POLYMORPHISMS IN DIFFERENT GENOTYPES OF HCV (Especially HCV-6) WK - PowerPoint PPT Presentation

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 Genotype 6 (n=220) (n=101) Route of Transmission (n=138) (n=78) Transfusion Transfusion 16% 20% IV drug use IV drug use 9% 28% 56% 71% Others 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

HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY Genotype 1 p=0.358 6 Probability of cirrhotic complications 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

Future Trends in HCV Therapy Combo DAA 1 st DAA + 2 nd DAA 100% NO IFN Triple Rx 12 wks Protease inhibitor + PEG/RBV 24 weeks 75% 95-100% Cure rate PEG/RBV 75% 48 weeks 50% 45% IFN/RBV 48 weeks 25% IFN- α 2b 27% IFN- α 2b 48 weeks 24 weeks 9% 4% 0% 2015 1985 20yrs 2004 2011

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 86% - 2008 California, USA Lam et al Hepatology 79% 70% 2010 Vietnam Thu Thuy et al J 86% 81% Hepatol 2012

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

CLINICAL IMPACT OF GWAS HCV Fatty Liver IL28B PNPLA3 rs12979860 / rs738409 rs8099917 Tanaka et al Nat Genet 2009

IFN-lambda ( λ ) is a compelling biological candidate • Type 3 IFN • IFN λ -1/ 2/ 3 = IL29, IL28A, IL28B • All signal via the IFNL-R • Expression of IFNL-R restricted • IFN λ 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

IL28B -TYPE PREDICTS SVR p <0.0001 p <0.0001 p =0.02 p =0.2 p =0.7 p =0.3 p =0.09 100 SVR rate (%) 80 69 56 60 48 38 40 33 27 27 15 20 13 TT CT CC TT CT CC TT CT CC 0 Caucasians African Hispanics Americans N=1171 N=300 N=116 Thompson et al Gastroenterology 2010

IL28 B 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 s teatosis (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 Selected Mangia et al Gastoenterology 2010 Populations No Moghaddam et al Hepatology 2011 Yes Asselah et al J Hepatol 2012

IL28B GENOTYPE IS ASSOCIATED WITH INCREASED SVR IN NON-RVR G2/3 PATIENTS P=0.34 P=0.0002 100 78 84 83 80 80 SVR rate (%) 58 60 40 32 20 TT CT CC TT CT CC 0 RVR no RVR (61%) (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

ITPA RS1127354 POSSIBLY PREDICTS SVR IN HCV-1 SVR Kurosaki et al Antivir Ther 2011

Thompson et al J Hepatol 2012 Platelet ? ITPA Polymorphism s 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 Other genotypes: Genotype 1: 105 Genotype 6: 97 26 28 patients consent not obtained 6 patients defaulted follow- up 2 patients co- infected with HBV 1 patient co- infected with HIV 60 patients included in current study Seto et al J Viral Hepat in press

ITPA IL28B rs1127354 rs8099917 Chromosome Chromosome 20 19 Applied Biosystems TaqMan SNP Genotyping Assay Seto et al J Viral Hepat in press

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

FACTORS ASSOCIATED WITH SVR Factor p Factor p Age 0.498 HCV RNA 0.968 Gender 0.601 APRI 0.617 Type of IFN 0.553 Ribavirin dose 0.160 reduction Albumin 0.707 IL28B 0.014 Bilirubin 0.747 ITPA 0.387 ALT 0.697 AST 0.500 Platelet 0.161 Seto et al J Viral Hepat in press

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

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

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

THE CONFUSING FUTURE OF HCV THERAPY Preclinical DAA combinations Nuc- Polymerase Gilea Phase I BI inhibitors d Roche Japan Phase II R0622 (Roche) Vertex Tobacco Medivir (Tibotec) R7128 Others BMS/Pharmasse GL59393 (GSK) (Roche/Pharmass Nitazoxanide t Phase III et) (Romark) PSI938(Pharmasset) Biocryst PSI-7977 Taribavirin INF lambada (Pharmasset) Approved (Valeant) (Zymogen / INX189 (Inhibitex) NovoNordisk DEB025 cyclophilins IDX-184 (Idenix) Boceprevir Telaprevir BMS-791325 (nuc/non-nuc BMS790052 NSSA (MSD) (J&J/Vertex) MSD AZD07259 NSSA BMS)) (BMS) (AZN) GS9190 ABT33. TMC435 Idenix (Gilead) ABT7072 (J&J/Tobizer) ANA598 (ABT) (Anadys) BI201335 GS IDX375 Presidio (BI) K (Idenix/NV VX222 BMS824393 S) (Vertex) NS5A BMS650032 NSSA inhibitor (BMS) Enanta (BMS) BI201127 Non Nuc- (BI) GS9256 MK7009 Verte Polymerase ITMN-191/R7227 (Gilead) (MSD) inhibitors x (Roche/Intermune) MK5172 ACH1625 (MSD) ABT450 (Achillion) (ABT) Protease inhibitors

IL28B STILL USEFUL IN TRIPLE THERAPY FOR HCV-1 (SPRINT-2 TRIAL) % SVR 50 63 44 33 67 82 10 23 26 64 77 55 116 103 115 37 42 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!