Hepati tis web study HEPATITIS WEB STUDY HEPATITIS C ONLINE Treatment of Chronic HCV Genotype 2 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 14, 2014
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Hepatitis web study H EPATITIS W EB S TUDY H EPATITIS C O NLINE Treatment of Chronic HCV Genotype 2 Robert G. Gish MD Staff Physician, Stanford University.
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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)
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 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
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
Hepatitisweb study
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
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.