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Individualisation of HCV Therapy. Achieving an SVR What is the evidence? Dr Allister J Grant. Achieving an SVR. The ability to achieve SVR is the result of two independent steps: 1. Achieving a virologic response a. Interferon/peginterferon dose b. The presence of ribavirin

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Individualisation of hcv therapy

Individualisation of HCV Therapy

Achieving an SVR

What is the evidence?

Dr Allister J Grant


Achieving an svr
Achieving an SVR

The ability to achieve SVR is the result of two independent steps:

1. Achieving a virologic response

a. Interferon/peginterferon dose

b. The presence of ribavirin

2. Not relapsing

a. How fast the patient becomes HCV RNA undetectable

b. How long the patient remains on treatment

c. Dose of ribavirin


Rx duration

Wk 12 PCR

“EVR”

48 weeks

Neg/2log drop

Genotype 1,4-6

Stop

Pos

24 weeks

Genotype 2,3



Win r trial w eight based in terferon and r ibavirin trial aasld 2005

Ribavirin 800mg/d (FD) vs 800-1400mg/d

PEG IFN 2b

G1 48wks

G2/3 randomised to 24/48 wks

Community based US study

4913 patients

G1 significant advantage in WBD of RBV

No advantage for G2/3 but…..

WIN-R trial Weight based Interferon and Ribavirin TrialAASLD 2005


Win r trial
WIN-R Trial

  • Analysis of SVR by weight

  • More dose reductions

  • No more discontinuations

49%

52%

45%

44%

42%

39%

47%

34%

P<0.0001 p=0.11


Win r trial1
WIN–R Trial

G2 had a higher SVR and lower relapse rate than those with G3

(72% vs. 60% and 6% vs.10% respectively). Investigators concluded that higher

weight-based doses of ribavirin appear to be necessary to achieve similar

SVR rates in G3 patients



Evr treatment outcome all genotypes
EVR – Treatment Outcome (All Genotypes) a predictor of SVR?

PEG IFN alfa-2a 180 g + ribavirin 1,000–1,200 mg

Week 72

Week 12

Start of study

No SVR

35%

(n=137/390)

EVR

86%

(n=390/453)

SVR

65%

(n=253/390)

Overall

SVR

56%

(255/453)

Total study

population

(n=453)

SVR

3%

(n=2/63)

No EVR

14%

(n=63/453)

No SVR

97%

(n=61/63)

Fried et al. NEJM 2002


Evr treatment outcome all genotypes1
EVR – Treatment Outcome (All Genotypes) a predictor of SVR?

PEG IFN alfa-2b 1.5 g/kg + ribavirin 10.6 mg/kg

Week 72

Week 12

Start of study

No SVR

20%

(n=29/143)

EVR

76%

(n=143/188)

SVR

80%

(n=114/143

Total study

population

(n=188)

Overall

SVR

61%

(114/188)

SVR

0%

(n=0/45)

No EVR

24%

(n=45/188)

No SVR

100%

(n=45/45)

Davis G, et al. Hepatology 2003



Evr week 12 in genotype 1
EVR – Week 12 in Genotype 1 a predictor of SVR?

(Patients HCV RNA negative and patients HCV RNA positive >2 Log at week 12)

PEG-IFN α-2a 180 g

+ ribavirin 1,000-1,200 mg

N=298

19%

No EVR

N=58

81%

Achieved EVR

N=240

58%

Achieve SVR

N=139

2%

Achieve SVR

N=1

PPV=58%

NPV=98%

Ferenci P et al. J Hepatol 2005;43(3):425-33.


Evr week 12 in genotype 11
EVR – Week 12 in Genotype 1 a predictor of SVR?

(Patients HCV RNA Negative and patients HCV RNA positive >2 Log at week 12)

PEG-IFN α-2a 180 g

+ ribavirin 1,000-1,200 mg

N=569

84%

Achieved EVR

N=477

16%

No EVR

N=58

58%

Achieve SVR

N=264

NA%

Achieve SVR

N=NA

PPV=58%

NPV=NA

Reddy K et al. DDW2005, Abstract # S1540



Treatment of chronic hcv predicting svr over time
Treatment Of Chronic HCV a predictor of SVR?Predicting SVR Over Time

PEG-IFN-2a

+ Ribavirin

The later a patient becomes HCV RNA undetectable, regardless of EVR the lower the chance for SVR.

HCV RNA +

at week 24

P Ferrenci et al.

J Hepatology 2005; 43:425-33.


Relapse rate relationship to first time hcv rna negativity
Relapse Rate Relationship to First Time HCV RNA Negativity a predictor of SVR?

Data on file Schering-Plough Corp. Adapted Poynard T. et al, Lancet 1998, McHutchison JG, NEJM, 1998, Lindsay K. et al, Hepatology 2001


Rapid virologic response
RAPID VIROLOGIC RESPONSE a predictor of SVR?

  • Rapid virologic response (RVR) defined as HCV RNA (-) by week 4

  • Occurs regardless of the interferon type or if ribavirin utilised or not

P Ferrenci et al.

J Hepatology 2005; 43:425-33.


Rvr effect of genotype
RVR- Effect Of Genotype a predictor of SVR?

P Ferrenci et al. J Hepatology 2005; 43:425-33.

ML Shiffman et al. EASL 2006.


Rvr frequency
RVR- Frequency a predictor of SVR?

P Ferrenci et al. J Hepatology 2005; 43:425-33

ML Shiffman et al. EASL 2006.


Individualisation of therapy according to hcv genotype and viral load
Individualisation of Therapy According to a predictor of SVR?HCV Genotype and Viral Load


Zeuzem et al j hepatol 2006

89% 85% a predictor of SVR?

81% 74%

50% 71%

Manns et al 2001

Zeuzem et al J.Hepatol 2006

  • Open multicentre, historical controlled trial to test whether HCV-1 patients with low viral load can be treated with 24 weeks therapy

    (PEG IFN 2b +Ribavirin 800-1400mg/)

  • 724 patients screened and 235 enrolled


Virologic response in patients with hcv 1 and hcv rna 600 000 iu ml
Virologic response in patients with HCV-1 and HCV RNA < 600,000 IU/mL

89%

80%

75%

Patients (%)

50%

37%

25%

17%

8%

(47%)

(26%)

(10%)

Time to first negative HCV RNAPEG-IFN a-2b + RBV

Zeuzem et al., J Hepatol 2006



Peginterferon alfa 2a 180 g qw ribavirin 1000 1200 mg qd
Peginterferon alfa-2a 180 µg qw + 600,000 IU/mLRibavirin 1000-1200 mg qd

HCV-RNA

A

N = 71

< 600 IU/mL

B

N = 153

N = 69

C

N = 13

 600 IU/mL

0 4 8 12 16 20 24 48

follow-up period

weeks

v. Wagner, Gastroenterology 2005


End of treatment eot and sustained virologic response svr hcv genotypes 2 and 3 combined
End-of-treatment (EOT) and sustained virologic response (SVR)- HCV genotypes 2 and 3 combined -

SVR B vs C: P = 0.003

94%

86%

82%

81%

69%

Virologic response (%)

39%

67/71

58/71

59/69

56/69

9/13

5/13

(16 weeks)

(24 weeks)

(24 weeks)

v. Wagner et al, Gastroenterology 2005


Shortening treatment for g2 3 rapid virologic responders
SHORTENING TREATMENT FOR G2-3 (SVR)RAPID VIROLOGIC RESPONDERS

Shortening therapy even in patients with RVR doubles the relapse rate

M Von Wagner et al.

Gastroenterology. 2005;129:522-527.


Peginterferon alfa 2b 1 0 g kg ribavirin 1000 1200 mg qd
Peginterferon alfa-2b 1.0 µg/kg+ (SVR)Ribavirin 1000-1200 mg qd

A

N = 70

HCV-RNA

B

-

N = 133

N = 213

C

+

N = 80

0 4 8 12 16 20 24 48

follow-up period

weeks

Mangia et al, N Engl J Med 2005


Sustained virologic response svr according to hcv genotype
Sustained virologic response (SVR) according to HCV genotype (SVR)

Rx: PEG-IFN alfa-2b 1.0 µg/kg + RBV 1000-1200 mg

87%

77%

76%

76%

72%

SVR (%)

41%

40/53

13/17

89/102

24/31

42/58

9/22

(24 weeks)

(12 weeks)

(24 weeks)

Mangia et al, N Engl J Med 2005


HCV Genotypes 2 & 3 (SVR)ACCELERATE TRIAL

N=1469

PEGASYS 180 mcg/wk

Ribavirn 800 mg/d

PEGASYS 180 mcg/wk

Ribavirin 800 mg/day

4

16

24

48

0

12

Weeks

ML Shiffman et al.

EASL 2006.


Hcv genotypes 2 3 accelerate trial
HCV Genotypes 2 & 3 (SVR)ACCELERATE TRIAL

N=1469

*

*

ML Shiffman et al.

EASL 2006.


Hcv genotypes 2 3 impact of rapid response
HCV Genotypes 2 & 3 (SVR)Impact Of Rapid Response

Rapid Virologic

Response:

*

*

ML Shiffman et al.

EASL 2006.


Viral load (SVR)

at baseline

Rx duration

Wk 4 PCR

Wk 12 PCR

48 weeks

Neg/2log drop*

Stop

Pos

Pos

Neg

Low

24 weeks

PPV 89%

Genotype 1,4-6

48 weeks

Neg

High

PPV75-85% / 46-72%

Pos

48 weeks

Neg/2log drop*

Pos

Stop

24G2(48G3)

Pos

Low

16G2/24G3

Neg

Genotype 2,3

PPV 82-90%

High

24 weeks

Neg

Pos

24G2(48G3)

Low= <600,000 IUml

<3x106 cpm

* If 2 log drop then PCR at 24 weeks



SUMMARY OF RECOMMENDATIONS (SVR)

Shorten duration of therapy for

Genotype 1 LVL with RVR………………24 weeks instead of 48

Genotype 2 LVL with RVR………………16 weeks instead of 24

Consider lengthening duration of therapy for

Genotype 3 who do not have RVR……..48 weeks instead of 24

Do PCR at

4 weeks for everyone

If 4 week PCR negative then no need for further PCR till 24 weeks post Rx

If 4 week PCR positive then do PCR at 12 weeks.

If PCR positive at 12 weeks stop therapy

If PCR shows 2 log drop at 12 weeks do PCR at 24 weeks


Extending treatment duration

48 weeks (SVR)

Pegasys 180 mg QW

Ribavirin 800 mg/d

72 weeks

EXTENDING TREATMENT DURATION

HCV RNA (+)

N=165

N=162

96

0

4

72

48

Weeks

JM Sanchez-Tapias et al.

Gastroenterology 2006; 131: 451-460.


Extending therapy
EXTENDING THERAPY (SVR)

Extending the duration of therapy reduced relapse from 47% to 13%

P=0.014

JM Sanchez-Tapias et al.

Gastroenterology 2006; 131: 451-460.

G1 without RVR

SVR 28%(48w) vs 44%(72w)


Urgent treatment recommended for
Urgent Treatment Recommended For (SVR)

  • Acute HCV

  • Stable compensated cirrhotics

  • HCV with cryoglobulinaemia/renal involvement

  • Occupation where HCV infection is hazardous


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