How to optimize treatment of G4 patients?

• Case:

• 26 Y male, HCV positive on pre-employment• Transfused at age 3 for hemolysis due to G6PD

deficiency

» ALT normal, » RNA 2,500,000 IU/ml » Fibroscan 7KPa, » Bx A1F1, » IL-28 CT

• NTX is a broad spectrum antiviral drug (a thiazolides)

• Inhibitor of hepatitis C virus in replicon studies

• Use as a single agent decreased virema

Nitazoxanide in G-4Nitazoxanide in G-4

Korba BE, et al. Antivir Res. 2008;77:56-63.

Rossignol JF, et al. Aliment Pharmacol Ther 2008; 28, 574–580

• NTX synergistic with IFN

• Studies in patients with G 4 suggest that NTX can improve response

Peg-IFN = pegylated interferon alfa-2a 180 µg/wk; RBV = ribavirin 1,000 or 1,200 mg/day;

NTX = nitazoxanide 500 mg bid

240 48 72Weeks

12 6036

NTZ + Peg-IFN Follow-upNTX/IFN

n=28NTZ

SVR

Follow-upControln=40

Peg-IFN + RBV SVR

NTZ + Peg-IFN + RBV Follow-upNTZ SVRNTX/IFN/RBV

n=28

Rossignol JF, et al. Gastroenterology. 2009 Mar;136(3):856-62. Epub 2008 Nov 19.

Nitazoxanide in G-4Nitazoxanide in G-4

Improved virologic response in chronic hepatitis C G-4 treated with nitazoxanide, peginterferon, and ribavirin.

Nitazoxanide in G-4Nitazoxanide in G-4

Rossignol JF, et al. Gastroenterology. 2009 Mar;136(3):856-62. Epub 2008 Nov 19.

NTZ + Peg-IFN + RBV Follow-upFollow-upNTZ

SVRNTX/12 Wksn=50

NTX = nitazoxanide 500 mg bid

0 48 72Weeks

-12

NTZ + Peg-IFN + RBVNTZ + Peg-IFN + RBVFollow-upFollow-up

NTX/4 Wksn=50

NTZ SVR

Follow-upFollow-upSOCn=25

Peg-IFN + RBV SVR

-4

Nitazoxanide in G-4Nitazoxanide in G-4

NTX trial in National Liver Institute: G4 Naiive, NTX+PEG-IFN+RBV (4 vs 12 wk lead in) vs SOC

Nitazoxanide in G-4Nitazoxanide in G-4

• NTX lead in had no effect on viral load

Nitazoxanide in G-4Nitazoxanide in G-4

• NTX addition to PEG-RBV did not increase virological response

• NTX does NOT appear to be the solution to increase response in patients with G4

• NTX addition to PEG-RBV did not increase virological response

• NTX does NOT appear to be the solution to increase response in patients with G4

• MOH ongoing trial • NTX 3 mths + SOC (100 pts) vs SOC (100 pts)• EVR: NTX 76%, SOC 82%

• MOH ongoing trial • NTX 3 mths + SOC (100 pts) vs SOC (100 pts)• EVR: NTX 76%, SOC 82%

■ Boceprevir and telaprevir are not indicated for treatment of HCV G4

■ Daclatasvir (BMS-790052) is a highly selective HCV NS5A replication complex inhibitor with broad genotypic coverage in vitro.

■ Daclatasvir (BMS-790052) combined with pegylated interferon-alfa-2a (peg-alfa) and ribavirin (RBV) showed high rates of SVR in a phase 2a study.

DAA for G4DAA for G4

BMS-790052, A NS5A Replication Complex Inhibitor, Combined with Peginterferon-Alfa-2a and Ribavirin in Treatment-Naive HCV-Genotype 1 or

4 Subjects: Phase 2b AI444010 Study Interim Week 12 Results

C Hézode, GM Hirschfield, W Ghesquiere, W Sievert, M Rodriguez-Torres, S Shafran, PJ Thuluvath, HA Tatum, I Waked, G Esmat, EJ Lawitz, VK Rustgi, S Pol, N Weis, P Pockros, M Bourlière, L Serfaty, JM

Vierling, MW Fried, O Weiland, MR Brunetto, GT Everson, S Zeuzem, PY Kwo, M Sulkowski, PD Yin, U Diva, EA Hughes, M Wind-Rotolo, S Schnittman

AASLD, 2011

DAA for G4DAA for G4

• Randomized, blinded, controlled, Phase 2b clinical trial

• Patients– HCV genotype 1 (n=365) or 4 (n=30) infection

– Treatment naïve, aged 18–70 years

– METAVIR stage F0–F4

• Treatment– BMS-790052 (Daclatasvir) 20 mg or 60 mg or placebo once daily in

combination with

– Weekly peg-alfa and RBV twice daily

DAA for G4DAA for G4Methods

AASLD, 2011

DAA for G4DAA for G4

HCV RNA <LLQ and Detectable

HCV RNA Undetectable

Week 4

Per

cent

age

of P

atie

nts

With

Res

pons

e

100

33

12 6n =

Week 1212 6n =

Virologic Responses Through Week 12: Virologic Responses Through Week 12:

AASLD, 2011

DAA for G4DAA for G4P

erce

ntag

e of

Pat

ient

sW

ith R

espo

nse

94

n =

9ETR

4

n =

9SVR 24 2

ETR

n =

Virologic Responses Through Week 48: (single center data, unpubished)

Virologic Responses Through Week 48: (single center data, unpubished)