DAA HCV Regimen effective in pts with cirrhosis

Posted on May 2, 2015

Interferon free, direct acting antiviral HCV regimen ledipasvir-sofosbuvir with and without ribavirin is effective and well tolerated in adult patients with HCV genotype 1 and cirrhosis who have failed previous HCV therapy

Chronically infected patients with cirrhosis, especially those who have failed previous hepatitis C therapy, achieve consistently lower rates of SVR than those without cirrhosis, in both clinical trials and real-world settings. Patients with HCV genotype 1-associated cirrhosis poorly tolerate interferon-based regimens, and many experience high rates of severe and serious adverse events that cause them to discontinue these regimens. Results of the SIRIUS trial, a randomized, double-blind, placebo-controlled, Phase 2 trial designed to assess the efficacy and safety of the interferon free, direct acting antiviral regimen ledipasvir-sofosbuvir with and without ribavirin in adult patients with HCV genotype 1 and cirrhosis who had failed previous therapy, were recently published in the March 13 issue of the journal Lancet (Bourlière M et al. Lancet Infect Dis. 2015;15: 397–404: available free in the specialist section of the AJM Hepatitis C Resource Center). This study was conducted between Oct 21, 2013, and Oct 30, 2014 at 20 sites in France.

  • Eligible patients had not achieved SVR after being treated first with peginterferon and ribavirin and then with a protease inhibitor plus peginterferon and ribavirin
  • Patients with evidence of decompensation (ie, clinical ascites, encephalopathy, or variceal hemorrhage) or hepatocellular carcinoma were excluded from this study
  • Most enrolled patients were men, white, infected with HCV genotype 1a, and had non-CC alleles of the IL28B gene.

Of 172 patients screened, 155 patients were randomly assigned to receive one of the following regimens:

  • 90 mg ledipasvir and 400 mg sofosbuvir in a fixed-dose combination tablet plus placebo for 12 weeks followed by ledipasvir-sofosbuvir once daily plus ribavirin given in a divided daily dose for 12 weeks (n = 77)
  • Once daily ledipasvir-sofosbuvir plus placebo for 24 weeks (n = 78)

All 155 patients experienced rapid reductions in HCV RNA concentrations after beginning treatment. SVR12 rates were 96% (95% CI 89–99) in the ledipasvir-sofosbuvir plus ribavirin group and 97% (95% CI 91–100) in the ledipasvir-sofosbuvir group (P = 0·63), and did not differ by demographic or disease characteristics.

  • Five (3%) had virological failure: three (4%) of those in the ledipasvir-sofosbuvir plus ribavirin group (two by 4 weeks and one by 12 weeks after the end of treatment) and two (3%) in the ledipasvir-sofosbuvir group (all by 4 weeks after treatment).
    • No patient had the NS5B Ser282Thr variant, which is associated with reduced susceptibility to sofosbuvir, at baseline or relapse, and no variants associated with sofosbuvir resistance were seen at baseline or during treatment in patients who relapsed

Most patients had at least one treatment-emergent adverse event. The most common event in the two groups was asthenia, followed by pruritus and headache in the ledipasvir-sofosbuvir plus ribavirin group and headache and fatigue in the ledipasvir-sofosbuvir group

  • One patient assigned to ledipasvir-sofosbuvir plus ribavirin discontinued study treatment due to bacterial arthritis and decompensated cirrhosis during the placebo phase and, therefore, these events were not deemed to be related to study treatment. No other patients discontinued therapy prematurely.
  • Treatment-emergent serious adverse events were reported in 12 patients. Only one serious adverse event was deemed by investigators to be related to study treatment, which was anemia in a woman aged 57 years who was in the ledipasvir-sofosbuvir plus ribavirin group.
  • Most grade 3 and all grade 4 laboratory abnormalities occurred in patients while they were taking only placebo

Patients with HCV genotype 1 infection and compensated cirrhosis who had not previously achieved SVR with standard treatment, achieved high SVR12 rates after treatment with ledipasvir-sofosbuvir plus ribavirin for 12 weeks or ledipasvir-sofosbuvir for 24 weeks, with no clinical or statistical differences in rates between groups. The two treatment regimens used were safe and well tolerated.

  • A limitation of this study is that it excluded patients with decompensated liver disease. However, authors noted that two large studies are underway that will assess the efficacy and safety of ledipasvir-sofosbuvir with ribavirin in patients with recurrent HCV infection after liver transplantation, including those with decompensated cirrhosis and fibrosing cholestatic hepatitis.

Authors concluded the following: “Patients with HCV genotype 1 and cirrhosis who have not achieved SVR are in urgent need of safe and effective treatments to halt the progression of liver disease. Our results suggest that ledipasvir-sofosbuvir plus ribavirin for 12 weeks and ledipasvir-sofosbuvir for 24 weeks could address this unmet need. These two treatment options are currently recommended as first-line therapy for patients with HCV genotype 1 and cirrhosis who have previously failed either peginterferon and ribavirin or protease inhibitor plus peginterferon and ribavirin therapy.”


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