Management of non naïve patients with hepatitis C "Non-Responders" 3rd Paris Hepatitis Conference, Paris, 19.01.2009 Christoph Sarrazin J. W. Goethe-University.

Management of non naïve patients

with hepatitis C

"Non-Responders"

3rd Paris Hepatitis Conference, Paris, 19.01.2009

Christoph SarrazinJ. W. Goethe-University Hospital, Frankfurt

Medizinische Klinik I

Germany

Definition of virologic non-response

Currently used definitions of non-response

• Less than 2 log decline of HCV RNA concentration at week 12 of therapy

• Detectable HCV RNA at week 24 of therapy

Problems:

- PEG-IFN dose, ribavirin dose

- Compliance, dose reductions, interruptions

- Discont. due to and management of side effects

- HCV assays - inter-assay variability- detection limits (5 - 10 - 50 IU/ml)

-1,30

-0,80

-0,30

0,20

0,70

GT1ab(n=30)

GT2(n=12)

GT3a(n=16)

GT4(n=4)

GT5(n=3)

log10 I

U/m

L

real-time HCV

CAP/CTM

bDNA

Quantification of HCV RNA by diff. assays CobasTaqMan (CAP) / RealTimeHCV / Versant bDNA

clinical samples (n=65)

Differences between HCV RNA assays:may be up to 0,7 log steps (factor 3 - 4)

Differences between HCV RNA assays:may be up to 0,7 log steps (factor 3 - 4)

Vermehren et al., J Clin Microbiol 2008

Detection limits of old and new assays

Stopping rule at week 24 for pts. with detectable HCV RNA with negative predictive values of 98-100%

• Based on assays with detection limits 30-50 IU/ml

• Based on 48 weeks max. treatment duration

Problems: - Currently used assays have detection limits of 5-10

IU/ml

- Extension of treatment duration to 72 weeks

- Negative predictive values for detectable HCV RNA at week 24 for pts treated for 72 wks only 90%

Davis et al., Hepatology 2003, Berg et al., Gastroenterology 2007

Definition of virologic non-response

Differentiation between partial non-response and null-response

• Partial non-response: - HCV RNA detectable at week 24

• Null-response:- decline of less than 1 log at week 4- decline of less than 2 log at week 12

Your approach for discontinuation

What is your personal approach for treatment discontinuation?

1.Strict application to the 2 log decline and HCV RNA detectable at week 24 rules

2.Strict application to the 2 log decline rule but discontinuation at week 24 only in patients with HCV RNA >50 IU/ml

3.Continuation of therapy as long as HCV RNA declines and becomes undetectable at week 24 by a highly sensitive assay (<5-10 IU/ml)

4.Continuation of therapy as long as HCV RNA declines, is at least below 15 IU/ml at week 24 and becomes undetectable at week 30

Options for re-treatment

1. PEG-Interferon and Ribavirin

2. PEG-Interferon and Ribavirin and STAT-C

EPIC3 Study design and baseline characteristics

• Patients with chronic hepatitis C and compensated liver disease (METAVIR- F2 - F4)

• Nonresponse or Relapse to - standard interferon plus ribavirin or - PEG-interferon plus ribavirin

• n=1336

• Treatment duration 48 weeks if 2 log decline at week 12

• 80% genotype 1

• 77% IFN + riba versus 22% PEG-IFN + riba

• 42% F4 fibrosis (cirrhosis)

Poynard et al., AASLD 2006

EPIC3sustained virologic response rates

IFN/Ribavirin PegIFN/Ribavirin SVR (%) (n) 95% CI SVR (%) (n) 95% CI

All patients 24.7% (254/1030) 21.2, 28.1 16.1% (48/299) 10.6, 21.5

Previous tx. response

Relapse 44.6% (95/213) 35.8, 53.4 35.7% (40/112) 24.1, 47.4

Nonresponse 17.2% (116/673) 13.5, 21.0 4.1% (7/172) 0.2, 8.0

Genotype

1 16.7% (138/825) 13.4, 20.1 11.5% (28/243) 6.3, 16.8

2/3 61.5% (102/166) 51.7, 71.2 43.6% (17/39) 23.1, 64

4 31.3% (10/32) 10.1, 52.4 20.0% (3/15) ---

METAVIR Fibrosis

F2 31.8% (92/289) 24.9, 38.9 22.7% (15/66) 9.4, 36.0

F3 26.3% (85/323) 20.0, 32.6 17.4% (16/92) 7.2, 27.6

F4 18.5% (77/416) 13.6, 23.4 12.1% (17/141) 5.0, 19.1

Baseline viral load

HVL (>600,000 IU/mL) 20.5% (116/566) 16.1, 24.9 10.7% (18/169) 4.5, 16.8

LVL (<600,000 IU/mL) 29.7% (138/464) 24.3, 35.2 23.3% (30/129) 13.7, 32.8

(Rel.+NR)(Rel.+NR)(Rel.+NR)

REPEATstudy design and baseline characteristics

Randomization (105 centers, 2:1:1:2, n=950)

R Study weeks0 482412 36 60 72 84 96

Follow-up360 µgplus RBV 1000/1200 mg

Peg-IFN alfa-2a (40KD) 180 µg

Follow-up360 µgplus RBV 1000/1200 mg

180 µg

Follow-upplus RBV 1000/1200 mg

Follow-upplus RBV 1000/1200 mg

A

B

D

Peg-IFN alfa-2a (40KD)

Peg-IFN alfa-2a (40KD)180 µg

Peg-IFN alfa-2a (40KD)180 µgC

R

Jensen et al., AASLD 2007

Patients with non-response to PEG-2b + riba 91% genotype 1 25-30% F3-4 fibrosis

REPEAT sustained virologic response rates

p=0.006, Odds ratio 2.0 (95% CI 1.21, 3.31)

7%

14%

9%

16%

0%

20%

SV

R

360/180 µg72 weeks

(A)

360/180 µg48 weeks

(B)

180 µg 72 weeks

(C)

180 µg48 weeks

(D)

52/317 11/156 22/156 27/313

10%

REPEATImpact of cirrhosis in genotype 1

26/304

9%

3%6/116 54/312

5%

17%

72 weeks(360/180 µg and 180 µg)

(A+C)

48 weeks(360/180 µg and 180 µg)

(B+D)

Cirrhotic Non-cirrhotic Cirrhotic Non-cirrhotic4/1200%

20%

10%SV

R

SVR rates in GT-1 patients: - 11% (72 wks.)- 6% (48 wks.)

REPEATPredictive value HCV RNA <50 IU/mL at week 12

All patients treated (n=942)

0%

20%

40%

60%

80%

100%

57/100 20/57

57%

35%

15/373 17/412

4% 4%

72 weeks(360/180 µg and 180 µg) (A+C)

48 weeks(360/180 µg and 180 µg) (B+D)

SVR<50 IU/mL at week 12:

YES

17%(157 / 942)

<50 IU/mL at week 12:

NO

83%(785 / 942)

SVR

0%

20%

40%

60%

80%

100%

Boceprevir (SCH503034)Triple-Therapy for PEG/R NR, GT 1, 48 Wks., n=357

Boc PEG2b Riba Change Wk 12-17 EOT SVR

100 yes no Riba + B 800 6% 2%

200 yes no Riba + B 800 16% 12%

400 yes yes B 800 20% 14%

400 yes no Riba + B 800 13% 5%

800 yes no Riba 21% 4%

Plac yes yes B 800 TW12 pos. 32% 7%

Schiff et al., EASL 2008

- SVR prediction: response at wk 8, >24-36 wks HCV RNA neg.- AE: anemia +1,5g/dl, nausea, fatigue, 8% discont.- Resistance in patients with break-through / withouth SVR

Results PROVE 3 Study (USA/EU)HCV Genotyp 1, Telaprevir, Nonresponder

McHutchison et al. AASLD 2008

0

20

40

60

80

100

HC

V R

NA

ne

gativ

e [%

] 83

8%

12 + 12TVR+PEG2a+Riba

→PEG2a+Riba

ETR

65

StandardPEG2a+Riba

41 ?

SVR12 ETR SVR12

24 + 24TVR+PEG2a+Riba

→PEG2a+Riba

73

? 30%

n=66 n=68

Relapser Non-Responder

n=40Wk 12

Non-Responder

8871

55

n=64Wk 12 ETR SVR12Wk 12 Wk36 SVR12Wk 12

Relapser and Non-Responder

?

German HCV Guideline 2009Recommendation for Non-responders

Non-response to (PEG)-interferon-alfa-monotherapie: re-treatment with

PEG-interferon-alfa / ribavirin combination therapy [B].

Non-response to (PEG)-interferon-alfa/ ribavirin combination therapy: check initial treatment for improvement (dose of PEG-interferon, dose of ribavirin, dose reductions, tx interruptions, tx duration, HCV RNA kinetics, managment of side effects, compliance …) [C].

If HCV-RNA is detectable at week 12 [A] or at week 24 [C] in patients with slow response in the initial therapy, re-treatment should be discontinued.

In patients with virologic response treatment should be performed for 72 weeks [A].

No general recommendation for low-dose PEG-interferon monotherapy for prevention of fibrosis progression or complications of liver disease [A].

Consensus: 98%

Sarrazin et al., German HCV Consensus Conference 2008

Your approach for selection of non-responders for re-treatment

What is your personal approach for selection of non-responders for re-treatment?

1.Re-treatment of all non-responders who whish to receive a second course of therapy

2.Re-treatment only if a patient achieved at least a partial-response during the first course of therapy

3.Re-treatment only if dose of peg-interferon, and ribavirin as well as the management of side effects can be optimized

4.General recommendation to wait for future treatment options

Management of non naïve patients

with hepatitis C

"Non-Responders"

3rd Paris Hepatitis Conference, Paris, 19.01.2009

Christoph SarrazinJ. W. Goethe-University Hospital, Frankfurt

Medizinische Klinik I

Germany