggressive type of tumor than what we usually see in the course of disease," said lead investigator Alfredo Alberti, MD, professor of gastroenterology at the University of Padova in Italy.

Dr Alberti and his colleagues followed 3075 patients with hepatitis C infection for a mean of 300.8 days after the start of direct-acting antiviral therapy. He presented the results here at The Liver Meeting 2016.

Cumulative incidence rates of hepatocellular carcinoma were not significantly different for patients with stage F3 advanced fibrosis (0.23% per person per year), cirrhosis patients with a Child–Pugh A score (1.64%), or cirrhosis patients with a Child–Pugh B score (2.92%). And the incidence rates were no different than those seen in historic control cohorts with similar patients from the same geographic region (Northern Italy) who did not receive antiviral therapy.

This suggests that fibrosis and cirrhosis stage is the driving factor, not oral direct-acting antiviral agents, Dr Alberti explained.

But the severity of hepatocellular carcinoma did appear to correlate with the antiviral therapy over a 540-day follow-up period.

Table. Disease Severity in the 41 Patients Who Developed Hepatocellular Carcinoma

Disease Severity n %
1 nodule, with typical vascular patterns 20 48.8
2 or 3 nodules 5 12.2
>3 nodules or infiltrative hepatocellular carcinoma 16 39.0


Five (12.2%) of the patients who developed liver cancer had portal vein thromboses, and four (9.7%) had extrahepatic metastases.

At 12 weeks, cancers were more aggressive in the hepatocellular carcinoma patients who did not achieve a sustained viral response to direct-acting antiviral therapy than in those who achieved a response and in those whose response was undetermined (53.8% vs 33.3% vs 28.6%).

Liver cancer was diagnosed at week 4 in three patients, at week 8 in three patients, at week 12 in six patients, from week 12 to week 23 in 13 patients, and after the end of treatment in 16 patients.

On multivariate analysis that looked at sex, hepatitis C genotype, aspartate transaminase to platelet ratio index (APRI), Child–Pugh score, direct-acting antiviral regimen, and sustained viral response at 12 weeks, the only significant predictor of hepatocellular carcinoma was achievement of sustained viral response at 12 weeks (hazard ratio [HR], 0.20; P = .001).

There was a trend toward hepatocellular carcinoma in patients with an APRI score of at least 2.5 (HR, 1.83), but it was not significant.

Continued Monitoring

Dr Alberti and his colleagues hypothesize that when viral replication is halted, there are dramatic changes in the immunologic and molecular microenvironment in the liver and in tumor suppression mechanisms, which could allow or even promote the growth of previously undiagnosed microscopic hepatocellular carcinoma foci.

"Therefore, it is mandatory that patients treated with DAAs with advanced liver disease continue to be monitored for HCC," Dr Alberti emphasized.

We're done with the virus, but we're not done with liver care.

This finding points to the need for careful pretreatment screening and continued monitoring of patients treated with direct-acting antivirals for hepatitis C, said session moderator Raymond Chung, MD, director of hepatology at the Massachusetts General Hospital in Boston.

"We have to be clear about who the patients are who have advanced fibrosis, and are therefore at risk for liver cancer," he told with Medscape Medical News.

"We don't want to simply return these patients to sender and say that we're done. We are not done with them; we're done with the virus, but we're not done with liver care," he explained.

Dr Alberti reports being on advisory committees or review panels for Merck, Roche, Gilead, AbbVie, and Janssen; receiving grants or research support from Merck, Gilead, AbbVie, and Janssen; and speaking for Novartis and BMS. Dr Chung reports receiving institutional grants from Gilead, AbbVie, Merck, and BMS.

The Liver Meeting 2016: American Association for the Study of Liver Diseases (AASLD): Abstract 19. Presented November 13, 2016.


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