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
HCV GENOTYPES: HK SCENARIO N=1055 (1998-2004) Zhou et al J Med Virol 2006
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
HCV-6: MOST COMMON GENOTYPE IN GUANGDONG PROVINCE, CHINA HCV Genotype Mean age: 34.4 years Fu et al J Viral Hepat 2011
PHYLOGENETIC ANALYSIS OF HCV-6 IN DRUG USERS (N=210) Fu et al PLoS One 2012
HCV GENOTYPE 6 INCREASING PREVALENCE IN SOUTHERN CHINA Fu et al PLoS One 2012
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
HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY Genotype 1 6 p=0.648 Seto WK et al J Hepatol 2010
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 95-100% 50% IFN/RBV 48 weeks PEG/RBV 48 weeks 45% 75% 25% 0% IFN-α2b 24 weeks 4% IFN-α2b 48 weeks 9% 27% 1985 20yrs 2004 2011 2015
SVR FOR DIFFERENT GENOTYPES (PEG-IFN AND RIBAVIRIN) Genotype
SVR FOR HCV GENOTYPE 6 REGION STUDY SVR 48 weeks SVR 24 weeks Hong Kong Fung et al J Infect Dis 2008 86% - California, USA Lam et al Hepatology 2010 79% 70% Vietnam Thu Thuy et al J Hepatol 2012 86% 81%
GENOME-WIDE ASSOCIATION STUDIES (GWAS) Gastroenterology 2010 Hepatology 2010
CLINICAL IMPACT OF GWAS Fatty Liver PNPLA3 rs738409 HCV IL28B rs12979860 / rs8099917 Tanaka et al Nat Genet 2009
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
C allele (rs12979860) is associated with SVR Ge et al, Nature, 2009
SVR rate (%) IL28B-TYPE PREDICTS SVR p<0.0001 p=0.2 p<0.0001 p=0.7 p=0.02 p=0.3 p=0.09 100 80 60 40 20 0 27 33 Caucasians N=1171 69 13 15 48 African Americans N=300 27 38 Hispanics N=116 56 TT CT CC TT CT CC TT CT CC Thompson et al Gastroenterology 2010
IL28B POLYMORPHISM IS STRONGEST BASELINE PREDICTOR OF SVR USING PEGIFN/RBV Odds ratio (95% CI) P < 0.0001 P = 0.004 P < 0.0001 P < 0.0001 P < 0.0001 P < 0.0001 N = 1,604 Covariates: rs12979860 (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;139:120-129.
The global prevalence of C/T alleles at SNP rs12979860 may explain the recognized geographical variation in SVR rates rs12979860: High proportion of CC allele in Asia Reprinted with permission from Macmillan Publishers Ltd: Nature. 2009;461:798-801.
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
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
SVR rate (%) IL28B GENOTYPE IS ASSOCIATED WITH INCREASED SVR IN NON-RVR G2/3 PATIENTS P=0.34 P=0.0002 100 80 80 83 84 58 78 60 40 20 0 TT CT CC 32 TT CT CC RVR (61%) no RVR (39%) Mangia et al Gastro, 2010
INOSINE TRIPHOSPHATASE (ITPA) Fellay et al Nature 2010
ITPA VARIANTS PROTECT AGAINST RIBAVIRIN- RELATED ANEMIA IN HCV GENOTYPE 1 Thompson et al Gastroenterology 2010
SVR ITPA RS1127354 POSSIBLY PREDICTS SVR IN HCV-1 Kurosaki et al Antivir Ther 2011
Thompson et al J Hepatol 2012 ITPA Polymorphism s? Platelet Hb
HOW ABOUT HCV GENOTYPE 6? Experience in QMH and PMH
Seto WK et al. Am J Gastroenterol 2011
228 patients treated with pegylated interferon and ribavirin Genotype 1: 105 Genotype 6: 97 Other genotypes: 26 28 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
IL28B rs8099917 Chromosome 19 ITPA rs1127354 Chromosome 20 Applied Biosystems TaqMan SNP Genotyping Assay Seto et al J Viral Hepat in press
Effect of IL28B and ITPA genotypes on SVR rates p=0.014 p=0.640 IL28B Genotype ITPA Genotype
FACTORS ASSOCIATED WITH SVR Factor p Factor p Age 0.498 Gender 0.601 Type of IFN 0.553 Albumin 0.707 Bilirubin 0.747 ALT 0.697 HCV RNA 0.968 APRI 0.617 Ribavirin dose reduction 0.160 IL28B 0.014 ITPA 0.387 AST 0.500 Platelet 0.161 Seto et al J Viral Hepat in press
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
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
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
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 BMS824393 NSSA (BMS) Vertex Roche BMS/Pharmasse t BMS790052 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) BI201335 (BI) BMS650032 (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) BI201127 (BI) R0622 (Roche) Medivir (Tibotec) BMS-791325 (nuc/non-nuc BMS)) ABT33. ABT7072 (ABT) IDX375 (Idenix/NV S) GL59393 (GSK) Non Nuc- Polymerase inhibitors PSI938(Pharmasset) Biocryst INX189 (Inhibitex) Protease inhibitors
% SVR IL28B STILL USEFUL IN TRIPLE THERAPY FOR HCV-1 (SPRINT-2 TRIAL) 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 * *~90% eligible for short duration therapy Poordad et al Gastroenterology 2012
IL28B AND IFN-FREE REGIMENS (DANOPREVIR AND MERICITABINE) Chu et al Gastroenterology 2012
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
ACKNOWLEDGEMENTS Prof. MF Yuen Prof. CL Lai Dr. Kevin Liu Dr. Owen TY Tsang (PMH) Dr. Jacky MC Chan (PMH)
THANK YOU!