Saturday, April 21, 2018

Hepatocellular carcinoma as a consequence of hepatitis C direct-acting anti-virals-the great urban myth of hepatology

Aliment Pharmacol Ther. 2018 May;47(10):1418-1419. doi: 10.1111/apt.14634.

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This editorial is linked to Singer et al paper; Direct‐acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study, published 7 March 2018

Editorial: hepatocellular carcinoma as a consequence of hepatitis C direct‐acting anti‐virals—the great urban myth of hepatology
Hussaini T1,2, Zhu J2,3, Yoshida EM2,3.

Achieving sustained virologic response (SVR), the surrogate marker for the cure of chronic hepatitis C virus (HCV) infection, has long been associated with decreased all‐cause and liver‐related mortality including progression to end stage liver disease or development of hepatocellular carcinoma.1 During the interferon (IFN) era, many studies demonstrated decreased incidence of HCC after HCV eradication, although the risk was not eliminated, especially in patients with advanced hepatic fibrosis or cirrhosis.2-4 With the availability of direct acting antiviral agents (DAAs), offering high SVR rates of greater than 90%, a dramatic decrease in HCC incidence was expected. Single‐center observational studies, however, reported an unexpected increase in both HCC occurrence and recurrence following DAA associated SVR.5-8 The majority of these studies were limited by methodological flaws: small sample size, lack of control groups and short follow‐up time, resulting in a suspicion of selection bias and other potential confounders. Nonetheless, these reports raised concern that DAA therapy may promote HCC recurrence by altering immune surveillance after HCV eradication.

Recently, the results of a large retrospective cohort trial studying 62 352 HCV infected patients treated with IFN, DAAs, or a combination of both, challenged the findings of the earlier studies.9 Based on HCV treatment regimens, patients were divided into three groups; IFN only (N = 35 871), DAAs + IFN (N = 4535), and DAA only (N = 21 948). Although the HCC incidence was higher with DAA only therapy, after adjusting for important baseline confounders, there was no difference in HCC incidence between the groups. In fact, SVR was associated with significantly lower incidence of HCC regardless of regimen utilised.

In a recent issue of Alimentary Pharmacology & Therapeutics, Singer and colleagues, report the results of another large population based study that further dispels the myth of increased HCC occurrence after DAA associated SVR. They studied 30 183 patients treated with DAAs, 12 948 patients treated with IFN‐based therapy and 137 502 treatment‐naïve patients.10 The unadjusted incidence rate of HCC was higher in DAA treated group as compared to both IFN treated (unadjusted HR = 1.22, 95% CI: 1.04‐1.42) and treatment naïve patients (unadjusted HR of 1.84 (95% CI: 1.65‐2.05). However, after adjusting for known baseline risk factors for HCC such as older age, male gender and advanced liver disease, DAA therapy was associated with reduced incidence of HCC as compared to untreated (adjusted HR = 0.84, 95% CI: 0.73‐0.96) and IFN treated individuals (adjusted HR = 0.84, 95% CI: 0.73‐0.96).

The introductions of DAA regimens have revolutionised HCV therapy, both in terms of outstanding SVR rates and excellent tolerability profiles. They offer a chance for virological cure in those with few treatment options due to age or advanced liver disease. Therefore, it is not surprising that the unadjusted incident rate of HCC is higher in cohorts treated with DAAs as compared to IFN based therapy. The results of the recent large studies that were designed to control for known HCC risk factors such as older age and advanced liver disease have again demonstrated that HCV eradication reduces the risk of HCC regardless of anti‐viral regimen. We are therefore confident that DAAs do not increase the risk of HCC.

Declaration of personal: Drs. Hussaini and Zhu have no conflict of interest to declare Dr. Eric Yoshida has been an investigator of clinical trials sponsored by Gilead, Merck, Abbvie, Janssen, Intercept, Genfit, Springbank. He has received honoraria for CM/ad board lectures from Gilead Canada, Abbvie Canada, Merck Canada, Celgene Canada, Intercept Canada.


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