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

ROLE OF IL28B AND ITPA POLYMORPHISMS IN DIFFERENT GENOTYPES OF HCV

WK Seto Clinical Assistant Professor Department of Medicine Queen Mary Hospital The University of Hong Kong

(Especially HCV-6)

HCV GENOTYPES: HK SCENARIO

N=1055 (1998-2004)

Zhou et al J Med Virol 2006

HCV: HK SCENARIO (QMH)

56% 28% 16%

(n=78)

Transfusion IV drug use Others 71% 9% 20%

(n=138)

Transfusion IV drug use Others

Route of Transmission

Seto WK et al. J Hepatol 2010 p<0.001

Genotype 1 (n=220) Genotype 6 (n=101)

HCV-6: MOST COMMON GENOTYPE IN GUANGDONG PROVINCE, CHINA

Mean age: 34.4 years

HCV Genotype 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 Time to develop complications (Years)

Genotype

6 1 p=0.358 Seto WK et al J Hepatol 2010

HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY

Genotype

6 1 p=0.648 Seto WK et al J Hepatol 2010

HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY

1985 20yrs 2004

Future Trends in HCV Therapy

0% 25% 50% 75% 100%

Cure rate

IFN-α2b 48 weeks 9% IFN-α2b 24 weeks 4% IFN/RBV 48 weeks 27% PEG/RBV 48 weeks 45%

Triple Rx

Protease inhibitor + PEG/RBV

24 weeks 75%

2011

Combo DAA 1st DAA + 2nd DAA NO IFN 12 wks

95-100%

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

IL28B-TYPE PREDICTS SVR

20 40 60 80 100 SVR rate (%) 33 Caucasians N=1171 African Americans N=300 Hispanics N=116 27 69 15 13 48 38 27 56 TT CT CC TT CT CC TT CT CC

p<0.0001 p=0.2 p<0.0001 p=0.02 p=0.7 p=0.3 p=0.09 Thompson et al Gastroenterology 2010

IL28B POLYMORPHISM IS STRONGEST BASELINE PREDICTOR OF SVR USING PEGIFN/RBV

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)

P < 0.0001 P < 0.0001 P < 0.0001 P < 0.0001 P < 0.0001 P = 0.004

Thompson AJ, et al. Gastroenterology 2010;139:120-129.

Odds ratio (95% CI)

N = 1,604

Reprinted with permission from Macmillan Publishers Ltd: Nature. 2009;461:798-801.

rs12979860: High proportion

• f CC allele

in Asia

The global prevalence of C/T alleles at SNP rs12979860 may explain the recognized geographical variation in SVR rates

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?

Yes Selected Populations No Yes

Thompson et al Gastoenterology 2010 Mangia et al Gastoenterology 2010 Moghaddam et al Hepatology 2011 Asselah et al J Hepatol 2012

IL28B GENOTYPE IS ASSOCIATED WITH INCREASED SVR IN NON-RVR G2/3 PATIENTS

20 40 60 80 100 SVR rate (%)

RVR (61%) no RVR (39%)

58 32 78

P=0.34 P=0.0002

83 80 84 TT CT CC TT CT CC

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

Platelet Hb

Thompson et al J Hepatol 2012

ITPA Polymorphism s

?

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 60 patients included in current study 28 patients consent not

• btained

6 patients defaulted follow- up 2 patients co- infected with HBV 1 patient co- infected with HIV Other genotypes: 26

Seto et al J Viral Hepat in press

Applied Biosystems TaqMan SNP Genotyping Assay

IL28B

rs8099917 Chromosome 19

ITPA

rs1127354 Chromosome 20

Seto et al J Viral Hepat in press

p=0.014

IL28B Genotype ITPA Genotype

p=0.640

Effect of IL28B and ITPA genotypes on SVR rates

FACTORS ASSOCIATED WITH SVR

Factor p Age 0.498 Gender 0.601 Type of IFN 0.553 Albumin 0.707 Bilirubin 0.747 ALT 0.697 AST 0.500 Platelet 0.161 Factor p HCV RNA 0.968 APRI 0.617 Ribavirin dose reduction 0.160 IL28B 0.014 ITPA 0.387 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

ITPA genotypes and the median reduction in hemoglobin from baseline

CC genotype (n=37) CA genotype (n=23) Median reduction in hemoglobin (g/dL)

Error bars depict interquartile range

p<0.05 (all time points) Seto et al J Viral Hepat in press

CC genotype (n=37) CA genotype (n=23)

ITPA genotypes and the median reduction in platelet count from baseline

Error bars depict interquartile range

Median reduction in platelet count (x 109/L)

Seto et al J Viral Hepat in press

THE CONFUSING FUTURE OF HCV THERAPY

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

IL28B STILL USEFUL IN TRIPLE THERAPY FOR HCV-1 (SPRINT-2 TRIAL)

% SVR

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!