How to optimize the treatment of HCV-4 patients?

Nabil Antaki MD, FRCPC

Aleppo, Syria

Paris, January 30, 2012

Case Presentation

• A 39-year-old Syrian male was diagnosed

6 months ago with genotype 4 HCV infection discovered during screening before blood donation.

He had no symptoms. BMI 27. No alcohol

His physical examination revealed no

abnormalities and his liver was not enlarged.

The patient's initial laboratory results

• WBC: 5000 cells/mm3• Hemoglobin:15.4 g/dL • Platelet count: 168,000 cells/mm3• AST: 72 U/L ALT: 101 U/L• Total bilirubin: 0.4 mg/dL• Albumin: 4 g/L• HCV RNA: 900,000 IU/mL• Genotype 4c/d

The patient's initial laboratory results

• Prothrombin time: 10.9 seconds; INR 1• TSH: 2.5 IU/mL (normal: 0.60-3.30 IU/mL)• Ferritin: 150 ng/mL (normal: 27-377 ng/mL)• Iron saturation: 30%• Alpha-fetoprotein: 2.5 ng/mL• liver biopsy :grade 2 and stage 2

(Metavir score)• IL28B: rs12979860 :CT

• He was started on Peg-INF alfa-2a

180 µg/week plus RBV 1000 mg/day, and treatment was planned for 48 weeks.

What are the pre-treatment predictors of response in this

patient?• Ethnicity?• Viral load?• Genotype sub-type?• Fibrosis?• IL28B?

Fibrosis Stage and SVR Rates

65

46.646.4

21.236

27.3

0

100

F0 - F1 - F2 F3 - F4

Egyptian

French

African

• PEG-IFN-α-2b (1.5 μg / kg / week) plus RBV (1,000 – 1,200 mg / day) for 48 weeks

Roulot et al, J Viral Hepatol 2007

p=0.01

SVR (%)

Fibrosis score

Baseline Viral Load and SVR Rates

67

2113

48

14

38

0

100

SVR Relapse Non-responder

HCV RNA at baseline<600,000, IU/ML (n=24)

HCV RNA at baseline>600,000, IU/ML (n=21)

Huepper et al, AASLD 2007

Patients (%)

_

HCV-4 Subtypes & SVR Rates

54.9

40.332.4

0

100

Egypt France Africa

• Better SVR rates observed in patients with HCV-4a subtypes

Roulot et al, J Viral Hepat 2007n=242, p=<0.05

SVR (%)PEGIFN α-2b (1.5 mg / kg / week) plus RBV (1000 – 1200 mg / day) for 48 weeks

(4a) (4a,4d) (Multiple)

Factors Associated with SVR in 108 HCV-4 Patients: Multiple Logistic Regression Analysis

Variable Odds Ratio 95% CI P value

Geographical Origin (Egyptian) 13.119 (3.089 – 55.706) <0.001

Insulin Sensitivity (HOMA-IR < 2) 5.314 (1.953 – 14.459) 0.001

Non-Severe Fibrosis (F0 - F2) 8.059 (2.512 – 25.855) <0.001

Factors associated with SVR

rates

0

20

40

60

80

Egyptians Caucasians Africans

%63

53

39

Moucari, J Hepatol 2009

C Allele is Associated with SVR (HCV-1)Percentage SVR by Genotype of rs12979860

0 20 40 60 80 100

C/C

T/C

T/T

SVR

CombinedEuropean AmericansAfrican AmericansHispanics

n = 70

n = 14

n = 102

n = 91n = 35

n = 433

n = 186

n = 559

n = 392

n = 30n = 26

n = 336 P = 1.37 x 10-28 vs T/T

Ge D, et al. Nature. 2009;461:399-401.

IL28B in HCV-4Ethnicity CC (%) CT(%) TT(%) SVR(%)

Stättermayer1

n=10298% Egyptian 33.3 54 12.7 57

De Nicola2

n= 10368% Egyptian32% European

23 63 14 49

Asselah3

n= 8251%Egyptian34% European13%African

26.8 52.4 20.8 2

Antaki4

n= 194100% Caucasian 30.4 55.2 12 45

Worldwide distribution in Caucasian

38 50 12

1. Stättermayer et al,Clin Gastro and Hepatol, 2011. 2. De Nicola et al. Hepatology 2011.3 Assellah et al. J Hepatol 2011. 4. Antaki et al. submitted article

SVR in HCV-4 stratified by IL28B genotype (rs12979860)

Stattermayer N=102

De Nicola N=103

Asselah N=82

Antaki N=194

0%10%20%30%40%50%60%70%80%90%

100%

CCCTTT

SVR in HCV-4 stratified by IL28B genotype (rs8099917)

0%

10%

20%

30%

40%

50%

60%

70%

Stattermayer et al N=102 Antaki et al N=194

TT

TG/GG

Week 4

• Following 4 weeks of HCV treatment, the patient presents with no anemia (Hb: 12.5 g/dL; HCT: 37.5%) and mild neutropenia (WBC: 2600 cells/mm3; ANC: 1600 cells/mm3). Neither condition requires dose reduction or addition of epoetin at this time.

• ALT and AST normal• The patient's HCV RNA is now undetectable.

How would you manage his treatment at Week 4?

A. The patient is a responder and treatment should continue for 48 weeksB. The patient achieved RVR and 24 weeks of therapy is recommended C. The patient achieved RVR but his rs12979860 genotype is CT. He should continue therapy for 48 weeks

Optimizing the response:

RESPONSE GUIDED THERAPY

The faster after initiating treatment, HCV RNA becomes undetectable, the higher is the SVR rate and shorter is the duration of treatment.

Shorter treatment in HCV-4?Yes, If.....

Impact of RVR

RVR, EVR as a guide for 24 w, 36 w or 48w

358 patients

Adaptive

N=308

Fixed

N=50

24 wRVR

N=6936 w

cEVR

N=79 48 wpEVR

N=160

48 w

Kamal et al, Hepatology. 2007

EOT and SVR rates in HCV-G4 patients with RVR & EVR

9086

6570

86

76

56 58

0

25

50

75

100

Patients withRVR

Patients withcomplete EVR

Patients withpartial EVR

Fixed 48 weeks

EOT SVR

Kamal et al, Hepatology. 2007

% R

espo

nse

RVR in HCV - 4

• 66 HCV-4 patients, Peg IFN α 2a and RBV

• RVR achieved in 45%• 26 RVR patients (86.7%) achieved an

SVR when treated for 24 weeks only• No relation: with baseline viral load

with dose of RBV

Ferenci P, et al. Gastroenterol. 2008

SVR rates in HCV-G4 patients with RVR & EVR

Ferenci P, et al. Gastroenterol. 2008

0

20

40

60

80

100

≤ 400,000 400,000 -800,000

> 800,000

SV

R in

Pat

ien

ts A

chie

vin

g R

VR

(%

)

AllGenotype 1

F0-F2 F3-F4

By Baseline HCV RNA (IU/mL) By METAVIR Fibrosis Stage

Genotype 486.5 90.081.3 82.2 85.7

80.6

70.8

83.3

66.7

81.588.5

79.675.0 75.075.0

n/N = 61/74 52/64 9/10 37/45 25/31 12/14 17/24 12/18 5/6 97/119 74/93 23/26 18/24 3/415/20

Impact of RVR and IL28B on SVR

• RVR achieved in 25.4 to 41% of patients.• In De Nicola study:

RVR 34% SVR 80% (CC100%, CT/TT 70%, p= 0.06)

No RVR 66% SVR 32% (CC 75%, CT/TT 23%, p= 0.001)

Pre-treatment predictors of response

• Univariate analysis:1. Fibrosis (yes 1, 2, 4; no 3)

2. Ethnicity ( yes 2, no 3)

3. IL28B CC

4. Viral load

On-treatment predictors of response

• Univariate analysis:1. Fibrosis (yes 1, 2, 4 no 3)

2. Ethnicity ( yes 2, no 3)

3. IL28B CC

4. Viral load

5. RVR

predictors of response

• Multivariate analysis:1. Fibrosis

2. IL28B CC

3. RVR : the strongest predictor of SVR

W 24

• At Week 24 of HCV therapy, the patient is tolerating treatment and remains fully compliant. The patient's liver enzymes are normal (AST: 23 IU/mL;

ALT: 19 IU/mL).• His current HCV RNA is undetectable

What would you do?

• A. The patient should continue his current regimen through 48 weeks

• B. The patient should discontinue treatment and be monitored for the next 6 months to determine whether he has achieved SVR

What would you do?

• The patient has no advanced fibrosis• His pre-treatment viral load was 900,000 IU

but this is not a poor predictive factor of response if he achieves RVR

• Although his IL28B genotype is CT, he achieved RVR (no statistical significance in SVR between CC and CT/TT in RVR patients)

• Treatment was stopped at W 24

W 24 after ETR

• The patient returns 6 months after stopping treatment to determine whether he has achieved SVR.

• His liver enzymes remain within the normal range and HCV RNA remains negative, indicating that he has achieved SVR.

The HCV- 4 algorithm: 2009

24 weeks

48 weeks

72Weeks ?

Week 4

Week 12

Week 24

-

-

-

+

- Or + >2log

-

+

+ <2log

-

Mild FibrosisLVL

Week 4 _ + +

Week 12 _ (- )or > 2 log and CC

(+) or < 2 log CC or (-) but CT/TT

Week 24 _ _ _

Mild Fibrosis

24 weeks

48 weeks

72Weeks ???

The HCV- 4 proposed algorithm: 2012