AI444040

AI444040 Study: DCV + SOF ± RBV for genotypes 1, 2 and 3
Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection
Sulkowski MS. NEJM 2014;370:211-21

Anti-HCV
Daclatasvir
Sofosbuvir
Genotype
1
2
3
Treatment history
Naive
PI-experienced
Cirrhosis
No

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Design

Baseline characteristics and dosing of medication

  • DCV : 60 mg qd
  • SOF : 400 mg qd
  • RBV (bid dosing) : weight based in genotype 1 : 1000 mg/day if < 75 kg or 1200 mg/day if = 75 kg ; 800 mg/day in genotype 2 or 3 ; dose reduction to 600 mg/day if hemoglobin decreased < 10g/ dL

Baseline characteristics (second cohort) and Objective

  • Primary efficacy endpoint : SVR12 (HCV RNA < 25 IU/ml) by mITT analysis
  • Secondary endpoints :
    • SVR4
    • SVR24
    • Safety : adverse events, discontinuation for adverse events, grade 3-4 laboratory abnormalities

HCV RNA < 25 IU/ml

  • All patients had HCV RNA < 25 IU/ml at end of treatment , except 1 in group B (DCV + SOF 24W)

Virologic relapse post-treatment : 1 patient with genotype 3 who did not received RBV

  • NS5A A30K polymorphism (DCV resistance) at baseline and failure

Resistance testing (sequencing)

  • NS5A polymorphisms associated with loss of susceptibility to DCV in vitro detected at baseline in 32 patients : 8% in genotype 1, 61% in genotype 2, 28% in genotype 3
  • Most frequent mutations : Q30H (genotype 1a), L31M
    (genotype 1b and 2), Y93H (genotype 3)
  • Except the patient with relapse, all other patients with preexisting DCV resistant variants had a SVR
  • No mutation (S282T) to SOF at baseline or in the patient with breakthrough

Adverse events , n (%)

  • Most common : fatigue, headache, nausea (= 25% in any group)
  • Grade 3-4 adverse events : 7 (3.3%)
  • Discontinuation of treatment for adverse events : 2 (both achieved SVR)
    • DCV-SOF 24W : 1 cerebrovascular accident
    • DCV-SOF + RBV 24W : 1 fibromyalgia exacerbation
  • Serious adverse events : 10 (4.7%)
  • Most common grade 3-4 laboratory abnormalities : low phosphorus and elevation of glucose levels
  • Hemoglobin level more reduced in groups with RBV
    • Reduction of RBV dose in 5 patients because of anemia

Summary

  • DCV + SOF was assessed in untreated patients and patients in whom previous treatment with telaprevir or boceprevir had failed
  • Most patients had a SVR,
    • including 98% of patients with genotype 1 infection, regardless of viral subtype or failure of prior treatment with PI,
    • and 91% of naïve patients infected with genotype 2 or 3
  • The most common adverse event was fatigue, which was reported in approximately one third of patients
  • Virologic breakthrough and relapse were rare and were not observed in any of the patients infected with HCV genotype 1 or 2, despite preexisting DCV-resistant variants in 14%
  • In genotype 3, 1 relapse in a patient with baseline DCV-resistant variant
  • No additional benefit of RBV addition but greater decrease in hemoglobin