Olysio (simeprivir) Policy Number: Last Review: 09/2017 Origination: 09/2013 Next Review: 09/2018

Transcription

1 Olysio (simeprivir) Policy Number: Last Review: 09/2017 Origination: 09/2013 Next Review: 09/2018 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will provide coverage for Olysio (simeprivir) when it is determined to be medically necessary because the following criteria have been met. When Policy Topic is covered Coverage of Olysio is recommended in those who meet the following criteria and ONLY if Viekira or Harvoni is contraindicated: Food and Drug Administration (FDA)-Approved Indications 1. Chronic Hepatitis C (CHC) Genotype 1. Approve Olysio for the specified duration in patients that meet the all of following criteria (A, B, C, and D): A) The patient is 18 years of age; AND B) The patient does not have recurrent hepatitis C virus (HCV) following liver transplantation (see Criteria 2); AND C) Olysio is prescribed by or in consultation with a gastroenterologist, hepatologist, infectious diseases physician, or a liver transplant physician; AND D) The patient has previously been treated for HCV with Viekira Pak or the member has contraindications for its use; AND The patient meets ONE of the following conditions (i or ii): i. Olysio will be prescribed in combination with PR: Approve for 12 weeks if the patient does not have genotype 1a AND the Q80K polymorphism. (Note: testing for the Q80K polymorphism is not required for patients with genotype 1b); OR ii. Olysio will be prescribed in combination with approve for the duration specified if the patient meets ONE of the following conditions (1 or 2): (1) Approve for 12 weeks if the patient does not have cirrhosis and meets one of the following (a or b): a. The patient is HCV treatment-naïve; OR b. The patient has previously been treated (i.e., prior null responder, prior partial responder, prior relapser) with interferon or peginterferon ± ribavirin. (2) Approve for 24 weeks if the patient has cirrhosis and meets ONE of the following (a or b): a. The patient is HCV treatment-naïve; OR b. The patient has previously been treated (i.e., prior null responder, prior partial responder, prior relapser) with interferon or peginterferon ± ribavirin. Olysio is indicated in as a component of an antiviral regimen in adults with genotype 1 CHC. 1 The efficacy of Olysio in combination with PR is substantially reduced in patients infected with genotype 1a CHC with a NS3 Q80K polymorphism at baseline compared with patients infected with HCV genotype 1a without the Q80K polymorphism. Screening patients with genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended. Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism.

2 When used in combination with, testing for the Q80K polymorphism may be considered but is not strongly recommended. In combination with PR, the recommended duration of therapy for all patients is 12 weeks unless ontreatment viral stopping rules are met. 1 The turnaround time for HCV RNA testing varies and may be up to 2 weeks. To prevent treatment failure, the dose of Olysio must not be reduced or interrupted. In combination with, Olysio is indicated for patients with genotype 1 CHC who are treatment-naïve or have previously been treated with an interferon-containing regimen (it has not been studied in patients with a prior HCV protease inhibitor (PI) treatment history). The American Association for the Study of Liver Diseases/Infectious Diseases Society of America/International Antiviral Society-USA (AASLD/IDSA/IAS-USA) guidance recognize that an accurate assessment of fibrosis is imperative in assessment of the urgency for treatment. 9 Treatment is assigned the highest priority for patients with advanced fibrosis (Metavir F3), patients with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic manifestations of HCV. Occupational exposure via skin injury potentially causes up to 16,000 new cases of HCV annually with nurses experiencing the highest exposure rates, followed by medical residents. 12 Fatigue and deviations from infection control practices are contributing factors. Most of these injuries can be prevented by standard precautions, the use of protective gowns and goggles, increased awareness and strict supervision. The average rate of seroconversion after an occupational exposure to HCV-infected blood through accidental needle stick is 1.8%. Individuals who have achieved SVR no longer transmit the virus to others, and thus successful treatment benefits public health. 9 The prevalence of HCV is elevated in individuals on hemodialysis ranging from 7.8% to 8.9% and it is thought that nosocomial transmission, among other risk factors plays a role in acquisition in such patients. Additionally, HCV infection has a detrimental effect on kidney transplant outcomes. Other Uses with Supportive Evidence 2. Recurrent HCV Post-Liver Transplantation, Genotype 1. Approve Olysio for 12 weeks in patients who meet all of the following criteria (A, B, C, and D): A) The patient is 18 years of age; AND B) The patient has genotype 1 recurrent HCV after a liver transplantation; AND C) Olysio is prescribed by or in consultation with one of the following prescribers who is affiliated with a liver transplant center 14, a gastroenterologist, hepatologist, infectious diseases physician, or a liver transplant physician; AND D) Olysio is prescribed in combination with. The AASLD/IDSA/IAS-USA offer with Olysio ± ribavirin for 12 weeks as an alternative regimen in patients with genotype 1 in the allograft liver, including those with compensated cirrhosis (no level of evidence provided). 9 There are limited data assessing the combination of Olysio and in the post-transplant setting. A multicenter study assessed the combination with or without ribavirin for 12 weeks in patients with recurrent HCV genotype 1 post liver transplant (n = 109). 13 There were 66 patients who reached the timeframe for SVR12 assessment. The median duration from liver transplant was 29 months, 62% of patients were genotype 1a, 29% of patients had advanced fibrosis or cirrhosis (F3/F4) and prior treatment failure included PR (69% of patients), PR + PI (12% of patients) and PR sofosbuvir (1% of patients). Most patients in the study were receiving tacrolimus (n = 99) as their immunosuppressant. In the intent-to-treat (ITT) analysis, 91% of patients achieved SVR12 (n = 60/66) and the addition of

3 ribavirin did not appear to affect outcome (89% SVR12 with ribavirin vs. 91% without ribavirin). Patients with a prior HCV PI/ failure had a lower rate of response 80% (n = 8/10) vs. (n = 52/56) and patients with genotype 1a also appeared to have a lower response 88% (n = 38/43) vs. 96% (n = 22/23), respectively. Significantly fewer patients with F3/F4 achieved SVR12 compared to patients with F0 through F2 disease (96% vs. 76%, respectively; P = 0.03); this pattern held for patients with genotype 1a, but not for those with genotype 1b. According to the AASLD/IDSA/IAS-USA guidance, clinicians may consider the use of with Olysio as described for non-transplant patients, particularly those expected to have difficulty tolerating ribavirin (e.g., patients with impaired renal function and anemia). Consideration should be given to pretreatment resistance testing for the Q80K polymorphism in genotype 1a infected patients. 3. CHC Genotype 4 Adults. Approve for 12 weeks in patients that meet the all of following criteria (A, B, C, and D): A) The patient is 18 years of age; AND B) Olysio is prescribed by or in consultation with a gastroenterologist, hepatologist, infectious diseases physician, or a liver transplant physician; AND C) Olysio is prescribed in combination with ; AND D) The patient is HCV treatment-naïve. According to the AASLD/IDSA/IAS-USA guidelines, the combination of Olysio with ± ribavirin is an alternative recommendation for treatment-naïve adults with CHC. 9 The recommended duration of therapy is 12 weeks (Class IIb, Level B). 4. Patient Has Been Started on Olysio. Approve for an indication or condition addressed as an approval in the Recommended Authorization Criteria section (FDA-Approved Indications) or other use with supportive evidence to complete a course of therapy. Authorization for Olysio should not exceed 24 weeks of therapy. For example if a patient is eligible for 12 weeks of therapy and has received 3 weeks of therapy, approve 9 weeks of therapy to complete the 12-week course. When Policy Topic is not covered Coverage of Olysio is recommended in circumstances that are listed in the Recommended Authorization Criteria (FDA-Approved Indications and Other Uses with Supportive Evidence). The following provides rationale for specific Exclusions. This is not an exhaustive list of Exclusions. 1. CHC, Awaiting Liver Transplantation. The efficacy of Olysio in patients awaiting liver transplantation has not been established. Olysio is not recommended in patients with decompensated liver disease CHC, Genotype 1a with Q80K Polymorphism or Q80K Polymorphism Status Unknown, Unless Olysio is Prescribed in Combination with (see approval criteria above). The efficacy of Olysio in combination with PR is substantially reduced in patients infected with genotype 1a CHC with an NS3 Q80K polymorphism at baseline compared to patients infected with HCV genotype 1a without the Q80K polymorphism. 1 Screening patients with genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism. However, in contrast to using Olysio to treat a genotype 1a patients with PR when the mutation significantly alters the probability of an SVR, the finding of the Q80K polymorphism does not preclude treatment with Olysio and. 9 To date virologic failure has not been observed in patients in either cohort of the COSMOS trial infected with HCV genotype 1b and with genotype 1a in the absence of Q80K. Thus Q80K testing can be considered but is not strongly recommended for combination use of with Olysio.

4 3. Life Expectancy < 12 Months Due to Non-Liver Related Comorbidities. Patients with limited life expectancy for whom HCV therapy would not improve symptoms or prognosis do not require treatment. 9 According to AASLD guidance, little evidence exists to support initiation of HCV treatment in patients with limited life expectancy (less than 12 months) due to non liver-related comorbid conditions. For these patients, the benefits of HCV treatment are unlikely to be realized, and palliative care strategies should take precedence. 4. Monotherapy with Olysio. Olysio must not be used as monotherapy. 1,9 5. Pediatric Patients (Age < 18 years). The safety and efficacy of Olysio have not been established in pediatric patients. Olysio is indicated for use in adult patients with genotype 1 chronic HCV. 1 Guidelines from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Practice (NASPGHAN) for the diagnosis and management of hepatitis C infection in infants, children, and adolescents state that the protease inhibitors (Victrelis and Incivek) should only be used in children in the context of a clinical trial as they have not been studied in children nor are there published pharmacokinetic or safety data in the pediatric population. 14 In the opinion of a specialist physician reviewing the data we have adopted this criterion. 6. Patient Has Failed Therapy with Olysio or Another NS3/4A Protease Inhibitor for HCV (i.e., Incivek or Victrelis). [Note: this does not include patients who have discontinued Incivek or Victrelis due to an adverse reaction to Incivek or Victrelis. Failure includes prior null response, partial response, or relapse] The efficacy of Olysio has not been studied in patients who have previously failed therapy with a treatment regimen that includes Olysio or other HCV protease inhibitors. 1 Olysio is an alternative regimen for patients who have had a prior non-response (null response, partial response, or relapse) to PR only (not to triple therapy with a protease inhibitor and PR). 7. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. Considerations This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers. Olysio is a pharmacy benefit. Description of Procedure or Service Olysio is a hepatitis C virus (HCV) non-serine 3/4A (NS3/4A) protease inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. 1 The following points should be considered when initiating Olysio for treatment of CHC: Olysio must not be used as monotherapy; The efficacy of Olysio in combination with peginterferon and ribavirin (PR) is substantially reduced in patients infected with genotype 1a CHC with an NS3 Q80K polymorphism at baseline compared with patients infected with HCV genotype 1a without the Q80K polymorphism. Screening patients with genotype 1a infection for the presence of virus with the NS3 Q80K polymorphism at baseline is strongly recommended Alternative therapy should be considered for patients infected with HCV genotype 1a containing the Q80K polymorphism; and

5 The efficacy of Olysio has not been studied in patients who have previously failed therapy with a treatment regimen that includes Olysio or other HCV protease inhibitors (PIs) [i.e., Incivek (telaprevir tablets) and Victrelis (boceprevir capsules)]. The prescribing information notes that prior to initiation of treatment with Olysio, screening patients infected with HCV genotype 1a for the presence of virus with the NS3 Q80K polymorphism is not strongly recommended but may be considered. 1 There are no data directly comparing the clinical efficacy of Olysio with the other NS3/4A protease inhibitors. However, efficacy (sustained virologic response [SVR]) has been established in treatmentnaïve adults with genotype 1 CHC as well as prior treatment-failure (null responders and partial responders) and relapse patients. 2-6 The approval of Olysio in combination with represents the second approved all-oral (interferon-free regimen approved for patients with genotype 1 CHC. Rationale Dosing PR Olysio Food and Drug Administration (FDA)-approved for once-daily (QD) dosing administered in combination with PR (as triple therapy) for 12 weeks. 1 To prevent treatment failure, the dose of Olysio must not be reduced or interrupted. In all patients, treatment with Olysio should be initiated in combination with PR and should be administered for 12 weeks. All treatment-naïve and prior relapse patients, including those with cirrhosis, should receive an additional 12 weeks of PR after completing 12 weeks of triple-therapy with Olysio PR (total treatment duration of 24 weeks). All prior non-responder patients (including partial and null responders), including those with cirrhosis, should receive an additional 36 weeks of PR after completing 12 weeks of treatment with Olysio PR (total duration of treatment 48 weeks). In patients without cirrhosis who are treatment-naïve or have previously been treated with PR the recommended treatment regimen is for 12 weeks; in patients with cirrhosis who are treatment-naïve or have previously been treated with PR the recommended treatment regimen is Olysio + for 24 weeks. 1 Q80K Polymorphism In the pooled analysis of the Phase III trials with Olysio PR(QUEST-1, QUEST-2, and PROMISE), the efficacy of Olysio in combination with PR was substantially reduced in patients infected with HCV genotype 1a with the NS3 Q80K polymorphism at baseline. 1 Culture studies have indicated that Q80K expression was associated with an approximately 10-fold decrease in the susceptibility of HCV to Olysio relative to wild-type controls. 7 The difference was noted in both of the pooled treatment-naïve studies and the relapser study (SVR rates of 84% vs. 43%, respectively [treatment-naïve] and 78% vs. 24%, respectively [relapse study]). 9 The overall SVR in the subgroup of patients with baseline Q80K polymorphism was no better than that in the placebo group. Although in prior non-responder patients (including null, partial, and relapse patients) in the Phase IIb ASPIRE 6 trial SVR rates did not differ between patients with and without the Q80K polymorphism, prescribing information still supports the use of the test prior to initiating Olysio and does not support use in patients with the polymorphism. 1 If used in combination with, baseline resistance testing for the Q80K polymorphism may be considered in patients with genotype 1a HCV. 14 However, in contrast to using Olysio to treat genotype 1a patients with PR where the mutation significantly alters the probability of an SVR, the finding of the Q80K polymorphism does not preclude treatment with Olysio and, because the SVR rate was

6 high in patients with genotype 1a/Q80K infection (see Combination Use with ). Thus Q80K testing can be considered but is not strongly recommended for combination use of with Olysio. The Q80K polymorphism is a common polymorphism found in patients with Genotype 1a in the US. 7 In an analysis pooling patients from the Phase III and Phase IIb trials with Olysio, of the 298 patients with CHC genotype 1a from the US with sequencing data, 48% had the Q80K polymorphism at baseline. None of the genotype 1b patients in the US with sequencing data had the Q80K polymorphism at baseline. The observed prevalence of the Q80K polymorphism was 30% in patients with genotype 1a and 0.5% in patients with genotype 1b in the Phase IIb and III trials. 1 The Division of Anti-viral Products (DAVP) recommends that all genotype 1a patients be screened for the Q80K polymorphism given the high frequency of the Q80K polymorphism in the US population and its significant impact on rates of sustained viral response 12 weeks after the end of treatment (SVR12). 7 Alternative treatment options for patients with this polymorphism should be considered, notably, no Q80K-related reduction in efficacy was observed during the pivotal trials with Incivek or Victrelis. The HCV GenoSure NS3/4A drug resistance test has been approved to screen for the Q80K polymorphism. 8 It also provides a comprehensive sequence-based analysis of drug resistance for HCV protease inhibitors. Combination Use with The approval of the combination of is based on data from the COSMOS (COmbination of SiMeprevir and in HCV genotype 1 naïve and null responders with METAVIR stage F3 to F4 infected patients) trial [n = 168] Eligible patients were at least 18 years of age with genotype 1 compensated CHC. COSMOS did not enroll patients with HIV co-infection. There were two sequentially enrolled cohorts. Patients eligible for Cohort 1 were required to be previous nonresponders to PR and have moderate liver fibrosis (Metavir F0 through F2), based on liver biopsy within 3 years of screening. Patients eligible for Cohort 2 were required to be previous non-responders to PR or treatment-naïve and have severe liver fibrosis (Metavir F3 to F4), based on a liver biopsy at any time. Patients were randomized 2:2:1:1 to one of four treatment groups: + R for 24 weeks (group 1), for 24 weeks (group 2), + R for 12 weeks (group 3), for 12 weeks (group 4). The dose of ribavirin was weight-based. Patients were followed-up for 24 weeks after 24 weeks of treatment or for those treated for 12 weeks, followed-up for 36 weeks. The primary endpoint was SVR12, secondary endpoints were SVR 24 weeks after treatment completion (SVR24), rapid viral response ([RVR] HCV RNA undetectable 4 weeks after the start of treatment), on-treatment failure, and viral relapse. The primary analysis was conducted in the intent-to-treat (ITT) population (all randomized patients who received at least one dose of study medication, n = 167). A post-hoc analysis of the primary endpoint was conducted that excluded patients who discontinued treatment prematurely for non-virological response or for whom assessment data were missing. With the exception of previous treatment response, Q80K polymorphism, and fibrosis stage, baseline demographics were similar across the two cohorts and all four treatment groups. Most patients were White males. The median age was 57 years (range 27 to 70 years). Most patients were infected with genotype 1a, 45% of patients had the Q80K polymorphism (none with genotype 1b). Results. In the ITT population 92% of patients achieved SVR12 (n = 154/167). In Cohort 1, SVR was achieved in 90% (95% CI: 81, 96) of patients and in Cohort 2 SVR12 was achieved in 94% (95% CI 87, 98) of patients. Table 1 breaks down the SVR12 results by treatment arm and cohort. Rates of SVR remained high in patients with genotype 1a, including those with the Q80K polymorphism. SVR was achieved in similar proportions of patients with IL28B CC and non-cc genotypes, irrespective of whether they received ribavirin. The rates of SVR also remained high when patients with compensated cirrhosis (Metavir F4) were considered separately, including the presence of the Q80K polymorphism at baseline (92%). Rates of SVR were not significantly altered by the use of ribavirin, duration of treatment, or by use of previous treatment. In the ITT population SVR12 was achieved in 91% of patients (n = 98/108) who received ribavirin vs. 95% of patients (n = 56/59) who did not receive

7 ribavirin. Rates were similar by prior treatment status (SVR 12 was achieved in 95% of treatment-naïve patients [n = 38/40] and 91% of prior non-responders [n = 116/127]) or treatment duration (SVR12 was achieved in 94% of patients treated for 12 weeks [n = 77/82] and 91% of patients treated for 24 weeks [n = 77/85]). In patients with the Q80K polymorphism, neither ribavirin treatment nor treatment duration had a clear effect on SVR. The only baseline characteristic that notably affected virological response was age 45 years, which was associated with a disproportionate number of non-virological failures. Table 1. Efficacy Results from COSMOS from the Intent-to-Treat Population Cohort 1 (Prior non-responders to PR and Metavir F0/F1 or F2) Cohort 2 (Prior non-responders to PR or treatment-naïve with Metavir F3/F4) 12-Week 24-Week 12-Week 24-Week Treatment + R Treatment + R Treatment + R Treatment + R SVR4, % (n/n) 96% (26/27) (13/14) 83% (20/24) (14/15) 96% (26/27) 100% (14/14) (28/30) 100% (16/16) SVR12, % (n/n) 96% (26/27) (13/14) 79% * (19/24) (14/15) (25/27) (13/14) (28/30) 100% (16/16) COmbination of SiMeprevir and in HCV genotype 1 naïve and null responders with METAVIR stage F3 to F4 infected patients; R Ribavirin; RVR Rapid viral response (data based on patients with available stat at Week 4); SVR4 Sustained viral response 4 weeks after planned treatment end; SVR12 Sustained viral response 12 weeks after planned treatment end; * The lower rate of SVR12 was due to patients discontinuing treatment for non-virological reasons or missing data at the time of viral response assessment. Prior authorization is recommended for prescription benefit coverage of Olysio. Criteria for whom to treat are based on the guidance issued by American Association for the Study of Liver Diseases/Infectious Diseases Society of America/International Antiviral Society-USA (AASLD/IDSA/IAS-USA) and expert review. Successful treatment of HCV results in SVR and is expected to benefit nearly all chronically infected persons. Evidence clearly supports treatment in all HCV-infected individuals, except those with limited life expectancy (< 12 months) due to non-liverrelated comorbid conditions. Urgent initiation of treatment is recommended for some patients, such as those with advanced fibrosis or compensated cirrhosis. Immediate treatment is assigned the highest priority for those patients with advanced fibrosis, those with compensated cirrhosis, liver transplant recipients, and patients with severe extrahepatic HCV. Based on available resources, immediate treatment should be prioritized as necessary so that patients at high risk for liver-related complications and severe extrahepatic hepatitis HCV complications are given high priority. Because of the specialized skills required for evaluation and diagnosis of patients treated with Olysio as well as the monitoring required for adverse events (AEs) and efficacy, approval requires Olysio to be prescribed by or in consultation with a gastroenterologist, hepatologist, infectious diseases physician, or liver transplant physician. The duration of approval is 12 or 24 weeks. References 1. Olysio capsules [prescribing information]. Titusville, NJ: Janssen; November Food and Drug Administration Center for Drug Evaluation Research Office of Antimicrobial Products Division of Antiviral Products. FDA Antiviral Drugs Advisory Committee Meeting. October 24, Background package for NDA Simeprevir (TMC435). 3. Jacobson I, Dore GJ, Foster GR, et al. Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-1, a Phase III trial. J Hepatol. 2013;58:S567-S Manns M, Marcellin P, Poordad FFP, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naïve patients: results from QUEST-2, a Phase III trial. J Hepatol. 2013;58:S567-S577.

8 5. Lawitz E, Forns X, Zeuzem S, et al. Simeprevir (TMC435) with peginterferon/ribavirin for treatment of chronic HCV genotype 1 in patients who relapsed after previous interferons-based therapy: results from PROMISE, a Phase III trial. Gastroenterology. 2013;144(Suppl 5); s Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology Oct 31. [Epub ahead of print]. 7. Food and Drug Administration Center for Drug Evaluation Research Office of Antimicrobial Products Division of Antiviral Products. FDA Antiviral Drugs Advisory Committee Meeting. October 24, Background package for NDA Simeprevir (TMC435). 8. HCV GenoSure Drug Resistance Testing. Monogram biosciences and LabCorp. Available at: MLXyM3AyNjMycDU2dXQwN3M6B8JG55AwMCuv088nNT9SP1o8zjQ11Ngg09LY0N_N2DjQw8g439T fym_mzmlaz0q_qjxygkiveqksinkdfudvqeaoj2twa!/dl2/d1/l0ljwxbwzyehl3dirujguufnc2fb RUJyQ0svWUk1eWx3ISEvN19VRTRTMUk5MzBPR1MyMElTM080TjJONjY4MC92aWV3VGVzdA!!/?te stid= Accessed on November 10, American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Testing, managing, and treating hepatitis C. Available at: Updated January 19, Accessed on: January 20, Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014 July 28 [Epub ahead of print]. 11. Supplement to: Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014 July 28 [Epub ahead of print]. 12. Negro F. inpractice - Hepatitis C virus transmission to healthcare workers. Last reviewed: 07/30/2014. Available at: _Diagnosis_and_Natural_History/Chapter-Pages/Page-2/subpage-6.aspx. Accessed on: 11/10/ Pungapng S, Werner KT, Agel B, et al. Multicenter experience using sofosbuvir and simeprevir with/without ribavirin to treat HCV genotype 1 after liver transplantation [oral presentation]. Presented at: American Association for the Study of Liver Diseases; Boston, PA; November 9, Mack CL, Gonzalez-Peralta RP, Gupta N, et al. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Practice Guidelines: Diagnosis and Management of Hepatitis C Infection in Infants, Children and Adolescents. J Pediatr Gastroenterol Nutr. 2012;54(6): Billing Coding/Physician Documentation Information Olysio is a pharmacy benefit. Additional Policy Key Words Policy Implementation/Update Information 09/2013 New policy titled Olysio (simeprivir) 09/2014 Policy reviewed no changes made 10/2014 Policy reviewed - Limitations on who to treat were added to criteria for genotype 1 CHC. Exclusion criteria were added for the following: Patients with life expectancy < 12 months due to a non-liver related cause and for patients awaiting liver transplantation 09/2015 Policy reviewed no changes made

9 10/2015 Policy reviewed deleted requirement of fibrosis 08/2016 Added Zepatier as preferred treatment for genotypes 1 and 4 03/2017 Replaced Zepatier with Viekira or Harvoni as preferred treatment for genotypes 1 and 4 08/2017 Reviewed no changes to policy statement State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.