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Treatment of Chronic HCV Genotype 2Robert 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 2Hepatitisweb studyHepatitisweb studyBackground and DefinitionsTreatment of Chronic Hepatitis C: Genotype 2Hepatitisweb studyHepatitisweb studyTreatment of Chronic HCV Genotype 2BackgroundHCV infects ~ 5 million people in the US todayGenotype 2 is second most common HCV genotype in USUp to 85% of patients have contraindications for interferon therapySmall proportion of untreated patients are genotype 2 today due to historically high treatment and cure ratesHepatitisweb 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 Failure 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 22, 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 2Hepatitisweb 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 2 Chronic HCVPatients with GT 2 HCV: Initial Treatment & Retreatment of Relapsers*Recommended Therapy, Regardless of Eligibility for Interferon Therapy Sofosbuvir + Ribavirin x 12 weeksAlternative Therapy, Regardless of Eligibility for Interferon Therapy NoneNot 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 therapyHepatitisweb studyTreatment-Nave & Prior Relapsers with GT2 Chronic HCVKey Studies that Support Treatment RecommendationsSofosbuvir + Ribavirin- FISSION- POSITRON- VALENCEHepatitisweb 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 2SVR12 for Treatment-Nave GT 2Source: Zeuzem S, et al. AASLD. Nov, 2013. Abstract 1085. Sofosbuvir (Sovaldi) Prescribing Information. Gilead Sciences. Hepatitisweb study16Retreatment of Prior NonrespondersTreatment of Chronic Hepatitis C: Genotype 2Hepatitisweb studyHepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed April 22, 2014AASLD/IDSA/IAS-USA 2014 HCV Treatment RecommendationsRetreatment of Patients with Genotype 2 Chronic HCVPatients with GT 2 HCV: Retreatment of Prior Nonresponders*Recommended Therapy Sofosbuvir + Ribavirin x 12 weeks^Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeksNot 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 weeksHepatitisweb studyTreatment Experienced Nonresponders with GT2 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 GT2SVR12 for Treatment-Experienced GT2Source: Jacobson I, et al. N Engl J Med. 2013;368:1867-77.SOF = Sofosbuvir; RBV = Ribavirin31/3630/3225/266/1023/237/9Hepatitisweb study21Source: Zeuzem S, et al. AASLD. Nov, 2013. Abstract 1085.2436Week012Sofosbuvir + Ribavirin for Treatment Nave & Experienced HCV GT 2 or 3VALENCE: 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 2SVR12 for Treatment-Experienced GT 2Source: Zeuzem S, et al. AASLD. Nov, 2013. Abstract 1085. Sofosbuvir (Sovaldi) Prescribing Information. Gilead Sciences. Hepatitisweb study23Source: 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 study25Issues and ControversiesTreatment of Chronic Hepatitis C: Genotype 2Hepatitisweb studyHepatitisweb studyTreatment of Genotype 2 Chronic HCVIssues and ControversiesCost 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 obviatedDegree of Liver Fibrosis- How to stage?- MRE, Fibroscan, Supersonic, Spleen Size, APRI score, platelet count Hepatitisweb studyHow is cost of therapy impacting treatment decisions?Hepatitisweb studyHepatitisweb studyHepatitis C Genotype 2Estimated Medication Costs for Treatment-Nave & Prior RelapsersPatients with GT 2 HCV: Initial Treatment & Retreatment of RelapsersRegimen and DurationRegimen CostRecommended Therapy Sofosbuvir + Ribavirin x 12 weeks$85,000Alternative Therapy NoneNAHepatitisweb study29Hepatitis C Genotype 2Estimated Medication Costs for Retreatment of NonrespondersPatients with GT 2 HCV: Retreatment of NonrespondersRegimen and DurationRegimen CostRecommended Therapy Sofosbuvir + Ribavirin x 12 weeks$85,000 Sofosbuvir + Ribavirin x 16 weeks*$113,000Alternative Therapy Sofosbuvir + Peginterferon + Ribavirin x 12 weeks$97,000 *Note: some experts extend therapy to 16 weeks in nonresponder GT2 patients with cirrhosisHepatitisweb study30Source 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 12/7/2013.HCV Therapy for Genotype 2 Chronic HCVCost Analysis Based on Cost per SVRPatient CharacteristicsRegimen OptionsSVRCost per SVRNave, no cirrhosisSOF + RBV x 12 wks92-98%$95,263PEG + RBV x 24 wks80%$53,350Nave, cirrhosisSOF + RBV x 12 wks91-94%$97,312Treatment experienced, no cirrhosisSOF + RBV x 12 wks91-96%$96,276Treatment experienced, cirrhosis SOF + RBV x 16 wks78%$154,658SOF + PEG + RBV x 12 wks93%$113,269Hepatitisweb studyTreat now or defer therapy? Hepatitisweb studyHepatitisweb studyFactors Favoring Treat GT2 NowAdvanced Fibrosis (F3-F4)- Platelet count < 150,000/uL- Large spleen and/or portal vein- Esophageal varicesSynthetic dysfunctionSystemic disease- Cryoglobulinemia ([+] Rheumatoid Factor)Highly motivated patients/symptomatic patientsPatients with Increased Mortality Risk- All cause- HCC riskHepatitisweb studyFuture Treatment OptionsHepatitis C: Genotype 2Hepatitisweb studyHepatitisweb studyFuture Regimens for GT-2Daclatasvir + 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: 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 or 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: Results for Treatment-Nave GT 2SVR12 for Patient with GT 2, by Treatment RegimenSource: Sulkowski MS, et al. N Engl J Med. 2014;370:211-21.DCV = daclatasvir; SOF = sofosbuvir; RBV = ribavirin9/98/85/7Hepatitisweb studySummary Points for Treatment of Chronic HCV GT-2Genotype 2 highly responsive to 12 weeks of all-oral therapyRelatively little retreatment data since high SVR rates with therapy in nave patientsFew GT2 studies moving forward with new therapiesWill be difficult to enroll large studies required for licensing trialsNew pangenotypic drugs will be used for genotype 2 off-label (prediction)Hepatitisweb 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