Management of non naïve patients with hepatitis C Relapsers Alessandra Mangia Liver Unit & Division of Gastroenterology “CSS” San Giovanni Rotondo, Italy

Management of non naïve patients with hepatitis C

Relapsers

Alessandra MangiaLiver Unit & Division of Gastroenterology

“CSS”San Giovanni Rotondo, Italy

3rd Hepatitis Conference Paris 19-20 January 2009

Topics to be covered

* Relapse rates following combination tx of standard or short duration

* Predictors of relapse Duration of treatment RBV/IFN dosages

* Re-treatment of relapsers

Background

Non responders diverse groups of pts including

Null responders20%

Partial responders15%

Breakthrough10%

Relapsers15%

Definition:Relapse vs nonresponders

0 12 24 48 72

HC

V R

NA

Limit of detection

PegInterferon/Ribavirin

>4 log decline

Weeks

0 12 24 48 72

HC

V R

NA

How to recognize the pattern?

HCV RNA should be assessed at 3 and 6 months after end of treatment

To rule out late relapse HCV RNA assessment should be repeated 18 months after treatment

Sensitivity of the assay should be at least 50 IU/ml

LATE RELAPSE AFTER COMBINATION TX

Author/yrs Patients FU RNA+ve LDL of the

HCV RNA

No (yrs) (%) assay

Marcellin ‘97 80 pts 4 7 50 IU/ml

Lau ‘98 5 pts 6-13 0 100 cp/ml

Swain ‘04 300 pts 2-3 1 50 IU/ml

McHutchison ‘02 395 pts 3 2 1 cp/µg

Veldt ’04 286 pts 4 5 <103 cp/ml

Ferenci ‘05 175 pts >12 0 50 IU/ml

Why a relapse occur ?

Insufficient length of therapy

Reduction of IFN or RBV

Duration of Treatment and Relapse: GT2/3 All Patients

Hadziyannis S, et al. Ann Intern Med. 2004;140:346-355.

24 Weeks-LD

0

20

40

60

Pat

ien

ts (

%)

24 Weeks-SD

80

100

48 Weeks-LD

48 Weeks-SD

9484

9081

11 104

7982 8580

6

SVR

EOT

REL

Relapse rate after short tx in G2 and 3: the Accelerate

27%

14%

31%28%

18%

9%

0%

20%

40%

60%

80%

100%

Any HCV genotype HCV genotipe 2 HCV genotype 3

16 wks 24 wksPeg IFNα2a+RBV 800 md/daily

Shiffman M, et al.NEJM. 2007 .

Duration of Treatment and Relapse: GT1 All Patients

Hadziyannis S, et al. Ann Intern Med. 2004;140:346-355.

24 Weeks-LD

0

20

40

60

Pat

ien

ts (

%)

24 Weeks-SD

80

100

48 Weeks-LD

48 Weeks-SD

68

29

78

42

39 36

19

41

60

69

52

6

SVR

EOT

REL

Relapse rates in G1 pts treated with PEGIFN 2 plus RBV based on time of first

negative HCVRNA Time to first neg

HCVRNA

24 wks virological

relapse

48 wks virological

relapse

wk 4 9/106 (8%) 1/12 (8%)

wk 12 44/59 (75%) 0/14 (0%)

wk 24 (EOT) 16/20 (80%) 0/2 (0%)

ALL 69/185 (37%) 1/28 (4%)

Zeuzem S. J Hepatol 2005

Re-treatment of relapser pts after an initial short (24 or 12 wks)

treatment courseStudy Schedule SVR (%)

HCV G1 Berg C, 2006 Pegα2a+

RBV >1000 mg/daily

18/35 (51%)

HCV G2/3 Mangia A,2009 Pegα2a+

RBV 1000-1200 mg/daily

30/43

(70%)

Impact of Peg-IFN dose reductionPegIFN 135 µg is sufficient for treatment of chronic HCV 2 and 3 infection

when combined with RBV doses daily according to body weight

Weiland O, et al. J Viral Hepat. 2008;15:641-645.

0

20

40

60

Pat

ien

ts (

%)

EOT

80

100

Relapse SVR

98 97

8,912,5

85 86

G 3

G 2

> 97 97-81 80-61

n = 218 65 31 11

Rel

apse

(%

)

0

20

40

60

80

Cumulative Ribavirin Dose (%)

17 17

40

56

60-0

Impact of RBV dose reduction

Reddy KR, et al. Clin Gastroenterol Hepatol 2007.

Significant decrease in SVR for total relapse p=.0006

Treatment of Chronic HCVImpact of stopping Ribavirin

0 24 48

HCV RNA negative

Peg-IFNα2a 180 µg/wk and RBV 800 mg/day (N=516)

Continuing Peg-IFNStop RBV

N=176

Continuing Peg-IFNand RBV

N=173

Wk

Bronowicki J-P, et al. Gastroenterology 2006; 131: 1040

Effect of discontinuing RBV on HCV G1 pts responding to Tx

Outcome Treatment during last 24 wks P value

PegIFNα2a + RBV (n=173)

PegIFNα2a

(n=176)

SVR (ITT) 68.2 52.6 .004

SVR (PP) 71.5 56.7 .006

Bronowicki J-P, et al. Gastroenterology 2006; 131: 1040

Intensive regimen in “difficult to cure” G1, high HCVRNA, >85 Kg

PegIFNα-2a 180 µg/wk+ RBV 1200 mg/day

(n=46)


(n=47)


(n=47)


(n=47)

Treatment-naïvePts with G1, HCVRNA >

800,000 IU/ml andBody Weight > 85 kg

N=188

Fried M et al, Hepatology 2008

wk 48

Follow-up

Intensive regimen Tx resistant Relapse diminished

• Relapse rate

- PegIFN 180 µg/wk +RBV 1200 mg/day: 40%




Fried M et al, Hepatology 2008

Re-treatment of relapsers after std IFN + RBV

PegIFN alfa + RBV in Previous Relapsers

Sherman M, et a. Gut 2006;55:1631-1638 Maucari R. et al J Hepatol 2007; 46:596-604Jacobson IM, et al. Am J Gastroenterol. 2005;100:2453-2462.

0

10

20

30

40

50

60

70

80

100

90

38

5350

32

PegIFN 2b 1.5 µg/kg/wk + RBV 800 mg/day (n = 30 )

PegIFN 2b 1.0 µg/kg/wk + RBV 1000-1200 mg/day (n = 25)

SV

R (

%)

IFN + RBV(n = 53)

IFN + RBV(n = 55)

IFN + RBV(n = 77)

48 Wks

PegIFN 2a + RBV 800 mg/day (n = 85 )

PegIFN 2b 1.5 µg/kg/wk + RBV 1000-1200 mg/day (n = 53)

SVR3%No

68 (44%)

SVR49%

Yes86 (56%)

Maucari R, et al.J Hepatol. 2007

At Week 12

(N = 154)

Predictive value of EVR

SVR97%

SVR51%

Yes

No

Yes

No

Treatment of Relapsers after PegIFN + RBV given for

48 weeks

Study Treatment GT N (Previous Treatment)

SVR Rate(Previous

Treatment)

Kaiser[1]

CIFN 9 µg/day+ RBV x 72

weeks

1 120 69%

PegIFN alfa-2a+ RBV x 72

weeks

42%

EPIC3[2]

PegIFN alfa-2b+ RBV x 48

weeks

1 (81%)2/3

(15%)

164 (PegIFN alfa-2a)

180 (PegIFN alfa-2b)

34% (PegIFN alfa-2a)

32% (PegIFN alfa-2b)

Outcomes in Relapsers to PegIFN-Based Therapy

1. Kaiser S, et al. AASLD 2007. Abstract 1310. 2. Gross J, et al. AASLD 2005. Abstract 60.

EPIC3 NR StudyHCV pts (18-65 yrs) with Metvir score F2-4 n=2293

Previous Tx = 62% IFN/RBV, 21% PegIFN alfa-2b, 16% alfa 2a

22

14

38

25

18

43

17

7

32

18

6

34

05

1015202530354045

All IFN/RBV Peg-a2b/RBV

Peg-a2a/RBV

All

Prior NR

Prior Relapse

Poynard EASL 2008

Pat

ien

ts (

%)

PegIFN alfa-2b 1.5 µg/Kg/wk +Weight-based RBV 800-1400 mg/day/48 wks

Does the presence of an advanced liver disease influence

the relapse rate?

Predictors of relapse in 485 patients with RVR following a short (12 weeks) therapy

• Peg INF α2b (1.5 μg/kg) + RBV (800-1200 mg)

• EOT: 96%; SVR: 82%, Relapse: 14%

Predictors oPredictors of relapse p OR; 95% CI

Age >45 years 0.004 -

BMI >30 kg / m2 0.0001 2.5;

1.49 – 4.20*

Platelet counts <140.000 m3

0.0001 1.7;

1.03 – 2.70*

*independently associated with SVR Mangia et al, Hepatology 2009

Total SVR Relapse

Pts without risk factors*

316 290 (91,8%) 26 (8,2%)

Pts with 1 or 2 risk factors*

169 128 (74,4%) 41 (25,6%)

SVR and relapse rates in 485 RVR genotypes 2 and 3 patients after short therapy (12 wks), according to the presence or absence of risk

factors*

Mangia et al, Hepatology 2009

* BMI >30 and/or PLT <140,000

Final Results from the EPIC3 Program

Poynard T et al EASL 2008

Study Outline: PegIFN-α2b 1.5 mcg/Kg week + Rbv 800-1400 mg/day

NR and RR to combo therapy with any IFN

GenotypePeg-α2b(n=180)

Peg-α2a(n=164)

IFN alfa(n=300)

G1 F2 37% 27% 42%

F4 18% 20% 26%

G2/3 F2 75% 50% 76%

F4 36% 58% 59%

SVR in Prior Relapsers

New agents

Telaprevir + Pegasys + Copegus in G1 NR or Relapsers to Peg-IFN + RBV

PROVE 3

Study Weeks 480

Placebo plus PEGASYS®† plus COPEGUS®††

TVR‡ 750 mg q8h plus PEGASYS®† plus COPEGUS®††

TVR‡ 750 mg q8h plus PEGASYS®†

CH

C,

G1,

NR

an

d R

EL

to

p

eg-I

FN

+ R

BV

, n

=45

3

24$12§

f/u 24 wks

PEGASYS®† plus COPEGUS®††

TVR‡ 750 mg q8h plus PEGASYS®† plus

COPEGUS®††

f/u 24 wks

f/u 48 wks

A

B

C

D Placebo plus PEGASYS®† plus COPEGUS®††

f/u 48 wks

PEGASYS®† plus COPEGUS®††

PROVE 3 – Interim Results in Prior G1 Relapsers

0%

17%

71%78%

72%78%

69%

36%

80%88%

83%

72%

0%

20%

40%

60%

80%

100%

Week 4 Week 12 EoT SVR12

HC

V R

NA

neg

ativ

ity

[%]

0%

17%

71%78%

72%78%

69%

36%

80%88%

83%

72%

0%

20%

40%

60%

80%

100%

Week 4 Week 12 EoT SVR12

HC

V R

NA

neg

ati

vit

y [

%]

SOC (n=42) 48 wk Arm (n=41) No RBV Arm (n=39) 24 wk Arm (n=40)

McHutchison et al, AASLD 2008

Telaprevir + PegIFN alfa-2a + RBV in Nonresponders or Relapsers

• Open-label treatment of patients from control arms of PROVE1-3 trials

Poordad F, et al. EASL 2008. Abstract 1000.

0

20

40

60

80

100

Un

det

ecta

ble

HC

V R

NA

, <

10 IU

/mL

(%

)

Wk 4 (RVR)

33

50

79

Wk 4 Null Responder*

Wk 12 Null Responder†

Partial Responder‡

Wk 20 Breakthrough

Relapser

67

100 10089

100 100 100

80

100100 100

Wk 8 Wk 12

*< 1 log10 drop at Wk 4. †<2 log10 drop at Wk 12. ‡≥ 2 log10 drop at Wk 12; detectable HCV RNA at Wk 24.

Conclusions

• Relapsers are good candidates to re-treatment with PegIFN and RBV combination

• EVR stopping rule recommended

• Optimize weight-based RBV dose during re-treatment

• Consider longer duration of re-treatment (cirrhotic, obese)

• Higher doses of PegIFN alpha may be superior to standard dose in selected patients (G1, obese)

• Potential role for cIFN

Q.1

• Which factors, among the following, are associated with a relapse in patients infected with genotype 1?

• Short duration of initial course

• Low dose of ribavirin

• Severe liver damage

• All the previous

Q.2

• For how long should a cirrhotic patient with genotype 2 infection who relapsed after 12-14 wks of treatment be re-treated ?

Q.3

• Which treatment would you advise for a genotype 1 65 yr-old non-cirrhotic pt relapsing after 48 wks of PegIFN and RBV combination?

Telaprevir and PegIFN

9 mcg of CIFN + RBV for 72 wks

PegIFN and RBV for 48 wks

Q.3

• Which is the minimum decline on treatment and at what time should it be assessed to decide not to stop re-treatment?

• If a minimum of a 1 log decline occurs at wk 12 it may be reasonable to continue tx and reassess HCV RNA periodically

Relapse rates in Genotype 2 and 3 after RVR

12 – 16 wks12 – 16 wks 24 wks

%%

10 10,8

2

5,3

0

5

10

15

20

25

30

35

Mang ia 2005 Dalg ard 2008

Key Questions for HCV Patients Facing Retreatment

1. What were you treated with, at what dosage, and for how long?

2. What type of response did you have?

3. What is your GT?

4. Did you require dose reductions or treatment interruptions during previous therapy? What adverse effects caused these interruptions/dose reductions?

5. Were you overweight during previous courses of therapy?

6. Were there adherence issues?

7. Do you have any significant comorbidities/other conditions that may affect your response to treatment?

8. Did you have a good support system during previous courses of treatment? What do you have now?

Summary : re-treatment of Relapsers

Response pattern

IFN

Response

Re-Treatment strategy

Maintenance Tx

Relapse Yes Treat for 72 weeks

Yes, if it can keep RNA-ve

Documents

Management of non naïve patients with hepatitis C Relapsers Alessandra Mangia Liver Unit & Division of Gastroenterology “CSS” San Giovanni Rotondo, Italy