Persistent inflammation after HCV eradication may explain liver carcinogenesis

By Wayne Kuznar, for MDLinx
Published May 8, 2018

Key Takeaways

Persistent hepatic inflammation after successful treatment of hepatitis C virus (HCV) infection or liver cirrhosis may contribute to the development of hepatocellular carcinoma (HCC), according to Japanese researchers.

In their study, histopathologic assessment at the time of HCC resection in 10 patients who had achieved a sustained virologic response (SVR) following interferon treatment showed persistence of mild inflammatory changes despite improvement in fibrosis and steatosis.

“Before starting this study, it was our view that histological inflammation would disappear completely after the attainment of an SVR. However, we observed that a mild inflammatory change persisted from 1.8 years to 16.5 years after the confirmation of an SVR in some cases,” they wrote in the International Journal of Medical Sciences.

“To our knowledge, there are no reports indicating that the HCV RNA genome becomes integrated into the human genome,” they added. “HCV is apparently not carcinogenic on its own. We thus speculate that a prolonged histological inflammation is one of the causes of carcinogenesis and that it can be effective even after HCV has been eradicated.”

They studied 602 patients with chronic HCV infection or liver cirrhosis who were treated with interferon between 1992 and 2015, with ribavirin added to those treated between 2009 and 2012, and simeprevir also added to patients treated in 2015. A total of 287 patients achieved SVR, defined as serum negative for HCV RNA for >24 weeks after completing therapy, 14 of whom developed HCC. Nine patients had surgery and one underwent radiofrequency ablation to treat their HCC. A comparison of histopathologic findings before interferon administration with findings at the time of HCC surgery was performed for these 10 patients.

Predicting HCC development solely on the basis of laboratory findings was difficult, the authors revealed. There were no significant changes (P = 0.96) in histologic scores in the 10 patients between interferon treatment and HCC diagnosis.

On histopathology, the shortest time between interferon and HCC detection was 1.8 years in one patient, who showed no evidence of HCC on either computed tomography or ultrasonography prior to interferon treatment. In another interferon-treated patient, carcinogenic changes were documented 16.5 years after the confirmation of SVR. The average time between SVR and HCC detection was 7.2 years.

“While it is not possible to confirm that none of these 10 patients had HCC at the time of the SVR, the longest period from the SVR until HCC detection was 16.5 years, making carcinoma at the time of SVR confirmation extremely unlikely,” the investigators reasoned.

Histopathologic activity scores improved significantly (P = 0.023) from before interferon to the time of surgery for HCC, and all patients showed reductions in both fibrosis and inflammation. However, fibrosis and inflammation were still detectable in all patients.

Nine of the 10 patients had steatosis of the liver before interferon administration. After treatment with interferon, either alone or in combination with other agents, all nine patients still had steatosis.

This study did not include patients treated with relatively new direct-acting antivirals (DAAs). Studies investigating whether HCC development is suppressed in patients successfully treated with DAAs have shown conflicting results.

“This issue merits further study,” the researchers wrote. “Histological examination of the non-cancerous areas around an HCC after an SVR obtained with direct-acting antiviral drugs might be very useful for an optimal treatment selection.”

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