Treating HCV Genotype 2 & 3regist2.virology-education.com/2013/3HCVad/docs/06... · 2013-12-14 · Treating HCV Genotype 2 & 3 . 3rd Workshop on HCV Therapy Advances, Rome 14.12.2013

Christoph Sarrazin Klinikum der J. W. Goethe-Universität Frankfurt am Main, Germany

Treating HCV Genotype 2 & 3

3rd Workshop on HCV Therapy Advances, Rome 14.12.2013

HCV Genotypes 2 & 3

Laurel and Hardy

Geographical distribution and prevalence Genotype 2 and 3 in Europe

Cornberg et al. Liver International 2011; Suppl 2:30-60

Canada Norway Germany Sweden Czech Republic Poland

Russia

Hungary UK

France

Portugal

Spain Switzerland Italy Greece Israel Romania Turkey

<1% 1-1,9% 2-2,9% >3% unknown

HCV Prevalence

Geographical distribution and prevalence Genotype 2 and 3 Global

Sievert et al. Liver International 2011; Suppl 2:61-80

Syria Iraq Iran Pakistan China

Korea

Japan

Taiwan

Australia Vietnam

Thailand

India Saudi Arabia Jordan

Egypt

Lebanon

HCV Prävalenz

<1%

1-1,9%

2-2,9%

>3%

Nicht untersucht

Summary distribution and clinical features Genotype 2 and 3

Ferri et al., Autoimmun Rev 2007; Bochud et al., J Hepatol 2009, Probst et al., J Viral Hepatitis 2011

Genotype 2 Approx. 8% of HCV infections globally High prevalence in - Italy - Korea - Japan - Taiwan HCV associated NHL?

Genotype 3 Approx. 10% of HCV infections globally High prevalence in - Pakistan - India - Thailand - Europe - Australia Hepatic steatosis Faster fibrosis progression?

Treatment options Genotype 2 and 3

Country specific availability / approval and coverage by health insurance - PEG-Interferon alfa and ribavirin - Boceprevir / Telaprevir - Sofosbuvir, Simeprevir / Faldaprevir - Future drugs

Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (treatment naive)

PEG-IFN-α plus Ribavirin (24 weeks)

97

76 82

93 92

76 71 78

0

20

40

60

80

100

120

Dalgard etal.

Mangia etal.

Shiffman etal.

Zeuzem etal.

Genotype 2Genotype 3

Dalgard et al., Hepatology 2008; Mangia et al., NEJM 2005; Shiffman et al., NEJM 2007; Zeuzem et al., J Hepatol 2004

SVR

(%)


Meta-Analysis of 8 studies with PEG-IFN-α plus Ribavirin (12-16 versus 24 weeks in RVR patients irresp. of baseline viral load)

83 84 84 86

0102030405060708090

100

Genotype 2 Genotype 3

12-16 weeks (RVR)24 weeks (RVR)

Andriulli et al., Alim Pharm Ther 2008

SVR

(%)


Meta-Analysis of 8 studies with PEG-IFN-α plus Ribavirin (non-RVR patients with 24 weeks of treatment)

46

62

0102030405060708090

100


24 weeks (non-RVR)

Genotype 2Genotype 3

Andriulli et al., Alim Pharm Ther 2008

SVR

(%)


Extension of treatment duration in non-RVR patients? N-Core Study design

CHC G2/3 patients on PegIFN alfa-

2a/ RBV

0 4 8 12 24 48 72

RVR: continue treatment outside the

study

Non-RVR: enrolled in the study

n=400 PegIFN alfa-2a/

RBV n=160

STOP n=160

48 week follow-up

24 week follow-up

Entry into study at week 8 if no RVR

Randomization of patients without RVR, but with undetectable HCV RNA or ≥2-log drop in HCV RNA from baseline at week 12

n=235

n=95

n=93


Cheinquer H et al. AASLD 2012; #156 (S271A)

Odds ratio 0.68 0.63 0.44

95% CI 0.38–1.21 0.35–1.16 0.22–0.89

p value 0.1934 0.1461 0.0231

CI = confidence interval; ITT = intent-to-treat; PP = per protocol; SC = study completer; SVR24 = sustained virologic response ≥140 days after end of treatment.

80

70

60

50

40

30

20

10

0 ITT (n=188) PP (n=176) SC (n=153)

52

61

52

63

54

73

PegIFN 2a/RBV 24 weeks

PegIFN 2a/RBV 48 weeks

SVR2

4 (%

of p

atie

nts)

SC population: Significantly higher SVR24 rates with 48 weeks vs. 24 weeks of PegIFN 2a/RBV

Treatment options Genotyp 2/3 PEG-Interferon alfa and Ribavirin (Relapser/NR)

Poynard et al., Gastroenterology 2009

EPIC-3 Study: relapser / non-responder to (PEG)IFN + ribavirin

48 weeks PEG-IFN plus Ribavirin

59 55 61

46

0102030405060708090

100

Genotype 2(n=75)

Genotype 3(n=292)

GT2/3 Relapser GT2/3 Non-Responder

SVR

(%)



Treatment options Genotype 2/3 Telaprevir

Foster et al. Gastroenterology 2011; 141: 881-889

-5,0

-6,0 -6,0

-4,0

-3,0

-2,0

-1,0

0,0

2 3 4 7 12 15 Time (days)

Baseline Med

ian

HC

V R

NA

decl

ine

(log 1

0 IU

/ml)

Telaprevir monotherapy Telaprevir plus Peg-IFN/RBV Peg-IFN/RBV

Genotype 2 A

-3,65

-4,83

-5,51 -5,0

-6,0 -6,0

-4,0

-3,0

-2,0

-1,0

0,0

2 3 4 7 12 15 Time (days)

Baseline

Genotype 3 B

-0,54

-4,72 -4,85


Telaprevir monotherapy Telaprevir monotherapy

Med

ian

HC

V R

NA

decl

ine

(log 1

0 IU

/ml)

Treatment options Genotype 2/3 Boceprevir

Antiviral activity of Boceprevir monotherapy in genotype 2/3

Silva et al. J Hepatol 2013

Treatment options Genotype 2/3 Telaprevir and Boceprevir

0

1

2

3

4

5

6

GT 1 GT 2 GT 3 GT 4 GT 5 GT 6

Mean maximum log10 HCV RNA decline during mono-therapies 7-14 days

Telaprevr 750mg TID; Reesink et al., Gastro 2006, Foster et al., Gastro 2011, Benhamou et al., EASL 2009

HC

V R

NA

log1

0 de

clin

e

4,4 3,9

0,5 0,9

Boceprevir 400mg TID (current dose 800mg TID); Sarrazin et al., Gastroenterology 2007; Silva et al., APASL 2011

2,1 1,4

1,7 no data


Rescue treatment in patients with incomplete virologic response

0

1

2

3

4

5

6

7

1 2 3 4 5 6 7 8

vira

l loa

d lo

g 10

dec

line

Treatment week

Case: 45 years female 80kg (BMI 26) Genotype 3 F4 (cirrhosis) treatment-naive PEG-2a 180

plus 1200 Riba



vira

l loa

d lo

g 10

dec

line

Treatment week

Case: 45 years female 80kg (BMI 26) Genotype 3 F-3 fibrosis treatment-naive PEG-2a 180

plus 1200 Riba 0

1

2

3

4

5

6

7

1 2 3 4 5 6 7 8

Add-on Boceprevir 3x800mg per die



HCV Genotype

Fibrosis Metavir IL28B*

Pre-Tx Status

Protease-Inhibitor

Viral load PI baseline

Virological response

2a 4 CT Relapse Telaprevir 6400 SVR 2a 2 CT Partial-NR Telaprevir 46300 Relapse 3a 4 CC Naive Boceprevir 20500 SVR 3a 2 CT Naive Boceprevir 320 SVR 3a 4 CT Naive Boceprevir 1120 BT 3a 4 CT Relapse Boceprevir 1250 Relapse 3a 4 CC Naive Boceprevir 125 SVR

*rs12979860



Treatment options Genotype 2/3 Sofosbuvir Monotherapy: antiviral activities

Lam et al., AAC 2012; Gane et al., AASLD 2011; Lawitz et al., EASL 2011

-5

-4

-3

-2

-1

0

0 1 2 3 4 5 6 7Days

Medi

an H

CV R

NA ch

ange

from

ba

selin

e (lo

g IU

/mL)

PSI-7977 400 mg QD In HCV GT2/3 (ELECTRON)

PSI-7977 400 mg QD In HCV GT1 (NUCLEAR)1

EC50 (µM)

GT1b con1

GT1a H77

GT2a JFH-1

GT1b/2a J6

GT1b/2b pt

GT1b/3a pt

SOF 0.048 0.044 0.037 0.0047 0.020 0.016

Treatment options Genotype 2/3 Sofosbuvir + Riba: IFN-intolerant tx-naive (Positron)

Jacobson et al., EASL 2013; #61 and NEJM 2013

92 94

68

21

0

20

40

60

80

100

GT 2 GT 3

SV

R12

(%)

85/92 16/17 57/84 3/14

No cirrhosis Cirrhosis

100% on tx response, no viral break-through, failure = relapse No resistance (deep and phenotypic)

Treatment options Genotype 2/3 Sofosbuvir plus Riba vs. PEG/R tx-naive (Fission)

Gane et al., EASL 2013; #5 and NEJM 2013

98 82

91

62

61 71

34 30

0

20

40

60

80

100

SOF + RBV Peg-IFN + RBV

GT 2 GT 3

SVR

12 (%

)

No cirrhosis No cirrhosis Cirrhosis Cirrhosis

58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37

Treatment options Genotype 2/3 Sofosbuvir plus Ribavirin in tx-experienced (Fusion)

Gane et al., EASL 2013 and NEJM 2013

96 100

60 78

0

20

40

60

80

100

37

63

19

61

0

20

40

60

80

100

6/10 5/26

SV

R12

(%)

25/26 7/9 23/23 14/38 14/23 25/40

No cirrhosis

SOF + RBV 12 weeks SOF + RBV 16 weeks

No cirrhosis Cirrhosis Cirrhosis

GT 2 GT 3

Treatment options Genotype 2/3 Sofosbuvir plus Ribavirin 12 vs. 24 wks. (Valence)

Zeuzem et al., AASLD 2013; 1085

Genotype 2/3, tx-naive and Non-Responder: Extension of treatment

duration in GT3 patients

Treatment options Genotype 2/3 Sofosbuvir plus Ribavirin 12 vs. 24 wks. (Valence)

Zeuzem et al., AASLD 2013; 1085 Zeuzem et al., AASLD 2013; 1085

Genotyp 2/3, Tx-naive and Non-Responder: Extension of treatment duration in genotype 3 patients

Treatment options Genotype 2/3 Sofosbuvir+ PEG + Riba: tx-experienced (Lonestar 2)

Lawitz et al., AASLD 2013; LB4

Genotyp 2/3, Re-treatment (85% BT or Relapse), 50% F4, n=47 Sofosbuvir 400mg QD plus PEG-2a + Riba for 12 weeks

96 83

100

83 93

83

0

20

40

60

80

100

120


SVR

12 (%

)

allno cirrhosiscirrhosis

Relapse 2 1 1

22/23 20/24

Treatment options Genotype 2/3 Sofosbuvir + Riba +/- PEG: Adverse events

Preferred term, n (%) SOF + RBV

n=207 Placebo

n=71

p-value* Fatigue 91 (44) 17 (24) 0.003 Nausea 46 (22) 13 (18) 0.614 Headache 43 (21) 14 (20) 1.00 Insomnia 39 (19) 3 (4) 0.002 Pruritus 23 (11) 6 (9) 0.655 Anemia 27 (13) 0 <0.001

Jacobson et al., EASL 2013; #61

Patients, n (%) SOF + RBV n=207 Placebo n=71

Overall safety

AEs 185 (89) 55 (78) Serious AEs 11 (5) 2 (3) Treatment disc. due to AEs 4 (2) 3 (4)

Hematologic abnormalities

Hemoglobin <10 g/dL 15 (7) 0 Hemoglobin <8.5 g/dL 2 (1) 0 Absolute neutrophil count <750/mm3 0 1 (1) Platelets <50,000/mm3 0 2 (3)

Treatment options Genotype 2/3 Simeprevir

Moreno et al., J Hepatol 2012

-2.19 log

-2.73 log

-3.52 log

-0 log

Genotype 1: -3.8 log decline

Treatment options Genotype 2/3 Faldaprevir Potentcy of BI 201335 (Faldaprevir), telaprevir, and boceprevir against NS3-NS4A proteins of differnt HCV genotypes

White et al., AAC 2010

Treatment options Genotype 2/3 Sofosbuvir: FDA approval Dec. 13



Treatment options Genotype 2/3 Future drugs

NS3 Protease-Inhibitors − MK-5172 (activity against genotype 3 at toxic doses only) NS5A-Inhibitors: − Daclatasvir (lower activity against GT3 versus GT1) − Ledipasvir (in vitro low activity against GT3) − ABT-267 (in vitro lower activity against GT3 versus GT1) − GS-5816 (improved activity against GT3) Non-nucleoside Polymerase-Inhibitors − no clinical data Nucleoside Polymerase-Inhibitors − several compounds in phase 1/2 (VX-135, IDX-20963, ACH3422)

Summary

Different geographical distribution of genotypes (GT) 2 and 3

Countries with high prevalence of GT 2 or 3 (>30%) PEG-Interferon plus ribavirin for 12-16 weeks in

patients with RVR (without cirrhosis, <45 years and BMI <30)

PEG-Interferon plus ribavirin for 48 weeks in non-RVR and previous Rel/NR patients?

Rescue treatment with Boceprevir / Telaprevir? Sofosbuvir plus Ribavirin for 12 weeks in genotype 2 Sofosbuvir plus Ribavirin for 24 weeks in genotype 3

(Sofosbuvir + Riba + PEG for 12 weeks?) No efficacy / data for Simeprevir and Faldaprevir

HCV Genotypes 2 & 3

Laurel and Hardy

Documents

Treating HCV Genotype 2 & 3regist2.virology-education.com/2013/3HCVad/docs/06... · 2013-12-14 · Treating HCV Genotype 2 & 3 . 3rd Workshop on HCV Therapy Advances, Rome 14.12.2013