Association of serum interferon‐λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct‐acting antiviral agents

Abstract

Aim Although the efficacy of hepatitis C virus (HCV) treatment is improved dramatically by direct‐acting antiviral agents (DAAs), the assessment of hepatocellular carcinoma (HCC) remains important. Interferon lambda 3 (IFN‐λ3) is associated with liver fibrosis and inflammation in chronic hepatitis C (CHC) patients, but its impact on carcinogenesis remains controversial and little is known about its effects after viral clearance. To determine the contribution of IFN‐λ3 to hepatocarcinogenesis after HCV clearance, we analyzed IFNL3 genotypes and serial serum IFN‐λ3 levels in CHC patients who achieved sustained virologic responses (SVR). Methods This study comprised 201 CHC patients treated with DAAs. Serum samples were collected sequentially and IFN‐λ3 levels were quantified by chemiluminescence enzyme immunoassay. The IFNL3 polymorphism (rs8099917) was genotyped in 195 patients. Results One hundred and twenty‐five patients were rs8099917 T/T and 70 were non‐T/T. Serum IFN‐λ3 levels did not differ significantly with IFNL3 genotype, dropped markedly by 1 week and remained low up to 24 weeks after the end of treatment. Interferon‐λ3 levels were significantly higher after viral clearance in patients who developed HCC and were associated with a higher potential for hepatocarcinogenesis, such as a higher frequency of non‐hypervascular hypointensive nodules (P = 0.046), higher stages of liver fibrosis (P < 0.001), and higher post‐treatment levels of Wisteria floribunda agglutinin positive Mac‐2 binding protein (P < 0.001) and alanine aminotransferase (P < 0.001). Conclusions Serum IFN‐λ3 levels after HCV clearance are associated with the potential for HCC development. Interferon‐λ3 could be helpful for elucidating the relationships among immunologic status, liver fibrosis, liver inflammation, and hepatocarcinogenesis, after achieving SVR.

Comparison of tenofovir versus entecavir on reducing incidence of hepatocellular carcinoma in chronic hepatitis B patients: A systematic review and meta‐analysis

“…Second, our main findings may only be observed in patients treated with nucleotide analogues (adefovir dipivoxil and TDF), but not in those treated with nucleoside analogues (lamivudine and ETV) 46 . NAs have higher serum interferon λ3 level, which has been frequently reported 47 . Interferon λ3 has been shown to have potent antitumor activity in murine HCC models 48 .…”

Residual risk of liver disease after hepatitis C virus eradication

“…Interestingly, a Japanese study on 195 patients with chronic hepatitis C treated with DAAs reported that serum IFN-k3 levels were significantly higher after SVR in patients who developed HCC, although they bore no correlation with IFNL3 genotypes, in part probably due to the rarity of the rs8099917 genotype GG among Japanese patients. 78 Finally, Huang et al 79 analysed variants of the major histocompatibility complex class I chain-related A (MICA) marker rs2596542 in 42 patients who developed HCC and 84 age-, sex-and cirrhosis propensity scorematched controls who did not develop HCC, all after SVR. Although serum MICA levels predicted HCC, the correlation between increased MICA levels and HCC risk was only present in patients with the GG genotype.…”

Repurposing approved drugs on the pathway to novel therapies

“…As IFN levels in uninfected individuals are typically vanishingly low, the high persistent presence of IFNs and/or their induced genes (ISGs) may also complicate or even cause other diseases, such as lupus or atopic dermatitis. Recent results indicate that high serum IFN‐ʎ3 levels after treatment for HCV with DAAs may correlate with the development of hepatic carcinoma . Thus several IFN neutralizing therapies have been tested for lupus.…”