Effect of the PNPLA3 I148M polymorphism on the outcome of peg-interferon plus ribavirin treatment in chronic hepatitis C

Background & Aims : Homozygosity for the Patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M polymorphism (p.148M/M) has been associated with steatosis, fibrosis progression, and hepatocellular carcinoma in chronic hepatitis C (CHC) patients, but the effect on treatment outcome is still controversial. Aim of this study was to evaluate the effect of p.148M/M on the rate of sustained virological response (SVR) and viral kinetics in CHC patients who underwent standard of care (SOC) antiviral therapy with peg-interferon and ribavirin, stratified according to viral genotype (genotype 2 (gen2) vs. others), and severity of fibrosis (Metavir < or > 2). Patients: 602 naïve consecutive patients from two tertiary referral centers in Milan and one in Vienna, for whom DNA samples and liver biopsy were available. Mean age 50.8±12 years, 39% were females, 61% gen1, 17% gen2, 6% gen3, 16% gen4, 30% had advanced fibrosis, 33% were IL28B rs12979860 CC. Results: p.148M/M was detected in 49 patients (8%), and was associated with advanced fibrosis (21/49, 43% vs. 158/553, 28%; p=0.049), but not with demographic, anthropometric, and virological parameters. The p.148M/M genotype was not significantly associated with SVR in the whole series (25/49, 51% vs. 326/553, 59%; p=0.29), but it was associated with a lower SVR rate in non-gen2 patients with advanced fibrosis (4/18, 22% vs. 64/135, 48%; p=0.047). In these subjects, p.148M/M was also associated with a lower rate of complete early viral response (5/18, 28% vs. 80/135, 59%; p=0.021). SVR was not influenced by p.148M/M in gen2 patients and in patients without advanced fibrosis. In non-gen2 patients, SVR was independently associated with younger age, absence of advanced fibrosis, IL28B CC genotype, completion of adequate dose treatment (≥80/80/80%), and p.148M/M (OR 0.70, 95% c.i 0.46-1.0). Conclusions: PNPLA3 genotype seems to represent a negative prognostic factor for antiviral treatment outcome independently of the effect on fibrosis progression, but only in a very selected subgroup of difficult-to-cure CHC patients (3% in this series). However, whether it also influences the outcome of triple therapies with direct antiviral agents needs to be evaluated in future studies