Search

Introduction: The minor IL28b SNPs rs8099917& rs12979860 have been associated with progression to chronic infection and failure of antiviral therapy in HCV patients. Considerable variation in carriage frequencies have been reported in different ethnicities. Our AIM was to study their allele frequency and genotype distribution in our ethnic specific general population and in a cohort of chronic liver diseases patients. Methods: Rs8099917 genotyping was performed by PCR/SSCP analysis; rs12979860 by PCR/RFLP. A total of 255 subjects were studied. The control Group A consisted of 79 randomized and anonymized ethnic DNA bank samples; Group B – 50 chronic HBV patients; Group C – 83 HCV patients; Group D – 43 patients, advanced liver disease and transplanted livers (Ci/Ltx). HCV RNA, HBV DNA and genotyping was done by Roche TaqMan IVD FDA approved RT-PCR. Results: The allele frequency of rs8099917 in the control group reached Hardy Weinberg equilibrium (HWE); the study population did not. The frequencies of GG,GT and TT genotypes were as follows. In Group A: 0.05, 0.33, 0.62; in Group B: 0.07, 0.4, 0.54; in Group C: 0.07, 043, 0.33 Group D: 0.05, 0.25, 0.13 respectively. The difference of the allele frequencies was statistically significant for Group A vs. combined (B+C+D), p =0.0071 and for Group A vs. Group D, p =0.0062, two-tailed Fisher’s exact test. Peg-interferon/ribavirin therapy received 28 HCV (genotype G1=25). Of those who completed 48 week therapy, 6 had SVR and 8 were non-responders or relapsers. In the SVR group, G containing genotypes were significantly lower compared to the NR/R group Chi sq.=5.091, P =0.012. For rs12979860 the control group is not yet studied, but the patients group (No=80) was in HWE, with genotype frequency of CC 0.325, CT 0.475, TT 0.2. Conclusion: The frequency of rs8099917 in healthy individuals in our region is similar to that of Italians from Toscana. The prevalence of the minor/heterozygous genotype in HCV patients was higher as compared to the reported for Spanish, Australian and Swiss populations. Minor allele frequency was greater in the HCV therapy non-responder patients. The rs12979860 genotype frequency in patients with advanced chronic liver disease and liver transplant recipients was similar to the recently reported for Ci/Ltx by Fabris in J.Hepatol. References: Fabris C. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC. J Hepatol 2011;54(4):716–22. [Copyright &y& Elsevier]

Background: Management of nonalcoholic steatohepatitis (NASH) is an unmet clinical need. Lanifibranor is a pan-PPAR (peroxisome proliferator-activated receptor) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH.Methods: In this phase 2b, double-blind, randomized, placebo-controlled trial, patients with noncirrhotic, highly active NASH were randomly assigned in a 1:1:1 ratio to receive 1200 mg or 800 mg of lanifibranor or placebo once daily for 24 weeks. The primary end point was a decrease of at least 2 points in the SAF-A score (the activity part of the Steatosis, Activity, Fibrosis [SAF] scoring system that incorporates scores for ballooning and inflammation) without worsening of fibrosis; SAF-A scores range from 0 to 4, with higher scores indicating more-severe disease activity. Secondary end points included resolution of NASH and regression of fibrosis.Results: A total of 247 patients underwent randomization, of whom 103 (42%) had type 2 diabetes mellitus and 188 (76%) had significant (moderate) or advanced fibrosis. The percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher among those who received the 1200-mg dose, but not among those who received the 800-mg dose, of lanifibranor than among those who received placebo (1200-mg dose vs. placebo, 55% vs. 33%, P = 0.007; 800-mg dose vs. placebo, 48% vs. 33%, P = 0.07). The results favored both the 1200-mg and 800-mg doses of lanifibranor over placebo for resolution of NASH without worsening of fibrosis (49% and 39%, respectively, vs. 22%), improvement in fibrosis stage of at least 1 without worsening of NASH (48% and 34%, respectively, vs. 29%), and resolution of NASH plus improvement in fibrosis stage of at least 1 (35% and 25%, respectively, vs. 9%). Liver enzyme levels decreased and the levels of the majority of lipid, inflammatory, and fibrosis biomarkers improved in the lanifibranor groups. The dropout rate for adverse events was less than 5% and was similar across the trial groups. Diarrhea, nausea, peripheral edema, anemia, and weight gain occurred more frequently with lanifibranor than with placebo.Conclusions: In this phase 2b trial involving patients with active NASH, the percentage of patients who had a decrease of at least 2 points in the SAF-A score without worsening of fibrosis was significantly higher with the 1200-mg dose of lanifibranor than with placebo. These findings support further assessment of lanifibranor in phase 3 trials. (Funded by Inventiva Pharma; NATIVE ClinicalTrials.gov number, NCT03008070.). [ABSTRACT FROM AUTHOR]