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)
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HCV GENOTYPES: HK SCENARIO
N=1055 (1998-2004)
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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)
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HCV-6: MOST COMMON GENOTYPE IN GUANGDONG PROVINCE, CHINA
Mean age: 34.4 years
HCV Genotype
Fu et al J Viral Hepat 2011 HKASLD HKASLD
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PHYLOGENETIC ANALYSIS OF HCV-6 IN DRUG USERS (N=210)
Fu et al PLoS One 2012
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HCV GENOTYPE 6 – INCREASING PREVALENCE IN SOUTHERN CHINA
Fu et al PLoS One 2012
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Prob
abili
ty o
f cirr
hotic
co
mpl
icat
ions
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
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Genotype
6 1
p=0.648
Seto WK et al J Hepatol 2010
HCV-1 AND HCV-6: SIMILAR NATURAL HISTORY
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1985 20yrs 2004
Future Trends in HCV Therapy
0%
25%
50%
75%
100%
Cur
e ra
te
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 HKASLD HKASLD
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SVR FOR DIFFERENT GENOTYPES (PEG-IFN AND RIBAVIRIN)
Genotype HKASLD HKASLD
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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%
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GENOME-WIDE ASSOCIATION STUDIES (GWAS)
Gastroenterology 2010 Hepatology 2010
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CLINICAL IMPACT OF GWAS
Fatty Liver PNPLA3 rs738409
HCV IL28B
rs12979860 / rs8099917
Tanaka et al Nat Genet 2009
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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 HKASLD HKASLD
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C allele (rs12979860) is associated with SVR
Ge et al, Nature, 2009
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IL28B-TYPE PREDICTS SVR
0
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
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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)
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Reprinted with permission from Macmillan Publishers Ltd: Nature. 2009;461:798-801.
rs12979860: High proportion of CC allele
in Asia
The global prevalence of C/T alleles at SNP rs12979860 may explain the recognized geographical variation in SVR rates
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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
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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 HKASLD HKASLD
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IL28B GENOTYPE IS ASSOCIATED WITH INCREASED SVR IN NON-RVR G2/3 PATIENTS
0
20
40
60
80
100
SV
R ra
te (%
)
RVR (61%)
no RVR (39%)
58
32
78
P=0.34 P=0.0002
83 80 84
TT CT CC TT CT CC
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INOSINE TRIPHOSPHATASE (ITPA)
Fellay et al Nature 2010 HKASLD HKASLD
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ITPA VARIANTS PROTECT AGAINST RIBAVIRIN-RELATED ANEMIA IN HCV GENOTYPE 1
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ITPA RS1127354 POSSIBLY PREDICTS SVR IN HCV-1
SV
R
Kurosaki et al Antivir Ther 2011 HKASLD HKASLD
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Platelet
Hb
Thompson et al J Hepatol 2012
ITPA Polymorphism
s
?
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HOW ABOUT HCV GENOTYPE 6?
Experience in QMH and PMH
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Seto WK et al. Am J Gastroenterol 2011
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228 patients treated with pegylated interferon and ribavirin
Genotype 1: 105 Genotype 6: 97
60 patients included in current
study
28 patients consent not
obtained 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
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Applied Biosystems
TaqMan SNP Genotyping
Assay
IL28B rs8099917
Chromosome 19
ITPA rs1127354
Chromosome 20
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p=0.014
IL28B Genotype ITPA Genotype
p=0.640
Effect of IL28B and ITPA genotypes on SVR rates
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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
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RIBAVIRIN DOSE REDUCTION
´ 19 patients require reduction of ribavirin dose after median treatment duration of 8 (range 2-32) weeks
37.8%
21.7%
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ITPA genotypes and the median reduction in hemoglobin from baseline
CC genotype (n=37)
CA genotype (n=23)
Med
ian
redu
ctio
n in
hem
oglo
bin
(g/d
L)
Error bars depict interquartile range
p<0.05 (all time points)
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CC genotype (n=37)
CA genotype (n=23)
ITPA genotypes and the median reduction in platelet count from baseline
Error bars depict interquartile range
Med
ian
redu
ctio
n in
pla
tele
t cou
nt (x
109 /
L)
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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 GSK
BMS824393 NSSA (BMS) Enanta
Vertex
Vertex
BMS/Pharmasset
Roche
Gilead
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/NVS)
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)
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IL28B STILL USEFUL IN TRIPLE THERAPY FOR HCV-1 (SPRINT-2 TRIAL)
% S
VR
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
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IL28B AND IFN-FREE REGIMENS (DANOPREVIR AND MERICITABINE)
Chu et al Gastroenterology 2012
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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
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ACKNOWLEDGEMENTS
´ Prof. MF Yuen ´ Prof. CL Lai ´ Dr. Kevin Liu ´ Dr. Owen TY Tsang (PMH) ´ Dr. Jacky MC Chan (PMH)
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THANK YOU!
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