Hepatitisweb study

HEPATITIS WEB STUDY HEPATITIS C ONLINE

Treatment of Chronic HCV Genotype 2

Robert G. Gish MDStaff Physician, Stanford University Medical CenterSenior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, ArizonaClinical Professor of Medicine, University of Nevada, Las VegasMedical Director, Hepatitis B FoundationVice Chair, Executive Committee, National Viral Hepatitis Roundtable (NVHR)

Last Updated: May 14, 2014

Hepatitisweb study

Hepatitisweb study

• Background and Definitions

• Initial Treatment and Retreatment of Prior Relapsers

• Retreatment of Prior Nonresponders

• Issues and Controversies

• Future Therapies

• Summary

Treatment of Chronic HCV Genotype 2

Hepatitisweb study

Hepatitisweb study

Background and DefinitionsTREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 2

Hepatitisweb study

Treatment of Chronic HCV Genotype 2

Background

• HCV infects ~ 5 million people in the US today

• Genotype 2 is second most common HCV genotype in US

• Up to 85% of patients have contraindications for interferon therapy

• Small proportion of untreated patients are genotype 2 today due to historically high treatment and cure rates

Hepatitisweb study

Virologic Responses with HCV TherapySustained Virologic Response at 12 Weeks Post Therapy (SVR12)

Sustained Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post Treatment

-8 -4 0 4 8 12 16 20 24 28 32 36 40 44 481

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Treatment Week

HC

V R

NA

IU

/ml

Undetectable

Treatment Post Treatment

12 Weeks

End of Treatment

SVR12

Hepatitisweb study

Virologic Failure with HCV TherapyRelapser and Nonresponder (Null and Partial)

Different Types of Virologic Failure with HCV Therapy

-8 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 801

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Treatment Week

HC

V R

NA

IU

/ml

Treatment

Relapser

Partial Responder

Null Responder

Undetectable

Nonresponder

Nonresponder

Hepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Accessed May 12, 2014

AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsCriteria 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

Hepatitisweb study

Hepatitisweb study

Treatment-Naïve and Prior RelapsersTREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 2

Hepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

AASLD/IDSA/IAS-USA 2014 HCV Treatment Recommendations

Initial Therapy for Patients with Genotype 2 Chronic HCV

Patients with GT 2 HCV: Initial Treatment & Retreatment of Relapsers*

Recommended Therapy, Regardless of Eligibility for Interferon Therapy

Sofosbuvir + Ribavirin x 12 weeks

Alternative Therapy, Regardless of Eligibility for Interferon Therapy

None

Not Recommended

Peginterferon + Ribavirin x 24 weeks

Monotherapy with Peginterferon, Ribavirin, or a Direct Acting Antiviral Agent

Any Regimen with Telaprevir, Boceprevir, or Simeprevir

*Patients who experienced relapse after Peginterferon plus Ribavirin therapy

Hepatitisweb study

Treatment-Naïve & Prior Relapsers with GT2 Chronic HCVKey Studies that Support Treatment Recommendations

• Sofosbuvir + Ribavirin

- FISSION

- POSITRON

- VALENCE

Hepatitisweb studySource: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

24 36Week 0 12

N =243

N =256 SVR12

SVR12

Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3FISSION Trial: Design

Peginterferon + RBV (fixed-dose)

Sofosbuvir + RBV (weight-based)

Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyWeight-based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kgFixed-dose Ribavirin (in 2 divided doses): 800 mg/day

Hepatitisweb study

Sofosbuvir + Ribavirin for Treatment-Naïve HCV GT 2 or 3FISSION Trial: Results

SVR12 by Genotype

Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.

GT 2 and 3 _x000d_(n=496)

GT 2 _x000d_(n=137) GT 3_x000d_(n=359)0

20

40

60

80

100

67

97

56

67

78

63

Sofosbuvir + RBV PEG + RBV

Pat

ien

ts (

%)

wit

h S

VR

12

RBV = Ribavirin; PEG = Peginterferon

68/70 52/67 102/183 110/176170/253 162/243

Hepatitisweb studySource: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

N =71 Placebo12 weeks

Sofosbuvir + RBV12 weeks

N =207 SVR12

Sofosbuvir + Ribavirin for HCV GT 2 or 3 (PEG not an option)POSITRON Trial: Design

24Week 0 12

SVR12

Drug DosingSofosbuvir: 400 mg once dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

Hepatitisweb study

Sofosbuvir + Ribavirin for HCV GT 2,3 (PEG not an option)POSITRON: Results with Sofosbuvir + Ribavirin

SVR12 by HCV Genotype

Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

Placebo arm = 0% SVR12

GT 2 GT 3 0

20

40

60

80

100

93

61

Pat

ien

ts (

%)

SV

R12

101/109 60/98

Hepatitisweb studySource: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

24 36Week 0 12

Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3

VALENCE: Treatment Arms

SVR12Sofosbuvir + RBV

(n = 73)

SVR12Sofosbuvir + RBV

(n = 250)

GT 2

GT 3

Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment

Note: 85 patients enrolled in placebo arm

Hepatitisweb study

Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3

VALENCE: Results for Treatment-Naïve GT 2

SVR12 for Treatment-Naïve GT 2

Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

All Noncirrhotic Cirrhotic0

20

40

60

80

10097 97 100

Pa

tie

nts

(%

) w

ith

SV

R1

2

31/32 2/229/30

Hepatitisweb study

Hepatitisweb study

Retreatment of Prior NonrespondersTREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 2

Hepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014

AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsRetreatment of Patients with Genotype 2 Chronic HCV

Patients with GT 2 HCV: Retreatment of Prior Nonresponders*

Recommended Therapy

Sofosbuvir + Ribavirin x 12 weeks^

Alternative Therapy

Sofosbuvir + Peginterferon + Ribavirin x 12 weeks

Not Recommended

Peginterferon + Ribavirin +/- [Telaprevir, Boceprevir, or Simeprevir]

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^Patients with cirrhosis may benefit by extension of therapy to 16 weeks

Hepatitisweb study

Treatment Experienced Nonresponders with GT2 Chronic HCVKey Studies that Support Treatment Recommendations

• Sofosbuvir + Ribavirin- FUSION- VALENCE

• Sofosbuvir + Ribavirin + Peginterferon- LONESTAR-2

Hepatitisweb studySource: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

N =98 Sofosbuvir + RBV16 weeks

Sofosbuvir + RBV12 weeks

N =103

SVR12

Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Design

24Week 0 12 2816

SVR12Placebo

Drug DosingSofosbuvir: 400 mg once dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

Hepatitisweb study

Sofosbuvir + RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Results for GT2

SVR12 for Treatment-Experienced GT2

Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.

GT 2 (All) Without Cirrhosis With Cirrhosis0

20

40

60

80

100

86

96

60

94100

78

SOF + RBV (12 wks) SOF + RBV (16 wks)

Pat

ien

ts (

%)

wit

h S

VR

12

SOF = Sofosbuvir; RBV = Ribavirin

31/36 30/32 25/26 6/1023/23 7/9

Hepatitisweb studySource: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

24 36Week 0 12

Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3

VALENCE: Treatment Arms

SVR12Sofosbuvir + RBV

(n = 73)

SVR12Sofosbuvir + RBV

(n = 250)

GT 2

GT 3

Drug DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

Original Study Protocol: Placebo versus 12 weeks treatment for GT 2 and 3. Amended Protocol: GT3 treatment extended from 12 to 24 weeks; Placebo arm offered alternative treatment

Note: 85 patients enrolled in placebo arm

Hepatitisweb study

Sofosbuvir + Ribavirin for Treatment Naïve & Experienced HCV GT 2 or 3 VALENCE: Results for Treatment Experienced GT 2

SVR12 for Treatment-Experienced GT 2

Source: Zeuzem S, et al. N Engl J Med. 2014 May 4. [Epub ahead of print]

All Noncirrhotic Cirrhotic0

20

40

60

80

100

9094

78

Pa

tie

nts

(%

) w

ith

SV

R1

2

37/41 7/930/32

Hepatitisweb studySource: Lawitz E, et al. 64th AASLD; Washington, DC. 2013. Abstract LB-4.

Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3LONESTAR-2 Trial: Design

24Week 0 12

Sofosbuvir + Peginterferon + Ribavirin

N = 47 SVR12

Drug DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 µg once weeklyRibavirin (weight-based and in 2 divided doses): 1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg

GT 2 or 3

Hepatitisweb study

Sofosbuvir + PEG + RBV in Treatment-Experienced HCV GT 2 or 3LONESTAR-2 Trial: Results

SVR12 in Treatment-Experienced by HCV Genotype

Source: Lawitz E, et al. 64th AASLD; Washington, DC. 2013. Abstract LB-4.

Overall GT 2 GT 30

20

40

60

80

100

8996

83

Pat

ien

ts w

ith

SV

R 1

2 (%

)

42/47 22/23 20/24

Hepatitisweb study

Hepatitisweb study

Issues and ControversiesTREATMENT OF CHRONIC HEPATITIS C: GENOTYPE 2

Hepatitisweb study

Treatment of Genotype 2 Chronic HCV

Issues and Controversies

• Cost of Therapy: wait for price competition?

• With cure rates as high as 96%, are we over-treating most patients?

- Can we shorten therapy to 4 or 6 weeks to save treatment costs?

• When to Defer Therapy:

- Decisions on when to warehouse?

- Based on mild histology or lack of evidence of systemic disease

• (Non) Role of IL-28b Testing, now obviated

• Degree of Liver Fibrosis

- How to stage?

- MRE, Fibroscan, Supersonic, Spleen Size, APRI score, platelet count

Hepatitisweb study

Hepatitisweb study

How is cost of therapy impacting treatment decisions?

Hepatitisweb study

Hepatitis C Genotype 2Estimated Medication Costs for Treatment-Naïve & Prior Relapsers

Patients with GT 2 HCV: Initial Treatment & Retreatment of Relapsers

Regimen and DurationRegimen

Cost

Recommended Therapy

Sofosbuvir + Ribavirin x 12 weeks $85,000

Alternative Therapy

None NA

Hepatitisweb study

Hepatitis C Genotype 2Estimated Medication Costs for Retreatment of Nonresponders

Patients with GT 2 HCV: Retreatment of Nonresponders

Regimen and DurationRegimen

Cost

Recommended Therapy

Sofosbuvir + Ribavirin x 12 weeks $85,000

Sofosbuvir + Ribavirin x 16 weeks* $113,000

Alternative Therapy

Sofosbuvir + Peginterferon + Ribavirin x 12 weeks $97,000

*Note: some experts extend therapy to 16 weeks in nonresponder GT2 patients with cirrhosis

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Source for Figure: Camilla Graham, MD, MPH. Beth Israel Deaconess Medical Center

Data Sources: (1) Lawitz E, et al. NEJM 2013; 368:1878-87. (2) Jacobson I, et al. NEJM 2013; 368:1867-77. (3) Antiviral Drugs Advisory Committee Meeting, FDA and Gilead reviews, 10/25/2013. (4) Package Insert, Gilead.com 12/7/2013.

HCV Therapy for Genotype 2 Chronic HCVCost Analysis Based on Cost per SVR

Patient Characteristics Regimen Options SVR Cost per SVR

Naïve, no cirrhosisSOF + RBV x 12 wks 92-98% $95,263

PEG + RBV x 24 wks 80% $53,350

Naïve, cirrhosis SOF + RBV x 12 wks 91-94% $97,312

Treatment experienced, no cirrhosis SOF + RBV x 12 wks 91-96% $96,276

Treatment experienced, cirrhosis

SOF + RBV x 16 wks 78% $154,658

SOF + PEG + RBV x 12 wks 93% $113,269

Hepatitisweb study

Hepatitisweb study

Treat now or defer therapy?

Hepatitisweb study

Factors Favoring Treat GT2 Now

• Advanced Fibrosis (F3-F4)- Platelet count < 150,000/uL- Large spleen and/or portal vein- Esophageal varices

• Synthetic dysfunction

• Systemic disease- Cryoglobulinemia ([+] Rheumatoid Factor)

• Highly motivated patients/symptomatic patients

• Patients with Increased Mortality Risk- All cause- HCC risk

Hepatitisweb study

Hepatitisweb study

Future Treatment OptionsHEPATITIS C: GENOTYPE 2

Hepatitisweb study

Future Regimens for GT-2

• Daclatasvir + Sofosbuvir

- Daclatasvir: NS5A replication inhibitor

- Sofosbuvir: NS5B polymerase inhibitor

• ABT-450/r-Ombitasvir +/- Ribavirin

- ABT-450/r: NS3 protease inhibitor with ritonavir boosting

- Ombitasvir (formerly ABT-267): NS5A replication inhibitor

Hepatitisweb studySource: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3A1444-040 Design: Treatment-Naïve 24 Week Rx

SOF × 7 days, then DCV + SOF SVR12

Week 0 24

N =14

Drug DosingDaclatasvir (DCV): 60 mg once dailySofosbuvir (SOF): 400 mg once dailyRibavirin (RBV): GT1, given weight-based and divided bid (1000 mg/day if < 75 kg or 1200 mg/day if ≥ 75 kg)Ribavirin (RBV): GT 2 or 3 (800 mg/day)

36

Rx NaïveGT 2 or 3

n = 44

n = 14

n = 16

12

DCV + SOF

n = 14 DCV + SOF + RBV

SVR12

SVR12

SOF × 7 days, then DCV + SOF SVR12Rx NaïveGT 1a/1b

n = 44

n = 14

n = 15

DCV + SOF

n = 15 DCV + SOF + RBV

SVR12

SVR12

Hepatitisweb study

Daclatasvir + Sofosbuvir +/- Ribavirin for HCV GT 1-3

A1444-040: Results for Treatment-Naïve GT 2

SVR12 for Patient with GT 2, by Treatment Regimen

Source: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.

SOF x 7d, DCV + SOF DCV + SOF DCV + SOF + RBV0

20

40

60

80

100100 100

71

Pat

ien

ts w

ith

SV

R12

(%

)

DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin

9/9 8/8 5/7

Hepatitisweb study

Summary Points for Treatment of Chronic HCV GT-2

• Genotype 2 highly responsive to 12 weeks of all-oral therapy

• Relatively little retreatment data since high SVR rates with therapy in naïve patients

• Few GT2 studies moving forward with new therapies

• Will be difficult to enroll large studies required for licensing trials

• New pangenotypic drugs will be used for genotype 2 off-label (prediction)

Hepatitisweb study

Hepatitisweb study

This slide deck is from the University of Washington’s Hepatitis C Online and Hepatitis Web Study projects.

Hepatitis C Online

www.hepatitisc.uw.edu

Hepatitis Web Study

http://depts.washington.edu/hepstudy/

Funded by a grant from the Centers for Disease Control and Prevention.