Coverage Policy Manual
Policy #: 2017037
Category: Pharmacy
Initiated: December 2017
Last Review: May 2018
  Direct Acting Antiviral Medications for Treatment of Chronic Hepatitis C

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.
 
HCV is primarily transmitted through percutaneous exposure to blood. Other modes of transmission include mother-to-infant and contaminated devices shared for non-injection drug use; sexual transmission also occurs but generally seems to be inefficient except among HIV-infected men who have unprotected sex with men. The most important risk for HCV infection is injection drug use, accounting for at least 60% of acute HCV infections in the United States. Healthcare exposures are important sources of transmission, including the receipt of blood products before 1992 (after which routine screening of blood supply was implemented), receipt of clotting factor concentrates before 1987, long-term hemodialysis, needlestick injuries among healthcare workers, and patient-to-patient transmission resulting from poor infection control practices. Other risk factors include having been born to an HCV-infected mother, having been incarcerated, and percutaneous or parenteral exposures in an unregulated setting: examples are tattoos received outside of licensed parlors and medical procedures done internationally or domestically where strict infection control procedure may not have been followed (eg surgery before the implementation of universal precautions.
 
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
Direct acting antiviral (DAA) medications for hepatitis C specifically target proteins involved in the hepatitis C virus (HCV) life cycle, and thus disrupt viral replication. There are a number of DAAs that are currently U.S. Food and Drug Administration (FDA)‒approved and numerous other agents are in development. In patients with chronic hepatitis C, these medications offer the potential to improve cure rates with lower toxicity compared with treatment regimens that do not include DAAs.
 
The availability of DAAs represents a major advancement in the treatment of hepatitis C, with the potential to dramatically improve cure rates with less toxicity compared with standard treatment without DAAs. All of the DAAs that are currently FDA-approved have demonstrated treatment responses that are superior to standard care consisting of interferon and ribavirin. Direct comparisons of the different agents are lacking, but differences in treatment response and adverse effects (AEs) are reported. The first generation protease inhibitors, boceprevir and telaprevir, have response rates in the 60% to 80% range and a relatively high incidence of serious adverse effects (SAEs).  The second-generation protease inhibitor, simeprevir offers an improved risk/benefit ratio, and treatment with the RNA polymerase inhibitor sofosbuvir has resulted in higher response rates and less toxicity than any of the other available agents.
 
There is no direct evidence on immediate versus delayed treatment, but based on the natural history of the disease, it is reasonable to conclude that some patients can have treatment delayed without suffering adverse outcomes. These are generally patients with no fibrosis or early fibrosis. Outcomes will not be adversely impacted if these patients have close monitoring and if treatment is instituted before the onset of irreversible liver damage. For patients with more advanced disease, immediate treatment should be given to avoid progression of irreversible liver damage. Other patients who should be treated without delay include patients with serious extrahepatic manifestations of hepatitis C and patients with hepatocellular carcinoma (HCC) awaiting transplant.

Policy/
Coverage:
Meets Primary Coverage Criteria or Is Covered For Contracts Without Primary Coverage Criteria
 
The use of DAA’s [including combinations specific for genotype] meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the treatment of chronic hepatitis C as evidence by HCV RNA >25 IU/ml within 6 months of treatment request with the following conditions:
    • Hepatocellular carcinoma when the member is a candidate for liver transplant (Milan criteria are met); OR  
    • Co-infection with HIV or HBV (criteria as specified below); OR  
    • Extrahepatic manifestations (criteria as specified below); OR   
    • Post liver transplant (criteria as specified below); OR
    • Hemochromatosis by genetic testing (Documented genetic testing results need to be submitted).
 
Requests for exceptions to allow DAA treatment regimens require clear documentation that ALL of the following General Coverage Criteria are met and that NONE of the Contraindications outlined below are present.  For treatment of extrahepatic manifestations and post liver transplant, additional criteria as outlined below must be met.  
 
GENERAL COVERAGE CRITERIA
    1. > 12 yrs of age for the use of SOF+LDV for GT 1, 4 and 6.  All other GT and treatment regimens are for age > 18 yrs of age.
[All documentation should be submitted with treatment regimen request, as this may be relevant to the choice of the best treatment regimen and to the prevention of the possible need for retreatment.]
 
Provider must submit written documentation of ALL of the following:
2. A  medical care visit with the treating clinician to discuss  1) the risk factors for contraction of HCV, 2) the risk factors for fibrosis progression including a discussion of the benefits and risks of antiviral therapy, 3) the importance of adherence to treatment, and 4) counseling about the  means and prevention of transmission;  AND
3. Any history of IV or intranasal drug use (to include what drug and when last used) OR no history of prior drug use.  If a history of illicit drug use (IV or intranasal) has been identified, the following criteria must be met:
      • Documentation of a history of abstinence. The patient must have been abstinent from illicit drug use for the past 6 months. Medical records must indicate that patient has been free of illicit drug use and a negative drug screen is documented prior to start of treatment; OR
      • If the patient has been abstinent from illicit drug use less than 6 months but at least 3 months,      documentation of attendance in an approved drug rehabilitation program and a documented negative drug screen prior to start of treatment is required.
4. History of alcohol use OR of no prior history of alcohol use.  If the patient has a history of, or current alcohol use disorder, the provider must document:  
      • If there is current use: Amount and frequency
      • If there is a history of abuse, submit documentation of the following:
        • When patient stopped using alcohol, and  
        • That the patient has been abstinent from alcohol intake for the past six months, and submit a negative alcohol level; OR
        • That patient has been abstinent for 3 months with documentation of participation in an approved alcoholic rehabilitation program, and submit a negative alcohol level.  
5. Lab reports for the following tests performed within 6 months of treatment request:
      • HCV RNA viral load, liver function tests (LFTs), PT/INR, CBC (with platelet count), and HBV DAA
      • Genotype (1, 2, 3, 4, 5, or 6)  to show established infection
6. Current medication list.  
7. The degree of hepatic fibrosis/cirrhosis, if any, has been established by:  
      • Elastography (with measurement results submitted)  OR  
      • APRI (requires AST level and platelet count)  AND Fib-4 (Requires AST level, ALT level and platelet count);  OR
      • Liver biopsy (Need copy of  pathology report)
8. Indirect evidence of portal hypertension or findings suggestive of cirrhosis such as abdominal imaging (i.e. US; MRI; EGD) demonstrating:
      • Varices
      • Splenomegaly (>13 cm)
      • Ascites
      • Nodules
9. Any previous attempt(s) at treatment including:
      • Previous treatment regimen and duration of treatment
      • Response to treatment as shown by SVR 12 or SVR 24 (Lab results required) AND
      • Confirmation from provider/case manager there was adherence to the treatment regimen.
      • Current information and labs including genotype (GT) as outlined above.
 
PRIOR TO PROVIDING THE MEDICATION, the following is needed:
    • Confirmation by an ABCBS case manager that the member is:  aware of the prescribed regimen, is able to receive delivery of the prescribed regimen, will adhere to the prescribed regimen, and will have confirmation of viral clearance by SVR at 12-24 weeks post completion of treatment.  The pt will agree to be contacted by the case manager and provide a means by which they can be contacted.  
    • If the patient is on a PPI (i.e. omeprazole, pantoprazole), there must be a documented plan in the records to discontinue PPI use for the duration of treatment, unless evidence is provided to support continued use.  
 
ADDITIONAL INFORMATION (testing and additional evaluation)
  • Initial drug resistance testing (GT 1 NS5a or GT 3 analysis) is considered necessary only in select situations, (i.e. the use of elbasvir/grazoprevir).  Otherwise, drug resistance testing in the initial treatment will be denied as not meeting primary coverage criteria.
  • FibroSure, FibroTest, FibroSpect and other tests of this nature are denied as not meeting primary coverage criteria as there are other tests that are less costly alternatives (APRI, FIB-4).
  •  For members with high levels of complexity, high risk of hepatic decompensation, and/or high risk of problems with adherence, ABCBS may require evaluation by a transplant hepatologist prior to treatment.
 
CONTRAINDICATIONS
 
Documentation of ANY of the following contraindications would exclude coverage for DAA treatment for any indication addressed:
    • The patient is pregnant.
    • Creatinine clearance (CrCL), <30 mL/Min or on hemodialysis.
    • Use of drugs with contraindications to concomitant sofosbuvir use (tenofovir, amiodarone, etc)
    • Terminal diagnosis with life expectancy < 12 months
 
ADDITIONAL INDICATIONS
 
I. Extrahepatic Manifestations
The use of DAA’s for the treatment of extrahepatic HCV meets member benefit certificate primary coverage criteria when ALL of the general coverage criteria are met and NONE of the Contraindications are present for individuals with serious symptomatic cryoglobulinemia diagnosed with one of the following:
    • Cryoglobulinemia (i.e., positive cryoglobulin level), cryoglobulinemic glomerulonephritis (e.g. Membranoproliferative glomerulonephritis), cryoglobulinemic vasculitis (e.g., leukocytoclastic vasculitis); OR
    • HCV associated B Cell NHL; OR
    • Type 2 or Type 3 essential mixed cryoglobulinemia with end organ manifestations.
 
II. Post Liver Transplant
The use of sofosbuvir as a component of combination therapy, with treatment regimen specific for Genotype, post liver transplant for end-stage liver disease due to HCV meets member benefit certificate primary coverage criteria when ALL of the general coverage criteria are met, NONE of the Contraindications are present and the following additional criteria are met:
    • Genotype; AND
    • Positive hepatitis C viral load;  
 
TREATMENT REGIMENS
 
  1. Sofosbuvir/Velpatasvir (SOF/VPR) - Epclusa    
 
Genotype 1, 2, 3, 4, 5 or 6 (treatment naïve or experienced)
      • With compensated cirrhosis (Child-Pugh A)  or without cirrhosis SOF/VPR X 12 weeks
      • With decompensated cirrhosis (Child-Pugh B and C) SOF/VPR/RBV x 12 weeks
 
*EXCEPTION:  a patient with genotype 1, treatment naïve, non-cirrhotic and viral load <6million, would reflex to SOF + LDV x 8 weeks (see SOF+LDV).
 
2. Sofosbuvir/Ledipasvir (SOF+LDV) - Harvoni  
 
Genotype 1
 
1.  Treatment Naïve, viral load <6,000,000 IU/ML
        • Without cirrhosis SOF+LDV x 8 weeks
 
The use of SOF + LDV x 12 weeks will be by exception only.  Documentation must show why
SOF + VPR should not be used.  
  
2. Treatment Naïve, viral load >6,000,000 IU/ML
        • Without cirrhosis SOF+LDV X 12 weeks  
        • Compensated Cirrhosis SOF+LDV +/- RBV  X 12 weeks
        • Liver transplant recipients without cirrhosis, or with compensated cirrhosis
SOF+LDV + RBV 12 weeks
 
3. Treatment Experienced
        • Without cirrhosis SOF+LDV X 12 weeks
        • With compensated cirrhosis SOF+LDV + RBV X 12 weeks  
        • Liver transplant recipients without cirrhosis or with compensated cirrhosis
SOF+LDV + RBV 12 weeks
 
Genotype 4 and 6
 
1. Treatment Naïve
        • Without cirrhosis SOF+LDV X 12 weeks  
        • With compensated Cirrhosis SOF+LDV +/- RBV  X 12 weeks
        • Liver transplant recipients without cirrhosis, or with compensated cirrhosis
       SOF+LDV + RBV 12 weeks
 
2. Treatment Experienced
        • Without cirrhosis SOF+LDV X 12 weeks
        • With compensated cirrhosis SOF+LDV /RBV X 12 weeks  
        • Liver transplant recipients without cirrhosis or with compensated cirrhosis   
SOF+LDV +RBV 12 weeks  
 
3. Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VPR/VOX) - Vosevi
 
GT 1, 2, 3, 4, 5 or 6  
        • Treatment experienced with an NS5A inhibitor (ledipasvir; velpatasvir; ombitasvir; daclatasvir; elbasvir), without cirrhosis or with compensated cirrhosis (Child-Pugh A)  SOF/VPR/VOX x 12 weeks
 
GT 1a or 3
        • Treatment experienced with sofosbuvir without an NS5A inhibitor Includes sofosbuvir with or without any of the following: peginterferon alfa/ribavirin, ribavirin, HCV NS3/4A protease inhibitor (boceprevir, simeprevir, or telaprevir) without cirrhosis or with compensated cirrhosis (Child-Pugh A) SOF/VPR/VOX x 12 weeks
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
I. Sofosbuvir as a Single agent or with other Direct Antiviral Agent(s)
 
The use of sofosbuvir as a single agent or in combination with ribavirin alone does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For members with contracts without primary coverage criteria, the use of sofosbuvir as a single agent or in combination with ribavirin alone is considered not medically necessary. Services that are not medically necessary are specific contract exclusions in most member benefit certificates of coverage.
 
II. Sofosbuvir in Combination with Simeprevir
 
The use of sofosbuvir in combination with simeprevir in the treatment of any disease does not meet member benefit certificate primary coverage criteria because there is a lack of data indicating this treatment regimen is more effective than other less costly treatment regimens. For members with contracts without primary coverage criteria, this use is considered not medically necessary. Services that are considered not medically necessary are specific contract exclusions in most member benefit certificates of coverage.
 
III. Sofosbuvir for Other Diseases or Indications
 
The use of sofosbuvir in the treatment of any other disease or chronic hepatitis C in any other circumstance does not meet primary coverage criteria. For members with contracts without primary coverage criteria, the use of sofosbuvir 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
 
DEFINITIONS
 
Child Pugh Classification Parameters
 
Points Assigned           1 point                             2 points                             3 points
Encephalopathy             None                               Minimal                            Advanced coma
Ascites                          None                               Easily controlled               Poorly controlled
Serum Bilirubin              less than2mg/Dl               2-3 mg/dL                         greater than 3 mg/dL
Serum Albumin              greater than 3.5 g/dL        2.8-3.5 g/dL                       less than 2.8 g/dL
INR                                Less than 1.7                  1.7-2.3                               greater than 2.3
 
Child Pugh Score Interpretation
Class A                 5-6 points                  Well compensated liver disease
Class B                 7-9 points                  Significant functional compromise
Class C                 10-15 points               Uncompensated liver disease
 
MILAN Criteria are defined as follow:
 
        • Tumor size 5cm or less in diameter with single hepatocellular carcinomas OR
        • 3 tumor nodules or less, each 3cm or less in diameter with multiple tumors AND
No extrahepatic manifestations of the cancer or evidence of vascular invasion of tumor.
 
 

Rationale:
Sofosbuvir (Sovaldi)
Evidence for the safety and efficacy of sofosbuvir comes from 6 phase 3 studies (4 published, 2 available as abstract or in FDA documents), with supporting documentation from 4 phase 2 studies. Four phase 3 trials (POSITRON [Jacobson, 2013], FUSION [Jacobson, 2013], FISSION [Lawitz, 2013],  VALENCE [Lawitz, 2013]) were randomized, one (NEUTRINO)[Zeuzem, 2013] was a single-arm study, and one (PHOTON-1) was a 3-arm uncontrolled study. In all phase 3 studies, sofosbuvir was dosed at 400 mg orally once daily.  The POSITRON, FUSION, FISSION, VALENCE, and PHOTON-1 trials evaluated 12- to 24-week all oral, IFN-free treatment regimens (ie, sofosbuvir plus RBV). Dose and regimen selections were based on findings from phase 2 trials. Although the VALENCE trial was intended to be a placebo-controlled randomized trial, emerging efficacy data led the investigators to terminate the placebo arm and a 12-week treatment arm for genotype 3, and therefore the analysis is that of 2 prospective cohorts (patients with genotype 2 and patients with genotype 3).
 
    • The POSITRON, FUSION, and FISSION and VALENCE trials enrolled adults (≥18 years of age) with chronic (>6 months) HCV-2 or -3 infection. In each trial, 20% to 60% of patients could have compensated cirrhosis. Patients with HBV and/or HIV coinfection were excluded. The primary efficacy outcome was SVR at 12 weeks (SVR12) after the end of treatment.
    • POSITRON (N=280) [Jacobson, 2013] compared an all oral, IFN-free regimen with placebo in patients who were unwilling (47%) or unable (due to comorbidities or intolerance to previous IFN, 52%) to take IFN.  Patients were randomized 3:1 to sofosbuvir plus RBV 1000 mg or 1200 mg (weight-based dosing) orally daily (n=207) or placebo plus RBV (n=71) for 12 weeks. Mean patient age was 52 years, 46% were female, 91% were white, and 5% were black. Rate of SVR12 was 78% in the sofosbuvir group and 0% in the placebo group, a statistically significant difference (p<0.001).
    • FUSION (N=202) [Jacobson, 2013] compared 2 different treatment durations of an IFN-free regimen in previous nonresponders with IFN-based therapy (25% null response, 75% breakthrough or relapse).  Patients were randomized 1:1 to sofosbuvir plus RBV (weight-based dosing) for 12 weeks (n=103) or 16 weeks (n=98). Mean patient age was 54, 30% were female, 87% were white, and 3% were black. Rate of SVR12 was 50% in the 12-week group and 73% in the 16-week group, a statistically significant difference (p<0.001).
    • FISSION (N=527) [Lawitz, 2013] was a noninferiority trial that compared an IFN-free regimen with PegIFN/RBV therapy in treatment-naive patients. Patients were randomized 1:1 to sofosbuvir plus RBV (weight-based dosing) for 12 weeks (n=256) or PegIFN 180 mg subcutaneously weekly plus RBV 800 mg orally daily for 24 weeks (n=264). This is the FDA-approved dose for patients who weigh less than 65 kg; it is unclear whether different RBV dosing between treatment arms introduced potential bias. Mean patient age was 48 years, 35% were female, 87% were white, and 4% were black. Rate of SVR12 was 67% in both groups. The lower limit of the 95% CI for the between-group difference (0.3 percentage points; 95% CI, -7.5 to 8.0) exceeded the noninferiority margin of -15 percentage points (p<0.001 for noninferiority).
    • VALENCE (N=419) [Lawitz, 2013]  was conducted in Europe and was originally a randomized placebo-controlled trial that compared sofosbuvir plus RBV with placebo in patients with genotypes 2 or 3 who were treatment-naive or -experienced. Randomization was 4:1 to receive sofosbuvir plus RBV (weight-based dosing; n=334) or placebo (n=85) for 12 weeks. However, protocol amendments included abandoning the placebo arm and changing the genotype 3 treatment from 12 to 24 weeks. The mean patient age was 50 years, 40% were female, and 93% were white.  Fifty-eight percent of patients were treatment experienced. Of these, 29% were prior nonresponders, 65% had a prior relapse, and 5% were intolerant to IFN. The SVR12 rates were 93% and 85% among patients with genotype 2 and genotype 3, respectively.
 
NEUTRINO (N=327) [Zeuzem, 2013] was a single-arm, open-label study that assessed 12 weeks of sofosbuvir triple therapy (ie, in combination with PegIFN and RBV [weight-based dosing]) in treatment-naive adults with chronic HCV-1 (n=292), -4 (n=28), -5 (n=1), or -6 (n=6) infection. Mean patient age was 52 years, 36% were female, 79% were white, and 17% were black. SVR12 rates were 90% overall; 89% in patients with HCV-1; and 97% in patients with HCV-4, -5, and -6. As in the randomized trials, SVR12 was lower in patients with cirrhosis (80% vs 92%; stratified analysis) and in patients with a non-CC IL28B genotype (87% vs 98%; prespecified subgroup analysis).
 
In addition to the primary outcome of SVR, the POSITRON, FUSION, FISSION, NEUTRINO, and VALENCE studies included health-related quality of life (HRQOL) assessments as exploratory end points (Gilead, 2013). Four self-administered patient-reported outcome (PRO) assessments were administered before during and after treatment interventions in the phase 3 program of sofosbuvir. They included the 36-Item Short-Form Health Survey (SF-36), the Functional Assessment of Chronic Illness Therapy‒Fatigue, the Chronic Liver Disease Questionnaire‒HCV Version, and Work Productivity and Activity Impairment score. No responder analyses (using minimum clinically important differences [MCID]) were presented. Additionally, because the trials could not be pooled due to the various comparator groups, and because the few flashes of group mean change from baseline in 1 or more subscales of the PRO instruments could not be differentiated from true change due to multiple comparisons, the analyses were useful only for general conclusions. The authors concluded that:
 
    • Treatment with sofosbuvir/RBV had little effect on patients’ HRQOL, as measured by the SF-36. Group means were lower at the end of treatment for all treatment arms, but returned to baseline by the end of follow-up.
    • There was minimal effect with sofosbuvir/RBV treatment compared with placebo in the POSITRON study. Group mean change from baseline was less than the MCID for SF-36 Physical Component Summary (PCS) and was 3.77 (MCID range, 2-5) for Mental Component Summary (MCS). Although a difference of 3.77 is consistent with the MCID for this instrument, this change was not statistically different.
    • Sofosbuvir treatment was associated with less impact on HRQOL compared with PegIFN/RBV treatment in the FISSON study. Both groups had lower HRQOL at the end of treatment than at baseline, but the decrement was greater for the IFN-treated patients than the IFN-free patients. The between-group difference in mean change from baseline was 4.46 for PCS and 3.96 for MCS scores of the SF-36 (MCID range, 2-5). Both PCS and MCS scores were statistically different as well (p<0.001 and p=0.012, respectively).
    • Extension of treatment to 16 weeks had no negative impact on HRQOL (group mean change from baseline was less than the MCID for both PCS and MCS).
 
Safety
Of 1470 patients who received sofosbuvir 400 mg daily in phase 2 and phase 3 studies, 99% also received RBV and 51% received PegIFN. The most commonly reported AEs were consistent with those associated with RBV and PegIFN: fatigue (41% in sofosbuvir-RBV groups vs 24% placebo-RBV), headache (25% vs 20%), and nausea (20% vs 18%). In phase 3 studies, treatment discontinuations due to AEs were most common in the 24-week PegIFN/RBV group (11% vs 0%-2% in sofosbuvir-RBV groups).
 
SAEs occurred in 5% of patients in the 12-week sofosbuvir groups in POSITRON and FUSION; the most commonly occurring SAE was malignant hepatic neoplasm in 3 patients (3%) in FUSION. Common AEs occurred with approximately similar frequency across the 4 sofosbuvir-RBV groups, less commonly in the placebo-RBV group (in POSITRON), and generally more commonly in the PegIFN groups.
 
In phase 3 studies, the incidence of anemia was higher among patients receiving sofosbuvir-RBV than among patients receiving placebo-RBV (9% vs 0%). Eight percent of sofosbuvir-RBV-treated patients had hemoglobin levels less than 10 mg/dL, and 0.8% had levels less than 8.5 mg/dL. All hematologic adverse  effects (anemia, lymphopenia, neutropenia, thrombocytopenia) occurred more commonly in patients who received PegIFN.
 
Combination Medications
 
Sofosbuvir-Ledipasvir
Pivotal trials of the sofosbuvir-ledipasvir combination include ION-134 and ION-335 in treatment-naive
adults and ION-234 in previously treated patients with HCV-1 infection. All 3 trials have been published in
a peer-reviewed journal. The primary efficacy outcome in all 3 trials was SVR at 12 weeks.
 
  • Overall, the 3 phase 3 trials included 1952 patients, 97% of whom achieved a SVR12. Among the 3% who did not have a response, almost half were lost to follow-up or withdrew consent. Two of 1952 patients had detectable levels of HCV RNA that was maintained during treatment  on-treatment virologic failure) and both patients were nonadherent to therapy as shown by lower than expected drug metabolite levels during treatment period. Furthermore, the relapse rate after stopping therapy was 2%. Relapses were more common with shorter courses of treatment: 5% among those who received 8 weeks; 2% among those who received 12 weeks, and 0.2% among those who received 24 weeks.
  • In terms of individual analyses of the trials, in both the ION-1 and ION-2 trials, addition of RBV to the sofosbuvir-ledipasvir combination or extension of treatment from 12 to 24 weeks did not result in substantial additional benefit in SVR. Therefore, Gilead Sciences’s regulatory filings sought an 8-week, RBV-free regimen with sofosbuvir-ledipasvir for treatment-naive patients and a 12-week, RBV-free regimen with sofosbuvir-ledipasvir for patients with cirrhosis and those who had failed prior treatment (including previous protease inhibitor-based therapies).
  • Among treatment-naive patients, SVR12 rates were 94%, 99% and 98% with the 8-, 12-, and 24- week sofosbuvir-ledipasvir combination. SVR rates were similar between cirrhotics (97%) and noncirrhotics (100%).
 
Safety
Because there were no control groups in any of the ION-trials, it is difficult to judge whether AEs were caused by the drug or disease. The following conclusions about AEs in these trials can be made:
    • Most patients in all the 3 ION trials reported at least 1 AE. Most were mild to moderate in severity Fatigue and headache were the 2 most common AEs across all treatment arms in all 3 ION trials.The incidence of fatigue was consistently higher in groups that received the medication containing RBV versus the RBV-free regimen. The addition of IFN is known to exacerbate fatigue.
    • The overall treatment discontinuation rates due to AEs in the ION-1, ION-2, and ION-3 trials were low; 1% (10/865), 0%, and less than 1% (3/647), respectively. By comparison, treatment discontinuation rates in the pivotal NEUTRINO trial31 of sofosbuvir plus PegIFN/RBV for 12 weeks was 2% (5/327).
    • The overall incidence of SAEs in the ION-1, -2, and -3 trials were 4% (33/865), 2% (9/440), and 2% (10/647), respectively. See the Safety subsection for a full description of SAEs.
    • In the ION-1 study, none of the patients who received the RBV-free regimen reported anemia while 10% to 12% of those receiving the regimen with RBV reported anemia. A similar trend was reported in ION-2 and -3. The incidence of anemia in patients receiving regimen with RBV was 8% to 11% in ION-2 and 8% in ION-3, while 1% patients who received the RBV-free regimen also reported anemia in ION-2 and -3.
    •  
For the AbbVie regimen, pivotal trials include 3 trials that included RBV as part of therapy (SAPPHIRE-I, SAPPHIRE-II, TURQUOISE-II) and 3 that compared the regimen with or without RBV (PEARL trials). The SAPPHIRE-I36 and -II37 studies were randomized, historical control trials of the AOD regimen plus RBV for 12 weeks in treatment-naive (SAPPHIRE-I) and treatment-experienced (SAPPHIRE-II) patients with HCV- 1 infection and no cirrhosis. TURQUOISE-II38 was the only pivotal trial of the 6 to enroll patients with compensated cirrhosis (either previously treated or untreated HCV-1) and compared open-label AOD plus RBV for 12 weeks versus 24 weeks. The PEARL trials all compared open-label AOD with or without RBV for 12 weeks and included previously treated patients with genotype 1b patients with previously untreated HCV-1b, or previously untreated patients with HCV-1a (PEARL-IV).39 The primary efficacy outcome for all 6 trials was SVR at 12 weeks.
 
    • Overall rates of SVR12 in the trials of AOD with RBV were approximately 95% and ranged from 92% (in cirrhotic patients receiving AOD plus RBV for 12 weeks in TURQUOISE-II) to 96% in the other arms of the other trials. These rates were superior to the historical control rates for each study.
    • Overall rates of SVR12 were also high (>90%) in the PEARL trials of AOD regimen with or without RBV, ranging from 90% in patients with HCV-1a treated without RBV in PEARL-IV to 100% in patients with previously treated HCV-1b treated without RBV in PEARL-II.
    • Relapse rates in the AOD plus RBV trials were generally low (ie, 1%-2%) with the exception of the 12-week arm of the TURQUOISE-II trial in cirrhotic patients (6%). Patients treated with 24 weeks of therapy in the TURQUOISE-II trial had a relapse rate of 0.6%.
    • Relapse rates in the PEARL trials (with or without RBV) were very low (ie, 0%-1%) with the exception of the PEARL-IV (GT-1a) trial arm that did not receive RBV (10/194 [5.2%]).
    • Virologic  failure rates in the AOD plus RBV trials were less than 2% and less than 3% in the trials with or without RBV.
 
Safety
Most patients across all arms of the 6 pivotal trials experienced at least 1 AE. The most common AEs across all trials were fatigue, nausea, pruritus, insomnia, diarrhea, and asthenia. Overall rates of SAEs across all 6 trials were low (≤3%). In TURQUOISE-II (patients with compensated cirrhosis), grade 3 or 4 elevations in the total bilirubin level occurred in approximately 10% of patients; however, this did not lead to discontinuation, peaked after 2 weeks of treatment, and resolved to baseline following treatment.
 
Rates  of treatment discontinuation across all arms of the AOD trials with RBV were low (ie, <2%). The rate of discontinuation in the PEARL-II trial was 2% in the arm receiving RBV and none in the arm receiving AOD alone. In the article reporting both the PEARL-III and IV trials, the only treatment discontinuations noted were 2 patients in the PEARL-IV (HCV-1a) study.
 
In SAPPHIRE-I, reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients receiving active treatment, while grade 1 reductions occurred in 2.5% of the patients receiving placebo. In SAPPHIRE-II, hemoglobin values of grade 2 and grade 3 occurred in 4.7% and 0.3% of patients in the active regimen group, respectively, versus 0% in the placebo arm. In the PEARL-III and -IV trials, hemoglobin less than the lower limit of normal occurred in 51% and 42% of the patients in the RBV arms, respectively, versus 3.4 and 3.9% of the AOD therapy-alone arms, respectively. Hemoglobin 10 g/dL or less occurred in 9% and 4% of the RBV arms of these trials, respectively, versus 0% in the RBV-free arms.
 
Kowdley, Sundaram, et al, (Hepatology 2017) evaluated the effectiveness of 8 weeks therapy of LDV/SOF and used individual patient data from the IFI (Institut für Interdisziplinäre Medizin), Burman’s Pharmacy, and Kaiser Permanente Southern California.  A systematic review and meta-analysis of six additional real-world cohorts were performed to compare effectiveness of 8 weeks to 12 weeks duration.  The conclusion was that an 8 week duration of treatment with LDV/SOF is highly effective in properly selected patients and greater use of this regimen was recommended.
 
Sofosbuvir and Velpatasvir (Epclusa)
 AASLD guidelines (04/2017): Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the FDA for the treatment of HCV genotype 3 infection in patients with and without cirrhosis. ASTRAL-3 demonstrated superiority of 12 weeks of  sofosbuvir/velpatasvir to 24 weeks sofosbuvir plus ribavirin in 552 treatment-naive  and  -experienced subjects with and  without cirrhosis (Foster, 2015). In those with cirrhosis SVR12 was 93% (40/43) compared to 73% (33/45), respectively. Of the 250 subjects that received sofosbuvir/velpatasvir 43 (16%) had baseline NS5A RASs; of which 88% achieved SVR12 compared to 97% without baseline substitutions. 84% (21/25) with Y93H achieved SVR12. Pending further data on optimal therapy in the setting of baseline Y93 substitution, the addition of ribavirin for patients with cirrhosis is recommended.
 
Feld et al. (2015) reported on a phase 3 double-blind, placebo-controlled study (ASTRAL-1) involving untreated and previously treated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis. Patients with HCV genotype 1, 2, 4, or 6 were randomly assigned in a 5:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir in a once-daily, fixed-dose combination tablet or matching placebo for 12 weeks. Because of the low prevalence of genotype 5 in the study regions, patients with genotype 5 did not undergo randomization but were assigned to the sofosbuvir-velpatasvir group. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
 
The results showed that of the 624 patients who received treatment with sofosbuvir-velpatasvir, 34% had HCV genotype 1a, 19% genotype 1b, 17% genotype 2, 19% genotype 4, 6% genotype 5, and 7% genotype 6. A total of 8% of patients were black, 19% had cirrhosis, and 32% had been previously treated for HCV. The rate of sustained virologic response among patients receiving sofosbuvir-velpatasvir was 99% (95% confidence interval, 98 to >99). Two patients receiving sofosbuvir-velpatasvir, both with HCV genotype 1, had a virologic relapse. None of the 116 patients receiving placebo had a sustained virologic response. Serious adverse events were reported in 15 patients (2%) in the sofosbuvir-velpatasvir group and none in the placebo group.
 
The authors concluded that once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis.
 
Foster et al. (2015) reported on two randomized, phase 3, open-label studies (ASTRAL-2 and ASTRAL-3) involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy.
 
Results showed that among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia.
 
The authors concluded that among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin.
 
Curry et al (2015) reported on a phase 3, open-label study (ASTRAL-4) involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy.
The results showed that of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin.
 
The authors concluded that treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis.
 
 
Sofosbuvir+Velpatasvir+Voxilaprevir  (Vosevi)
Bourlière, et al. (2017) published the results of two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen.   Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.
In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir–velpatasvir–voxilaprevir (163 patients) or sofosbuvir–velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir–velpatasvir–voxilaprevir group.
In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir–velpatasvir–voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir–velpatasvir–voxilaprevir and 90% with sofosbuvir–velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.
The authors concluded that Sofosbuvir–velpatasvir–voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed.
 

CPT/HCPCS:
87902Infectious agent genotype analysis by nucleic acid (DNA or RNA); Hepatitis C virus
J8499Prescription drug, oral, nonchemotherapeutic, NOS

References: AASLD.(2017) HCV Guidelines. 2017. http://www.hcvguidelines.org/treatment-naive/gt3/compensated-cirrhosis

Afdhal N, Reddy KR, Nelson DR, et al.(2014) Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. Apr 17 2014;370(16):1483-1493. PMID 24725238.

Bourlière, Marc, Gordon, Stuart, Flamm, Steen, et.al.(2017) Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med 2017; 376:2134-2146.

Curry MP, O'Leary JG, Bzowej N, et al.(2015) Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med.2015 Dec 31;373(27):2618-28. PMID: 26569658.

Feld, JJ, Jacobson, IM, Hezode, C, et al.(2015) Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med 2015; 373:2599-2607.

Food and Drug Administration.(2013) Sofosbuvir For Treatment of Chronic Hepatitis C Infection.Gilead Sciences Briefing Document for Antiviral Drugs Advisory Committee Meeting, 25 October 2013 (NDA 204671). http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/antiviraldrugsadvisorycommittee/ucm371877.pdf.

Foster GR, Afdhal N, Roberts SK, et al.(2015) Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015 Dec 31;373(27):2608-17. PMID:26575258.

Jacobson IM, Gordon SC, Kowdley KV, et al.(2013) Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. May 16 2013;368(20):1867-1877. PMID 23607593

Kowdley K, Sundaram V, Jeon C, et al(2017) Eight Weeks of Ledipasvir/Sofosbuvir Is Effective for Selected Patients With Genotype 1 Hepatitis C Virus Infection. Hepatology, Vol 65, No. 4, 2017; 1094-1103

Lawitz E, Mangia A, Wyles D, et al.(2013) Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med. 2013;368:1878-1887.

Zeuzem S, Dusheiko GM, Salupere R, et al.(2013) Sofosbuvir + ribavirin for 12 or 24 weeks for patients with HCV genotype 2 or 3: the VALENCE trial. Hepatology. 2013;58(4):733A-734A.


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