Treating hepatitis C virus (HCV) with pegylated interferon (pegIFN) -2b

Overview of efficacy and safety data for pegIFN -2b, including Asian data

Outline
Epidemiology and disease burden Definitions of HCV treatment responses Evolution of HCV treatment and current guidelines Treatment outcomes with pegIFN plus ribavirin (RBV) Durability of response Predictors of treatment success Evidence supporting response-guided therapy
HCV-1: RVR and EVR are important predictors of SVR HCV-2/3: RVR is an important predictor of SVR

Adverse events Difficult-to-treat HCV populations

Epidemiology and disease burden

Global incidence of hepatitis C

Estimated hepatitis C infections, by region1
70

62.2

Patients (Millions)

60
50

40
30

31.9 21.3
13.1 8.9

32.3

20
10

0
Africa Americas Eastern Mediterranean Europe Southeast Asia Western Pacific

World Health Organization (WHO) estimates that ~180 million people are infected with hepatitis C worldwide2
1. Sy T et al. Int J Med Sci. 2006;3:41-46; 2. Ghany MG et al. Hepatology. 2009;49:1335-1374.

Prevalence of HCV in Asia Pacific

Sievert W, et al. Liver Int 2011;31 Suppl 2:61-80.

HCV genotype distribution by country in Asia Pacific

Sievert W, et al. Liver Int 2011;31 Suppl 2:61-80.

Burden and impact of HCV

Approximately 5585% of newly infected HCV cases progress to chronic HCV (CHC).1 Of those, 2030% will develop liver fibrosis, cirrhosis, and liver failure, and 25% will progress to HCC.1 In the WHO EU region (2002):2
HCV caused more than 86,000 deaths, accounting for 35% of cirrhosis and 32% of liver cancer deaths.

In the US:1,3
HCV-related mortality (death from liver failure or HCC) has risen from 3,700 in 1998 and is expected to peak at 13,000 in 2030.

HCV-related mortality is currently 8,00010,000 annually.

In Southeast Asia:4
HCV caused 14,000 deaths in 2002.
1. El-Kamary SS, et al. Clin Infect Dis 2011;53:150-157; 2. Muhlberger N, et al. BMC Public Health 2009;9:34; 3. Deuffic-Burban, S, et al. J Viral Hepat. 2007;14:107-115; 4. WHO global burden of disease, 2004 update. Available at: http://www.who.int/healthinfo/global_burden_disease/ GBD_report_2004update_full.pdf; accessed November 2011.

Clinical outcomes of HCV: Risk of mortality and HCC increase if HCV is not cured
HCV Ab-negative General population chronic HCV infection SVR No SVR

HCC and liver-related mortality1,2

5-year mortality3

4248 7918

2089 815

1097 697

Ab, antibody; SVR, sustained virologic response

1. El-Kamary SS, et al. Clin Infect Dis 2011;53:150-157; 2. Cardoso AC, et al. J Hepatol 2010;52:652-657; 3. Backus LI, et al. Clin Gastroenterol Hepatol 2011;9:509-516.

Definitions of HCV treatment responses

Types of virologic responses to HCV treatment

8 Treatment: PegIFN /RBV

Viral load: HCV RNA (log10 IU/mL)

Null response

Relapse 2 log10 decline

pEVR
2

Slow response cEVR

ETR

Limit of detection SVR

(24 wk post Tx)

0 4

12

24

36

48

72

Weeks RVR
(4 wk)

EVR
(12 wk)

pegIFN, peginterferon; RBV, ribavirin; RVR, rapid virological response; EVR, early virological response; cEVR, complete early virologic response; SVR, sustained virological response; ETR, end of treatment response; Tx, treatment.

Evolution of HCV treatment and current guidelines

Progressive improvement in treatment outcomes for chronic HCV-1

PegIFN- 2b/ RBV/BOC Tx-naive ~6366%7,8 PegIFN- 2b/ RBV/BOC Tx-failure ~5966%9

SVR rate (%)

IFN/RBV 48 Weeks 2837%1,2 IFN 48 Weeks 711%1,2

PegIFN- 2b/ RBV 48 Weeks ~40%3-6

19901997

19982009

20102011

IFN, interferon; RBV, ribavirin; BOC, boceprevir; Tx, treatment.

1. McHutchison JG, et al. N Engl J Med 1998;339:1485-1492; 2. Poynard T, et al. Lancet 1998;352:1426-1432; 3. Manns MP, et al. Lancet 2001;358:958965; 4. Lindsay KL, et al. Hepatology 2001;34:395-403; 5. Fried MW, et al. N Engl J Med 2002;347:975-982; 6. McHutchison JG, et al. N Engl J Med 2009;361:580-593; 7. Kwo PY, et al. Lancet 2010;376:705-716; 8. Bacon BR, et al. N Engl J Med 2011;364:1207-1217.

Progress in HCV treatment outcomes in Asia by genotype

1990
2009

SVR, sustained virological response; IFN, interferon; MU, million units; wks, weeks; RBV, ribavirin; Peg, peginterferon; RVR + ve, subgroup of patients who achieved a rapid virological response, defined as PCRseronegative for HCV RNA after 4 weeks of therapy.
Yu ML and Chuang WL. J Gastroenterol Hepatol 2009;24:336-345.

EASL recommendations on goals and endpoints of HCV treatment

PegIFN plus RBV is the current standard of care. The goal of therapy is to eradicate HCV infection (A1). The endpoint of therapy is SVR (A1). Once obtained, SVR equates to cure of infection in > 99% of patients. Intermediate endpoints to assess the likelihood of an SVR are HCV RNA levels at 4, 12, and 24 weeks of therapy (B2). In treatment-nave patients, strongest baseline predictors of SVR are: HCV genotype (A1). Genetic polymorphisms located in chromosome 19 (IL28B), particularly in genotype 1 patients (A1). Stage of liver fibrosis (A1).
EASL: European Association for the Study of the Liver; RBV, ribavirin
EASL Clinical Practice Guidelines. J Hepatol 2011;55:245-264.

EASL guidelines 2011: Response-guided therapy with pegIFN /RBV for HCV-1

EASL: European Association for the Study of the Liver applies also to HCV genotype 4
EASL Clinical Practice Guidelines. J Hepatol 2011;55:245-264.

EASL guidelines 2011: Response-guided therapy with pegIFN /RBV for HCV-2/3

* Marginally less effective due to higher relapse rates, especially for G3 with high viral load. EASL: European Association for the Study of the Liver applies also to genotypes 5 and 6, excluding 1216 weeks
EASL Clinical Practice Guidelines. J Hepatol 2011;55:245-264.

AASLD practice guidelines

HCV-1: Optimal therapy for treatment-nave patients and treatment failure is boceprevir or telaprevir combined with pegIFN and weight-based RBV (Class 1, Level A).1 HCV-4: Treatment with pegIFN plus weight-based RBV (800 1,400 mg) for 48 weeks (Class I, Level A).1,2 HCV-2/3: Treatment with pegIFN plus RBV for 24 weeks, using a RBV dose of 800 mg (Class I, Level A). 2
AASLD, American Association for the Study of Liver Diseases
1. Ghany MG, et al. Hepatology 2011;54:1433-1444; 2. Ghany MG, et al. Hepatology 2009;49:1335-1374.

Treatment outcomes with pegIFN /RBV in CHC

SVR in HCV-1 patients: 20012010

PegIFN -2b plus RBV
Korean study
70
63 52* 40 35 33 32 49

Smaller trials (< 1,000)

Larger trials (> 1,000)

N = 5,515
44 40 39

SVR rate (%)

60 50
40

42

39

30 20
10
37 100 16
Lee 2010 Muir 2004

52

93

87

338

348

951

1019

1161

1313

Yenice 2006

Ascione Almasio Witthoeft Cooper 2010 2005 2010 2009 Cozzolongo Rumi Manns McHutchison Jacobson 2006 2010 2001 2009 2007

*SVR of non-Hispanic white patient cohort with 98% of them having genotype 1. 99% of patients had HCV-1. Estimated SVR analysis: intended to account for patients with undetectable HCV RNA at the end of treatment and who lacked follow-up data and were considered nonresponders in the primary analysis. SVR, sustained virologic response, i.e. negative HCV RNA 24 weeks after completion of therapy. Yenice N, et al. Turk J Gastroenterol. 2006;17:94-98; Muir AJ, et al. N Engl J Med. 2004;350:2265-2271; Lee S, et al. Intervirology. 2010;53:146-153; Cozzolongo R, et al. Abstract presented at: 41st Annual EASL; April 26-30, 2006; Vienna, Austria. No. 563; Ascione A, et al. Gastroenterology. 2010;138:116-122; Rumi MG et al. Gastroenterology. 2010;138:108-115; Almasio PL et al. Poster presented at: 56th Annual AASLD; November 11-15, 2005; San Francisco, CA. No. LB03; Manns MP, et al. Lancet. 2001;358:958-965; Witthoeft T, et al. J Viral Hepat. 2010;17:459-468; McHutchison JG, et al. N Engl J Med. 2009;361:580-593; Cooper C, et al. Poster presented at: 60th Annual AASLD; October 30-November 3, 2009; Boston, MA. No. 820; Jacobson IM, et al. Hepatology. 2007;46:971-981.

HCV-1: Consistent SVR in five largest Western trials

PegIFN -2b plus RBV
42 44 40 39 39*

These trials included

10,291 HCV-1 patients, of which 7,862 were treated with pegIFN -2b plus RBV.

SVR rate (%)

Of these, 4,792 were

treated with the standard dose and schedule of pegIFN -2b (1.5 g/ kg/wk for 48 weeks). N = 4,792

348
Manns 2001

951
Witthoeft 2010

1019

1161

1313

McHutchison Cooper Jacobson 2009 2009 2007

*Estimated SVR analysis: intended to account for patients with undetectable HCV RNA at the end of treatment who lacked follow-up data and were considered non-responders in the primary analysis. Patients treated with standard dose and schedule of PegIFN -2b combination therapy. SVR, sustained virologic response, i.e. negative HCV RNA 24 weeks after completion of therapy.
Manns MP, et al. Lancet. 2001;358:958-965. Witthoeft T, et al. J Viral Hepat. 2010;17:459-468; McHutchison JG, et al. N Engl J Med. 2009;361:580-593; Cooper C, et al. Poster presented at: 60th Annual AASLD; October 30-November 3, 2009; Boston, MA. No. 820. 5. Jacobson IM, et al. Hepatology. 2007;46:971-981.

IDEAL study: PegIFN -2b compared with pegIFN -2a in HCV-1, treatment-nave, US patients
N = 1,019 PegIFN -2b 1.5 g/kg/wk + RBV 8001,400 mg/d x 48 weeks N = 1,016 PegIFN -2b 1.0 g/kg/wk + RBV 8001,400 mg/d x 48 weeks N=1,035 PegIFN -2a 180 g/wk + RBV 10001,200 mg/d x 48 weeks
Follow-up 24 weeks

Screening

Follow-up 24 weeks

Follow-up 24 weeks

Weeks

12

24

48

12

24

Stratified by baseline viral load (> or 600,000 IU/mL) and race (African American) Standard response stop criteria applied at Weeks 12 (no EVR) and 24 (HCV-RNA +)
Sulkowski M et al. EASL 2008. Abstract 991; Oral Presentation. Available at: http://www.hcv.pl/galeria/popularnonaukowe/Sulkowski_IDEAL.pdf.

Time course of response: Proportion of patients with undetectable HCV-RNA (ITT)

PegIFN -2b 1.5 + RBV N = 1,019 PegIFN -2b 1.0 + RBV N = 1,016 PegIFN -2a 180 + RBV N = 1,035

Patients with undetectable HCV RNA (%)

80
62 51 45 53 48 64

60
40

P = 0.57

49
40 38 41

40

36

20
11 8 12

0 TW4 TW12 TW24 EOT SVR

ITT, intention-to-treat; TW, treatment week; EOT, end of treatment, SVR, sustained virologic response
Sulkowski M et al. EASL 2008. Abstract 991; Oral Presentation. Available at: http://www.hcv.pl/galeria/popularnonaukowe/Sulkowski_IDEAL.pdf.

Rates of relapse with pegIFN -2b vs. pegIFN -2a

Rate of relapse (%)
PegIFN -2b PegIFN -2a

Almasio PL et al. Poster presented at: 56th Annual AASLD; November 11-15, 2005; San Francisco, CA. No. LB03; Cozzolongo R, et al. Abstract presented at: 41st Annual EASL; April 26-30, 2006; Vienna, Austria. No. 563; McHutchison JG, et al. N Engl J Med. 2009;361:580-593; Lee S, et al. Intervirology. 2010;53:146-153; Witthoeft T, et al. J Viral Hepat. 2010;17:459-468; Ascione A, et al. Gastroenterology. 2010;138:116-122; Rumi MG et al. Gastroenterology. 2010;138:108-115.

SVR in Asian studies of HCV-1 patients

PegIFN plus RBV

133

65

21

107

38

70

50

47

Patients

all achieved EVR and received 48 weeks' therapy

Chu CJ, et al. Aliment Pharmacol Ther 2009;29:46-54; Chu CJ, et al. Hepatogastroenterology 2007;54:866-870; Fung J, et al. J Infect Dis 2008;198:808-812; Hung CH, et al. Liver Int 2006;26:1079-1086; Lee SD, et al. J Viral Hepat 2005;12:283-291; Tsang OT, et al. J Gastroenterol Hepatol 2010;25:766-771; Kim MN, et al. Korean J Hepatol 2009;15:496-503, Lee S, et al. Intervirology 2010;53:146-153.

SVR in Western studies of HCV-2/3 patients

PegIFN -2b plus RBV
90

Patients were treated with

pegIFN -2b (1.5 g/kg/wk) plus RBV for 481 or 2425 weeks.

SVR rate (%)

82

81 76 72

82

80

Patients with HCV-2/3

often respond more readily to pegIFN -2b and RBV than do patients with HCV-1.

70
147 Manns 20011 224 283 775 180

60

Zeuzem Mangia Jacobson Manns 20042 20115 20053 20074

Estimated

SVR analysis: intended to account for patients with undetectable HCV RNA at the end of treatment and who lacked follow-up data and were considered non-responders in the primary analysis. Completers analysis, i.e. had both end-of-treatment and 24-week follow-up results. SVR, sustained virologic response, i.e. negative HCV RNA 24 weeks after completion of therapy.
1. Manns MP, et al. Lancet. 2001;358:958-965; 2. Zeuzem S, et al. J Hepatol. 2004;40:993-999; 3. Mangia A, et al. N Engl J Med. 2005;352:2609-2617; 4. Jacobson IM, et al. Hepatology. 2007;46:971-981; 5. Manns M, et al. J Hepatol 2011;55:554-563.

REDD 2/3: Reduced dose and duration of pegIFN -2b and weight-based RBV in European and Asian HCV-2/3 patients
A: PegIFN -2b 1.5/RBV (24 weeks) B: PegIFN -2b 1.0/RBV (24 weeks) C: PegIFN -2b 1.5/RBV (16 weeks)

SVR in completers
100
82 80a
80 81 68b 59 83 79

SVR in patients with RVR

75

SVR rate (%)

75 50 25 0

A (24 weeks): 75.3% B (24 weeks): 75.9% C (16 weeks): 72.4%

All patients (N = 520)

HepNet cohort International (N = 233) cohort (N = 287)

In patients who achieved RVR, 16 weeks Tx may be considered, as SVR was similar to that with 24 weeks Tx.

136/167

139/174

121/179

56/70

66/82

48/81

80/97

73/92

Treatment differences (one-sided 95% CI): aGrp A Grp B: -0.02 (-0.09); P = 0.024; bGrp A Grp C: -0.14 (-0.21); P = 0.798. Non-inferiority not achieved for all patients and individual cohorts. Tx, treatment.
Manns M, et al. J Hepatol 2011;55:554-563.

73/98

REDD 2/3: SVR by genotype

A: PegIFN -2b 1.5/RBV (24 weeks) B: PegIFN -2b 1.0/RBV (24 weeks) C: PegIFN -2b 1.5/RBV (16 weeks)

HCV-2
100
78 73 67 61 54 53 60 73

HCV-3

SVR rate (%)

75

75 70 64

50

46

21/27

19/31

14/26

12/18

16/22

47/89

50/84

41/90

77/103

25
8/11

63/91

0
HepNet cohort (N = 84)
Manns M, et al. J Hepatol 2011;55:554-563.

International cohort (N = 51)

HepNet cohort (N = 263)

International cohort (N = 284)

58/90

REDD 2/3: SVR according to ethnicity

A: PegIFN -2b 1.5/RBV (24 weeks) B: PegIFN -2b 1.0/RBV (24 weeks) C: PegIFN -2b 1.5/RBV (16 weeks)

Asian
100
76

Caucasian

SVR rate (%)

75

70

74 66 59 60 47

68

66

50

68/116

69/115

43/57

41/59

40/61

55/116

25

42/57

34/50

0 International cohort (N = 177)

Manns M, et al. J Hepatol 2011;55:554-563.

HepNet cohort (N = 347)

International cohort (N = 158)

34/51

SVR in Asian studies of non-HCV-1 genotype patients

PegIFN plus RBV

65

21

242

38

70

HCV-6

only; 237/242 were HCV-2

Chu CJ, et al. Hepatogastroenterology 2007;54:866-870; Fung J, et al. J Infect Dis 2008;198:808-812; Hung CH, et al. Liver Int 2006;26:1079-1086; Lee SD, et al. J Viral Hepat 2005;12:283-291; Tsang OT, et al. J Gastroenterol Hepatol 2010;25:766-771.

Durability of response

Durability of SVR: Long-term follow-up data (5 years)

Phase 3b, multicenter, long-term, follow-up study of 567 patients previously treated for CHC in 2 large, international clinical trials.1, 2
100

Durability of SVR (%)

95 90 85 80 60 40 20 0

99% of patients who attained SVR maintained long-term viral clearance3

Year

SVR after treatment with pegIFN -2b RBV predicts long-term clearance of HCV3

1. Manns MP et al. Lancet. 2001; 358:958-965; 2. Lindsay KL et al. Hepatology. 2001; 34:395-403; 3. Manns, M, et al. Presented at 43rd Annual Meeting of the European Association for the Study of the Liver, April 23-27, 2008, Milan, Italy.

Durability of response to Peg IFN -2b/RBV in children: 5-year follow-up

Multicenter study of 97 pediatric patients (316 years) treated with pegIFN -2b (3 MIU/m2) three times per week plus RBV (815 mg/kg/day) for 24 weeks, who were followed up for 5 years. Overall SVR was 58%: SVR in HCV-1: 47%; SVR in HCV-2/3: 95%). Only one patient had virologic relapse during longterm 5-year follow-up (98% durability of response). Mean height percentile (44th percentile) at the end of the long-term follow-up was slightly below the mean pretreatment baseline height percentile (48th percentile).

Kelly DA, et al. J Viral Hepat 2011:doi:10.1111/j.1365-2893.2011.01544.x.

Predictors of treatment success

Predictors of treatment success

Viral factors
Genotype Viral load at baseline

Host factors

On-treatment responses

Age RVR (Week 4) Ethnicity EVR (Week 12) Genomics cEVR Immune status Weight Severity of liver disease Hepatic steatosis Insulin resistance

RVR, rapid virological response; EVR, early virological response; cEVR, complete early virological response

Patient IL28B SNP genotype confers a higher chance of achieving SVR

SNP rs12979860
100 TT
P < 0.0001 P < 0.0001 69 P = 0.02 56 38 27

CT

CC

IL28B encodes IFN-3, and SNP found near this gene can predict SVR. Patients homozygous for the CC allele at SNP rs12979860 have the best chance of achieving SVR, compared to those with the TT or TC genotypes.1

SVR rate (%)

80 60

48

40
27

33

20 0 Caucasians (N = 1,171)

13 15

African Americans (N = 300)

SNPs rs12979860 and rs8099917 can be used as Hispanics independent predictors of Tx response.2
(N = 116)

SNP, single nucleotide polymorphism

1. Thompson AJ, et al. Gastroenterology 2010;139:120-129; 2. Li S, et al. Hepat Mon. 2011;11:163-172 .

IL28B C allele varies in frequency among geographically distinct ethnic groups

rs12979860: High proportion of CC allele in Asia

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

IL28B polymorphism is strongest baseline predictor of SVR using pegIFN/RBV

Odds ratio (95% CI)
Fasting serum glucose <5.6 mmol/L Hispanic vs. Black Metavir F0/F1
Caucasian vs. Black VL<600,000 IU/mL IL28B: CC vs. non-CC
P < 0.0001
P = 0.004 P < 0.0001 P < 0.0001 P < 0.0001 P < 0.0001

N = 1,604

10

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.

RVR is strongest predictor of SVR when treatment is pegIFN/RBV

Odds ratio (95% CI)
Fasting serum glucose <5.6 mmol/L Hispanic vs. Black Caucasian vs. Black
VL<600,000 IU/mL
P = 0.0001 P = 0.0361 P < 0.001 P < 0.001 P < 0.001

Metavir F0/F1 IL28B CC non-RVR All RVR 0 2 4

P < 0.001
P < 0.001

10

12

14

Comparison of RVR vs. no RVR + non-CC genotype; Comparison of no-RVR + CC genotype vs. no-RVR + nonCC genotype; Covariates: RVR vs. no RVR + CC genotype vs. no RVR + non-CC genotype (3-level), ethnicity (4level), 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.

IL28B genotype associated with RVR but not SVR in Taiwanese HCV-2 patients
non-TT
P = 0.017

TT
P > 0.05

100 85 SVR rate (%) 80 60 40 20 0 72

89

86

RVR
N = 482
Yu ML, Huang CF, Huang JF, et al. Hepatology 2011;53:7-13.

SVR

In Asian HCV-2 patients, the rs8099917 TT genotype near IL28B is significantly independently predictive of RVR, which is in turn the single best predictor of SVR.

Predictors of SVR in Asian studies of pegIFN -2b therapy

Genotype (Fung 2008; Lee 2005, Tsang 2010, Chu 2007; Lee 2010) Insulin resistance (Chu 2009) Degree of hepatic fibrosis (Chu 2007; Tsang 2010) Mutations in interferon sensitivity-determining region (ISDR) (Yen 2008) IL28B single nucleotide polymorphism (SNP) rs12979860 (Lin 2011) EVR (Chu 2007; Lee 2005) Adherence to treatment (Jeong 2009, Kim 2009) Age < 5055 years (Kim 2009; Tsang 2010) Baseline HCV RNA 200,000 IU/mL (Tsang 2010)

Insulin resistance, fibrosis and SVR in Chinese HCV-1 patients on pegIFN -2b/RBV
HOMA-IR < 2 100 SVR rate (%)
95** 75 54 39 35 75*

2 < HOMA-IR < 4

HOMA-IR > 4

80
60 40 20 0

Insulin resistance increased with the severity of hepatic fibrosis. Insulin resistance was a major determinant of SVR in HCV-1 patients who received 24 weeks of pegIFN combination therapy the greater the insulin resistance, the lower the SVR rates.

F1-F2 fibrosis (N = 86)

Chu CJ, et al. Aliment Pharmacol Ther 2009;29:46-54.

F3-F4 fibrosis (N = 47)

HOMA-IR, homeostasis model assessment of insulin resistance; **P < 0.004; *P = 0.325

Evidence supporting responseguided therapy

Virological response to treatment predicts outcome (i.e. SVR)

Predictors of treatment success

Viral factors
Genotype Viral load at baseline

Host factors

On-treatment responses

Age RVR (Week 4) Genomics EVR (Week 12) Ethnicity cEVR Immune status Severity of liver disease Hepatic steatosis Insulin resistance

RVR, rapid virological response; EVR, early virological response; cEVR, complete early virological response

HCV-1: RVR and EVR are important predictors of SVR

IDEAL: Week 4 and Week 12 viral response are key predictors of SVR for HCV-1
SVR rate (%) 1

328/407

344/466

107/116

98/123

68/156

PPV of 2 SVR

Week 4
PegIFN 2b/RBV PegIFN 2a/RBV

Week 12
PegIFN 2b/RBV PegIFN 2a/RBV

94%

89%

82%

76%

PPV, positive predictive value

1. McHutchison JG, et al. N Engl J Med 2009;361:580-593; 2. Sulkowski M, et al. EASL 2008. Abstract 991.

Predictability of treatment response is greater with pegIFN -2b than with pegIFN -2a at Weeks 4 and 12.

72/203

IDEAL: High correlation between Week 4 and Week 12 as definition for null response
High positive correlation between HCV-RNA decline at Weeks 4 and 12 (P < 0.001 for each treatment arm): PegIFN -2b 1.5 g/kg/wk + RBV: r = 0.76 (see graph) PegIFN -2a 180 g/wk + RBV: r = 0.73 High concordance (89%) for both treatment arms between: <1-log10 decline at Week 4 and null response at Week 12, or 1-log10 decline at Week 4 and non-null response at Week 12.
Patients with 3-log10 decline in HCV-RNA at Week 4 (N = 1,862)
Treatment Week 12 log10 drop

Treatment Week 4 log10 drop

Poordad F, et al. Asian Pacific Digestive Week. Singapore, October 2011.

Conclusions: Week 4 viral load decline of < 1-log10 approximates < 2-log10 decline at Week 12. Correlation between low Week 4 viral load decline and Week 12 null response may aid early treatment decisions.

IDEAL: Summary of predictors of SVR

Earlier time to first undetectable HCV RNA level was associated with a greater likelihood of achieving SVR.1 Predictability of treatment response is greater with pegIFN -2b than with pegIFN -2a at Weeks 4 and 12.2 Correlation between low Week 4 viral load decline and Week 12 null response may aid early treatment decisions.3 A polymorphism upstream of IL28B (CC vs. CT or TT) is also associated with increased on-treatment and sustained virologic response and effectively predicts treatment outcome.4

1. McHutchison JG, et al. N Engl J Med 2009;361:580-593.2. Sulkowski M, et al. EASL 2008. Abstract 991; 3. Poordad F, et al. Asian Pacific Digestive Week. Singapore, October 2011; 4. Thompson AJ, et al. Gastroenterology 2010;139:120-129 e118.

HCV-1 patients with RVR: Six months treatment sufficient if viral load is low
PegIFN -2a or -2b + RBV 10001200 mg
P = 0.12 P = 0.83
84

P = 0.14
87 73

24 weeks 48 weeks

100
87

80 SVR rate (%) 60

77

83

40 20
123 62 45 24 78 38

All
HVL, high viral load; LVL, low viral load
Mangia A, et al. Hepatology. 2008;47:43-50.

LVL
< 400,000 IU/mL

HVL
400,000 IU/mL

Six months' pegIFN -2b sufficient for HCV-1 patients with low viral load who attain RVR
Treatment-nave HCV-1 patients with baseline viral load < 600,000 IU/mL

149/170

16/165

98/110

9/106

11/13

1/12

1. Craxi A, et al. J Viral Hepat 2011:doi:10.1111/j.1365-2893.2011.01515.x; 2. Zeuzem S, et al. J Hepatol 2006;44:97-103; 3. Manns MP, et al. Lancet 2001;358:958-965.

HCV-1: Using response to determine duration of therapy

24 wk pegIFN + RBV 48 wk pegIFN + RBV 72 wk pegIFN + RBV

Patients with RVR at Wk 4

Slower responders

100

89

88 77

87

pEVR

SVR rate (%)

80
60

No RVR, cEVR
64

23-log10 decline in HCV RNA at Week 12

47 40 20 0
110 170 123 62

38 18
49 52

38 25

21

52

16

15

PegIFN -2b 1.5 g PegIFN -2b 1.5 g/ PegIFN -2b 1.5 g PegIFN -2b 1.5 g/ PegIFN -2b 1.5 g/ + RBV 8001,400 mg1,2 PegIFN -2a 180 g/ + RBV 8001,400 mg4 PegIFN -2a 180 g/ + RBV 8001,400 mg5 + RBV 1,0001,200 mg3 + RBV 1,0001,200 mg3
1. Zeuzem S, et al. J Hepatol 2006;44:97-103; 2. Craxi A, et al. J Viral Hepat 2011:doi:10.1111/j.1365-2893.2011.01515.x; 3. Mangia A, et al. Hepatology, 2008; 47:43-50; 4. Pearlman BL, et al. Hepatology. 2007;46:1688-94; 5. Buti M, et al. Hepatology 2010;52:1201-1207.

INDIV2: Relapse rates in HCV-1 according to treatment response and viral load
* Baseline viral load

N = 225 TMA, transcription-mediated amplification. *P < 0.0005

Wiegand J, et al. Clin Infect Dis 2011. doi 10.1093/cid/cir670.

INDIV-2: Relapse rates greater in HCV-1 patients with residual viremia

0/29

3/71

9/101

Many patients who achieve undetectable HCV RNA levels by quantitative assays still have detectable viremia by highly sensitive assays (e.g. TMA). These patients have an increased risk for relapse. Baseline viral load and early viral kinetics should be included in treatment algorithms to further individualize treatment strategies and prevent relapse.

14/44

TMA, transcription-mediated amplification. Defined as negative branched DNA assay, positive TMA assay
Wiegand J, et al. Clin Infect Dis 2011. doi 10.1093/cid/cir670.

16/29

6/29

HCV-2/3: RVR is an important predictor of SVR

HCV-2/3: Role of RVR in determining treatment duration

RVR
Yes

Treatment duration
1416 wks 24 wks 1416 wks 24 wks 1416 wks 24 wks 1416 wks 24 wks

PPV for SVR

83.2% 89.3%

NPV for No SVR

HCV-2
No Yes

71.8% 44.3% 82.4% 86.4% 73.5% 58.2%

HCV-3
No

RVR had a high PPV for SVR regardless of treatment duration. NPV was clearly related to treatment duration. HCV-2/3 patients with detectable HCV RNA at Week 4 should have a minimum of 24 weeks of treatment.
RVR, rapid virologic response; SVR, sustained virologic response; PPV, positive predictive value; NPV, negative predictive value
Poordad FF. Aliment Pharmacol Ther. 2010;31:1251-1267.

HCV-2/3: Short-course therapy effective in patients with RVR

Short duration of treatment (121 or 162 weeks) Standard duration of treatment (24 weeks) P = 0.938 72 75

100
85

91

SVR rate (%)

80
60

40
20
133 45 97 87

PegIFN -2b 1.0 g/kg/wk + RBV 1,0001,200 mg1

PegIFN -2b 1.5 g/kg/wk + RBV 8001,200 mg2

1. Mangia A, et al. N Engl J Med 2005;352:2609-2617; 2. Manns M, et al. J Hepatol 2011;55:554-563.

Relapse rates in HCV-2/3 patients with RVR treated for 1216 weeks

476

374

102 1

277

35

242 2

Multivariate analysis of predictors of relapse

Relapse rates higher in Asians than in Caucasians.2 Relapse rates lower with HCV-2 (0%) than HCV-3 (18%) in BMI, body mass index; Tx, treatment. 2 patients treated for 24 weeks. 1. Mangia A, et al. Hepatology. 2009;49:358-63; 2. Manns M, et al. J Hepatol 2011;55:554-563. BMI 30 (P = 0.036) Platelets 140,000 (P = 0.001)1

Independent predictors for relapse in patients with HCV-3

Patients who achieved RVR (albinterferon -2b or pegIFN -2a plus fixed-dose RBV)

23

148

118

113

Hepatic steatosis was the strongest predictor of relapse (OR 3.0; 95%CI 1.56.1; P < 0.003), irrespective of viral load, in HCV-3 patients who achieved RVR. High baseline HCV RNA level was the strongest predictor of steatosis (OR 6.3; 95% CI 3.610.8; P < 0.001).

Shah SR, et al. Clin Gastroenterol Hepatol 2011;9:688-693.

SVR also depends on RBV dose

SVR likelihood can be increased if RBV dosage is weight-based. SVR rates were higher in all groups where RBV dose was > 10.6 mg/kg bodyweight (lower end of optimum dose range).

For an average 75 kg man, doses of 10.6 mg/kg, 13.2 mg/kg, and 15 mg/kg represent daily doses of 800 mg, 1000 mg, and 1200 mg RBV, respectively.
Manns MP, et al. Lancet 2001;358:958-965.

Early termination of pegIFN/RBV therapy: Taiwanese study

Of 617 patients assigned 24 weeks of pegIFN /RBV, 29 (4.7%) terminated treatment at < 20 weeks.
Five (17.2%) patients achieved SVR, comprising: 0/16 HCV-1 (0%)

5/13 HCV-2 (38.5%; P = 0.001).

All sustained responders were HCV RNA seronegative at week 4 of treatment (i.e. achieved RVR) and received > 8 weeks' treatment.

Most common reasons for early termination were flulike symptoms/signs (n = 9).

Yu ML, et al. Antivir Ther 2006;11:1015-1019.

Adherence to therapy regimen results in optimal SVR (Korean study)

Jeong SW, et al. Korean J Hepatol 2009;15:338-349.

Adverse events

IDEAL: Most common adverse events

PegIFN -2b/RBV Adverse event, (%)
(1.0 g) N = 1,016 (1.5 g) N = 1,019

PegIFN -2a/RBV
N = 1,035

Fatigue
Headache Nausea Insomnia Pyrexia Anemia Myalgia

66.5
47.8 37.1 38.3 32.6 28.8 26.6

65.9
49.9 42.5 39.4 34.9 33.9 26.9

63.4
42.3 36.4 41.4 22.9 33.6 22.5

Neutropenia
Depression Irritability Rash
McHutchison JG, et al. N Engl J Med 2009;361:580-593.

18.5
19.4 25.8 21.9

25.8
25.5 25.1 22.1

31.5
21.0 25.3 28.0

Common adverse events associated with pegIFN/RBV therapy

Influenza-like (fatigue, headache, fever, and rigors): > 50% Psychiatric (depression, irritability, and insomnia): 2231% Neutropenia (ANC < 1500/mm3): 1820%1,2 Severe neutropenia* (ANC < 500/mm3): 4% Serious infections are uncommon and G-CSF is rarely necessary.3 Anemia (Hb < 12 g/dL): ~ 30%1,2 Nadir occurs within 68 weeks. Anemia requiring action (Hb < 10 g/dL): 915% Laboratory abnormalities are the most common reasons for HCV therapy dose reduction.
ANC, absolute neutrophil count; G-CSF, granulocyte-specific colony-stimulating factor; Hb, hemoglobin. *And treatment discontinuation. And dose modification.
1. Manns MP, et al. Lancet. 2001;358:958-965.; 2. Fried MW, et al. N Engl J Med. 2002;347:975-982; 3. Soza A, et al. Hepatology. 2002;36:1273-1279.

Time course of major treatment-associated adverse events

Increase in incidence / severity

Depression Fatigue Anxiety

Flu-like symptoms 0 1 2 Months 3 4

Dan A, et al. J Hepatol. 2006;44:491-498; Constant A, et al. J Clin Psychiatry. 2005;66:1050-1057.

Adverse events leading to early termination of therapy: Japanese study

In 2,871 Japanese patients treated with pegIFN -2b + RBV, the most common reasons for withdrawal were: neurovegetative symptoms (30.8%), depressionrelated syndromes (18.4%), hematologic effects (6.4%) and dermatologic effects (10.8%). Withdrawal rates were 13% in patients aged 65 years and 7% of those aged <65 years. Rates of withdrawal due to neurovegetative symptoms, depression-related syndrome, and hematologic effects was significantly higher in men aged 65 years than in those aged < 65 years (P = 0.0001, P = 0.0016, and P = 0.0170, respectively); this was not observed in women.
Ogawa E, et al. J Gastroenterol Hepatol. 2011 (http://onlinelibrary.wiley.com/doi/10.1111/j.1440-1746.2011.06965.x/pdf)

IDEAL: Early onset anemia and SVR

A higher magnitude of hemoglobin decline was associated with a higher likelihood of SVR.
P < 0.0001 P < 0.001 P < 0.0001

Hemoglobin decline
(N = 2,250)
(N = 773)

Sulkowski M, et al. EASL 2009. Copenhagen, Denmark. Abstract 126.

IDEAL: Anemia and erythropoietin (EPO): Impact on relapse rates

Patients with anemia who received PegIFN -2b and were not treated with EPO had lower relapse rates than those who did not have anemia.

(N = 2,158)

(N = 416)

(N = 449)

Sulkowski M, et al. EASL 2009. Copenhagen, Denmark. Abstract 126.

Correlation between SVR and anemia in Taiwanese HCV-1 patients

In 466 CHC patients treated with pegIFN /RBV for 24 weeks, a correlation was found between SVR rate and period of anemia during treatment in HCV-1 patients.
r = 0.107, P = 0.754 r = 0.774, P = 0.003 r = 0.960, P < 0.001

HCV-1: N = 205 Non-HCV-1: N = 261

Hung CH, et al. Liver Int 2006;26:1079-1086.

IDEAL : Neutropenia, anemia, and thrombocytopenia

Mean (SD) Nadir Hematologic Values PegIFN -2b 1.5/RBV (N=1,019) Neutrophil count, x 109/L Platelet count, x 109/L Hemoglobin conc., g/L 1.15 (0.55) 145 (53) 10.9 (1.5) PegIFN -2a/RBV (N=1,035) 1.09 (0.56) 130 (51) 10.9 (1.5) P-value < 0.001 < 0.001 0.43

Treatment with pegIFN -2a/RBV caused significantly more neutropenia and thrombocytopenia than either of the pegIFN -2b/RBV regimens, particularly in patients with low body weight.
May reflect increased bone marrow exposure to IFN based on body weight in the pegIFN -2a arm in the lower weight groups, and possible inherent differences among the different pegIFN molecules.
Poordad F, et al. Presented at the 59th AASLD, October 31-November 4, 2008, San Francisco, CA.

IDEAL: Grade 34 neutropenia by treatment arm and baseline weight

Neutropenia was related to body weight in the pegIFN -2a arm

Patients with lower body weights had higher rates of dose reduction and discontinuation than did those with higher body weights
Poordad F, et al. Presented at the 59th AASLD, October 31-November 4, 2008, San Francisco, CA

Thyroid dysfunction in Taiwanese patients treated with IFN-2b or PegIFN -2b/RBV

In 461 CHC patients with normal baseline thyroid functions, incidence of thyroid dysfunction (TSH < 0.1 or > 5 mU/L) was 12.6% after 2448 weeks of treatment. Female gender was significantly associated with thyroid dysfunction (P < 0.001). No difference in incidence of thyroid dysfunction for standard IFN vs. pegIFN-treated patients (49/391 vs. 9/70; P=1.00). Significant association between higher positive rates of pretreatment TMA and patients who developed thyroid dysfunction (OR: 5.8, 95% CI: 1.227.9). ~ 2% remained thyroid dysfunctional at the end of follow up (median, 26.5 months), no risk factors were found.
TSH, thyroid stimulating hormone; TMA, thyroid microsomal antibody
Kee KM, et al. J Gastroenterol Hepatol 2006;21:319-326.

Difficult-to-treat HCV populations

PROTECT: PegIFN -2b/RBV for HCV recurrence after orthotopic liver transplantation (OLT)
Study completion analysis*
80
70 SVR rate (%) 60 50 40 30 20 10 0 All Patients HCV-1 HCV-2/3
36/66 25/50 11/16 ITT: 29% ITT: 24%

69 55 50
ITT: 55%

SVR rates were higher among patients who completed treatment.

RVR, cEVR, and EOT response were predictive of SVR.

Rejection rate was low.

*Patients who completed 48 weeks of treatment and 24 weeks of follow-up. ITT, intention-to-treat.
Gordon FD, et al. Presented at 45th EASL, April 2010 , Vienna, Austria.

Patients with HCV-related cirrhosis

Meta-analysis of 11 studies of 1,133 patients with HCVrelated cirrhosis treated with pegIFN/RBV for 48 weeks:1
Overall SVR rate 33.8% (HCV-1/4: 21.6%;HCV-2/3: 37.8%).

Korean study (N = 86) of pegIFN/RBV in HCV-related cirrhosis patients:2

Overall SVR rate 34.9% (HCV-1: 20.8%; non-HCV-1: 2.6%). Independent predictors of treatment failure were HCV-1 (P = 0.003), high baseline viral load (> 8.0105 IU/mL, P = 0.012).

AEs leading to withdrawal were thrombocytopenia (2 patients), and depression, anxiety disorder and cerebral vascular hemorrhage (each 1 patient).
1. Bota S, et al. 19th United European Gastroenterology Week of the United European Gastroenterology Federation, Stockholm, Sweden, October 2011, Abstract P1213; 2. Kim KH, et al. Korean J Hepatol 2011;17:220-225.

HCV patients co-infected with HIV

SVR rates following pegIFN /RBV therapy in HCV/HIV co-infected patients are 1520% lower than in patients with HCV alone.1 Predictors of treatment response are largely hepatitis C factors: genotype, HCV viral load, and liver disease stage. 1 Recommended HCV treatment is pegIFN/RBV for 48 weeks; weightbased RBV dosing should be considered for HCV-1 patients. 1 Meta-analysis2 of 6 studies of IFN vs. pegIFN in 1,717 patients coinfected with HCV and HIV showed that: For HCV-1/4 and HIV-co-infected patients, both types of pegIFN, -2a and -2b, achieved higher SVRs than IFN. SVRs achieved in patients infected with HCV-1/4 treated with pegIFN and RBV were lower than in those infected with HCV-2/3 (26% vs. 55%).
1. McCaughan GW , et al. J Gastroenterol Hepatol 2007;22:615-633; 2. Zhao S, et al. Eur J Clin Microbiol Infect Dis 2008;27:1183-1192.

HCV patients with ESRD on hemodialysis

Management of CHC is more complicated in hemodialysis patients due to altered pharmacokinetics and drug-related toxicity, particularly RBV-induced anemia.1 Malaysian study2 of escalating pegIFN -2b monotherapy (N = 46; 0.5 g/kg/week 4 weeks, then 1.0 g/kg/week 2044 weeks) showed SVR rates for HCV-1: 37.5%; HCV-3: 80%. In Indian study (N = 6), pegIFN -2b (1.0 g/kg/week for 24 weeks) was safe and effective (SVR rate 50%).3 Meta-analyses show that ~33% of ESRD patients with CHC achieve SVR after IFN or pegIFN monotherapy.4 PegIFN or IFN plus low-dose RBV can increase SVR rates, but close monitoring of hemoglobin levels and high-dose EPO needed to prevent severe anemia.4
ESRD, end-stage renal disease; EPO, erythropoietin
1. Berenguer M. Hepatology 2008;48:1690-1699; 2. Tan SS, et al. J Viral Hepat 2010;17:410-418; 3. Amarapurkar DN, Patel ND and Kirpalani AL. Trop Gastroenterol 2007;28:16-18; 4. Liu CH and Kao JH. J Gastroenterol Hepatol 2011;26:228-239.

Additional slides
Details of Asian studies

Summary of treatment responses to pegIFN -2b/RBV for CHC in Asia

Reference, country
Chu 20091 Chinese pts
Chu 20072 Chinese pts

Regimen
pegIFN -2b + RBV 24 wks
1.5 g/kg/wk + RBV 24 wks pegIFN -2a or pegIFN -2b + RBV 48 wks

Genotype

SVR

Comment/findings
Insulin resistance is major determinant of SVR
EVR predictor of response: 24wks may be adequate for HCV-1 early responders 48 weeks' treatment with pegIFN 2a or -2b resulted in significantly higher SVR for HCV-6 patients (P = 0.019) Significant correlation between SVR rate and time of anemia during therapy

133

HCV- 1

66%

65

HCV-1 non-HCV-1

69% 93%

Fung Hong Kong

20083

42

HCV-1 HCV-6

52% 86%

Hung 20064 Taiwan

466

pegIFN -2a or 1-1.5 g/kg/wk pegIFN -2b + RBV 48 wks

HCV-1 non-HCV-1 (98% were HCV-2)

52% 93%

Summary of treatment responses to pegIFN -2b/RBV for CHC in Asia

Reference, country
Jeong 20095 Korea

N
92

Regimen
180 g pegIFN -2a or 1.5 g/kg/wk pegIFN -2b + RBV 48 wks (HCV-1) or 24 wks (non-1) 3MU IFN -2b t.i.w. + RBV or 1.5 g/kg/wk pegIFN -2b + RBV 24 wks 180 g pegIFN -2a or 1.5 g/kg/wk pegIFN -2b + RBV 48 wks

Genotype

SVR
In those who received 80% therapy: 86.7% 100% 41.0% 86.8% 65.8% 68.4% 57.1% 75.7%

Comment/findings
SVR rates differed significantly with degree of adherence to the treatment. Adherence to therapy is a key factor in achieving SVR. Supportive strategies to improve adherence will increase overall SVR rates. HCV-1 relapse was greater in IFN group (52.9% vs. 28.6% with pegIFN ). EVR at week 12 and non-HCV-1 genotype were significant predictors of SVR. Age 55 years, HCV genotype, liver biopsy staging and baseline hepatitis C virus RNA ( 200,000 IU/mL) were independent predictors of SVR.

HCV-1 non-HCV-1 HCV-1 non-HCV-1 HCV-1 non-HCV-1 HCV-1 HCV-6

Lee 20056 Taiwan

153

Tsang 20107 Hong Kong

70

Summary of treatment responses to pegIFN -2b/RBV for CHC in Asia

Reference, country
Yu 20068 Taiwan

N
60

Regimen
80100 g/kg/wk pegIFN -2b + RBV 24 or 48 wks 180 g pegIFN -2a or 1.5 g/kg/wk pegIFN -2b + RBV 24 or 48 wks 180 g pegIFN -2a or 1.5 g/kg/wk pegIFN -2b + RBV 48 wks (HCV-1) or 24 wks (non-1)

Genotype
HCV-1b

SVR
24wks: 48.9% 48wks: 80.0%

Comment/findings
In 19 patients without an unfavorable predictor, SVR rate was comparable in the 24-week (78.6%) and 48-week (75.0%) groups. Patients who relapsed after 24 weeks of treatment were treated for further 24 weeks and 42.9% achieved SVR. The 24-week + additional split 24-week therapy following failure is useful treatment strategy for HCV-1 patients. Whether patients had HCV genotype 1 or non-1, treatment responses were not significantly different for pegIFN treatments. HCV genotype was the only independent factor that affected SVR (P = 0.048).

Kim 20099 Korea

130

HCV-1

24 wks: 52.9% 48wks: 74.0%

Lee 201010 Korea

126

HCV-1

pegIFN 2a:70.9 % pegIFN 2b:72.3%