Sofosbuvir-ledipasvir (Harvoni���)

Information for Prescribers / Healthcare Providers
Sofosbuvir-ledipasvir (Harvoni™) for chronic hepatitis C infection genotype 1
and
sofosbuvir (Sovaldi®) for chronic hepatitis C infection genotypes 1, 2 and 3
Sofosbuvir-ledipasvir (Harvoni™) and sofosbuvir (Sovaldi®) are direct-acting antivirals (DAA) for the treatment of hepatitis C virus
(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
Sofosbuvir-ledipasvir (HarvoniTM)
Sofosbuvir-ledipasvir (Harvoni™) is an interferon-free regimen indicated for treatment of genotype 1 (GT1) HCV infection.
Sofosbuvir-ledipasvir 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, sofosbuvir-ledipasvir is preferable to other therapies that PharmaCare currently covers for treatment-naïve
and treatment-experienced GT1 patients.
In clinical trials, sofosbuvir-ledipasvir reported high sustained viral response (SVR), ranging from 93-99% in treatmentnaïve 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 sofosbuvir-ledipasvir.2,4 In patients with compensated cirrhosis who are treatmentexperienced (with either pegylated interferon and ribavirin (PegIFN/RBV) or in combination with a protease inhibitor), a
24-week regimen of sofosbuvir-ledipasvir is reasonable.4 Special Authority requests for coverage of 24 weeks of
sofosbuvir-ledipasvir 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), sofosbuvir-ledipasvir is costeffective 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 treatmentexperienced—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
disorders
Autoimmune
conditions
Ischemic disorders
Retinal diseases
Neurologic conditions
Endocrine conditions
Hematologic
Documented suicidal attempt or ideation; previous hospitalization for severe
depression; severe psychiatric, bipolar or schizoaffective disorder; history of
homicidal ideation.
Systemic lupus erythematosus, myositis, severe rheumatoid arthritis, severe
psoriasis
Pre-existing cardiac abnormalities (e.g. cardiomyopathy, cardiac failure), unstable
cardiac disease, conditions which put patient at high risk of stroke or ischemic
events
Retinal hemorrhages, papilledema, serous retinal detachment history
Uncontrolled high-risk seizure disorder, multiple sclerosis
Uncontrolled diabetes or thyroid diseases
Prior aplastic anemia, baseline severe cytopenias, certain hemoglobinopathies
(sickle cell disease, major thalassemia) and bone marrow transplant (BMT)
Documentation is required
of significant clinical
comorbidities due to past
medical history, including
strategies to optimize
control. Other
documentation related to
specialist consultations
and/or relevant lab test
results to support the
coverage request may also
be required.
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): 18891898.
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 – Gilead Sciences 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