Direct–acting Antiviral Treatment for Hepatitis C Virus Infection and Risk of Incident Liver Cancer

A Retrospective Cohort Study

A. W. Singer; K. R. Reddy; L. E. Telep; A. O. Osinusi; D. M. Brainard; M. Buti; A. P. Chokkalingam


Aliment Pharmacol Ther. 2018;47(9):1278-1287. 

In This Article

Abstract and Introduction


Background Eradication of hepatitis C virus (HCV) infection via interferon–based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon–free treatment.

Aims The objective of this retrospective cohort study was to examine the association of direct–acting antiviral (DAA) exposure with risk of incident liver cancer in real–world data.

Methods From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods.

Results Relative to untreated HCV patients, DAA–treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73–0.96), and relative to interferon–based treatment in the pre–DAA era (HR = 0.69, 95% CI: 0.59–0.81).

Conclusions In this large, population–based study, DAA–based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon–based treatment in the pre–DAA era. As additional follow–up time of DAA–treated patients accrues, we anticipate that the long–term benefits of DAA treatment will become more apparent.


Chronic infection with hepatitis C virus (HCV) is a leading cause of hepatocellular carcinoma (HCC) globally.[1] Although the presence of fibrosis and cirrhosis are the primary risk factors for the development of HCC among HCV–infected persons, a number of other patient characteristics, including older age, male sex, diabetes, obesity, smoking, HCV genotype 3 infection, heavy alcohol use and hepatitis B virus co–infection, have been demonstrated to influence HCC risk.[2–8]

A substantial body of evidence indicates that sustained virological response (SVR) following treatment with interferon–based therapy dramatically reduces, but does not eliminate, the risk of developing HCC.[2,9–13] A recent meta–analysis found an approximate 75% reduction in risk following SVR among HCV patients at all stages of fibrosis,[14] though HCV patients still remain at increased risk of HCC for many years following attainment of SVR.[11,15]

Based on the evidence of a reduced risk of HCC following SVR with interferon–based therapy, it has been postulated that the uptake of direct–acting antiviral (DAA) therapy, with its associated high SVR rates and ability to treat populations at the highest risk of HCC, will lead to reductions in HCC incidence among HCV–infected populations.[16,17] In contrast, some recent studies have reported unexpected high incidence[18,19] and recurrence[20] rates of HCC following treatment with DAA therapy, while other studies have found no increased rates or risk of HCC incidence or recurrence[21–26] following DAA treatment. Conclusions from these studies have been complicated by methodological limitations, such as the lack of appropriate control groups, potential confounding and limited follow–up time.[22,27,28] The seriousness of HCC as a potential treatment–related outcome, contrasted with the serious implications of withholding HCV treatment from sick patients due to a potentially unfounded concern of an increased risk of HCC development after DAA therapy,[27] warrants further investigation.

The objective of this study was to examine whether DAA therapy in HCV patients has an impact on the development of liver cancer when compared to untreated and interferon–treated HCV patients in a large, population–based administrative claims database from the United States.