HCT Pharmaceutical Policy

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1 HCT Pharmaceutical Policy Treatment of Chronic Hepatitis C Policy # HCT118 Current Effective Date: 10/6/2015 Pharmaceutical Policies are developed by HealthyCT to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Pharmaceutical Policy contains only a partial, general description of plan or program benefits and does not constitute a contract. HealthyCT does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of HealthyCT or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Pharmaceutical Policy may be updated and therefore is subject to change. Policy Statement This policy addresses the use of medication therapy for Treatment of Chronic Hepatitis. The primary intent is to ensure timely access of treatment for members with advanced disease who are at higher risk for morbidity and mortality from their disease and liver status. The policy utilizes standard criteria to evaluate requests for therapy with patient-specific supporting clinical evidence and prescriber-provided documentation supporting the use of safe, effective and most affordable medication therapy. Page 1 of 22

2 Overview Sovaldi (sofosbuvir) is indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. The efficacy of Sovaldi (sofosbuvir) has been established in patients with HCV genotype 1, 2, 3 or 4 infection, including those with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation) and those with HCV/HIV-1 co-infection. Harvoni (ledipasvir/sofosbuvir) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infections in adults. Ledipasvir is available only in combination with sofosbuvir and marketed as a fixed dose combination of 90 mg of ledipasvir and 400mg of sofosbuvir indicated to be taken orally once a day with or without food for the treatment of chronic hepatitis C genotype 1 infection in adults. INCLUSION CRITERIA: Initial Requests 1. Member is at least 18 years of age 2. Treatment is prescribed by one of the following board-certified physicians: Infectious Disease specialist Gastroenterologist Hepatologist Transplant specialist HCV/HIV specialist 3. Diagnosis of chronic hepatitis C infection confirmed by detectable serum HCV RNA by quantitative assay. Documentation of HCV genotype and HCV quantitative viral load (drawn within the past 6 months before initiation of chronic hepatitis therapy) required. 4. Stage 3 or greater fibrosis documented by one of the following: Liver biopsy: METAVIR F2, F3 or F4, or Ishak score 3 or greater* *Treatment is assigned the high priority for those patients with fibrosis (METAVIR F2) advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4); liver transplant recipients; Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (e.g., vasculitis); Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis; HIV-1 coinfection; Hepatitis B virus (HBV) coinfection; Other coexistent liver disease (e.g., [NASH]); Type 2 Diabetes mellitus (insulin resistant); Porphyria cutanea tarda; HCV-infected women of child-bearing potential desiring to get pregnant Page 2 of 22

3 Reference: American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA). Recommendations for Testing, Managing, and Treating Hepatitis C. Revised Date: December 19, Available at: Accessed February 2015 Ultrasound based transient elastography Fibroscan* score: Greater than or equal to 9.5 kpa *Fibrosure, Fibrotest, or Fibrospect will not be accepted. In cases where both liver biopsy and transient elastography are available, liver biopsy results supersede the results obtained by Fibroscan. APRI score greater than 1.5 Radiological imaging consistent with cirrhosis (e.g. evidence of portal hypertension) 5. ONE of the following is confirmed: a) HCV Genotype 1 with Stage 3 or greater fibrosis b) HCV Genotype 2 with Stage 3 or greater fibrosis c) HCV Genotype 3 with Stage 3 or greater fibrosis d) HCV Genotype 4 with Stage 3 or greater fibrosis e) HCV Genotype 1, 2, 3, or 4 with concurrent hepatic carcinoma(s) awaiting liver transplantation AND BOTH of the following criteria are met: 1) Milan criteria is met as follows: Single hepatocellular carcinoma, presence of tumor 5cm or less in diameter, OR multiple tumors with each being 3 cm or less in diameter NO extrahepatic manifestations of cancer or evidence of vascular invasion of tumor 2) Member has met all criteria for liver transplant 6. Compensated liver disease [Child-Pugh score less than or equal to 6 (class A)]* documented within 30 days prior to submission of request *Members with hepatic decompensation (Child-Pugh B or C: score greater than or equal to 7) does NOT meet criterion. 7. Documented interferon intolerance or interferon contraindication as applicable depending on genotype and chronic hepatitis C treatment regimen prescribed): Decompensated liver cirrhosis, i.e. Child-Pugh score greater than 6 (Class B or C) before or during interferon treatment *# Severe thrombocytopenia (platelet count < 50,000 mm 3 ) that occurred during previous interferon therapy Hepatocellular cancer awaiting liver transplant Page 3 of 22

4 Baseline neutrophil count below 1500/μL * Baseline platelet count below 90,000/μL * Baseline hemoglobin below 10 g/dl * A history of preexisting cardiac disease * Severe intolerance to interferon * as demonstrated by side effects with objectively measured impact on health or quality of life Severe reaction to previous interferon therapy (i.e. urticarial, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome, depression, ophthalmologic disorder, thyroid disorder or refractory diabetes mellitus) Autoimmune hepatitis and other autoimmune disorders * Severe, untreated depression, schizophrenia and bipolar disorder, or clinical features consistent with uncontrolled depression, schizophrenia, and bipolar disorder D during previous interferon therapy. Documentation of evaluation by a Psychiatrist (or in the case of depression, by a PHQ-9 score of 10 or greater) and clearance for the requested chronic hepatitis C therapy regimen required. PHQ-9 available at: *Reference: American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA). Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: Accessed October 2014 #Reference: Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368: Available at: Published POSITRON and FUSION Trials (Jacobson et al., 2013) Urine Drug Screen and a screen for substance abuse using a validated screening tool* confirming negative alcohol/drug/substance abuse. Must be administered within 30 days prior to submission of this request. *Validated tools may include: Alcohol Use Disorders Identification Test (AUDIT), Tolerance, Worried, Eye-opener, Amnesia, and Cut down (TWEAC; for pregnant women), Michigan Alcohol Screening Test (MAST, MAST-Geriatric [MAST-G]), CAGE Survey, Substance Abuse Subtle Screening Inventory (SASSI), Drug Abuse Screening Test (DAST). 9. Negative pregnancy test (as applicable to member) within 30 days prior to submission of this request for medications for treatment of chronic hepatitis C Page 4 of 22

5 10. Documented attestation from Prescriber that member has been counseled on importance of therapy and assessed for potential nonadherence and assess if member has been: Previously screened and/or vaccinated for Hepatitis A and Hepatitis B vaccines; consideration vaccination if appropriate. Previously screened for HIV; if not, consider testing for HIV EXCLUSIONS TO THERAPY Authorization will not be granted if ANY of the following conditions apply Renal impairment (egfr must be > 30mL/min/1.73m 2 ) or end stage renal disease (ESRD) There are currently no HCV treatment guidelines or indications for those patients who are in End Stage Renal Disease (ESRD). The safety of sofosbuvir or ledipasvir/sofosbuvir has not been established in patients with severe renal impairment or ESRD requiring hemodialysis. No dosage recommendation can be given for patients with severe renal impairment or ESRD. Significant or unstable cardiovascular disease (applicable for ribavirin and/or interferon-containing regimens only) Clinically-significant medical disorder(s) or medical/psychiatric/social comorbidities which may result in: Limited life expectancy (less than 12 months) According to AASLD/IDSA HCV Guidelines, patients with limited life expectancy for whom HCV therapy would not improve symptoms or prognosis do not require treatment. Chronic hepatitis C is associated with a wide range of comorbid conditions. 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. Interference with treatment, assessment or compliance with the requested HCV therapy, or Less than optimal response to requested HCV therapy Chronic HCV-infected patients with minimal fibrosis (METAVIR stage 0 or 1 based on an adequate liver biopsy specimen) and no other risk factors for liver disease are at lower risk for developing advanced liver disease in the short-term. Treatment should be reconsidered if liver disease progresses. Modifiable risk factors for progression of liver disease, such as alcohol use, should be addressed. Concurrent condition(s) that is/are likely to cause non-adherence such as: Page 5 of 22

6 History of non-compliance or non-adherence as verified by medication fill history or prescription drug profile Ongoing adherence issues to prior drug therapy, comorbidity, or failure to complete HCV disease evaluation appointments and procedures* *Individuals with any of these conditions are not appropriate candidates for therapy until those issues have been resolved. Ongoing substance abuse, ongoing alcohol consumption or unstable psychiatric condition within the past 6 months* *Documentation (lab reports, chart notes, medical records, etc.) of abstinence from alcohol/drug use and stable psychiatric condition within the past 6 months required Contraindications to therapy with medications for treatment of chronic hepatitis C Non-FDA approved indications Hypersensitivity to any of the components of the medications for treatment of chronic hepatitis C For ribavirin containing treatment regimens only: pregnancy and for men whose partners are pregnant or whose female partners cannot practice birth control Decompensated hepatic disease or decompensated cirrhosis [defined as Child-Pugh B or C; score greater than or equal to 7] Drug interactions: For sofosbuvir: Co-administration with Medications known to decrease the concentration of Sovaldi (sofosbuvir) (e.g. carbamazepine, phenytoin, phenobarbital, oxcarbazepine, rifabutin, rifampin, rifapentine, St. John s Wort, Aptivus (tipranavir)/norvir (ritonavir), Atripla (efavirenz/emtriciatbine/tenofovir) For ledipasvir/sofosbuvir: Co-administration with rifampin, rifabutin, rifapentine, St. John s wort, carbamazepine, phenytoin, phenobarbital, oxcarbazepine, elvitegravir/cobicistat/emtricitabine/tenofovir, tipranavir/ritonavir, simeprevir, or rosuvastatin. Exclusions to requested treatment of Chronic Hepatitis C Genotype 5 or 6 CHC: Presently, limited data exists regarding the use medications for treatment of chronic hepatitis C in patients with genotype 5 or 6 CHC. Severe concurrent medical disease (i.e. poorly controlled diabetes, cardiac failure, significant coronary artery heart disease, severe hypertension, severe chronic obstructive pulmonary disease, active tuberculosis, or active cancer) Concurrent non-fda approved medical/pharmaceutical therapy (i.e. concurrent treatment with non-fda approved medical/pharmaceutical therapy, such as medical marijuana) Page 6 of 22

7 Concurrent medical/psychiatric/social comorbidities which may result in: 1) a short life expectancy (of less than 10 years), 2) interference with treatment, assessment or compliance with the requested HCV therapy, or 3) less than optimal response to requested HCV therapy REGIMENS FOR THE TREATMENT OF CHRONIC HEPATITIS C INFECTION Treatment regimen and duration based upon HCV Genotype and patient characteristics in accordance to the dosage and administration recommended by the FDA approved labeling and in accordance to current ASLD/IDSA HCV Guidelines. Refer to Tables 1, 2, and 3 below. Ledipasvir/sofosbuvir regimen (i.e., two-drug fixed-dose combination product) One tablet (90mg of ledipasvir and 400mg of sofosbuvir) taken orally once daily with or without food Sofosbuvir and ribavirin regimen Sofosbuvir 400mg orally once daily with or without food in combination with ribavirin (in 2 divided doses) with food (<75 kg: 1000 mg/day or 75 kg: 1200 mg/day). Sofosbuvir, peginterferon, and ribavirin regimen Sofosbuvir 400mg orally once daily with or without food plus peginterferon (either peginterferon alfa-2a 180 mcg/week or alfa-2b 1.5 mcg/kg/week) in combination with ribavirin (in 2 divided doses) with food (<75 kg: 1000 mg/day or 75 kg: 1200 mg/day) Page 7 of 22

8 Patient Population [includes patients with HCV monoinfected, HCV/HIV-1 co-infected, or hepatocellular carcinoma (HCC)] HCV Genotype 1 Treatment-naïve without cirrhosis HCV RNA <6 million IU/mL HCV RNA 6 million IU/mL Treatment-naïve with cirrhosis Treatment-experienced* without cirrhosis Treatment-experienced* with cirrhosis *Treatment-experienced was defined as previous peginterferon/ribavirin with or without an NS3-4a protease inhibitor in clinical trials. Decompensated cirrhosis Treatment Regimens Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir OR Ledipasvir/sofosbuvir and ribavirin Ledipasvir/sofosbuvir and ribavirin (initiate ribavirin at 600mg/day and titrate up as tolerated) OR Ledipasvir/sofosbuvir (if unable to tolerate ribavirin) Total Treatment Duration 8 weeks 12 weeks 12 weeks 12 weeks 24 weeks 12 weeks 12 weeks 24 weeks HCV Genotype 2 Sofosbuvir plus ribavirin 12 weeks HCV Genotype 3 # Sofosbuvir plus ribavirin 24 weeks HCV Genotype 4, 5, or 6** Sofosbuvir plus peginterferon and ribavirin 12 weeks Page 8 of 22

9 COVERAGE LIMITATIONS The recommended treatment regimen and duration of therapy for treatment of chronic hepatitis C are dependent on both viral genotype and patient population. Dispensing limit for medications for treatment of chronic hepatitis C: A maximum supply of days will be dispensed at a time No additional authorizations will granted for individuals who have received a course of medications for chronic hepatitis C from HCT, or from member s previous health plan. Applicable to those who have received a full or partial* course of therapy. *Partial is defined as receiving an incomplete course of therapy prescribed, per confirmed genotype and individual s specific condition. This may be for any reason such as non-adherence, failure to abstain from alcohol/drug abuse, unstable psychiatric conditions, or discontinuation of therapy due to intolerance/adverse reaction/contraindication. Initial authorization Requested regimens for the treatment of chronic hepatitis C may be authorized up to weeks of initial therapy Continuation of treatment with requested therapy requires an HCV RNA viral load performed at 4 weeks and 12 weeks after initiation of treatment to determine response to therapy. Renewal requests will NOT be authorized for member who has not achieved a 2-log decrease in HCV RNA after 4 weeks of medications and an undetectable HCV RNA (less than 25 IU/mL) after 12 weeks of medication for treatment of chronic hepatitis C. HCV RNA viral load only required at 12 weeks for treatment regimens longer than 8 weeks. Prescribing physician to submit lab results to HCT for review as soon as available. Rationale: Monitoring of on-treatment viral levels does not affect management decisions of a treatment of chronic hepatitis C medication regimen; however in consideration of the high cost of the requested regiments and the potential risk of viral resistance with inappropriate use, HCV RNA quantitative testing at weeks 4 and 12 (end of treatment) in clinical practice is recommended. E Page 9 of 22

10 RENEWAL CRITERIA Continuation of therapy (after 6 week initial authorization) will be authorized in accordance to the prescribing information for the requested treatment and member s genotype for members meeting the following: 1) HCV RNA quantitative viral load performed at week 4 and week 12 (for treatment durations longer than 8 weeks) with the following results: E After 4 weeks: A 2-log decrease in viral load at week 4 to continue treatment after the initial authorization period* *Requests for renewal will NOT be authorized for individuals who have not achieved at least a 2 log reduction in HCV RNA from baseline value after 4 weeks of treatment. After 12 weeks (for treatment durations longer than 8 weeks): HCV RNA undetectable (< 25 IU/mL) 2) Compliance/Adherence to treatment regimen through regular office visits as verified by the Prescribing Physician and/or member s medication fill history. Demonstrated compliance and takes medications for treatment of chronic hepatitis C as prescribed. Renewal of therapy will NOT be authorized due to non-adherence. No indication(s) of high risk behavior (i.e. recurring alcoholism, IV drug use, etc.), unstable psychiatric conditions, or failure to complete HCV disease evaluation appointments Page 10 of 22

11 Scientific Rationale Chronic HCV is the leading cause of complications from chronic liver disease, including cirrhosis, liver failure, and hepatocellular carcinoma. In 2013, approximately 3.2 million individuals in the United States were living with a chronic HCV infection, but only 1.8 million have been diagnosed. Of these patients, 1 to 1.2 million (32% to 38%) were referred for care and 220,000 to 360,000 (7% to 11%) were treated. HCV genotype 1a and genotype 1b account for up to 73% of all HCV infections and are considered the more difficult forms of the hepatitis virus to treat. Historically, most of the drug regimens for the treatment of HCV genotype 1 have included an interferon product and ribavirin with or without another antiviral agent. The ultimate goal of CHC treatment is to reduce the occurrence of end-stage liver disease and its complications including decompensated cirrhosis, liver transplantation, and hepatocellular carcinoma. However, because progression of liver disease occurs over a long period of time, clinicians use sustained virologic response (SVR), defined as lack of detection of HCV RNA in blood several months after completing a course of treatment, to determine treatment success. SVR is considered a virologic cure. The choice of therapy for HCV is influenced by genotype. An SVR is defined as undetectable serum HCV RNA 6 months after the end of treatment. There is some evidence of an association of achieving an SVR and reductions in mortality, liver failure, and cancer. The two major predictors of SVR are viral genotype and the pre-treatment viral load. Other factors associated with an increased likelihood of achieving an SVR include female sex, age less than 40 years, non-black race, lower body weight, absence of insulin resistance, and absence of bridging fibrosis or cirrhosis on liver biopsy. In the United States, genotype 1 infection is found in around three-quarters of patients and is associated with a lower response to antiviral treatment than infection with genotypes 2 and 3, which are present in about 20% of patients. Sofosbuvir (Sovaldi) is the first direct-acting antiviral (DAA) agent in the nucleoside/nucleotide polymerase inhibitor class. Sofosbuvir is a nucleotide analog inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. Sofosbuvir is taken orally once daily with or without food as a component of an antiviral treatment regimen. The treatment regimen and duration is dependent on both the HCV genotype and patient characteristics. Depending on the type of HCV infection, the treatment regimen could include Sovaldi and ribavirin or Sovaldi, ribavirin and peginterferon-alfa. Sofosbuvir was FDA approved in December 2013 with a breakthrough therapy designation. The criteria for a breakthrough therapy designation from the FDA is that a) it is used for a serious condition, and b) preliminary clinical evidence demonstrates substantial improvement over Page 11 of 22

12 available therapy on one more clinically significant endpoints. Unlike the other available protease inhibitors, there is no response guided therapy criteria for its use. Sofosbuvir/ledipasvir (Harvoni) is a combination dosage form that was FDA approved in October 2014 and granted by the FDA a Priority Review and Breakthrough Therapy designation, which is given to investigational medicines that may offer major advances in treatment over available therapies. Harvoni is the first single tablet, all-oral combination therapy approved to treat chronic hepatitis C. It is a combination of sofosbuvir, a NS5B polymerase inhibitor (currently also available as a single ingredient medication under brand Sovaldi), with ledipasvir, a new NS5A inhibitor. Potential advantages for Harvoni include once daily dosing, excellent tolerability, improved SVR rates, and it is the first agent to offer an all-oral, interferon-free treatment option for all genotype 1 patients with treatment duration as short as 8 weeks for certain patients. Harvoni is the first interferon-free regimen to be FDA-approved to treat all genotype 1 patients. Ledipasvir/Sofosbuvir is approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infections in adults. Ledipasvir is available only in combination with sofosbuvir and marketed as a fixed dose combination of 90 mg of ledipasvir and 400mg of sofosbuvir indicated to be taken orally once a day with or without food for the treatment of chronic hepatitis C genotype 1 infection in adults. Ledipasvir/Sofosbuvir has been evaluated with and without ribavirin for 8, 12, or 24 weeks in treatment-naive and treatment-experienced patients with chronic HCV genotype 1 infections. It is also being evaluated for the treatment of HCV genotypes 2, 3, 4, 5, and 6. Sovaldi (sofosbuvir) Sovaldi s effectiveness was evaluated in six clinical trials consisting of 1,947 participants who had not previously received treatment for their disease (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants co-infected with HCV and HIV. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response), suggesting a participant s HCV infection has been treated. Pivotal phase III studies: POSITRON, FUSION, FISSION, and NEUTRINO The efficacy of Sovaldi (sofosbuvir) is primarily based on data from Phase 3 studies, NEUTRINO, FISSION, POSITRON and FUSION, which evaluated 12 or 16 weeks of treatment with Sovaldi (sofosbuvir) combined with either ribavirin (RBV) or RBV + peginterferon (IFN). In these pivotal trials, Sovaldi-based therapy was concluded as superior to historical controls (NEUTRINO and FUSION) or to placebo (POSITRON), or non-inferior to currently available treatment options (FISSION) based on the proportion of patients who had a sustained Page 12 of 22

13 virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered treated of HCV. Sovaldi (sofosbuvir) Pivotal Clinical Trials Clinical Trial Genotype Population Treatment Duration of Treatment (weeks) SVR % Regimen NEUTRINO N=327 GT 1,4,5,6 Treatment Naive PEG+RBV PEG+RBV+SOF weeks 12 weeks GT1: 89% GT4: 96% FISSION N=499 GT 2, 3 Treatment Naive PEG+RBV SOF + RBV 24 weeks 12 weeks GT2: 78% GT3: 56% FUSION N=201 GT 2, 3 Treatment Experienced SOF + RBV 12 weeks 16 weeks GT2: 82%/89% GT3: 30%/62% POSITRON N=278 GT 2,3 IFN unable SOF + RBV 12 weeks GT2: 93% GT3: 61% VALENCE GT 2, 3 SOF + RBV 12 weeks (GT2) GT2: 93% N=323 Treatment Naïve and 24 weeks (GT3) GT3: 84% PHOTON-1 N=182 Experienced GT 1,2,3 Treatment Naïve with HIV co-infection SOF + RBV 12 weeks (GT2) 24 weeks (GT1,3) GT2: 88% GT1: 76% GT3: 92% Page 13 of 22

14 Harvoni (ledipasvir/sofosbuvir) FDA approval of Harvoni is supported by data from three Phase 3 studies, ION-1, ION-2, and ION-3. These studies evaluated 8, 12, or 24 weeks of treatment, with or without ribavirin, among nearly 2,000 genotype 1 HCV patients with compensated liver disease. These studies included non-cirrhotic treatment-naïve patients, cirrhotic and non-cirrhotic treatment naïve-patients and cirrhotic and non-cirrhotic patients who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor. These trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after completing therapy (SVR12). Pivotal phase III studies: ION-1, ION-2, and ION-3 The efficacy of Harvoni was evaluated in three phase III clinical trials (ION-1, ION-2, and ION-3); the studies enrolled a total of 1518 adults with genotype 1 chronic hepatitis C with compensated liver disease. The primary efficacy endpoint for all studies was SVR, defined as HCV RNA below the lower limit of quantification, at 12 weeks after the end of treatment (SVR12). These studies evaluated 8, 12, or 24 weeks of treatment with Harvoni, with or without ribavirin, among nearly 2,000 genotype 1 HCV patients with compensated liver disease. In two of the trials, patients were randomized to receive ledipasvir/sofosbuvir with or without ribavirin for 12 or 24 weeks. In the other trial, patients were randomized to receive ledipasvir/sofosbuvir with or without ribavirin for 8 weeks or ledipasvir/sofosbuvir for 12 weeks. Primary efficacy endpoint was sustained viral response (SVR) at 12 weeks post-treatment. These studies included non-cirrhotic treatment-naïve patients (ION-3), cirrhotic and non-cirrhotic treatment-naïve patients (ION-1) and cirrhotic and non-cirrhotic patients who failed prior therapy with an interferon-based regimen, including regimens containing an HCV protease inhibitor (ION-2). The primary endpoint for each study was sustained virologic response (HCV undetectable) 12 weeks after completing therapy (SVR12). Ledipasvir/sofosbuvir with or without ribavirin achieved SVRs in the range of 94-99%. SVRs did not differ in patients receiving ledipasvir/sofosbuvir with or without ribavirin; therefore, FDA indications are without ribavirin. High rates of SVR12 were achieved with ledipasvir/sofosbuvir when used for the treatment of HCV genotype 1 infections following therapy for 8, 12, or 24 weeks. These two agents have also been administered in combination with ribavirin for the treatment of chronic HCV infection with good results; however, the incidence of adverse effects is increased due to the ribavirin portion of the triple-drug regimen. The ledipasvir/sofosbuvir dual-drug regimen appears to be a favorable option for the treatment of HCV genotype 1 infections, but data are lacking regarding its long-term efficacy (e.g., SVR beyond 12 weeks) and its effects on the long-term complications associated with HCV infections (e.g., cirrhosis, cancer). Page 14 of 22

15 Harvoni (ledipasvir/sofosbuvir) Pivotal Trials Clinical Trial Genotype Population Duration of Treatment # of Participants SVR % ION-1 GT 1, Treatment Naïve, 12 weeks N= wks: 99% with or without cirrhosis ION-2 GT 1, Treatment Experienced, 12 weeks N= wks: 94% with or without cirrhosis 24 weeks N=109 ION-3 GT 1, Treatment Naïve, without cirrhosis 8 weeks 12 weeks N=215 N= wks: 99% American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA) Guidance from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America (IDSA) Recommendations for Testing, Managing, and Treating hepatitis C. Available online at Current treatment guidelines for hepatitis C (October 2014) were published prior to the FDA approval of this agent, although treatment guidelines will likely be updated at a later date to include recommendations for Harvoni. The American Association for the Study of Liver Disease (AASLD) and Infectious Disease Society of America (IDSA) 2014 treatment recommendations for HCV genotype 1 vary based on whether the patient is eligible to receive interferon. For all interferon eligible patients with genotype 1, the current recommendation is Sovaldi triple therapy (sofosbuvir, peginterferon and ribavirin) regimen for 12 weeks. For those with genotype 1 who are interferon ineligible, the AASLD/IDSA recommend Olysio plus Sovaldi once daily for 12 weeks. The treatment recommendations offer alternative regimen suggestions; an alternate regimen for patients that are interferon eligible is Olysio for 12 weeks combined with peginterferon/ribavirin for 24 weeks, as long as they have either 1) genotype 1b or 2) genotype 1a without the Q80k polymorphism. An alternate regimen for interferon ineligible patients is Sovaldi plus ribavirin for 24 weeks; however, the panel noted that this regimen is less effective than the Olysio/Sovaldi combination, especially for patients with cirrhosis. Treatment is not recommended with triple therapy regimens that include Victrelis or Incivek. Page 15 of 22

16 Related Codes N/A References 1. Sovaldi [package insert]. Foster City; Gilead Sciences; December Available at: Accessed October Harvoni [package insert]. Foster City; Gilead Sciences; October Available at: 3. Facts & Comparisons. Sovaldi. [Facts & Comparisons website]. Available at: [via subscription only]. 4. Gold Standard, Inc. Sovaldi. Clinical Pharmacology [database online]. Available at: 5. FDA Newspress Announcement. FDA approves Sovaldi for chronic Hepatitis C. December 6, FDA Antiviral Drugs Advisory Committee Meeting. Sofosbuvir (GS-7977) Background Packet. October 25, Available at: Accessed January FDA Newspress Announcement. FDA approves first combination pill to treat hepatitis C. October 10, American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA). Recommendations for Testing, Managing, and Treating Hepatitis C. Complete revision made to this section on December 19, Additional changes made on January 26, 2015.Available at: 9. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases (AASLD). Hepatology. 2011;54(4): doi: /hep Chou R, Hartung D, Rahman B, Wasson N, Cottrell E, Fu R. Treatment for Hepatitis C Virus Infection in Adults. Rockville (MD): Agency for Healthcare Research and Quality (US); Available at: Accessed January 2014 Page 16 of 22

17 11. Chopra S, Muir AJ. Treatment Regimens for Chronic Hepatitis C Virus Genotype 1. UpToDate website. Available at: 1?source=search_result&search=olysio&selectedTitle=4%7E6#H Accessed January Sofosbuvir (Sovaldi) for Chronic Hepatitis C. The Medical Letter on Drugs and Therapeutics. January 20, Issue 1434: 5. Accessed January VA Office of Public Health Intranet Site Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med May 15;370(20): Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med Apr 17;370(16): Gane E, Stedman C, Hyland R et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med. 2013;36: Holmberg SD, Spradling PR, Moorman AC, Denniston MM. Hepatitis C in the United States. N Engl J Med. 2013;368(20): Jacobson IM, Gordon SC, Kowdley KV, et al; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013;368: Available at: Published POSITRON and FUSION Trials (Jacobson et al., 2013) Klevens RM, Hu DJ, Jiles R, Holmberg SD. Evolving epidemiology of hepatitis C virus in the United States. Clin Infect Dis. 2012;55(suppl 1):S3 S9. PubMed 20. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a brief depression severity measure. J Gen Intern Med 2001;16: Kowdley KV, Gordon SC, Reddy KR et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med May 15;370(20): Lawitz E, Mangia A, Wyles D et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368: Available at: Published FISSION and NEUTRINO Trials (Lawitz et al., 2013) - Page 17 of 22

18 GUIDELINES, PROFESSIONAL SOCIETIES, AUTHORITATIVE PUBLICATIONS American Association for the Study of Liver Diseases (AASLD) Recommendations from current AASLD/IDSA treatment guidelines for chronic hepatitis C for Testing, Managing, and Treating Hepatitis C ( NICE Guidance NICE technology appraisal in development. Hepatitis C (children and young people) peginterferon alfa and ribavirin. November 2013.NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of chronic hepatitis C. (TA200) NICE technology appraisal. Peginterferon alfa and ribavirin for the treatment of mild hepatitis C. (TA106) NICE technology appraisal. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of chronic hepatitis C. (TA75) TABLE 1: Treatment Naïve Patient Population Treatment naïve No cirrhosis Pre-treatment viral load < 6 million IU/mL Treatment naïve No cirrhosis Pre-treatment viral load > 6 million IU/mL Treatment naïve Interferon ineligible Genotypes 1a/1b ,6 Harvoni: 8wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Riba/Interferon: 12wks Sovaldi/Ribavirin/Interferon: 12wks Olysio/Riba/Interferon: 12wks Harvoni: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin/Interferon: 12wks Sovaldi/Ribavirin/ Interferon: 12wks Olysio/Ribavirin/Interferon: 12wks Harvoni: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Page 18 of 22

19 Treatment naïve Compensated Cirrhosis Treatment naïve Compensated cirrhosis Treatment naïve Decompensated cirrhosis Child-Pugh Class B or C Harvoni: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin/Interferon: 12wks Sovaldi/ Ribavirin/Interferon: 12wks Olysio/Ribavirin/Interferon: 12wks Harvoni: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks TABLE 2: Retreatment of Non-Responders and Relapsers Non- Responder/Relapser to Ribavirin/IFN No cirrhosis Non- Responder/Relapser to Riba/IFN Compensated cirrhosis Non- Rresponder/Relapser to Riba/IFN Interferon ineligible No cirrhosis Genotype 1a/1b , 6 Harvoni: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin/IFN: 12wks Sovaldi/Ribavirin/IFN: 12wks Olysio/Ribavirin/IFN: 12wks Sovaldi/Ribavirin/IFN: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin/IFN: 12wks Harvoni: 12wks Olysio/Ribavirin/IFN: 12wks Harvoni: 12wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Page 19 of 22

20 Non- Responder/Relapser to Ribavirin/IFN Non- Responder/Relapser to PI/Ribavirin/IFN Nonresponder/Relapser to PI/Riba/IFN Compensated cirrhosis Non- Responder/Relapser to Riba/IFN Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Harvoni: 24 wks Harvoni: 12wks Harvoni: 24 wks Abbreviations: Riba ribavirin, IFN interferon, PI Protease inhibitor (such as telaprevir or boceprevir, not Olysio); Non-Responder : A patient who received partial or null response to prior treatment; Relapser : A patient with a HCV RNA decrease that remained below the limit of detection (<50 IU/mL) during previous treatment but became detectable after cessation of treatment Page 20 of 22

21 TABLE 3: Unique Patient Populations: HCV/HIV co-infection, HCC awaiting liver transplant and post-liver transplant HIV: Co-infected patients should be managed in consultation with an experienced HIV provider. Pre-liver transplant: The decision to treat a member awaiting transplantation should be made in consultation with the transplant Genotype HCV/HIV co-infection Treatment naïve Relapser/Nonresponder with or without cirrhosis 1a/1b , 6 Sovaldi/Ribavirin/IFN : Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Riba/IFN: 12wks 12wks HCV/HIV co-infection Treatment Naïve Relapser/Nonresponder Interferon ineligible HCC awaiting liver transplant meets Milan criteria with or without compensated cirrhosis Post-liver transplant HCV reoccurrence Treatment naïve With or without compensated cirrhosis Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 12wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 24wks Sovaldi/Ribavirin: 48wks Sovaldi/Ribavirin: 48wks Sovaldi/Ribavirin: 48wks Sovaldi/Ribavirin : 48wks Sovaldi/Ribavirin/IFN: 24wks Sovaldi/Ribavirin: 24wks center where the member is listed and assessed on a case-by-case basis. Sovaldi/Ribavirin: 24wks Page 21 of 22

22 Abbreviations: HCV Hepatitis C virus, Riba ribavirin, IFN interferon, HCC hepatocellular carcinoma; Nonresponder: A patient who received partial or null response to prior treatment Relapser : patient with a HCV RNA decrease that remained below the limit of detection (<50 IU/mL) during previous treatment but became detectable after cessation of treatment Document History Date Action 10/6/2015 Original Version Page 22 of 22