Hepatitis C resistance to NS5A inhibitors:Is it going to be a problem?

Treatment of hepatitis C virus(HCV) infection has evolved greatly through the recent decade. The availability of direct-acting antiviral agents(DAAs) targeting the functional proteins of HCV has resulted in the introduction of DAA-based combination therapies,providing an optimal rate of treatment success. Among the DAAs,NS5 A inhibitors are used in most of the introduced and approved HCV antiviral regimens. Resistance-associated substitutions(RASs) are amino acid substitutions in HCV protein sequences that result in decreased antiviral efficacy of the HCV DAAs. Among the HCV RASs,the NS5 A RASs were found to effectively modify and decrease treatment response to NS5 A inhibitor-containing regimens. As a baseline predictor of treatment response,NS5 A RAS draws attention for pretreatment testing in targeted patient groups. Given NS5 A RASs are either naturally-occurring or DAA-selected,the application of NS5 A RAS testing can be considered in two settings of NS5 A inhibitor-na?ve patients and NS5 A inhibitor-experienced patients. Less than 5% of NS5 A inhibitor-na?ve patients harbor naturally-occurring NS5 A RAS with high resistance level(> 100 X resistance foldchange). In NS5 A inhibitor-na?ve patients,NS5 A RAS testing accompanied by treatment optimization cannot increase treatment response more than 2%-3%,while in NS5 A inhibitor-experienced patients,> 75% are found to have NS5 A RASs > 100 X and NS5 A RAS testing in this group of patients seems to be reasonable. This editorial will address the debate on the application of NS5 A RAS testing and will discuss if the NS5 A RAS testing has any role in clinical management of hepatitis C.

Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients

AIM: To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ(IFNL) polymorphisms. METHODS: This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type ofpegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a(Pegaferon®) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus(HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes.RESULTS: A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men(92.8%). The most frequent HCV genotype was type-1, infecting 93/152(61.2%) patients. Sustained virologic response(SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2%(52/57) of patients with the IFNL rs12979860 CC genotype and 82.1%(78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT(39/45; 86.7%) and non-TT(61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR(OR = 6.2; 95%CI: 1.2-31.9; P = 0.03).CONCLUSION: The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.

Primary liver cancer spectrum:current knowledge and the next steps

Hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)constitute the main subtypes of primary liver cancers(PLCs)as a major cause of cancer-related mortality and incidence.They emerge from varying quantities and levels of differentiation among major liver cells,comprising hepatocytes,mucin-or non-mucin-producing cholangiocytes,and hepatic progenitor cells(HPCs)with the capability to differentiate into either hepatocytes or cholangiocytes.