PowerPoint Presentation
Treatment of Chronic HCV Genotype 3Robert 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: April 27, 2014Hepatitis Web StudyHepatitis C
OnlineHepatitisweb studyBackground and DefinitionsInitial Treatment
and Retreatment of Prior RelapsersRetreatment of Prior
NonrespondersIssues and ControversiesFuture
TherapiesSummaryTreatment of Chronic HCV Genotype 3Hepatitisweb
studyHepatitisweb studyBackground and DefinitionsTreatment of
Chronic Hepatitis C: Genotype 3Hepatitisweb studyHepatitisweb
studyTreatment of Chronic HCV Genotype 3BackgroundHCV infects ~ 5
million people in the US todayGenotype 3 is the third most common
HCV genotype in USUp to 85% of patients have contraindications for
interferon therapyMajor linkage to IVDA in epidemiological
studiesInterferes with lipid metabolism in hepatocytes and linked
with fatty liverSlightly higher risk of developing cirrhosisHCV
Geno 3 is the new Geno 1 in terms of lower response rates
Hepatitisweb studyVirologic Responses with HCV TherapySustained
Virologic Response at 12 Weeks Post Therapy (SVR12)Sustained
Virologic Response (SVR12) = Undetectable HCV RNA 12 Weeks Post
TreatmentUndetectableTreatmentPost Treatment12 WeeksEnd of
TreatmentSVR12Hepatitisweb studyVirologic Responses with HCV
TherapyRelapser and Nonresponder (Null and Partial)Different Types
of Virologic Failure with HCV TherapyTreatmentRelapserPartial
ResponderNull ResponderUndetectableNonresponderNonresponder
Hepatitisweb studySource: AASLD/IDSA/IAS-USA
(www.hcvguidelines.org). Viewed April 8, 2014AASLD/IDSA/IAS-USA
2014 HCV Treatment RecommendationsCriteria for Interferon
IneligibleInterferon Ineligible is defined as one or more of the
following:Intolerance to interferonAutoimmune hepatitis and other
autoimmune disordersHypersensitivity to peginterferon or any of its
componentsDecompensated hepatic diseaseHistory of depression, or
clinical features consistent with depressionA baseline neutrophil
count below 1500/L, a baseline platelet count below 90,000/L or
baseline hemoglobin below 10 g/dLA history of preexisting cardiac
diseaseHepatitisweb studyTreatment-Nave and Prior
RelapsersTreatment of Chronic Hepatitis C: Genotype 3Hepatitisweb
studyHepatitisweb studySource: AASLD/IDSA/IAS-USA
(www.hcvguidelines.org). Viewed April 22, 2014AASLD/IDSA/IAS-USA
2014 HCV Treatment RecommendationsInitial Therapy for Patients with
Genotype 3 Chronic HCVPatients with GT 3 HCV: Initial Treatment
& Retreatment of Relapsers*Recommended Therapy, Regardless of
Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 24
weeksAlternative Therapy, Eligible for Interferon Therapy
Sofosbuvir + Peginterferon + Ribavirin x 12 weeksNot Recommended
Peginterferon + Ribavirin x 24-48 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
therapyHepatitisweb studyTreatment-Nave & Prior Relapsers with
GT3 Chronic HCVKey Studies that Support Treatment
RecommendationsSofosbuvir + Ribavirin- FISSION- POSITRON -
VALENCESofosbuvir + Ribavirin + Peginterferon- PROTONSofosbuvir +
Ribavirin or Sofosbuvir + Ribavirin + Peginterferon-
ELECTRONHepatitisweb studySource: Lawitz E, et al. N Engl J Med.
2013;368:1878-87.2436Week012N =243N =256SVR12SVR12Sofosbuvir +
Ribavirin for Treatment-Nave HCV GT 2 or 3FISSION Trial:
DesignPeginterferon + RBV (fixed-dose)Sofosbuvir + RBV
(weight-based)Drug DosingSofosbuvir: 400 mg once dailyPeginterferon
alfa-2a: 180 g 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/dayHepatitisweb
studySofosbuvir + Ribavirin for Treatment-Nave HCV GT 2 or 3FISSION
Trial: ResultsSVR12 by GenotypeSource: Lawitz E, et al. N Engl J
Med. 2013;368:1878-87.RBV = Ribavirin; PEG = Peginterferon
68/7052/67102/183110/176170/253162/243Hepatitisweb study12Source:
Jacobson I, et al. N Engl J Med. 2013;368:1867-77.N =71Placebo12
weeksSofosbuvir + RBV12 weeksN =207SVR12Sofosbuvir + Ribavirin for
HCV GT 2 or 3 (PEG not an option)POSITRON Trial:
Design24Week012SVR12Drug DosingSofosbuvir: 400 mg once
dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if
< 75 kg or 1200 mg/day if 75 kgHepatitisweb studySofosbuvir +
Ribavirin for HCV GT 2,3 (PEG not an option)POSITRON: Results with
Sofosbuvir + RibavirinSVR12 by HCV GenotypeSource: Jacobson I, et
al. N Engl J Med. 2013;368:1867-77.Placebo arm = 0%
SVR12101/10960/98Hepatitisweb study14Source: Zeuzem S, et al.
AASLD. Nov, 2013. Abstract 1085.2436Week012Sofosbuvir + Ribavirin
for Treatment Nave & Experienced HCV GT 2 or 3 VALENCE:
Treatment ArmsSVR12Sofosbuvir + RBV(n = 73)SVR12Sofosbuvir + RBV(n
= 250)GT 2GT 3Drug DosingSofosbuvir 400 mg once dailyRibavirin
(weight-based and divided bid): 1000 mg/day if < 75 kg or 1200
mg/day if 75 kgOriginal 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 treatmentNote:
85 patients enrolled in placebo armHepatitisweb studySofosbuvir +
Ribavirin for Treatment Nave & Experienced HCV GT 2 or 3
VALENCE: Results for Treatment-Nave GT 3 with 24 weeks All-Oral
TherapySVR12 for Treatment-Nave GT 3Source: Zeuzem S, et al. AASLD.
Nov, 2013. Abstract 1085. Sofosbuvir (Sovaldi) Prescribing
Information. Gilead Sciences. Hepatitisweb study16Source: Lawitz E,
et al. Lancet Infect Dis. 2013;13:401-8.Sofosbuvir + Peginterferon
+ Ribavirin in Treatment-Naive Genotypes 1-3PROTON Trial:
DesignWeek0N =14Drug DosingSofosbuvir (SOF): 400 mg once daily,
except as designated in arm that received 200 mg once
dailyRibavirin (RBV) weight-based and divided bid: 1000 mg/day if
< 75 kg or 1200 mg/day if 75 kgPeginterferferon alfa-2a (PEG):
180 g once weekly72n = 4812SOF + PEG + RBVn = 2548GT 2, 3GT 1SOF
(200 mg) + PEG + RBV+ RVRPEG + RBV24 - RVR PEG + RBVn = 47SOF (400
mg) + PEG + RBV+ RVRPEG + RBV - RVR PEG + RBVSOF + PEG + RBVn =
26Hepatitisweb study17Sofosbuvir + Ribavirin + Peginterferon in
Treatment-Naive Genotypes 1-3PROTON Trial: ResultsSVR 24 by
Genotype and Treatment RegimenSource: Lawitz E, et al. Lancet
Infect Dis. 2013;13:401-8.41/4842/4715/2623/25Genotype 1Genotype 2
or 3Hepatitisweb study18Source: Gane EJ, et al. N Engl J Med.
2013;368:34-44. Sofosbuvir and Ribavirin +/- Peginterferon in GT
1-3ELECTRON Trial (Arms 1-8): DesignSOF + RBV Week0N =14Drug
DosingSofosbuvir (SOF): 400 mg once dailyRibavirin (RBV)
weight-based and divided bid: 1000 mg/day if < 75 kg or 1200
mg/day if 75 kgPeginterferon alfa-2a (PEG): 180 g once weekly24n =
9n = 108SOF + RBV + PEG (week 1-4)12n = 10SOF + RBV + PEG (week
1-8)n = 11SOF + RBV + PEG SOFSOF + RBV + PEG SOF + RBVSOF + RBV
SVR12n = 10n = 10n = 10n =
25SVR12SVR12SVR12SVR12SVR12SVR12SVR1220GT 1 NullGT 2,3Nave GT 1
Naive Hepatitisweb study19Sofosbuvir and Ribavirin +/-
Peginterferon in GT 3ELECTRON: Subset AnalysisSVR 12 for
Treatment-Nave Genotype 3*Source: Gane EJ, et al. N Engl J Med.
2013;368:34-44. 6/6Treatment-Nave Genotype 36/66/67/710/10*Data for
sofosbuvir monotherapy not shownHepatitisweb study20Retreatment of
Prior NonrespondersTreatment of Chronic Hepatitis C: Genotype
3Hepatitisweb studyHepatitisweb studySource: AASLD/IDSA/IAS-USA
(www.hcvguidelines.org). Viewed April 22, 2014AASLD/IDSA/IAS-USA
2014 HCV Treatment RecommendationsRetreatment of Patients with
Genotype 3 Chronic HCVPatients with GT 3 HCV: Retreatment of Prior
Nonresponders*Recommended Therapy Sofosbuvir + Ribavirin x 24
weeksAlternative Therapy Sofosbuvir + Peginterferon + Ribavirin x
12 weeksNot 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
therapyHepatitisweb studyTreatment Experienced Nonresponders with
GT3 Chronic HCVKey Studies that Support Treatment
RecommendationsSofosbuvir + Ribavirin- FUSION- VALENCESofosbuvir +
Ribavirin + Peginterferon- LONESTAR-2Hepatitisweb studySource:
Jacobson I, et al. N Engl J Med. 2013;368:1867-77.N =98Sofosbuvir +
RBV16 weeksSofosbuvir + RBV12 weeksN =103SVR12Sofosbuvir + RBV in
Treatment-Experienced HCV GT 2 or 3FUSION Trial:
Design24Week0122816SVR12PlaceboDrug DosingSofosbuvir: 400 mg once
dailyWeight-Based Ribavirin (in 2 divided doses): 1000 mg/day if
< 75 kg or 1200 mg/day if 75 kgHepatitisweb studySofosbuvir +
RBV in Treatment-Experienced HCV GT 2 or 3FUSION Trial: Results for
GT3SVR12 for Treatment-Experienced GT3Source: Jacobson I, et al. N
Engl J Med. 2013;368:1867-77.SOF = Sofosbuvir; RBV =
Ribavirin19/6439/6314/385/2625/4014/23Hepatitisweb study25Source:
Zeuzem S, et al. AASLD. Nov, 2013. Abstract
1085.2436Week012Sofosbuvir + Ribavirin for Treatment Nave &
Experienced HCV GT 2 or 3 VALENCE: Treatment ArmsSVR12Sofosbuvir +
RBV(n = 73)SVR12Sofosbuvir + RBV(n = 250)GT 2GT 3Drug
DosingSofosbuvir 400 mg once dailyRibavirin (weight-based and
divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if 75
kgOriginal 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 treatmentNote: 85 patients
enrolled in placebo armHepatitisweb studySofosbuvir + Ribavirin for
Treatment Nave & Experienced HCV GT 2 or 3 VALENCE: Results for
Treatment Experienced GT 3SVR12 for Treatment-Experienced GT
3Source: Zeuzem S, et al. AASLD. Nov, 2013. Abstract 1085.
Sofosbuvir (Sovaldi) Prescribing Information. Gilead Sciences.
Hepatitisweb study27Source: 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:
Design24Week012Sofosbuvir + Peginterferon + RibavirinN =
47SVR12Drug DosingSofosbuvir: 400 mg once dailyPeginterferon
alfa-2a: 180 g once weeklyRibavirin (weight-based and in 2 divided
doses): 1000 mg/day if < 75 kg or 1200 mg/day if 75 kgGT 2 or
3Hepatitisweb studySofosbuvir + PEG + RBV in Treatment-Experienced
HCV GT 2 or 3LONESTAR-2 Trial: ResultsSVR12 in
Treatment-Experienced by HCV GenotypeSource: Lawitz E, et al. 64th
AASLD; Washington, DC. 2013. Abstract
LB-4.42/4722/2320/24Hepatitisweb study29Issues and
ControversiesTreatment of Chronic Hepatitis C: Genotype
3Hepatitisweb studyHepatitisweb studyIssues and ControversiesCost
of TherapySofosbuvir + PEG + RBV higher SVR than all oral (LONESTAR
data)- Treat selected Geno 3 patients with Sofosbuvir + PEG + RBV?-
Wait for FDC Ledipasvir-Sofosbuvir + RBV with 100% SVR?When to
Defer Therapy- Decisions on when to warehouse?(Non) Role of IL-28b
TestingDegree of Liver Fibrosis- How to stage?Hepatitisweb studyHow
is cost of therapy impacting treatment decisions?Hepatitisweb
studyHepatitisweb studyHepatitis C Genotype 3Estimated Medication
Costs for Treatment-Nave & Prior RelapsersPatients with GT 3
HCV: Initial Treatment & Retreatment of RelapsersRegimen and
DurationRegimen CostRecommended Therapy Sofosbuvir + Ribavirin x 24
weeks$169,000Alternative Therapy Sofosbuvir + Peginterferon +
Ribavirin x 12 weeks$97,000Hepatitisweb study33Hepatitis C Genotype
3Estimated Medication Costs for Retreatment of
NonrespondersPatients with GT 3 HCV: Retreatment of
NonrespondersRegimen and DurationRegimen CostRecommended Therapy
Sofosbuvir + Ribavirin x 24 weeks$169,000Alternative Therapy
Sofosbuvir + Peginterferon + Ribavirin x 12
weeks$97,000Hepatitisweb study34HCV Therapy for Genotype 3 Chronic
HCVCost Analysis Based on Cost per SVRPatient
CharacteristicsRegimen OptionsSVRCost per SVRNave, no cirrhosisSOF
+ RBV x 24 wks93%$194,624SOF + PEG + RBV x 12 wks??Nave,
cirrhosisSOF + RBV x 24 wks92%$196,739Treatment experienced, no
cirrhosisWait until.???SOF + RBV x 24 wks85%$212,941Treatment
experienced, cirrhosis SOF + RBV x 24 wks60%$301,667SOF + PEG + RBV
x 12 wks83%$126,915Source for Figure: Camilla Graham, MD, MPH. Beth
Israel Deaconess Medical CenterData 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
12/7/2013Hepatitisweb studyTreat now or defer therapy? Hepatitisweb
studyHepatitisweb studyFactors Favoring Treat NowAdvanced Fibrosis
(F3-F4)- Platelet count < 150,000/uL- Large spleen and/or portal
vein- Esophageal varicesSynthetic dysfunctionSystemic disease-
Cryoglobulinemia (+RhF)Highly motivated patients/symptomsPatients
with Increased Mortality Risk- All cause- HCC riskHepatitisweb
studyHow do you treat patient that failed Sofosbuvir + Ribavirin?
Hepatitisweb studyHepatitisweb studySource: Esteban R, et al. 49th
EASL; April 2014. Abstract 08.Retreatment of SOF + RBV Failure with
SOF-Containing Regimens in GT 2 or 3Study FeaturesRetreatment of
Sofosbuvir + Ribavirin Failure: FeaturesDesign: Open-label, study
for patients with GT 2 or 3 who had failure with sofosbuvir +
ribavirin in FISSION, POSITRON, or FUSION trialSetting: Europe,
United States, and CanadaEntry Criteria - N = 107 patients with
chronic HCV- HCV genotype 2 (10%) or HCV genotype 3 (90%)- Previous
relapse on sofosbuvir plus ribavirin- Patients with compensated
cirrhosis allowed to enrollRegimens (patients offered 2 possible
regimens)- Sofosbuvir + Ribavirin x 24 weeks- Sofosbuvir +
Peginterferon + Ribavirin x 12 weeksPrimary End-Point:
SVR12Hepatitisweb studySource: Esteban R, et al. 49th EASL; April
2014. Abstract 08.Retreatment of SOF + RBV Failure with
SOF-Containing Regimens in GT 2 or 3Study Design2436Week012N = 73N
= 34SVR12SVR12Sofosbuvir + RBVSofosbuvir + PEG + RBVDrug
DosingSofosbuvir: 400 mg once dailyPeginterferon alfa-2a: 180 g
once weeklyWeight-based Ribavirin (in 2 divided doses): 1000 mg/day
if < 75 kg or 1200 mg/day if 75 kgGT2 or GT3Hepatitisweb
studyRetreatment of SOF + RBV Failure with SOF-Containing Regimens
in GT 2 or 3Results, by Genotype SVR12 by Regimen and HCV
GenotypeSource: Esteban R, et al. 49th EASL; April 2014. Abstract
08.4/41/220/2224/38Hepatitisweb studyFuture Treatment
OptionsHepatitis C: Genotype 3Hepatitisweb studyHepatitisweb
studyFuture Regimens for GT-3Ledipasvir + Sofosbuvir- Lepidasvir:
NS5A replication inhibitor- Sofosbuvir: NS5B polymerase
inhibitorDaclatasvir + Sofosbuvir?- Daclatasvir: NS5A replication
inhibitor- Sofosbuvir: NS5B polymerase
inhibitorABT-450/r-Ombitasvir +/- Ribavirin?- ABT-450/r: NS3
protease inhibitor with ritonavir boosting- Ombitasvir (formerly
ABT-267): NS5A replication inhibitorHepatitisweb studySource: Gane
EJ, et al. 49th EASL. 2014: Abstract O6.Sofosbuvir-Ledipasvir +/-
Ribavirin in GT 1 & 3ELECTRON 2: Study DesignLDV-SOF +
RBVSVR12Week0N =14Drug DosingLedipasvir-sofosbuvir (90/400 mg):
fixed dose combination; one pill once dailyRibavirin (weight-based
and divided bid): 1000 mg/day if < 75 kg or 1200 mg/day if 75
kg24GT1Prior Sofobuvirn = 20n = 19GT1CTP Class B12n = 25LDV-SOF
SVR12n = 26LDV-SOF + RBVSVR12Abbreviations: LDV= ledipasvir; SOF =
sofosbuvir; RBV = ribavirin LDV-SOF SVR12GT3Treatment
NaiveHepatitisweb study44Sofosbuvir-Ledipasvir +/- Ribavirin in GT
1 & 3ELECTRON 2: Study DesignSVR 12, by GT and Treatment
RegimenSource: Gane EJ, et al. 49th EASL. 2014: Abstract O6.LDV=
ledipasvir; SOF = sofosbuvir; RBV =
ribavirin19/19SOF-ExperiencedTreatment Naive13/2016/2526/26CTP
Class BHepatitisweb study45Source: Sulkowski MS, et al. N Engl J
Med. 2014;370:211-21.Daclatasvir + Sofosbuvir +/- Ribavirin for HCV
GT 1-3A1444-040 Design: Treatment-Nave 24 Week RxSOF 7 days, then
DCV + SOFSVR12Week024N =14Drug 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)36Rx NaveGT
2 / 3
n = 44n = 14n = 1612DCV + SOFn = 14DCV + SOF + RBVSVR12SVR12SOF
7 days, then DCV + SOFSVR12Rx NaveGT 1a/1b
n = 44n = 14n = 15DCV + SOFn = 15DCV + SOF +
RBVSVR12SVR12Hepatitisweb studyDaclatasvir + Sofosbuvir +/-
Ribavirin for HCV GT 1-3A1444-040: Subset Analysis for
Treatment-Nave GT 3SVR12 by GT 3, by Treatment RegimenSource:
Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.DCV =
daclatasvir; SOF = sofosbuvir; RBV = ribavirin5/76/65/5Hepatitisweb
studySummary Points for Treatment of Chronic HCV GT-3Treat now with
Sofosbuvir + Ribavirin x 24 weeksConsider IFN-based Rx in select
patient who can tolerate IFN to shorten therapy, save costs and
have a nominally higher SVR rateStage patient for liver disease and
systemic diseaseLook for signs of fatty liver and metabolic
syndromeGT 3 may be the new GT 1 but high SVR rates can be seen in
selected patientsHepatitisweb studyThis slide deck is from the
University of Washingtons Hepatitis C Online and Hepatitis Web
Study projects.
Hepatitis C Onlinewww.hepatitisc.uw.edu
Hepatitis Web Studyhttp://depts.washington.edu/hepstudy/
Funded by a grant from the Centers for Disease Control and
Prevention. Hepatitisweb studyHepatitisweb study