1. Treatment of Chronic HCV Genotype 4
Robert G. Gish MD
Staff Physician, Stanford University Medical Center
Senior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, Arizona
Clinical Professor of Medicine, University of Nevada, Las Vegas
Medical Director, Hepatitis B Foundation
Vice Chair, Executive Committee, National Viral Hepatitis Roundtable (NVHR)
Last Updated: May 21, 2014

2. Treatment of Chronic HCV Genotype 4
Background and Definitions
Initial Treatment and Retreatment of Prior Relapsers
Retreatment of Prior Nonresponders
Issues and Controversies
Future Therapies
Summary

3. Background and Definitions
Treatment of Chronic Hepatitis C: Genotype 4
Background and Definitions

4. Treatment of Chronic HCV Genotype 4 Background
HCV infects ~ 5 million people in the US today
Genotype 4 accounts for about 1-2% of HCV infections in US
Genotype 4 very important in Egypt, Saudi Arabia, North Africa, and Southern Europe
Approximately 70% of patients with genotype 4 HCV have moderate to severe steatosis with or without sinusoidal fibrosis
Historic SVR rates with IFN-based therapy between GT1 and GT 2,3

5. Different Types of Virologic Failure with HCV Therapy
Virologic Responses with HCV Therapy Relapser and Nonresponder (Null and Partial)
Different Types of Virologic Failure with HCV Therapy
Treatment
Relapser
Nonresponder
Null Responder
Nonresponder
Partial Responder
Undetectable

6. AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Criteria for Interferon Ineligible
Interferon Ineligible is defined as one or more of the following:
Intolerance to interferon
Autoimmune hepatitis and other autoimmune disorders
Hypersensitivity to peginterferon or any of its components
Decompensated hepatic disease
Major uncontrolled depressive illness
A baseline neutrophil count below 1500/μL, a baseline platelet count below 90,000/μL or baseline hemoglobin below 10 g/dL
A history of preexisting cardiac disease
Source: AASLD/IDSA/IAS-USA ( Viewed April 8, 2014

7. Treatment-Naïve and Prior Relapsers
Treatment of Chronic Hepatitis C: Genotype 4
Treatment-Naïve and Prior Relapsers

8. AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Initial Therapy for Patients with Genotype 4 Chronic HCV
Patients with GT 4 HCV: Initial Treatment & Retreatment of Relapsers*
Recommended Therapy
Interferon Eligible Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
Not Interferon Eligible
Sofosbuvir + Ribavirin x 24 weeks
Alternative Therapy
Interferon Eligible Simeprevir x 12 weeks + [Peginterferon + Ribavirin] x weeks
Not Recommended
Peginterferon + Ribavirin x 48 weeks
Monotherapy with Peginterferon, Ribavirin, or a Direct-Acting Antiviral Agent
Telaprevir- or Boceprevir-based regimens
*Patients who experienced relapse after Peginterferon plus Ribavirin therapy
Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014

9. Treatment-Naïve & Prior Relapsers with GT4 Chronic HCV Key Studies that Support Treatment Recommendations
Sofosbuvir + Ribavirin + Peginterferon - NEUTRINO
Sofosbuvir + Ribavirin - Egyptian Ancestry
Simeprevir + Ribavirin + Peginterferon - RESTORE

10. Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Design
Week 12 24
Sofosbuvir + PEG + RBV
N =327
SVR12
Drug Dosing Sofosbuvir: 400 mg once daily Peginterferon alfa-2a: 180 µg once weekly Ribavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Source: Lawitz E, et al. N Engl J Med ;368:

11. NEUTRINO: SVR 12 by Genotype
Sofosbuvir + PEG + RBV: Treatment-Naive HCV GT 1,4,5,6 NEUTRINO Trial: Results
NEUTRINO: SVR 12 by Genotype
261/292
27/28
7/7
GT = genotype
Source: Lawitz E, et al. N Engl J Med ;368:

12. Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Design
Week 12 24 36
GT 4
Naïve or Experienced
Sofosbuvir + RBV (n = 31)
SVR12
Sofosbuvir + RBV (n = 29)
SVR12
Drug Dosing Sofosbuvir: 400 mg once daily Weight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.

13. Treatment Experienced
Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Results
SVR 12 by Regimen Duration and Treatment Experience
11/14
14/14
10/17
13/15
Treatment Naive
Treatment Experienced
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.

14. Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Study Design
Week 12 24 48
Simeprevir
Treatment-Naïve or Prior Relapse
RGT determines if PEG + RBV x 24 or 48 wks
Peginterferon + Ribavirin
Simeprevir
Peginterferon + Ribavirin
Partial Response or Null Response
Simeprevir
Peginterferon + Ribavirin
Response Guided Therapy (RGT) Criteria: Week 4 HCV RNA < 25 IU/mL (detectable or undetectable) and Week 12 HCV RNA < 25 IU/mL (undetectable)
Drug Dosing Simeprevir: 150 mg once daily
Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

15. Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Results
RESTORE: SVR12 by Prior Treatment Status
70/107
29/35
19/22
6/10
16/40
Treatment-Naïve & Experienced Relapsers
Treatment-Experienced Nonresponders
Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

16. Retreatment of Prior Nonresponders
Treatment of Chronic Hepatitis C: Genotype 4
Retreatment of Prior Nonresponders

17. AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations Retreatment of Patients with Genotype 4 Chronic HCV
Patients with GT 4 HCV: Retreatment of Prior Nonresponders*
Recommended Therapy
Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
Alternative Therapy
Sofosbuvir + Ribavirin x 24 weeks
Not Recommended
Peginterferon + Ribavirin +/- [Boceprevir or Simeprevir or Telaprevir]
Monotherapy with Peginterferon, Ribavirin, or a Direct-Acting Antiviral Agent
Treatment of Decompensated Cirrhosis with Peginterferon
*Patients who experienced nonresponse (partial or null) with Peginterferon plus Ribavirin therapy
Source: AASLD/IDSA/IAS-USA ( Viewed April 22, 2014

18. Sofosbuvir + Ribavirin - Egyptian Ancestry
Treatment Experienced Nonresponders with GT4 Chronic HCV Key Studies that Support Treatment Recommendations
Sofosbuvir + Ribavirin - Egyptian Ancestry
Simeprevir + Ribavirin + Peginterferon - RESTORE

19. Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Design
Week 12 24 36
GT 4
Naïve or Experienced
Sofosbuvir + RBV (n = 31)
SVR12
Sofosbuvir + RBV (n = 29)
SVR12
Drug Dosing Sofosbuvir: 400 mg once daily Weight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.

20. Treatment Experienced
Sofosbuvir and Ribavirin in HCV Genotype 4 Egyptian Ancestry Trial: Results
SVR 12 by Regimen Duration and Treatment Experience
11/14
14/14
10/17
13/15
Treatment Naive
Treatment Experienced
Source: Ruane P, et al. 49th EASL. April 2014: Abstract P1243.

21. Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Study Design
Week 12 24 48
Simeprevir
Treatment-Naïve or Prior Relapse
RGT determines if PEG + RBV x 24 or 48 wks
Peginterferon + Ribavirin
Simeprevir
Peginterferon + Ribavirin
Partial Response or Null Response
Simeprevir
Peginterferon + Ribavirin
Response Guided Therapy (RGT) Criteria: Week 4 HCV RNA < 25 IU/mL (detectable or undetectable) and Week 12 HCV RNA < 25 IU/mL (undetectable)
Drug Dosing Simeprevir: 150 mg once daily
Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

22. Simeprevir + Peginterferon + Ribavirin in Genotype 4 RESTORE: Results
RESTORE: SVR12 by Prior Treatment Status
70/107
29/35
19/22
6/10
16/40
Treatment-Naïve & Experienced Relapsers
Treatment-Experienced Nonresponders
Source: Moreno C, et al. 49th EASL. April 2014: Abstract P1319.

23. Issues and Controversies
Treatment of Chronic Hepatitis C: Genotype 4
Issues and Controversies

24. Issues and Controversies
Cost of Therapy
When to Defer Therapy - Decisions on when to warehouse?
(Non) Role of IL-28b Testing
Degree of Liver Fibrosis - How to stage?

25. How is cost of therapy impacting treatment decisions?

26. Hepatitis C Genotype 4 Estimated Medication Costs for Treatment-Naïve & Prior Relapsers
Patients with GT 4 HCV: Initial Treatment & Retreatment of Relapsers
Regimen and Duration
Regimen Cost
Recommended Therapy
Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
$97,000
Sofosbuvir + Ribavirin x 24 weeks
$169,000
Alternative Therapy
Simeprevir x 12 weeks + [Peginterferon + Ribavirin] x weeks
$79,000- $104,000

27. Hepatitis C Genotype 4 Estimated Medication Costs for Retreatment of Nonresponders
Patients with GT 4 HCV: Retreatment of Nonresponders
Regimen and Duration
Regimen Cost
Recommended Therapy
Sofosbuvir + Peginterferon + Ribavirin x 12 weeks
$97,000
Alternative Therapy
Sofosbuvir + Ribavirin x 24 weeks
$169,000

28. When to defer therapy?

29. Factors Favoring Treat Now for GT4
Advanced Fibrosis (F3-F4) - Platelet count < 150,000/uL - Large spleen and/or portal vein (Over 12 rule = Spleen >12 cm or PV > 12 mm) - Esophageal varices
Synthetic dysfunction, low albumin, high INR
Systemic disease - Cryoglobulinemia (+RhF)
Highly motivated patients/symptoms
Patients with Increased Mortality Risk - All cause - HCC risk

30. Future Treatment Options
Hepatitis C: Genotype 4
Future Treatment Options

31. Future Regimens for GT-4
ABT-450/r-Ombitasvir +/- Ribavirin - ABT-450/r: NS3 protease inhibitor with ritonavir boosting - Ombitasvir (formerly ABT-267): NS5A replication inhibitor
Ledipasvir + Sofosbuvir - Lepidasvir: NS5A replication inhibitor - Sofosbuvir+ NS5 NS5b polymerase inhibitor
Daclatasvir + Sofosbuvir? - Daclatasvir: NS5A replication inhibitor - Sofosbuvir+ NS5 NS5b polymerase inhibitor

32. ABT450/r + Ombitasvir +/- Ribavirin in GT 1b or 4 PEARL-I (Noncirrhotic Patients): Substudy 1 Design
Week 12 24
GT 4: Naïve
n = 44
ABT-450/r + Ombitasvir
SVR12
GT 1b: Naïve
n = 42
ABT-450/r + Ombitasvir
SVR12
GT 1b: Null
n = 40
ABT-450/r + Ombitasvir
SVR12
GT 4: Naïve
n = 42
ABT-450/r + Ombitasvir + RBV
SVR12
GT 4: Experienced*
n = x
ABT-450/r + Ombitasvir
SVR12
GT 4: Experienced*
n = 49
ABT-450/r + Ombitasvir + RBV
SVR12
*Experienced = Treatment Experienced (Partial/Null Responders and Relapsers)
Drug Dosing ABT-450/r (150/100 mg once daily) Ombitasvir: 25 mg once daily Ribavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75kg or 1200 mg/day if ≥ 75kg)
N =14
Source: Hezode C, et al. 49th EASL. April Abstract O58.

33. Treatment-Experienced
ABT450/r + Ombitasvir +/- Ribavirin in GT4 PEARL-I (Noncirrhotic Patients): Genotype 4 Analysis
PEARL I: Genotype 4 SVR
SVR 12 40/44
SVR 12 42/42
SVR 4* 37/37
Treatment-Naïve
Treatment-Experienced
*Note: for the two GT4 treatment experienced arms, limited available data (only SVR4 for 37 of 49 enrolled in one arm)
Source: Hezode C, et al. 49th EASL. April Abstract O58.

34. Ledipasvir-Sofosbuvir for GT-4
*Ledipasvir-Sofosbuvir in Patients with GT 4 or Phase 2 open-label study - Treatment-naïve and treatment-experienced - All patients receive 12 weeks of ledipasvir-sofosbuvir (fixed dose)
*Ledipasvir-Sofosbuvir in Patients with GT 1 or 4 & HIV Coinfection - Phase 3 open-label study - Treatment-naïve and treatment-experienced (including intolerant) - Initial treatment: 12 weeks of ledipasvir-sofosbuvir (fixed dose) - Retreatment: 24 weeks of ledipasvir-sofosbuvir (fixed dose) + ribavirin
*Studies are ongoing and treatment data not available

35. Summary Points for Treatment of Chronic HCV GT-4
HCV GT4 uncommon in US, but prevalent in Egypt, Saudi Arabia, North African, and southern Europe as well as immigrants from these regions to the US including Coptic population and horn of Africa (Sudan, Ethiopia and Eritrea)
For treatment-naïve and treatment-experienced patients with GT4, the recommended regimen is SOF + PEG + RBV x 12 weeks
For treatment-naïve and treatment-experienced patients with GT4, the alternative regimen is SOF + RBV x 24 weeks
For interferon ineligible or cost reduction: SOF + SIM (Cosmos protocol)
Several investigational agents appear promising for GT4

36. This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects.
Hepatitis C Online
Hepatitis Web Study
Funded by a grant from the Centers for Disease Control and Prevention.