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B – CRF – Infection diseases, including vaccina
F – 08 – Infectious complications
Daclatasvir plus Sofosbuvir for Previously Treated or Untreated
Chronic HCV Infection
Mark S. Sulkowski, M.D., David F. Gardiner, M.D., Maribel Rodriguez-Torres, M.D., K.
Rajender Reddy, M.D.,. for the AI444040 Study Group
N Engl J Med 2014; 370:211-221 January 16, 2014
ABSTRACT
Background
All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV)
infection. We 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.
Methods
In this open-label study, we initially randomly assigned 44 previously untreated patients with
HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at
a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with
or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients
with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or
without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients
who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa–
ribavirin). The primary end point was a sustained virologic response (an HCV RNA level of
<25 IU per milliliter) at week 12 after the end of therapy.
Results
Overall, 211 patients received treatment. Among patients with genotype 1 infection, 98% of
126 previously untreated patients and 98% of 41 patients who did not have a sustained
virologic response with HCV protease inhibitors had a sustained virologic response at week
12 after the end of therapy. A total of 92% of 26 patients with genotype 2 infection and 89%
of 18 patients with genotype 3 infection had a sustained virologic response at week 12. High
rates of sustained virologic response at week 12 were observed among patients with HCV
subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B
genotypes (93% and 98%, respectively), as well as among patients who received ribavirin
and those who did not (94% and 98%, respectively). The most common adverse events were
fatigue, headache, and nausea.
Conclusions
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. (Funded by Bristol-Myers
Squibb and Pharmasset (Gilead); A1444040 ClinicalTrials.gov number,
COMMENTS
Peginterferon alfa–ribavirin treatment for chronic HCV infection is associated with a
sustained virologic response (undetectable HCV RNA level after treatment) in approximately
40% of patients with genotype 1 infection and 75% of patients infected with genotype 2 or
3.9,10 Adding boceprevir or telaprevir has been shown to improve the response in patients
with genotype 1 infection.However, the addition of boceprevir or telaprevir is limited to HCV
genotype 1 and is associated with adverse events, complicated dose regimens, and viral
resistance. Currently, patients who have virologic failure (no sustained virologic response)
with telaprevir or boceprevir plus peginterferon alfa–ribavirin have no other treatment options.
Daclatasvir is a first-in-class HCV NS5A replication complex inhibitor, and sofosbuvir is a
nucleotide analogue HCV NS5B polymerase inhibitor. Both have potent antiviral activity and
broad genotypic coverage and are administered orally once daily.Each is effective in patients
infected with genotype 1, 2, or 3 when this treatment is combined with peginterferon alfa–
ribavirin, and sofosbuvir plus ribavirin is effective in patients infected with genotype 1, 2, or 3
in the absence of treatment with peginterferon alfa–ribavirin
In conclusion of this study, once-daily, oral treatment with the NS5A inhibitor daclatasvir plus
the NS5B polymerase inhibitor sofosbuvir was associated with high rates of sustained
virologic response in untreated patients infected with genotype 1, 2, or 3 and in patients with
genotype 1 infection in whom previous treatment with protease inhibitors had failed and who
had no current treatment options. The response rate was high across subgroups of patients
defined according to IL28B genotype, HCV genotype 1 subtype, receipt of ribavirin, and the
presence of HCV protease inhibitor–resistant variants.