ROLE OF IL28B AND ITPA POLYMORPHISMS IN DIFFERENT GENOTYPES OF HCV

Transcription

1 ROLE OF IL28B AND ITPA POLYMORPHISMS IN DIFFERENT GENOTYPES OF HCV (Especially HCV-6) WK Seto Clinical Assistant Professor Department of Medicine Queen Mary Hospital The University of Hong Kong

2 HCV GENOTYPES: HK SCENARIO N=1055 ( ) Zhou et al J Med Virol 2006

3 HCV: HK SCENARIO (QMH) Genotype 1 (n=220) (n=138) Route of Transmission Genotype 6 (n=101) (n=78) Transfusion Transfusion 9% 20% 71% IV drug use Others 28% 16% 56% IV drug use Others p<0.001 Seto WK et al. J Hepatol 2010

4 HCV-6: MOST COMMON GENOTYPE IN GUANGDONG PROVINCE, CHINA HCV Genotype Mean age: 34.4 years Fu et al J Viral Hepat 2011

5 PHYLOGENETIC ANALYSIS OF HCV-6 IN DRUG USERS (N=210) Fu et al PLoS One 2012

6 HCV GENOTYPE 6 INCREASING PREVALENCE IN SOUTHERN CHINA Fu et al PLoS One 2012

7 Probability of cirrhotic complications HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY Genotype 1 6 p=0.358 Time to develop complications (Years) Seto WK et al J Hepatol 2010

8 HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY Genotype 1 6 p=0.648 Seto WK et al J Hepatol 2010

9 Cure rate Future Trends in HCV Therapy 100% 75% Combo DAA 1 st DAA + 2 nd DAA Triple Rx NO IFN 12 wks Protease inhibitor + PEG/RBV 24 weeks % 50% IFN/RBV 48 weeks PEG/RBV 48 weeks 45% 75% 25% 0% IFN-α2b 24 weeks 4% IFN-α2b 48 weeks 9% 27% yrs

10 SVR FOR DIFFERENT GENOTYPES (PEG-IFN AND RIBAVIRIN) Genotype

11 SVR FOR HCV GENOTYPE 6 REGION STUDY SVR 48 weeks SVR 24 weeks Hong Kong Fung et al J Infect Dis % - California, USA Lam et al Hepatology % 70% Vietnam Thu Thuy et al J Hepatol % 81%

12 GENOME-WIDE ASSOCIATION STUDIES (GWAS) Gastroenterology 2010 Hepatology 2010

13 CLINICAL IMPACT OF GWAS Fatty Liver PNPLA3 rs HCV IL28B rs / rs Tanaka et al Nat Genet 2009

14 IFN-lambda (λ) is a compelling biological candidate Type 3 IFN IFNλ-1/ 2/ 3 = IL29, IL28A, IL28B All signal via the IFNL-R Expression of IFNL-R restricted IFNλ has antiviral activity against HCV Common signaling pathway Kelly et al Gut 2011

15 C allele (rs ) is associated with SVR Ge et al, Nature, 2009

16 SVR rate (%) IL28B-TYPE PREDICTS SVR p< p=0.2 p< p=0.7 p=0.02 p=0.3 p= Caucasians N= African Americans N= Hispanics N= TT CT CC TT CT CC TT CT CC Thompson et al Gastroenterology 2010

17 IL28B POLYMORPHISM IS STRONGEST BASELINE PREDICTOR OF SVR USING PEGIFN/RBV Odds ratio (95% CI) P < P = P < P < P < P < N = 1,604 Covariates: rs (2-level), ethnicity (4-level), age ( 40), gender, BMI (< 30), VL ( 600,000), ALT ( ULN), fasting glucose (< 5.6), hepatic steatosis (N/Y[> 0%]), fibrosis (METAVIR F012), RBV (> 13 mg/kg/d) Thompson AJ, et al. Gastroenterology 2010;139:

18 The global prevalence of C/T alleles at SNP rs may explain the recognized geographical variation in SVR rates rs : High proportion of CC allele in Asia Reprinted with permission from Macmillan Publishers Ltd: Nature. 2009;461:

19 SUMMARY : IL28B-TYPE AND GENOTYPE 1 HCV is strongly associated with increased SVR rate explains much of the ethnic differences in response rates is the strongest pre-treatment predictor of SVR increases SVR rate 2-fold in non-rvr patients

20 IL28B predicts SVR? Thompson et al Gastoenterology 2010 Yes Mangia et al Gastoenterology 2010 Selected Populations Moghaddam et al Hepatology 2011 No Asselah et al J Hepatol 2012 Yes

21 SVR rate (%) IL28B GENOTYPE IS ASSOCIATED WITH INCREASED SVR IN NON-RVR G2/3 PATIENTS P=0.34 P= TT CT CC 32 TT CT CC RVR (61%) no RVR (39%) Mangia et al Gastro, 2010

22 INOSINE TRIPHOSPHATASE (ITPA) Fellay et al Nature 2010

23 ITPA VARIANTS PROTECT AGAINST RIBAVIRIN- RELATED ANEMIA IN HCV GENOTYPE 1 Thompson et al Gastroenterology 2010

24 SVR ITPA RS POSSIBLY PREDICTS SVR IN HCV-1 Kurosaki et al Antivir Ther 2011

25 Thompson et al J Hepatol 2012 ITPA Polymorphism s? Platelet Hb

26 HOW ABOUT HCV GENOTYPE 6? Experience in QMH and PMH

27 Seto WK et al. Am J Gastroenterol 2011

28 228 patients treated with pegylated interferon and ribavirin Genotype 1: 105 Genotype 6: 97 Other genotypes: patients consent not obtained 6 patients defaulted followup 2 patients coinfected with HBV 1 patient coinfected with HIV 60 patients included in current study Seto et al J Viral Hepat in press

29 IL28B rs Chromosome 19 ITPA rs Chromosome 20 Applied Biosystems TaqMan SNP Genotyping Assay Seto et al J Viral Hepat in press

30 Effect of IL28B and ITPA genotypes on SVR rates p=0.014 p=0.640 IL28B Genotype ITPA Genotype

31 FACTORS ASSOCIATED WITH SVR Factor p Factor p Age Gender Type of IFN Albumin Bilirubin ALT HCV RNA APRI Ribavirin dose reduction IL28B ITPA AST Platelet Seto et al J Viral Hepat in press

32 RIBAVIRIN DOSE REDUCTION 19 patients require reduction of ribavirin dose after median treatment duration of 8 (range 2-32) weeks 37.8% 21.7% Seto et al J Viral Hepat in press

33 Median reduction in hemoglobin (g/dl) ITPA genotypes and the median reduction in hemoglobin from baseline CA genotype (n=23) CC genotype (n=37) p<0.05 (all time points) Error bars depict interquartile range Seto et al J Viral Hepat in press

34 Median reduction in platelet count (x 10 9 /L) ITPA genotypes and the median reduction in platelet count from baseline CA genotype (n=23) CC genotype (n=37) Error bars depict interquartile range Seto et al J Viral Hepat in press

35 THE CONFUSING FUTURE OF HCV THERAPY DAA combinations Gilea d Preclinical Phase I BI Nuc- Polymerase inhibitors Others NS5A inhibitor MSD Idenix GS K Nitazoxanide (Romark) INF lambada Taribavirin (Zymogen / (Valeant) NovoNordisk DEB025 cyclophilins AZD07259 NSSA (AZN) Presidio Enanta Verte x BMS NSSA (BMS) Vertex Roche BMS/Pharmasse t BMS NSSA (BMS) GS9256 (Gilead) TMC435 (J&J/Tobizer) MK7009 (MSD) MK5172 (MSD) Phase II Phase III Approved Boceprevir Telaprevir (MSD) (J&J/Vertex) ABT450 (ABT) BI (BI) BMS (BMS) ITMN-191/R7227 (Roche/Intermune) ACH1625 (Achillion) Japan Tobacco R7128 (Roche/Pharmass et) PSI-7977 (Pharmasset) IDX-184 (Idenix) GS9190 (Gilead) ANA598 (Anadys) VX222 (Vertex) BI (BI) R0622 (Roche) Medivir (Tibotec) BMS (nuc/non-nuc BMS)) ABT33. ABT7072 (ABT) IDX375 (Idenix/NV S) GL59393 (GSK) Non Nuc- Polymerase inhibitors PSI938(Pharmasset) Biocryst INX189 (Inhibitex) Protease inhibitors

36 % SVR IL28B STILL USEFUL IN TRIPLE THERAPY FOR HCV-1 (SPRINT-2 TRIAL) * *~90% eligible for short duration therapy Poordad et al Gastroenterology 2012

37 IL28B AND IFN-FREE REGIMENS (DANOPREVIR AND MERICITABINE) Chu et al Gastroenterology 2012

38 CONCLUSIONS Prevalence of HCV-6 increasing in Southern China IL28B polymorphisms predict SVR in chronic HCV-6 ITPA polymorphisms predict degree of ribavirin-related anemia in HCV-6 Usefulness of IL28B in new HCV therapies still present but attenuated

39 ACKNOWLEDGEMENTS Prof. MF Yuen Prof. CL Lai Dr. Kevin Liu Dr. Owen TY Tsang (PMH) Dr. Jacky MC Chan (PMH)

40 THANK YOU!