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Genotype 1

Genotype 1. Curtis Barry, MD UMASS ECHO 3/3/17. DISCLOSURE. NO Financial disclosures. GENOTYPE 1. Most common HCV infection in US 70-80% Historically has been difficult to treat. HCV G1, Treatment-Naïve Patients: Evolution of SVR rates. 80. 70. 60. 45%. 50. SVR (%). 40. 30%. 30.

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Genotype 1

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  1. Genotype 1 Curtis Barry, MD UMASS ECHO 3/3/17

  2. DISCLOSURE • NO Financial disclosures

  3. GENOTYPE 1 • Most common HCV infection in US 70-80% • Historically has been difficult to treat

  4. HCV G1, Treatment-Naïve Patients: Evolution of SVR rates 80 70 60 45% 50 SVR (%) 40 30% 30 20 6% 10 0 IFN(1991) IFN + RBV(1998) PEG-IFN + RBV (2001/2002)

  5. Pegylated Interferon and Ribavirin • Previous standard treatment regimen for HCV • Genotype 1: 48 wks with SVR of approx 45% • Genotype 2 and 3: 24 wks with SVR of approx 80% • Interferon: SQ injection once weekly • Induction of an antiviral state in their target cells • Cytokine secretion, recruitment of immune cells, and induction of cell differentiation • Ribavirin: synthetic guanosin analogue • Potentiates Interferon effect • Inhibits viral RNA polymerase in vitro

  6. Why Such Low SVR Rates for Genotype 1 HCV • IL28B Genotype • C/C genotype is more favorable to achieve SVR • Advanced fibrosis • Higher staging of fibrosis • BMI • Insulin resistance/NASH • High viral load • 800,000 international units/ml

  7. Peg-Interferon Side Effects • Flu-Like Syndrome (50%) • Myalgias • Fatigue • Fevers • Chills • Headache • Neuropsychiatric (20-30%) • Depression • Irritability • Insomnia • Hematologic • Thrombocytopenia • Neutropenia (20%) • Dermatologic • Rash • Injection Site Necrosis • Endocrine • Thyroid Disease • Hyperlipidemia

  8. Treatment Options • Until May 2011 • Pegylated interferon • Ribavirin • May 2011 (Protease inhibitors) • Boceprevir (Victrelis) • Telaprevir (Incivek)

  9. Protease Inhibitors • Telaprevir and Boceprevir • Used with standard therapy for genotype 1 HCV • Oral medication • Used in treatment naïve as well as non-responders

  10. SVR by Race and Cirrhosis

  11. Telaprevir: Adverse Reactions

  12. Overall SVR Rates by Prior Response

  13. SVR Rates by IL28B Genotype

  14. Drug Interactions with Telaprevir • Contraindicated • Rifampin, Ergot derivatives, Cisapride, St. John’s Wort, Atorvastatin, Lovastatin, Simvastatin, IV Sildenafil (Revatio) for treatmt pulm HTN, oral Midazolam, Triazolam • Not recommended • Tacrolimus, Voriconazole, Methylprednisolone, Prednisone, Cyclosporine, Colchicine, Budesonide • Use with caution • Alprazolam, Ambien, Amiodarone, Amlodipine, CCB, E-mycin, Methadone, Tenofovir, Trazodone, ED, Warfarin

  15. Boceprevir (Victrelis) • Treatment naïve, compensated cirrhotics, and previously treated patients • Dose: 800mg po q 7-9 hours (w/meal) • Metabolic pathway: CYP3A4 and aldoketo reductase • May not be used as monotherapy • Not studied in pts <18 yrs, >65 yrs, coinfxn HIV or HBV, organ transplant recipients • No dose reduction needed in ESRD

  16. Drug Interactions with Boceprevir • Contraindicated • Phenobarbital, Phenytoin, Carbamazepine, Rifampin, Ergot derivatives, Cisapride, St. John’s Wort, Lovastatin, Simvastatin, IV Sildenafil (Revatio), oral Midazolam, Triazolam • Not recommended • Tacrolimus, Voriconazole, Methylprednisolone, Prednisone, Cyclosporine, Colchicine, Budesonide • Use with caution • Alprazolam, Ambien, Amiodarone, Amlodipine, CCB, E-mycin, Methadone, Tenofovir, Trazodone, ED, Warfarin

  17. 2013-2014 • INTRODUCTION OF SOFOSBUVIR

  18. NEUTRINO SUMMARY

  19. PRESENT

  20. Ledipasvir-Sofosbuvir (HARVONI)

  21. HARVONI 8 vs 12 weeks

  22. Ledipasvir-Sofosbuvir in Treatment-Experienced GT1 with Cirrhosis SIRIUS Trial: Study Design 0 12 24 36 Week n = 77 Placebo LDV-SOF + RBV SVR12 n = 78 LDV-SOF SVR12 Drug 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 kg N =14 Abbreviations: LDV= ledipasvir; SOF = sofosbuvir; RBV = ribavirin Source: Bourliere M, et al. Lancet Infect Dis. 2015;15:397-404.

  23. Ledipasvir-Sofosbuvir in Treatment-Experienced GT1 with Cirrhosis SIRIUS Trial: Results SIRIUS: SVR 12 by Treatment Duration and Regimen 74/77 75/77 Source: Bourliere M, et al. Lancet Infect Dis. 2015;15:397-404.

  24. Sofosbuvir-Velpatasvir(EPCLUSA)

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