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Information for Prescribers / Healthcare Providers

Ledipasvir- (Harvoni™) for chronic C infection genotype 1 and sofosbuvir (Sovaldi®) for chronic infection genotypes 1, 2 and 3 Ledipasvir-sofosbuvir (Harvoni™) and sofosbuvir (Sovaldi®) are direct-acting antivirals (DAA) for the treatment of (HCV) infection. Both drugs were reviewed by the Common Drug Review (CDR) followed by the review through the B.C. drug review process and the Pan-Canadian Pharmaceutical Alliance. B.C. drug reviews are based on many considerations, including available clinical and pharmacoeconomic evidence; input from specialists; input from patients, caregivers, and patient groups gathered through the PharmaCare Your Voice web page and the recommendations of an independent advisory body called the Drug Benefit Council (the Council). See www.cadth.ca/en/products/cdr for the CDR recommendations.

Effective March 24, 2015, both drugs will be PharmaCare Limited Coverage benefits, through the Special Authority process, for patients who meet the specified criteria for the treatment of chronic HCV infection. PharmaCare coverage is currently available only to patients with liver fibrosis stage F2 or greater (Metavir scale or equivalent). This coverage approach is consistent with existing PharmaCare criteria for coverage of HCV therapies that provides coverage for patients at highest risk of liver-related morbidity.1 Further, this approach is also consistent with the CDR recommendations, may be more cost-effective and balances the need for sustainability of the PharmaCare program. For more information, see “Determining fibrosis stage for the treatment of chronic hepatitis” at www.health.gov.bc.ca/pharmacare/sa/criteria/restricted/pdf/fibrosis-info-sheet.pdf.

Genotype 1 Ledipasvir-sofosbuvir (HarvoniTM) Ledipasvir-sofosbuvir (Harvoni™) is an -free regimen indicated for treatment of genotype 1 (GT1) HCV infection. Ledipasvir-sofosbuvir has reported high cure rates (based upon sustained viral response), is dosed once-daily, is generally well-tolerated (compared to interferon-containing regimens) and offers a shorter duration of therapy for most patients. Therefore, ledipasvir-sofosbuvir is preferable to other therapies that PharmaCare currently covers for treatment-naïve and treatment-experienced GT1 patients. In clinical trials, ledipasvir-sofosbuvir reported high sustained viral response (SVR), ranging from 93-99% in treatment- naïve and -experienced GT1 patients.2-3 In treatment-naïve, non-cirrhotic patients, there is the option of utilizing a shorter 8-week course of therapy if the baseline HCV RNA is < 6 million IU/mL.3 In patients with an initial HCV RNA of > 6 million IU/mL a 12-week regimen is optimal, as shorter durations are associated with a higher relapse rate.3 Both treatment-naïve patients with compensated cirrhosis and treatment-experienced patients without cirrhosis reported high SVRs after 12 weeks with ledipasvir-sofosbuvir.2,4 In patients with compensated cirrhosis who are treatment- experienced (with either pegylated interferon and (PegIFN/RBV) or in combination with a protease inhibitor), a 24-week regimen of ledipasvir-sofosbuvir is reasonable.4 Special Authority requests for coverage of 24 weeks of ledipasvir- sofosbuvir will be considered only for patients who have had a liver biopsy or transient elastography (TE) showing evidence of cirrhosis. Based on the recommendation from the CDR’s Canadian Drug Expert Committee (CDEC), ledipasvir-sofosbuvir is cost-effective compared to other therapies in treatment-naïve patients and treatment-experienced patients without cirrhosis.

Medical Beneficiary and Pharmaceutical Services Division | Ministry of Health |March 2015

Sofosbuvir (Sovaldi®) in combination with peginterferon and ribavirin Sofosbuvir (Sovaldi®) in combination with PegIFN/RBV is eligible for PharmaCare coverage for GT1 treatment-naïve patients. However, due to lower tolerability with interferon regimens, sofosbuvir-ledipasvir is the preferred treatment option for GT1 patients.

Genotype 2 or 3 Sofosbuvir (Sovaldi®) in combination with ribavirin PharmaCare coverage of sofosbuvir in combination with RBV is available for the treatment of genotype 2 (GT2) and 3 (GT3) HCV infections in patients who are: • treatment-naïve and have a medical contraindication to interferon therapy; or • PegIFN/RBV treatment-experienced. Genotype 2—Sofosbuvir in combination with RBV has not been shown to be more effective than the standard treatment with PegINF/RBV for treatment-naïve patients.6 In the sofosbuvir phase III trial (FISSION), sofosbuvir in combination with RBV was shown not to be inferior to PegIFN/RBV for treatment-naïve GT2 patients.5 GT2 responds well to PegIFN/RBV (SVR rates of 80-90%), similar to those found with sofosbuvir, which costs more.9-11 At manufacturer list prices, sofosbuvir costs $57,750 for 12 weeks of therapy whereas a 24-week or 48-week course of PegIFN/RBV costs $9,500 to $19,500. Therefore, sofosbuvir in combination with RBV offers no apparent clinical advantage with respect to SVR rates and is more costly than PegIFN/RBV in treatment-naïve patients.6 In those patients for whom interferon-based treatment is contraindicated or for those who are treatment-experienced, treatment with sofosbuvir and RBV for 12 weeks is reasonable as no other effective therapy options are available. In other trials (FUSION and VALENCE) sofosbuvir in combination with RBV achieved high rates of SVR for treatment-experienced GT2 patients with and without cirrhosis.7,8 Genotype 3—GT3 infections are less common and SVR rates achieves with standard therapy of PegIFN/RBV range from 62-77%.12-15 In the VALENCE trial, mixed population of treatment-naïve and -experienced patients receiving 24 weeks of sofosbuvir in combination with RBV therapy achieved an SVR of 85%.8 At manufacturer list prices, sofosbuvir costs $115,500 for 24 weeks of therapy whereas a 24-week or 48-week course of PegIFN/RBV costs $9,500 to $19,500. In those patients for whom interferon-based treatment is contraindicated—or for those who are treatment- experienced—24 weeks of treatment with sofosbuvir and RBV is reasonable, particularly as no other effective therapy options are available. Contraindications to Interferon Therapy for Genotype 2 or 3—PharmaCare covers sofosbuvir in combination with RBV for GT2 or GT3 treatment-naïve patients who, due to contraindications to IFN, cannot be treated with IFN-based therapy; or presence of significant clinical morbidities which are deemed to have a high risk of worsening with IFN treatment. • Contraindications to IFN are defined as:16 o Hypersensitivity reactions (urticarial, angioedeoma, bronchoconstriction, anaphylaxis, Stevens Johnson syndrome and toxic epidermal necrolysis) to peginterferon or interferon alfa-2a or -2b, polyethylene glycol, or any component of the formulation resulting in discontinuation of therapy o Autoimmune hepatitis o Decompensated liver disease

• The presence of significant clinical comorbidities deemed at high risk of worsening with IFN treatment are considered relative contraindications. Significant clinical comorbidities include17-19: Neuropsychiatric Documented suicidal attempt or ideation; previous hospitalization for severe Documentation is required disorders depression; severe psychiatric, bipolar or schizoaffective disorder; history of of significant clinical homicidal ideation. comorbidities due to past Autoimmune Systemic lupus erythematosus, myositis, severe rheumatoid arthritis, severe medical history, including conditions psoriasis strategies to optimize Ischemic disorders Pre-existing cardiac abnormalities (e.g. cardiomyopathy, cardiac failure), unstable control. Other cardiac disease, conditions which put patient at high risk of stroke or ischemic documentation related to events specialist consultations Retinal diseases Retinal hemorrhages, papilledema, serous retinal detachment history and/or relevant lab test Neurologic conditions Uncontrolled high-risk seizure disorder, multiple sclerosis results to support the Endocrine conditions Uncontrolled diabetes or thyroid diseases coverage request may also Hematologic Prior aplastic anemia, baseline severe cytopenias, certain hemoglobinopathies be required. (sickle cell disease, major thalassemia) and bone marrow transplant (BMT)

References

1. Recommendations for Direct-Acting Antiviral Agents for Chronic Hepatitis C Genotype 1. CADTH Therapeutic Review. October 2014, Vol2 Issue 2C. Available at: www.cadth.ca/media/pdf/TR0007_HepC_RecsReport_e.pdf 2. Afdhal, Nezam, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. New England Journal of Medicine 370.16 (2014): 1483-1493. 3. Kowdley, Kris V., et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. New England Journal of Medicine 370.20 (2014): 1879-1888. 4. Afdhal, Nezam, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. New England Journal of Medicine 370.20 (2014): 1889- 1898. 5. Lawitz, Eric, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. New England Journal of Medicine 368.20 (2013): 1878-1887. 6. CDEC FINAL RECOMMENDATION. Sofosbuvir (Sovaldi – Canada, Inc. Notice of Final Recommendation August 18, 2014. Available at: www.cadth.ca/media/cdr/complete/cdr_complete_sovaldi_august_20_2014.pdf 7. Jacobson, Ira M., et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. New England Journal of Medicine 368.20 (2013): 1867-1877. 8. Zeuzem, S., et al. Sofosbuvir+ ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology 58.4 (2013): 733-4. 9. Aghemo A, Rumi MG, Monico S, et al. The pattern of pegylated interferon-alpha2b and ribavirin treatment failure in cirrhotic patients depends on hepatitisCvirus genotype. Antivir Ther. 2009;14(4):577–84. 10. Rumi MG, Aghemo A, Prati GM, et al. Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology. 2010;138(1):108–15. 11. von Wagner, Michael, et al. Peginterferon-α-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology 129.2 (2005): 522-527. 12. Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, et al. Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med. 2007;357:124–34. 13. Mangia A, Bandiera F, Montalto G, Mottola L, Piazzolla V, et al. Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3. J Hepatol. 2010;53:1000–5. 14. von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, et al. Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 2005;129:522–7. 15. Dalgard O, Bjoro K, Ring-Larsen H, Bjornsson E, Holberg-Petersen M, et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology. 2008;47:35–42. 16. Intron A Product Monograph. Merck Canada. Date of revision: March 24, 2011. Available at: www.merck.ca/assets/en/pdf/products/INTRON_A-PM_E.pdf 17. Supplementary Appendix. Supplement to: Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med 2013;368:1867-77. 18. Talal, A. H., et al. Absolute and relative contraindications to pegylated‐interferon or ribavirin in the US general patient population with chronic hepatitis C: results from a US database of over 45 000 HCV‐infected, evaluated patients. Alimentary pharmacology & therapeutics 37.4 (2013): 473-481. 19. Contraindications to interferon therapy for chronic hepatitis C. World Health Organization. Global Alert and Response. Hepatitis C. Available at: www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index5.html#contraint 20. Sofosbuvir (Sovaldi) Common Drug Review Clinical Report. Available at: www.cadth.ca/media/cdr/clinical/SR0356_Sovaldi_CL_Report_e.pdf