Olga Znoyko Moscow State University of Dentistry and Medicine, Moscow

1. Distribution of CC,CT,TT genotypes of IL28B rs12979860 SN and TT,GT,GG genotypes of IL28B rs8099917 SNP  in Moscow patients, clinical implications Olga Znoyko Moscow State University of Dentistry and Medicine, Moscow

2. Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). Successful treatment of chronic hepatitis C virus (HCV) infection with peginterferon/ribavirin is strongly associated with host factors - genetic polymorphisms near the interleukin-28B gene coding for the interferon (IFN)-λ-3 gene on chromosome 19. Clark PJ, Thompson AJ, McHutchison JG. IL28B Genomic-Based Treatment Paradigms for Patients With Chronic Hepatitis C Infection: The Future of Personalized HCV Therapies. Am J Gastroenterol. 2010

3. The Association Between IL-28B Genotype and Response to Peginterferon/Ribavirin in Hepatitis C Gene on chromosome 19, include 2 identified single nucleotide polymorphism (SNPs) that are closely linked rs12979860 and rs8099917 Ge D., 2009 (IDEAL, GWAS) n=1137 McCarthy JJ., 2010 (Candidate gene study) n=231 Tanaka Y..2009 n=142 Suppian V.,2009 (GWAS)n=293+555 Rauch A. 2010(GWAS)n=465 In studies evaluating IL-28B–associated genetic variation, genotype 1–infected persons with the favorable IL-28B genotype were substantially more likely to achieve a sustained virologic response (SVR) to peginterferon/ribavirin vs patients with the unfavorable genotype. Clark PJ, Thompson AJ, McHutchison JG. IL28B Genomic-Based Treatment Paradigms for Patients With Chronic Hepatitis C Infection: The Future of Personalized HCV Therapies. Am J Gastroenterol. 2010

4. The good response variant is associated with a twofold increase in the rate of cure. Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. SVR С/C- favorable IL-28B genotype GE D., Nature. 2009 Sep 17; Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.

5. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV (rs 8099917) N= 914 Rauch A, Kutalik Z, Gastroenterology. 2010 Jan 7. Genetic variation in IL28B Is Associated with Chronic Hepatitis C and Treatment Failure - A Genome-Wide Association Study.

6. The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type. Response Factors to Therapy of CHCWith Future Treatment Regimens Treatment regimen PegIFN exposure RBV exposure DAA exposure Host factors Age, sex, race, obesity, IR, ETOH Genetic factors (IL28B) Response factors IFN + RBV + DAA Viral factors Genotype HCV RNA level Quasispecies (baseline resistance) Disease features Fibrosis, steatosis, coinfection (HBV, HIV)

7. 100 80 60 40 20 0 Virologic Response and Predictors of SVR in G1 Patients Treated with PegIFN and Ribavirin SVR (%) 87% RVR (HCV RNA «-» on week 4 ) No EVR 68% 78 90 16% (90/569) 20% (111/569) 22% (128/569) 162 240 27% 42% (240/569) 34 128 5% 5 111 cEVR HCV RNA «-» on week 12 pEVR decreasing VL 2.0 log on week 12 < 2.0 log on week 12 pEVR RVR cEVR Marcellin P, et al. EASL. April 11-15, 2007;Barcelona, Spain. Poster 613.

8. Virologic Response (RVR and и EVR)andIL-28B genotype (rs12979860) European Americans African - Americans Hispanics Thompson et.al Gastroenterology 2010

9. Impact of IL28B Genotype on the Early and Sustained Virologic Response in Treatment-naïve Patients With Chronic Hepatitis C A. F. STÄTTERMAYERal al lImpact of IL28B Genotype on the Early and Sustained Virologic Response in Treatment-naïve Patients With Chronic Hepatitis C; Clinical Gastroenterology and Hepatology 2010, ;

10. Distribution of CC,CT,TT genotypes of IL28B rs12979860 SN and TT,GT,GG genotypes of IL28B rs8099917 SNP  in Moscow patients, N=164, male – 96, female – 68 and healthy population n=96 Genotype 1b – 46,3% The other genotypes – 53,6% (rs12979860) (rs 8099917) healthy 56%*7%37% * healthy 77% 21% 2% CHC CHC

11. Distribution of CC rs12979860 - TT rs8099917genotypes of IL28B n - 163 n (СС - ТТ) - 52; n (TT- gg) - 8.

12. SVR andDistribution of CC, CT, TT genotypes of IL28B rs12979860 SN SVR (n=25) all genotypes HCV SVR (n=8) 1b genotype HCV rs12979860 CC = 13 TT = 2 CT = 10 rs12979860 CC - 4 TT - 2 CT - 2

13. SVR anddistribution of TT, Тg, gg genotypes of IL28B rs8099917 SN SVR (n=25) all genotypes HCV SVR (n=8) 1b genotype HCV TT- 6 Tg – 1 gg – 1 TT- 17 Tg - 7 gg - 1

14. SVR RVR, EVRanddistribution of CC, CT, TT genotypes of IL28B rs12979860 SN SVR, RVR, EVR anddistribution of TT, Тg, gg genotypes of IL28B rs8099917 SN n – 39 CC- 22, TT- 3, CT - 14. n – 39 TT - 27, Tg - 11, gg - 1.

15. SVR RVR, EVRand distribution of CC, CT, TT genotypes of IL28B rs12979860 SN Patients with 1b genotype SVR, RVR, EVR and distribution of TT, Тg, gg genotypes of IL28B rs8099917 SN Patients with 1b genotype N-17 CC- 9, TT- 3, CT- 5. N – 17 TT -12, Tg – 4,gg – 1

16. Nonresponders ( no SVR) n - 21 TT - 6 Tg - 15 Gg - 0 n – 21 CC - 3 TT - 3 CT - 15.

17. Conclusion • rs12979860 SN distribution distinguish in healthy population and CHC patients • Distribution • of genotypes of IL28B rs12979860 and rs8099917 SNP  in population of CHC with genotype 1b and with SVR,RVR, EVR and in nonresponders is similarto data of previous reports