Hepatitis C Treatment HEPATITIS C TREATMENT HS-250. Policy Number: HS-250. Original Effective Date: 5/1/2014. Revised Date(s): N/A

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1 Easy Choice Health Plan, Inc. Harmony Health Plan of Illinois, Inc. Missouri Care, Inc. Ohana Health Plan, a plan offered by WellCare Health Insurance of Arizona, Inc. WellCare Health Insurance of Illinois, Inc. WellCare Health Plans of New Jersey, Inc. WellCare Health Insurance of Arizona, Inc. WellCare of Florida, Inc. WellCare of Connecticut, Inc. WellCare of Georgia, Inc. WellCare of Kentucky, Inc. WellCare of Louisiana, Inc. WellCare of New York, Inc. WellCare of Ohio, Inc. WellCare of South Carolina, Inc. WellCare of Texas, Inc. WellCare Prescription Insurance, Inc. Windsor Health Plan Windsor Rx Medicare Prescription Drug Plan Hepatitis C Treatment Policy Number: Original Effective Date: 5/1/2014 Revised Date(s): N/A APPLICATION STATEMENT The application of the Clinical Coverage Guideline is subject to the benefit determinations set forth by the Centers for Medicare and Medicaid Services (CMS) National and Local Coverage Determinations and state-specific Medicaid mandates, if any. Clinical Coverage Guideline page 1

2 DISCLAIMER The Clinical Coverage Guideline is intended to supplement certain standard WellCare benefit plans. The terms of a member s particular Benefit Plan, Evidence of Coverage, Certificate of Coverage, etc., may differ significantly from this Coverage Position. For example, a member s benefit plan may contain specific exclusions related to the topic addressed in this Clinical Coverage Guideline. When a conflict exists between the two documents, the Member s Benefit Plan always supersedes the information contained in the Clinical Coverage Guideline. Additionally, Clinical Coverage Guidelines relate exclusively to the administration of health benefit plans and are NOT recommendations for treatment, nor should they be used as treatment guidelines. The application of the Clinical Coverage Guideline is subject to the benefit determinations set forth by the Centers for Medicare and Medicaid Services (CMS) National and Local Coverage Determinations and state-specific Medicaid mandates, if any. Note: The lines of business (LOB) are subject to change without notice; consult for list of current LOBs. BACKGROUND HCV infection is the most common chronic blood borne infection in the United States; approximately 3.2 million persons are chronically infected. In 2011, there were 1,229 reported cases an increase of 45%. In 2011, the overall rate of acute hepatitis C increased from 2010, with the largest increases among persons aged 0-19 years (from 0.05 to 0.10 cases per 100,000 population) and years (from 0.75 to 1.18 cases per 100,000 population). When compared to all age groups, persons aged years had the highest rate and persons 60 years of age (0.07 cases per 100,000 population) had the lowest rate. Further, the rate of hepatitis C increased 51.6% among White non-hispanics (0.47 case per 100,000 population). Of the 646 case reports that had information about injection-drug use, 59.9% (n=387) noted use of these drugs. Viral-hepatitis-associated death rates in 2010 were highest among persons infected with HCV (4.65 deaths per 100,000 population), followed by HBV (0.52 deaths per 100,000 population), and HAV (0.03 deaths per 100,000 population). An estimated 3 to 4 million individuals in the U.S. are infected with hepatitis C virus (HCV); 70% are asymptomatic and unaware of their condition. Complications of chronic HCV infection include cirrhosis and hepatocellular carcinoma. Chronic HCV infection is the leading indication for liver transplantation in the U.S. There are 6 known genetically distinct strains (genotypes) of HCV. Genotype prevalence varies by geographic region. In the U.S., approximately 75% of patients are infected with genotype 1, approximately 20% to 25% are infected with genotype 2 or 3, and very small numbers are infected with genotype 4, 5, or 6. (Hayes, 2014). Treatment Profiles Characteristics of members for whom therapy is widely accepted: Are age 18 years or older; AND, HCV RNA positive in serum; AND, Liver biopsy shows chronic hepatitis with significant fibrosis (bridging fibrosis or higher); AND, Compensated liver disease (total serum bilirubin <1.5 g/dl; INR 1.5; serum albumin >3.4, platelet count 75,000 mm and no evidence of hepatic decompensation (hepatic encephalopathy or ascites); AND, Acceptable hematological and biochemical indices (hemoglobin 13 g/dl for men and 12 g/dl for women; neutrophil count 1500/mm 3 and serum creatinine <1.5 mg/dl; AND, Willing to be treated and to adhere to treatment requirements; AND, No contraindications (see below). Characteristics of members for whom therapy is currently contraindicated: Major uncontrolled depressive illness. Solid organ transplant (renal, heart or lung). Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peginterferon and ribavirin. Untreated thyroid disease. Pregnant or unwilling to comply with adequate contraception. Severe concurrent medical disease (e.g., severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, COPD). Clinical Coverage Guideline page 2

3 Known hypersensitivity to drugs used to treat HCV. Additional contraindications for use with peginterferon include members with any the following: Autoimmune hepatitis; OR, Hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before treatment; OR, Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before treatment Additional contraindications for use with ribavirin include members with any the following: Women who are pregnant; OR, Men whose female partners are pregnant; OR, Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) ; OR, Combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials. Provider Exchange of Information Documentation is a basic component of all patient care. However, when multiple disciplines and treatment strategies are involved, documentation becomes critical as a means of establishing progress toward the shared short-term and long-term goals. It is essential that necessary paperwork and patient-generated documentation such as follow up assessments, should be shared, but additionally all progress notes and reports should be made available to all team members. Appropriate follow-up is essential to confirm the effectiveness of the treatment plan, to identify problems, and to prevent and treat progression, flare ups, and relapses. (Turk, & et al., 2010). The interdisciplinary team may include (but is not limited to): Physicians (e.g., physiatrist, anesthesiologist, addictionologist) Nurses Psychologists Physical and/or occupational therapists Recreational therapists Pharmacists Social workers Support staff In addition to communication among members of interdisciplinary teams, communication should also incorporate patients, caregivers, and significant others. This involvement goes beyond the simple provision of information; it involves active participation of these individuals to the extent possible in treatment decisions and self-management. The involvement of patients, caregivers, and significant others requires that treatments be accommodated to patient s needs (e.g., availability of translators, strategies for interacting with patients who have limitations in their ability to communicate) and cultural sensitivities (e.g., religious and ethnic mores). The interdisciplinary team should have a shared philosophy, mission, and objectives that are patient and family centered in order to accomplish common, agreed upon goals. An integrated, interdependent approach will facilitate mutual respect and open communication. Communication should be direct, clear, and reciprocal to deliver a collaborative approach to clinical care, education, quality improvement and research. Clinical Coverage Guideline page 3

4 Member Treatment Compliance Treatment is continued for members with a regimen compliance rate of > 85%. This is confirmed by the Prescriber and member s pharmacy history (e.g., history of dispensing medication). To receive continued authorization, members must meet all the following criteria: 1. During the course of treatment, Member has not consecutively missed more than two (2) missed doses; AND, 2. During the six-week authorization timeframe, Member has not collectively missed more than six (6) doses; AND, 3. For Members on a 12-week total regimen, 85% compliance is defined as: No more than 12 missed doses collectively over the prescribed 12-week course of therapy; AND, Compliance of at least 71 days of the total prescribed treatment regimen 4. For Members on a 24-week total regimen, 85% compliance is defined as: No more than 24 doses missed collectively over the prescribed 24-week course of therapy; AND, Compliance of at least 142 days of the total prescribed treatment regimen Members who do not meet the compliance criteria above will be denied additional authorization. Treatment may be discontinued in Members when treatment compliance falls below 85%. Government Statements Food and Drug Administration (FDA) Sovaldi (Sofosbuvir; Glead Sciences Inc) received FDA approval in December According to documents on file with the FDA, Sovaldi is a hepatitis C virus (HCV) nucleotide analog NS5B polymerase inhibitor indicated for the treatment of chronic hepatitis C (CHC) infection as a component of a combination antiviral treatment regimen. Sovaldi efficacy has been established in subjects 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 coinfection The following points should be considered when initiating treatment with SOVALDI: Monotherapy of SOVALDI is not recommended for treatment of CHC. Treatment regimen and duration are dependent on both viral genotype and patient population. [See Dosage and Administration (2)]. Treatment response varies based on baseline host and viral factors. [See Use in Specific Populations (8) and Clinical Studies (14)] Sovaldi should be used in combination with ribavirin or in combination with pegylated interferon and ribavirin for the treatment of CHC in adults Sovaldi combination treatment with ribavirin or peginterferon alfa/ribavirin is contraindicated in women who are pregnant or may become pregnant and men whose female partners are pregnant because of the risks for birth defects and fetal death associated with ribavirin [See Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. The most common adverse events ( 20%) for Sovaldi + ribavirin combination therapy were fatigue and headache. The most common adverse events ( 20%) for Sovaldi + peginterferon alfa + ribavirin combination therapy were fatigue, headache, nausea, insomnia and anemia Safety and effectiveness of Sovaldi in children less than 18 years of age have not been established Clinical Coverage Guideline page 4

5 Centers for Medicare & Medicaid Services (CMS) No National Coverage Determination (NCD) for treatment of Hepatitis C using Sovaldi (sofosbuvir) was identified on the CMS website. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. Centers for Disease Control and Prevention (CDC) (2014) The CDC recommends genotyping of the hepatitis C virus for each patient as not all genotypes respond equally to the same treatments. Until recently, the mainstay of treatment for chronic hepatitis C virus (HCV) infection has been pegylated interferon and ribavirin, with possible addition of boceprevir (Victrelis ) and telaprevir (Incivek ) (both protease inhibitors) for HCV genotype 1 infection. After given for weeks, this treatment resulted in a sustained virologic response (a marker for cure), defined as undetectable HCV RNA in the patient's blood 24 weeks after the end of treatment in 50% 80% of patients (with higher SVR among persons with HCV genotypes 2 or 3 infections versus infections with HCV genotype 1, the most common genotype found in the United States). In late 2013, The Food and Drug Administration approved two new direct acting antiviral drugs, Sofosbuvir (Sovaldi ) and Simeprevir (Olysio ) to treat chronic HCV infection. Both medications have proven efficacy when used as a component of a combination antiviral regimen to treat HCV-infected adults with compensated liver disease, cirrhosis, HIV co-infection, and hepatocellular carcinoma awaiting liver transplant. Clinical trials have shown that these new medications achieve SVR in 80%-95% of patients after weeks of treatment. Sofosbuvir (Sovaldi ) is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B polymerase enzyme, which plays an important role in HCV replication. It is taken orally once a day at a 400-mg dose. The drug is approved for two chronic hepatitis C indications: In combination with pegylated interferon and ribavirin for treatmentnaïve adults with HCV genotype 1 and 4 infections, and in combination with ribavirin for adults with HCV genotypes 2 and 3 infection. The second indication is the first approval of an interferon-free regimen for the treatment of chronic HCV infection. Simeprevir (Olysio ) is a protease inhibitor that blocks a specific protein needed by the hepatitis C virus to replicate. It is to be used as a component of a combination antiviral treatment regimen of peginterferon-alfa and ribavirin for genotype 1 infections only. It is taken orally once a day at a 150-mg dose. The treatment duration is weeks depending on prior treatment history and response to treatment. Because the efficacy of simeprevir is substantially reduced in patients infected with HCV genotype 1a with an NS3 Q80K polymorphism, screening for this mutation is strongly recommended by the manufacturer before treatment initiation. United States Preventive Services Task Force The USPSTF (2013) recommends screening for hepatitis C virus (HCV) infection in persons at high risk for infection. The USPSTF also recommends offering one-time screening for HCV infection to adults born between 1945 and These new screening guidelines will increase the number of people diagnosed with Hepatitis C, and the total cost of treating HCV will increase. POSITION STATEMENT Applicable To: Medicaid Medicare Treatment for Hepatitis C requires a common chronic medical illness that requires an effort in prevention, education, screening, diagnosis and treatment. WellCare will develop policies, procedures and programs to effectively treat HCV using a holistic approach utilizing such components to provide accurate diagnosis and treatment of the Member. Clinical Coverage Guideline page 5

6 Screening WellCare considers one-time testing without prior ascertainment of Hepatitis C virus (HCV) risk medically necessary for persons born between 1945 to1965 (USPSTF, 2013). In addition, HCV screening is considered medically necessary when a member: 1. Is a child born to an HCV infected mother. 2. Is a child who is from a region with high prevalence of HCV infection. 3. Receives or has received hemodialysis. 4. Received blood transfusions or organ transplants prior to July 1992 or received blood from a donor who later tested positive for HCV infection. 5. Received clotting factor concentrates produced before Is HIV-positive. 7. Reports consistently abnormal ALT levels. 8. Identifies an exposure to HCV (e.g., health care workers, emergency medical personnel or public safety workers that suffer a needle stick, sharps or mucosal exposures). 9. Is an injection drug user or injected drugs in the past (including once or a few times). 10. Has a current HCV-infected sexual partner. HCV testing is not recommended unless the following have risk factors for infection: Health-care, emergency medical, and public safety workers Pregnant women Household (nonsexual) contacts of HCV-positive persons General population HCV testing for persons for whom routine HCV testing is of uncertain need: Recipients of transplanted tissue (e.g., corneal, musculoskeletal, skin, ova, sperm) Intranasal cocaine and other non-injecting illegal drug users Persons with a history of tattooing or body piercing Persons with a history of multiple sex partners or sexually transmitted diseases Long-term steady sex partners of HCV-positive persons Diagnosis Diagnosis of Chronic Hepatitis C (CHC) confirmed by detectable serum HCV RNA by quantitative assay. In addition, the following criteria must be met: Genotype is required to determine length of approval; AND, Member must have symptomatic / cirrhotic chronic Hepatitis C with symptoms of advanced liver disease (e.g., fever, fatigue, loss of appetite, NV-F agent, abdominal pain, dark urine, grey stools, jaundice, joint pain); AND, Provider shall document that counseling was provided and that the Member has verbalized understanding of treatment. Further, the Member states willingness to adhere to the drug regimen prescribed by the Provider; AND, Member shows no history of demonstrated non-adherence including initial HCV assessment and prior treatment plans as well. In addition, members with co-morbid conditions must show no history of demonstrated non-adherence for treatment of co-morbid conditions. Clinical Coverage Guideline page 6

7 Treatment In December 2013, the FDA approved Gilead Sciences Inc. for the release of Sovaldi, a new drug to treat the hepatitis C virus (HCV). 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. The Infectious Diseases Society of America(IDSA) and American Association for the Study of Liver Diseases (AASLD) have jointly published evidence-based, expert-developed recommendations for hepatitis C management which state the following in regard to the use of the newly approved direct acting agents for the treatment of genotype 1 hepatitis C infection: In many instances, however, it may be advisable to delay treatment for some patients with documented early fibrosis stage (F 0-2), because waiting for future highly effective, pangenotypic, direct acting agent combinations in interferon-free regimens may be prudent. In addition, a report issued in February 2014 by the Institute for Clinical and Economic Review (ICER) for the California Technology Assessment Forum (CTAF) recommended that Olysio and Sovaldi be used only for patients with severe hepatitis complications, such as liver cirrhosis. WellCare will provide benefit coverage in cases of hepatitis C infection when there is documented evidence of stage 3 or stage 4 hepatic fibrosis. Length of Authorization may vary by indication; refer to Dosing and Administration section. Monotherapy is not recommended for treatment. Treatment regimen and duration are dependent on both viral genotype and patient population. Treatment response varies based on baseline host and viral factors Hepatitis C is treated using a medical, behavioral and social approach. Treatment using Sovaldi is considered medically necessary when criteria from the three components below are met. 1. Member is age 18 years or older; AND, 2. Member has no contraindications (see Treatment Profiles below); AND, 3. Obtain pretreatment labs and documentation, including all of the following USDVA, 2012; AASLD, 2009 : Medical history, including complications of liver disease, presence of significant extrahepatic disease, and symptoms of chronic HCV that may diminish quality of life. Psychiatric history, including past or ongoing psychiatric, and substance use disorders Screening for depression and alcohol use Biochemical markers of liver injury and assessment of hepatic function, including serum ALT, serum albumin, serum bilirubin (including direct bilirubin), and prothrombin time Hemoglobin, hematocrit, WBC with differential, and platelet count TSH Serum creatinine Serum glucose Uric acid (while receiving TVR) Serum ferritin, iron saturation, and serum ANA Pregnancy test (in women of childbearing age) HIV serology Serum HBsAg, antihbc, antihbs, antihav (total) Quantitative HCV RNA measurement HCV genotype Clinical Coverage Guideline page 7

8 Previous antiviral therapies and response ECG in patients with preexisting cardiac disease In addition, the following may be necessary for some members to determine the course of treatment: Liver biopsy (if results will influence management) IL28B genotype (if results will influence management) Eye exam for retinopathy in patients with diabetes or hypertension Urine toxicology screen for opiates, cocaine, and amphetamines AND, 4. Member states willingness to adhere to the drug regimen prescribed by the Provider; AND, 5. Provider shall provide documentation the Member s Metavir Fibrosis Classification Schema score greater than 2. Stage 1 Stage 2 Stage 3 Stage 4 Metavir Fibrosis Classification Schema Portal/periportal fibrosis Septal fibrosis Bridging fibrosis w/ architectural distortion Cirrhosis, probable cirrhosis Or documentation of an Ishak Staging Scale greater than 3. Categorical Assignment Clinical Coverage Guideline page 8 Fibrous Measurement Ishak Staging Scale 0 1.9% No fibrosis (normal) 1 3.0% Fibrous expansion of some portal areas (+/-) short fibrous septa 2 3.6% Fibrous expansion of most portal areas (+/-) short fibrous septa 3 6.5% Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging % Fibrous expansion of portal areas with marked bridging (P-P) as well as portal to central (P-C) % Marked bridging (P-P and/or P-C), with occasional nodules (incomplete cirrhosis) % Cirrhosis, probable or definite In addition, an alternative scoring equivalent* (Transient elastography (Fibroscan) score greater than or equal to 9.5 kpa, FibroTest (FibroSURE) score of greater than or equal to 0.58, APRI score greater than 1.5, Radiological imaging consistent with cirrhosis (e.g., evidence of portal hypertension)). AND, 6. Providers shall document the Child Pugh Score to the prior authorization to define the Peg-interferon contraindication. See below. Child Pugh Classification Factor 1 Point 2 Points 3 Points Total Bilirubin < >50 Serum Albumin > <28 INR < >2.3

9 Ascites None Mild Moderate to Severe Hepatic None Grate 1-2 or controlled Grade 3-4 or refractory encephalopathy Note: Class A = 5-6 points; Class B = 7-9 points; Class C = points AND, 7. Prescribed by or in consultation with a gastroenterologist, hepatologist or infectious disease physician; AND, 8. Meets the criteria of ONE of the following AASLD, 2014; Jacobson & et al., 2013 : a. For HCV Genotype 1 with Stage 4 CHC members must meet at least one of the following criteria: Is intolerant, ineligible or treatment is contraindicated with interferon as demonstrated by side effects with objectively measured impact on the member s health or quality of life (e.g., conditions as anemia, alcohol abuse, advanced or decompensated cirrhosis, severe side effects, diminished quality of life, or severe psychiatric disorder). (Sovaldi should be used as triple therapy in combination with peginterferon alfa and ribavirin or as double therapy in combination with ribavirin for patients who are interferon ineligible); OR, Developed a reaction to previous interferon therapy (e.g., urticarial, angioedema, bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome, depression, ophthalmologic disorder, thyroid disorder or refractory diabetes mellitus); OR, Diagnosis of an autoimmune disorder, including autoimmune hepatitis; OR, Diagnosis or history of severe, untreated depression. Depression may be documented from prior treatment with interferon therapy, noted by a PHQ-9 score of 10 or greater and/or an evaluation by a psychiatrist 1 ; OR, Decompensated liver cirrhosis as evidenced by a Child-Pugh score greater than 6 (Class B or C) before or during interferon treatment documentation must be within 30 days prior to request submission; OR, Severe thrombocytopenia (platelet count < 50,000 mm3) ; OR, Hepatocellular cancer awaiting liver transplant; OR, Baseline neutrophil count below 1500/μL; OR, Baseline platelet count below 90,000/μL; OR, Baseline hemoglobin below 10 g/dl; OR, History of preexisting cardiac disease. 1 Evaluation (including a PHQ-9 score) by a psychiatrist may be required prior to receiving treatment with Sovaldi (sofosbuvir). b. For HCV Genotype 2 with Stage 3 CHC: Sovaldi must be used in combination with ribavirin; OR, c. HCV Genotype 3 with Stage 3 or greater fibrosis; OR, d. HCV Genotype 1, 2, 3, or 4 with concurrent hepatic carcinoma(s) and member is awaiting liver transplantation and both of the following criteria: Member meets Milan criteria defined as (a) single hepatocellular carcinoma, presence of tumor 5cm or less in diameter or multiple tumors with each being 3 cm or less in diameter AND no extrahepatic manifestations of cancer or evidence of vascular invasion of tumor; AND ONE OF THE FOLLOWING - Clinical Coverage Guideline page 9

10 Member meets all criteria for authorization of a liver transplant as indicated by C7CM MD 8.6 Transplant Case Management Policy and C7CM MD 8.6 PR-001Transplant Case Management Procedure or C7CM MR 8.6 Transplant Case Management Policy and C7CM MR 8.6 PR- 001Transplant Case Management Procedure; OR, For treatment of CHC in patients with hepatocellular carcinoma meeting Milan criteria (awaiting liver transplantation): must be used in combination with ribavirin. Milan criteria is defined as 1 lesion 5 cm, up to 3 lesions each of which are 3 cm, and no extrahepatic manifestations/no vascular invasion. For members awaiting transplant, the Provider shall use Milan criteria as well as documentation of Member s placement on a liver transplant list. Milan criteria is the presence of a tumor 5 cm or less in diameter in patients with single hepatocellular carcinomas and no more than 3 tumor nodules, each 3 cm or less in diameter in patients with multiple tumors and no extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor. AND, 9. Determine no contraindications exist for prescribing Ribavirin to Member; this includes (but is not limited to): Known hypersensitivity reactions to ribavirin (SJS, TEN, etc.) Autoimmune hepatitis DDI Didanosine CrCl less than 50 ml/min Women who are pregnant; OR, Men whose female partners are pregnant; OR, Patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia) ; OR, Combination with didanosine. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials. Drugs that are contraindicated with Sovaldi (sofosbuvir) include: Drug Class Drugs Clinical Comments Anticonvulsants Carbamazepine, phenytoin, phenobarbital, oxcarbazepine Dec. sofosbuvir plasma conc. Antimycobacterial Rifampin, Rifabutin, Rifapentine Dec. sofosbuvir plasma conc. Herbal Products St. John s wort Plasma conc. sofosbuvir are dec. HIV Protease Inhibitors Tipranavir/ritonavir Dec. sofosbuvir plasma conc. NOTE: Providers may elect to prescribe a combination of Sovaldi (sofosbuvir) and Rebetol (ribavirin) for members with interferon related depression. Traditional treatment methods for HCV include the use of pegylated interferon-alpha (INF-α) and the antiviral ribavirin. This treatment method has a high degree of adverse effects including fatigue, insomnia, irritability, low mood and major depressive disorder. Depressive symptoms occur in approximately 10 45% of all patients receiving INF-α therapy depending on the dose. Symptoms are common in the early stages of treatment, but typically peak between 4 and 16 weeks. Detecting and properly treating depressive symptoms is essential because of a decreased quality of life, suicidal ideation and lack of treatment adherence in those who experience them. (Ehret & Sobieraj, 2014). Clinical Coverage Guideline page 10

11 Dosing and Administration HCV Genotype 1 or 4 TRIPLE THERAPY: OLYSIO + PEG-INTERFERON ALFA + RIBAVIRIN Length of Authorization: Olysio to 12 weeks PEG & RBV x 24 weeks Documentation of concurrent (or planning to start) therapy with ribavirin and peg-interferon when starting OLYSIO for a 12-week duration HCV Genotype 2 DUAL THERAPY: SOVALD I + RIBAVIRIN Length of Authorization: Up to 12 weeks Documentation of concurrent (or planning to start) therapy with ribavirin when starting SOVALDI for a 12week duration HCV Genotype 3 DUAL THERAPY: PEG-INTERFERON ALFA + RIBAVIRIN Length of Authorization: Up to 24-48weeks Documentation of concurrent (or planning to start) therapy with ribavirin when starting Peg interferon for a 12 week duration Interferon ineligibility is defined as meeting one or more of the following criteria: Uncontrolled seizures Suicidal attempt within past year Moderate to severe retinopathy Neutrophils <750 cells/mm3, results within the past month Hemoglobin <10 g/dl results within the past month Platelets < cells/mm3, results within the past month Major uncontrolled depressive illness Solid organ transplant (renal, heart, or lung) Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peginterferon and ribavirin Untreated thyroid disease Pregnant or unwilling to comply with adequate contraception Severe concurrent medical disease such as severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, COPD Age less than 2 years Known hypersensitivity to drugs used to treat HCV Known hypersensitivity reactions such as urticaria, angioedema, bronchoconstriction, anaphylaxis, or Stevens-Johnson syndrome to alpha interferons, or any of its components Hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic patients before treatment Hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before treatment Clinical Coverage Guideline page 11

12 Diagnosis of Hepatocellular Carcinoma Awaiting Liver Transplantation HCV Genotypes 1, 2, 3, or 4 DUAL THERAPY: SOVALDI + RIBAVIRIN Length of Authorization: Up to 48 weeks (or up to time of transplant) Approve for 24 weeks at a time Patient must have documented HCV genotype 1, 2, 3 or 4 infection; AND Patient is an active candidate on the waiting list for a liver transplant and being managed in a liver transplant center AND Milan Criteria as above AND Documentation of concurrent (or planning to start) therapy with ribavirin when starting SOVALDI for a 48week duration or until the time of liver transplantation, whichever occurs first HCV Genotype 1 infection; AND interferon-ineligible DUAL THERAPY: SOVALDI + RIBAVIRIN Length of Authorization: Up to 24 weeks (maybe up to 48 weeks in decompensated cirrhosis) Interferon Ineligible: defined as o Intolerance to Interferon o Autoimmune hepatitis and other autoimmune disorders o Hypersensitivity to PEG or any of its components o Decompensated hepatic disease o Decompensated Cirrhosis = Child-Pugh Classification B or C o Documentation of concurrent (or planning to start) therapy with ribavirin when starting SOVALDI for a 24week duration This regimen should be considered only in those patients who require immediate treatment, because it is anticipated that safer and more effective IFN-free regimens will be available by HCV Genotype 5 or 6 DUAL THERAPY: PEG-INTERFERON ALFA + RIBAVIRIN Length of Authorization: Up to 48 weeks Insufficient data to recommend Sovaldi or Olysio use in patients with HCV genotypes 5 or 6 Patients in whom previous treatment with PEG/RBV plus either telaprevir or boceprevir*** has failed TRIPLE THERAPY: SOVALDI + PEG-INTERFERON ALFA + RIBAVIRIN Length of Authorization: Sovaldi up to 12 weeks PEG/RBV x weeks Patient must have documented HCV genotype 1 infection AND documented treatment failure; Note: Recently released guidelines for the treatment of HCV from the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD), regarding treatment with Sovaldi and Olysio, with or without weight-based ribavirin in interferon-ineligible patients infected with HCV genotype 1, state the following: This regimen should be considered only in those patients who require immediate treatment, because it is anticipated that safer and more effective IFN-free regimens will be available by Available at: (NOT FDA INDICATED AND NON-COVERED) HCV Genotype 1 infection; AND interferon-ineligible DUAL THERAPY: SOVALDI + OLYSIO Length of Authorization: Up to 12 weeks Patient must have documented HCV genotype 1 infection; AND interferon-ineligible (documentation of reason that patient is ineligible for interferon; e.g., intolerance and/or hypersensitivity to interferon, decompensated hepatic disease); AND Patient has not previously been treated with HCV protease inhibitors (Olysio, Incivek, Victrelis); AND Documentation of cirrhosis Child Pugh Classification B or C Note: Recently released guidelines for the treatment of HCV from the Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD), regarding treatment with Sovaldi and Olysio, with or without weight-based ribavirin in Clinical Coverage Guideline page 12

13 interferon-ineligible patients infected with HCV genotype 1, state the following: This regimen should be considered only in those patients who require immediate treatment, because it is anticipated that safer and more effective IFN-free regimens will be available by Available at: Post Liver Transplantation As per American Association for the Study of Liver Diseases (AASLD) guidelines. Available at: Recommended regimen for treatment-naive patients with HCV genotype 1 in the allograft liver, including those with compensated cirrhosis Daily Sovaldi plus Olysio with or without RBV (initial dose 600 mg/day, increased monthly by 200 mg/day as tolerated to weight-based dose of 1000 mg [<75 kg] to 1200 mg [>75 kg] 1200 mg), for 12 weeks to 24 weeks is recommended for patients with compensated allograft HCV genotype 1 infection. Recommended regimen for treatment-naive patients with HCV genotype 2 or 3 in the allograft liver, including those with compensated cirrhosis Daily Sovaldi and RBV (initial dose 600 mg/day, increased monthly by 200 mg/day as tolerated to weight-based dose of 1000 mg [<75 kg] to 1200 mg [>75 kg] 1200 mg) with consideration of the patient's CrCl value and hemoglobin level for 24 weeks is recommended for patients with compensated allograft HCV genotype 2 or 3 infection. Alternate regimen for treatment-naive patients with genotype 1 HCV in the allograft liver, including those with compensated cirrhosis. Daily Sovaldi and RBV (initial dose 600 mg/day, increased monthly by 200 mg/day as tolerated to weight-based dose of 1000 mg [<75 kg] to 1200 mg [>75 kg] 1200 mg) with consideration of the patient's CrCl value and hemoglobin level, with or without PEG (in the absence of contraindication to its use), for 24 weeks is recommended for patients with compensated allograft HCV genotype 1 infection. Behavioral and Social Prior to receiving treatment, the Member must meet the following criteria: 1. The member does not have a severe mood, thought, or cognitive disorder that would preclude their ability to adhere to the treatment plan; AND, 2. Member is drug and/or alcohol free prior to receiving treatment with Sovaldi (sofosbuvir); AND, 3. Member does not have ongoing alcohol or illicit drug use and/or an unstable psychiatric condition within the past 6 months*; AND, * As evidenced by documentation in the Member s medical record (e.g., laboratory results, medical records, records in member chart, etc.) of abstinence from alcohol and/or illicit drug use. For Members with prior substance or alcohol abuse: 1. Members with a prior history of treatment for of a behavioral health or psychological condition will be prescreened by a mental health professional or provide a letter from their attending psychiatrist or Clinical Coverage Guideline page 13

14 behavioral health provider that they are able to participate in the Hepatitis C treatment program; AND, 2. Be actively participating in a substance or alcohol abuse program (including relapse prevention); AND, 3. Provide ongoing documentation of attendance; AND, 4. Pass a urine drug screening and/or blood alcohol level, 30 days prior to treatment, and any additional time, random screening that will be ongoing throughout the course of treatment; AND, 5. Prior to authorization, and to signify the Member s commitment to successful treatment for Hepatitis C, the member will attend 90 meetings in 90 days through a program such as Narcotics Anonymous or Alcoholics Anonymous; AND, 6. Suboxone or Methadone may be required as part of a comprehensive treatment plan aimed at reducing the risk of relapse and non-adherence to the Hepatitis C drug protocol; AND, 7. Have positive BAL or UDS may be disqualified from the program; AND, 8. The treatment plan may include required educational programs such as living with a chronic illness, coping with cancer, awaiting a liver transplant, etc. All patients should be evaluated for current alcohol and other substance use, with validated screening instruments such as AUDITC or CAGE. The presence of current heavy alcohol use ( >14 drinks per week for men or >7 drinks per week for women), binge alcohol use ( >4 drinks per occasion at least once a month), or active injection drug use warrants referral to an addiction specialist before treatment initiation. Urine toxicology screens for opiates, cocaine, or amphetamines may be used to supplement patient self-report. Alcohol and illicit drug use may affect HCV treatment adherence and response to therapy; however, on a case-bycase basis, individuals with active alcohol or substance use have been treated successfully. Integrated care models have demonstrated that patients who have recently become abstinent can also be treated successfully. Patients with past or recent substance abuse disorders oft en require close monitoring, and care should be coordinated with addiction specialists. (Yee & et al., 2012). Exclusions Exclusions for coverage of Sovaldi (simeprevir) for the treatment of HCV include: Sovaldi (sofosbuvir) will be approved in combination with Olysio (simeprevir) only if the member is treatment naïve, cirrhotic, and is not eligible to receive interferon or the member is a prior non-responder to interferon and ribavirin therapy. WellCare will not cover pegylated interferon for Members with uncontrolled major depression due to increased risk of suicide during interferon treatment. WellCare will not cover other interferon preparations unless a Member has a contraindication to Pegasys. Coverage is limited to a 28-day supply for Pegasys (4 syringes) or the non-preferred medication Peg-Intron (4 syringes or vials). Members with significant or unstable cardiovascular disease as evidenced through a comprehensive cardiac evaluation by an internist or cardiologist; the evaluation includes, but is not limited to member medical history, clinical examination, a 12 lead electrocardiogram (ECG), echocardiography, cardiac exercise test. Members with a medical condition (including those with psychosocial comorbidities) that can lead to a Clinical Coverage Guideline page 14

15 decreased life expectancy of <10 years; disruption with treatment, evaluation or adherence with HCV therapy; or poor response to suggested treatment. Members utilizing concurrent treatment with non-fda approved medical or pharmaceutical treatment such as medical marijuana. Treatment of HCV as monotherapy. Quadruple therapy (Sovaldi+(Olysio, Incivek,or VIctrelis)+peginterferon+ribavirin) combination Treatment regimen that patient who has failed therapy with an NS3/4A protease inhibitor (e.g., boceprevir,simeprevir, telaprevir) Non-FDA approved indications, which are not listed in the Health Net Approved Indications and Usage Guidelines section, unless there is sufficient documentation of efficacy and safety in the published literature Post liver transplant Ongoing Management Providers should provide ongoing education to members with respect to prevention of HCV transmission (AASLD, 2014, 2009), especially those at significant risk of reinfection. This includes injection drug-users (past or current, including those who have injected only once) and intranasal illicit drug users. Persons with current (active) HCV infection should receive education and interventions aimed at reducing progression of liver disease and preventing transmission of HCV. Recommendations include: Abstinence from alcohol and, when appropriate, interventions to facilitate cessation of alcohol consumption should be advised for all persons with HCV infection. Evaluation for other conditions that may accelerate liver fibrosis, including HBV and HIV infections, is recommended for all persons with HCV infection. Evaluation for advanced fibrosis, using liver biopsy, imaging, or non-invasive markers, is recommended in all persons with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy and determine the need for initiating additional screening measures (eg, hepatocellular carcinoma [HCC] screening). Vaccination against hepatitis A and hepatitis B is recommended for all persons with HCV infection who are susceptible to these types of viral hepatitis. Persons with HCV should be educated by their Provider on how to avoid HCV transmission to others. Members should also be educated on risk exposures by their Provider which include, but are not limited to: Long-term hemodialysis (ever) Getting a tattoo in an unregulated setting Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-infected blood Children born to HCV-infected women Prior recipients of transfusions or organ transplants, including persons who: o were notified that they received blood from a donor who later tested positive for HCV infection; OR, o received a transfusion of blood and/or blood components or underwent an organ transplant before July 1992; OR, o received clotting factor concentrates produced before 1987; OR, Have been incarcerated Are HIV-positive Have unexplained chronic liver disease and chronic hepatitis including elevated alanine aminotransferase levels Clinical Coverage Guideline page 15

16 To reduce the chance of reinfection of HCV after treatment, Providers should provide education to Members that includes, but is not limited to: Avoid sharing dental and shaving items (e.g., toothbrushes, razors). Cover bleeding wounds to prevent transmission of blood. Avoid illicit drugs, including sharing or reusing syringes, water, cotton or other related items. Avoid donating blood, body organs and tissues of concern to prevent transmission to recipients. In addition, Providers should advise Members that transmission of HCV via sexual intercourse is low however safer sex practices should be implemented. CLINICAL EVIDENCE Gane and et al. (2014) analyzed an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection. The combination of SOF and a second direct-acting antiviral agent is highly effective in treatment-naïve patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. Koff (2014) reviewed clinical studies of the efficacy and safety of sofosbuvir-containing regimens in the treatment of chronic hepatitis C. The efficacy and safety of sofosbuvir-containing regimens with ribavirin alone or with peginterferon plus ribavirin signal a new era in treatment. Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events (Lawitz, & et al., 2014). Findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin. All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. Sulkowski and et al. (2014) evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. Results found that once-daily oral daclatasvir plus sofosbuvir was associated with high rates of sustained virologic response among patients infected with HCV genotype 1, 2, or 3, including patients with no response to prior therapy with telaprevir or boceprevir. Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. Lawitz and et al. ( ) evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. Sofosbuvir and GS alone and in combination - were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV. The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. Osinusi and et al. (2013) researched the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics. In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68%and 48%, respectively. Sofosbuvir (formerly GS-7977) is a pyrimidine nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B polymerase. Rodriguez-Torres and et al. (2013) assessed the safety, tolerability, antiviral activity, and Clinical Coverage Guideline page 16

17 pharmacokinetics of sofosbuvir plus pegylated-interferon (PegIFN)/ribavirin (RBV) in a 28-day, dose-ranging trial in treatment-naive patients infected with genotype 1 HCV. Results support further studies with sofosbuvir at 200 mg and 400 mg to determine the optimal dose and treatment duration of sofosbuvir in HCV genotype 1. The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. Kowdley and et al. (2013) assessed the safety and effi cacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. Findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. Two phase 3 studies were conducted in previously untreated patients with HCV infection ( 1 Lawitz, & et al., 2013). In a single-group, open-label study, a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin was administered in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. Patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3 for whom treatment with peginterferon is not an option, or who have not had a response to prior interferon treatment, currently have no approved treatment options. In phase 2 trials, regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection. Jacobson and et al. (2013) conducted two randomized, phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection. In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective. Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks. Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. In a two-cohort, phase 2 trial, the safety and efficacy of sofosbuvir was assessed in treatment-naive patients with genotype 1-3 HCV infection. Findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. ( 2 Lawitz, & et al., 2013) A study by Gane and et al. (2013) identified 10 patients who received Sovaldi monotherapy for 12 weeks and were classified with genotype 2 or 3 disease. Primary efficacy (SVR at 12 weeks after therapy stopped) was significantly lower on monotherapy (60%) versus those on combination therapy (100%). CODING CPT Codes None listed. HCPCS Codes J9999 Not otherwise classified, antineoplastic drugs Clinical Coverage Guideline page 17

18 ICD-9 CM Volume 1 - Diagnosis Code 042 Human immunodeficiency virus [HIV] disease Acute hepatitis C with hepatic coma Acute delta-(super) infection of hepatitis B carrier Chronic viral hepatitis C Acute hepatitis C without hepatic coma Chronic viral hepatitis C Unspecified viral hepatitis C without hepatic coma Unspecified viral hepatitis C with hepatic coma Alcohol abuse, uncomplicated Alcohol abuse with intoxication, uncomplicated Alcohol abuse with intoxication, unspecified Alcohol abuse, uncomplicated Alcohol abuse with intoxication, uncomplicated Alcohol abuse with intoxication, unspecified Alcohol abuse, uncomplicated Alcohol abuse with intoxication, uncomplicated Alcohol abuse with intoxication, unspecified Alcohol abuse, uncomplicated Alcohol abuse with intoxication, uncomplicated Alcohol abuse with intoxication, unspecified V01.79 Contact with and (suspected) exposure to viral hepatitis V01.79 Contact with and (suspected) exposure to human immunodeficiency virus [HIV] V01.79 Contact with and (suspected) exposure to other viral communicable diseases V02.60 Carrier of unspecified viral hepatitis V02.62 Carrier of viral hepatitis C V02.69 Carrier of other viral hepatitis V05.3 Encounter for immunization V08 Asymptomatic human immunodeficiency virus [HIV] infection status V69.2 High risk heterosexual behavior V69.2 High risk homosexual behavior V69.2 High risk bisexual behavior V77.8 Encounter for screening for other disorder V79.1 Encounter for screening for other disorder ICD-10 CM - Diagnosis Code B20 Human immunodeficiency virus [HIV] disease B17.11 Acute hepatitis C with hepatic coma B17.0 Acute delta-(super) infection of hepatitis B carrier B18.2 Chronic viral hepatitis C B17.10 Acute hepatitis C without hepatic coma B18.2 Chronic viral hepatitis C B19.20 Unspecified viral hepatitis C without hepatic coma B19.21 Unspecified viral hepatitis C with hepatic coma F10.10 Alcohol abuse, uncomplicated F Alcohol abuse with intoxication, uncomplicated F Alcohol abuse with intoxication, unspecified F10.10 Alcohol abuse, uncomplicated F Alcohol abuse with intoxication, uncomplicated F Alcohol abuse with intoxication, unspecified F10.10 Alcohol abuse, uncomplicated F Alcohol abuse with intoxication, uncomplicated Clinical Coverage Guideline page 18

19 F Alcohol abuse with intoxication, unspecified F10.10 Alcohol abuse, uncomplicated F Alcohol abuse with intoxication, uncomplicated F Alcohol abuse with intoxication, unspecified Z20.5 Contact with and (suspected) exposure to viral hepatitis Z20.6 Contact with and (suspected) exposure to human immunodeficiency virus [HIV] Z Contact with and (suspected) exposure to other viral communicable diseases Z22.50 Carrier of unspecified viral hepatitis Z22.52 Carrier of viral hepatitis C Z22.59 Carrier of other viral hepatitis Z23 Encounter for immunization Z21 Asymptomatic human immunodeficiency virus [HIV] infection status Z72.51 High risk heterosexual behavior Z72.52 High risk homosexual behavior Z72.53 High risk bisexual behavior Z13.89 Encounter for screening for other disorder Z13.89 Encounter for screening for other disorder *Current Procedural Terminology (CPT ) 2014 American Medical Association: Chicago, IL. REFERENCES Peer Reviewed 1. American Association for the Study of Liver Diseases, & Infectious Diseases Society of America. (2014). Recommendations for testing, managing, and treating Hepatitis C. Retrieved from 2. American Association for the Study of Liver Diseases, Ghany, M.G., Strader, D.B., Thomas, D.L., & Seeff, L.B. (2009). AASLD practice guidelines: diagnosis, management, and treatment of Hepatitis C: an update. Hepatology, 49(4), European Association for the Study of the Liver. (2014). EASL clinical practice guidelines: management of hepatitis C virus infection. Journal of Hepatology,60, Ehret, M., & Sobieraj, D.M. (2014). Prevention of interferon-alpha-associated depression with antidepressant medications in patients with hepatitis C virus: a systematic review and meta-analysis. International Journal of Clinical Practice, 68(2), Gane, E.J., Stedman, C.A., Hyland, R.H., Ding X., Svarovskaia, E., Subramanian, G.M., & et al. (2014). Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B nonnucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology, 146 (3), e1). 6. Gane, E.J., Stedman, C.A., Hyland, R.H., Ding, X., Svarovskaia, E., Symonds, W.T., & et al. (2013). Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. New England Journal of Medicine, 368(1), Ghany, M.G., Nelson, D.R., Strader, D.B., Thomas, D.L., & Seeff, L.B. (2011). 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. Hepatology, 54(4), doi: /hep Hayes Directory. (2014, April 7). Sovaldi (sofosbuvir; Gilead) for treatment of chronic hepatitis. Retrieved from Hayes Directory. (2014, February 18). Sovaldi (sofosbuvir) [archived on March 27, 2014]. Retrieved from Jacobson, I.M., Gordon, S.C., Kowdley, K.V., Yoshida, E.M., Rodriguez-Torres, M., Sulkowski, M.S., & et al. (2013). Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. New England Journal of Medicine, 368(20), Koff, R.S. (2014). The efficacy and safety of sofosbuvir, a novel, oral nucleotide NS5B polymerase inhibitor, in the treatment of chronic hepatitis C virus infection. Alimentary Pharmacology and Therapeutics, 39 (5), Clinical Coverage Guideline page 19

20 12. Kowdley, K.V., Lawitz, E., Crespo, I., Hassanein, T., Davis, M.N., Demicco, M., & et al. (2013). Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. The Lancet, 381(9883), Lawitz, E., Poordad, F.F., Pang, P.S., Hyland, R.H., Ding, X., Mo, H., Symonds, W.T., & et al. (2014). Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): An open-label, randomised, phase 2 trial. The Lancet, 383(9916), Lawitz, E., Mangia, A., Wyles, D., Rodriguez-Torres, M., Hassanein, T., Gordon, S.C., & et al. (2013). Sofosbuvir for previously untreated chronic hepatitis C infection. New England Journal of Medicine, 368(20), Lawitz, E., Lalezari, J.P., Hassanein, T., Kowdley, K.V., Poordad, F.F., Sheikh, A.M., & et al. (2013). Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: A randomised, double-blind, phase 2 trial. The Lancet Infectious Diseases, 13(5), Lawitz, E.J., Rodriguez-Torres, M., Denning, J., Mathias, A., Mo, H., Gao, B., & et al. (2013). All-oral therapy with nucleotide inhibitors sofosbuvir and GS-0938 for 14 days in treatment-naive genotype 1 hepatitis C (NUCLEAR). Journal of Viral Hepatitis, 20(10), Mazzaferro, V., Regalia, E., Doci, R., & et al. (1996). Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. New England Journal of Medicine, 334(11), National Institute for Health and Care Excellence. (2014). Hepatitis C (chronic) - sofosbuvir [ID654] (guidance in development). Retrieved from Osinusi, A., Meissner, E.G., Lee, Y.J., Bon, D., Heytens, L., Nelson, A., & et al. (2013). Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics a randomized clinical trial. Journal of the American Medical Association, 310(8), Rodriguez-Torres, M., Lawitz, E., Kowdley, K.V., Nelson, D.R., Dejesus, E., McHutchison, J.G., & et al. (2013). Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naive patients with HCV genotype 1: A randomized, 28-day, dose-ranging trial. Journal of Hepatology, 58(4), Sulkowski, M.S., Gardiner, D.F., Rodriguez-Torres, M., Reddy, K.R., Hassanein, T., Jacobson, I., & et al. (2014). Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. New England Journal of Medicine, 370(3), Turk, D.C., Stanos, S.P., Palmero, T.M., Paice, J.A., Jamison, R.N., Gordon, D.B., & et al. (2010). Interdisciplinary pain management. Retrieved White%20Paper-FINAL.pdf 23. Yee, H.S., Chang, M.F., Pocha, C., Lim, J., Ross, D., Morgan, T.R., & Monto, A. (2012). Update on the management and treatment of Hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Retrieved from Government Agencies, Professional and Medical Organizations 1. Centers for Disease Control and Prevention. (2014, February 10). Hepatitis C information for health professionals. Retrieved from 2. United States Department of Veterans Affairs. (2012). Update of the management and treatment of Hepatitis C viral infection, 2012: pretreatment assessment viral hepatitis pre. Retrieved from 3. United States Preventive Services Task Force. (2013). Screening for hepatitis C virus. Retrieved from Other 1. HealthNet. (2014, February). Prior authorization protocol: SOVALDI (sofosbuvir). Retrieved from Clinical Coverage Guideline page 20