Coverage Policy Manual
Policy #: 2015023
Category: Pharmacy
Initiated: August 2015
Last Review: April 2018
  Daclatasvir (Daklinza)

Description:
Chronic hepatitis C is the leading cause of cirrhosis leading to liver transplant and hepatocellular carcinoma in the United States. Approximately 3.2 to 4 million individuals have chronic HCV. It is estimated that between 17,000-20,000 become infected yearly. While the prevalence of infection has decreased significantly since the discovery of hepatitis C as a single-stranded RNA virus in 1989 (leading to screening of the blood supply and transplant donors beginning in 1992), the majority of existing cases derive from the prior period of blood product or tissue exposure before testing was
available. Each year an estimated 12,000 people die from HCV infection in the US.
 
In the past decade, the combination of pegylated interferon alpha and ribavirin became the standard of care with almost 50% (for genotype 1) achieving sustained virologic response (SVR) despite high rates of adverse effects including increased levels of depression, fatigue, neutropenia, anemia, and thrombocytopenia. Long term follow up studies documented marked improvement in disease-specific and overall survival as well as reduced progression to cirrhosis, liver transplant, and hepatocellular carcinoma for those fortunate to complete 48 weeks of therapy and achieve a durable SVR.
 
Evaluation for advanced fibrosis is necessary in all persons with HCV to facilitate an appropriate decision regarding HCV treatment and determine the need for additional screening measures (e.g. hepatocellular carcinoma screening). Additionally, other interventions aimed at reducing progression of disease and preventing repeated infection and/or transmission are essential:
 
· Abstinence from alcohol and/or alcohol cessation measures
· Evaluation for co-infection with HIV and/or HBV that may accelerate liver fibrosis Vaccination
against hepatitis A and B when appropriate
· Counseling and education to avoid transmission or re-infection
 
Daclatasvir (Daclinza™) is an HCV NS5A inhibitor approved by the U.S. Food and Drug Administration in July 2015 for use with sofosbuvir for the treatment of chronic HCV genotype 3 infection.

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of daclatasvir in combination with sofosbuvir meets member benefit certificate primary coverage criteria and is covered for treatment naïve or treatment experienced* chronic hepatitis C virus, genotype 3 without evidence of cirrhosis provided the following general coverage criteria (below) are met and none of the contraindications (below) exist.
 
Approved Treatment Regimen(s):
    • GT3 treatment naïve or treatment experienced* without cirrhosis:  12 weeks of sofosbuvir (400mg/day) and daclatasvir (60mg)   
 
    • GT3 treatment naïve or treatment experienced* with cirrhosis: 12 weeks of sofosbuvir plus daclatasvir +/- ribavirin  (Effective April 2016)
 
*treatment experienced is defined as a failure of or relapse from completed courses of therapy with either peginterferon alpha + ribavirin or HCV protease inhibitor (telaprevir, boceprevir, or simeprevir) + peginterferon alpha + ribavirinNOTE: For treatment of GT 3 Chronic HCV with cirrhosis, see policy #2014006 for sofosbuvir
 
GENERAL COVERAGE CRITERIA
    • The individual is >18 y/o; AND  
    • The patient does not have a history of illicit drug use (IV or intranasal) in the past 6 months with a negative drug screen before treatment is started, (if history of illicit drug use has been identified); AND
    • If the patient has a history of alcoholism the provider must document that the patient has been abstinent from alcohol intake for the past six months; AND
    • Patient has attended a documented medical care visit with the treating clinician to discuss the benefits and risks of antiviral therapy, the importance of adherence to treatment, and the risk factors for fibrosis progression; AND  
    • There is evidence of HCV RNA viral load within 6 months of treatment request; AND  
    • There is established infection with genotype 3; AND  
    • There is established evidence of compensated liver disease (METAVIR score of F2- F3) as measured by a liver biopsy greater than or equal to METAVIR score of F2. In absence of a liver biopsy, the following combinations of surrogate markers may be considered when making a coverage decision:
        • APRI (requires AST level and platelet count)
        • Abdominal imaging with findings suggestive of cirrhosis (e.g., nodules, ascites, portal hypertension)
        • Documentation of varices;
        • FIB 4 (requires AST level and platelet count )
        • Splenomegaly greater than 13 cm ; AND
    • There has been no previous use of sofosbuvir or Viekira for the treatment of the patient.  
 
CONTRAINDICATIONS
Documentation of ANY of the following contraindications would exclude coverage for the combination treatment of daclatasvir and sofosbuvir for any indication addressed:
    • The patient is pregnant.  
    • Decompensated liver disease (e.g. CPT >12 or MELD >20).
    • Creatinine clearance (CrCL), <30 mL/Min or on hemodialysis.
    • Severe end organ disease (e.g. heart, lung, renal) and not eligible for liver transplant (e.g. liver, heart, lung
    • Use of drugs with contraindications to concomitant daclatasvir use [ drugs that induce CYP3A including Anticonvulsants (phenytoin, carbamazepine) Antimycobacterial agents (rifampin) Herbal products (St. John’s wort) or sofosbuvir use (tenofovir, amiodarone, etc).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of daclatasvir as a single agent or in combination with other Direct Antiviral Agents does not meet primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the use of daclatasvir as a single agent or in combination with other Direct Antiviral Agents is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The use of daclatasvir in the treatment of chronic hepatitis C genotype 3 infection, with cirrhosis does not meet primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the use of daclatasvir in the treatment of chronic hepatitis C genotype 3 infection, with cirrhosis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The use of daclatasvir in the treatment of any other disease or chronic hepatitis C in any other circumstance does not meet primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, the use of daclatasvir in the treatment of any other disease or chronic hepatitis C in any other circumstance is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
The efficacy and safety of DAKLINZA in combination with sofosbuvir were evaluated in the phase 3 ALLY-3 clinical trial (Nelson, 2015). This phase III open-label trial included 152 subjects with chronic HCV genotype 3 infection and compensated liver disease who were treatment-naive (n=101) or treatment-experienced (n=51). Most treatment-experienced subjects had failed prior treatment with peginterferon/ribavirin, but 7 subjects had been treated previously
with a sofosbuvir regimen and 2 subjects with a regimen containing an investigational cyclophilin inhibitor.  Subjects received daclataasvir 60 mg plus sofosbuvir 400 mg once daily for 12 weeks and were monitored for 24 weeks post treatment. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. The authors concluded, “A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated” (Nelson, 2015).
 
April 2016 Update
AASLD gives a class IIa, Level B recommendation for sofosbuvir plus daclatasvir with or without ribavirin for treatment-naïve patients with HCV genotype 3 in patients with cirrhosis. The recommendation gives a treatment duration of 24 weeks. However, according to the guideline, “The exact duration of therapy for a treatment-naïve genotype 3 patient with compensated cirrhosis is not known” (AASLD-IDSA, 2016). The phase III study, ALLY3-+, investigated the combination of daclatasvir plus sofosbuvir and ribavirin for 12 weeks or 16 weeks in treatment-naïve and -experienced genotype 3 patients with both stage 3 and compensated cirrhosis. The study did not show a strong impact on SVR12 when extending the duration from 12 weeks (88% achieved SVR) to 16 weeks (89% achieved SVR). All patients (N=14) with stage 3 disease achieved SVR12 irrespective of treatment duration. (Leroy, 2016).
 
The policy statement has been changed to include a regimen of sofosbuvir plus daclatasvir with or without ribavirin for treatment-naïve patients with HCV genotype 3 for a total of 12 weeks. It should be noted that the AASLD recommendations give a Class I, Level A recommendation for sofosbuvir plus ribavirin plus peginterferon for 12 weeks (AASLD-IDSA, 2016).
 
2018 Update
A literature search conducted through April 2018 did not reveal any new information that would prompt a change in the coverage statement.  

CPT/HCPCS:
J8499Prescription drug, oral, nonchemotherapeutic, NOS

References: AASLD-IDSA.(2016) Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. April 2016. Last accessed April 27, 2016.

Daklinza. Prescribing Information. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206843Orig1s000lbl.pdf. Last accessed August 26, 2015.

Leroy V, Angus P, Bronowicki JP, et al.(2016) Daclatasvir, Sofosbuvir, and Ribavirin for Hepatitis C Virus Genotype 3 and Advanced Liver Disease: A Randomized Phase III Study (ALLY-3+). Hepatol. 2016; DOI:10.1002/hep.28473. [Epub ahead of print]

Nelson DR, Cooper JN, Lalezari JP et al.(2015) All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015 Apr;61(4):1127-35. doi: 10.1002/hep.27726. Epub 2015 Mar 10


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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