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.

Linked Content
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  https://doi.org/10.1111/apt.14593.

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.

ACKNOWLEDGEMENTS
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.

FUNDING INFORMATION
None.

References
1Van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all‐cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584‐2593.
Google Scholar
2Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck‐Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta‐analysis of observational studies. Ann Intern Med. 2013;158:329‐337.
Google Scholar
3Singal AK, Singh A, Jaganmohan S, et al. Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus‐related cirrhosis. Clin Gastroenterol Hepatol. 2010;8:192‐199.
Google Scholar
4Van der Meer AJ, Feld JJ, Hofer H, et al. Risk of cirrhosis‐related complications in patients with advanced fibrosis following hepatitis C virus eradication. J Hepatol. 2017;66:485‐493.
Google Scholar
5Reig M, Marino Z, Perello C, et al. Unexpected high rate of early tumor recurrence in patients with HCV‐ related HCC undergoing interferon‐free therapy. J Hepatol. 2016;65:719‐726.
Google Scholar
6Kozbial K, Moser S, Schwarzer R, et al. Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon‐free direct‐acting antiviral treatment. J Hepatol. 2016;65:856‐858.
Google Scholar
7Cardoso H, Vale AM, Rodrigues S, et al. High incidence of hepatocellular carcinoma following successful interferon‐free antiviral therapy for hepatitis C associated cirrhosis. J Hepatol. 2016;65:1070‐1071.
Google Scholar
8Conti F, Buonfiglioli F, Scuteri A, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV‐ related cirrhosis treated with direct‐acting antivirals. J Hepatol. 2016;65:727‐733.
Google Scholar
9Ioannou GN, Green PK, Berry K. HCV eradication induced by direct‐acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2018;68:25‐32.
Google Scholar
10Singer AW, Reddy KR, Telep LE, et al. Direct‐acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study. Aliment Pharmacol Ther. 2018;47:1278‐1287.
Google Scholar