Do DAAs for hepatitis C raise risk of hepatocellular carcinoma?

Naveed Saleh, MD, MS, for MDLinx | September 14, 2018

Direct-acting antivirals for hepatitis C virus (HCV) do not raise the risk for incident hepatocellular carcinoma, according to a recent article in the European Journal of Gastroenterology & Hepatology.


“There are no significant differences between DAA regimens in HCC risk after antiviral treatment,” the authors concluded.

“It is unclear whether there are differences between direct-acting antivirals (DAAs) for hepatitis C virus in risk of hepatocellular carcinoma (HCC) after antiviral therapy,” wrote the authors, led by Elijah J. Mun, MD, Department of Internal Medicine, University of Washington, Seattle, WA. “We aimed to compare different DAA regimens with respect to risk of de novo HCC following antiviral therapy.”

Certain studies have indicated that DAAs heighten the risk for HCC occurrence and recurrence as compared with HCC risk secondary to interferon-based therapy. Some of these studies, however, were low power, short, and lacked adjustment for confounders.

Furthermore, subsequent studies—including a meta-analysis of 41 studies involving more than 13,000 patients—showed no difference in HCC occurrence or recurrence between patients administered DAAs or interferon-based regimens.

Possible mechanisms underlying a relationship between DAAs and HCC are thought to include the impairment of tumor surveillance secondary to rapid suppression of viral replication. Alternatively, either one or more classes of DAA could be carcinogenic. The four classes of DAA include:

  • Nonstructural proteins 3/4A (NS3/4A) protease inhibitors
  • NS5B nucleoside polymerase inhibitors
  • NS5B non-nucleoside polymerase inhibitors
  • NS5A inhibitors

Each of these classes has a different structure and mechanism of action.

In the current study, researchers mined the Veterans Affairs healthcare system to identify 33,137 patients who started one of four DAA-only treatments fHCV between December 2013 and December 2015. The breakdown of sampled patients taking DAAs included:

  • Paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) (n=6,289)
  • Sofosbuvir (n=4,356)
  • Sofosbuvir plus simeprevir (n=3,210)
  • Ledipasvir/sofosbuvir (n=19,282)

The team followed patients in the study until June 2017. They determined HCC risk for each of the four classes using Cox proportional hazards regression with or without adjustment for 22 HCV-associated baseline covariates, including age, sex, race, treatment, genotype, SVR, and cirrhosis.

The mean follow-up for the current study was 1.52 years, and 741 HCC cases were identified by the researchers after 180 days of DAA treatment (annual incidence=1.47%).

Before adjustment for confounders, the proportion of patients taking one of four DAA treatment regimens were:

  • Sofosbuvir plus simeprevir (2.47%)
  • Sofosbuvir (1.91%)
  • Ledipasvir/sofosbuvir (1.26%)
  • PrOD (0.95%).

After adjustment for HCC-associated baseline characteristics, however, no difference in HCC risk was observed.

“Differences in HCC incidence between DAA regimens were explained by differences in baseline characteristics, especially cirrhosis, decompensated cirrhosis, aspartate aminotransferase/square root of alanine aminotransferase ratio, and platelet count,” wrote the authors.

In a secondary analysis that shifted the starting time point for the development of HCC to the initiation of DAA therapy, the researchers also found no differences in HCC incident risk. This finding indicated that DAAs failed to hasten HCC development.

One limitation of the current study is that the researchers assessed only HCC occurrence and not recurrence. They also included some DAA-only regimens that are now utilized only rarely with the advent of newer agents.

“There are no significant differences between DAA regimens in HCC risk after antiviral treatment,” the authors concluded. “This suggests that DAAs do not have direct carcinogenic effects as it would be unlikely for different DAAs to have identical carcinogenic effects.”

This study was funded by the NIH.