Back HCV Treatment EASL 2013: Daclatasvir plus Interferon Cures More Genotype 2/3 Hepatitis C Patients

EASL 2013: Daclatasvir plus Interferon Cures More Genotype 2/3 Hepatitis C Patients


Adding the HCV NS5A inhibitor daclatasvir to pegylated interferon and ribavirin for 12 or 16 weeks led to higher response rates for previously untreated people with genotype 2 or 3 hepatitis C, according to results from the COMMAND study reported last week at the EASL International Liver Congress(EASL 2013) in Amsterdam. People with genotype 3, however, did not respond as well as those with genotype 2.

Direct-acting antiviral agents (DAAs) have changed the treatment paradigm for chronic hepatitis C. While many patients and clinicians are awaiting all-oral regimens, others have progressive liver disease and need treatment now.

Gregory Dore from the University of New South Wales and colleagues evaluated the safety and effectiveness of adding daclatasvir (formerly BMS-790052) to pegylated interferon and ribavirin for people with HCV genotypes 2 or 3, traditionally considered "easier to treat." Genotype 2/3 patients already have a relatively high rate of response to a 24-week course of pegylated interferon/ribavirin, but including a DAA could allow for shorter treatment.

The COMMAND GT2/3 trial (study AI444-031) enrolled 151 treatment-naive chronic hepatitis C patients, 71 with genotype 2 and 80 with genotype 3. About half of the genotype 2 patients were men, their median age was approximately 53 years, 32% had the favorable IL28B CC gene pattern, and only 1 was known to have liver cirrhosis. Among genotype 3 patients, about 70% were men, the median age was about 45 years, 41% had the CC variant, and nearly one-quarter had cirrhosis.

Participants were randomly assigned to receive triple therapy using 60 mg once-daily daclatasvir, pegylated interferon alfa-2a (Pegasys), and 800 mg/day fixed-dose ribavirin for either 12 or 16 weeks, or else the same doses of pegylated interferon and ribavirin for 24 weeks (the standard interferon-based regimen for genotypes 2/3). Using a response-guided therapy algorithm, patients in the daclatasvir arms who did not experience protocol-defined response at weeks 4 and 10 stopped daclatasvir at week 12 and continued on pegylated interferon/ribavirin alone through week 24.

A number of studies presented at the congress showed divergent response rates for people with HCV genotypes 2 and 3, suggesting, in the opinion of many researchers, that they should no longer be "lumped together" as a single presumably easy-to-treat population. Dore reported the COMMAND efficacy findings broken out by genotype, and here too, genotype 2 responded better.


  • About 90% of daclatasvir recipients completed treatment compared with 82% in the standard therapy control arm, who were more likely to stop early due to lack of efficacy.
  • Looking first at genotype 2 patients, at week 4 of treatment, 88% in the daclatasvir 12-week arm and 74% in the daclatasvir 16-week arm achieved rapid virological response (RVR), compared with just 42% in the standard therapy arm.
  • At the end of treatment, 96%, 91% and 92%, respectively, had undetectable HCV RNA.
  • After 2 patients relapsed post-treatment, a modified intent-to-treat analysis showed that 88% and 83% in the 12-week and 16-week daclatasvir arms, and 71% in the control arm, achieved sustained virological response 12 weeks after finishing therapy (SVR12).
  • Corresponding SVR24 rates were 83%, 83%, and 63%.
  • When participants with missing post-treatment data were excluded, SVR24 rates rose to 95%, 100%, and 83%.
  • Turning to genotype 3 patients, response rates were similar during treatment, but a higher number of relapsers led to lower sustained response.
  • At week 4 of treatment, 85% in the daclatasvir 12-week arm, 74% in the 16-week arm and 37% in the standard therapy arm reached RVR.
  • End-of-treatment response rates were 96%, 89%, and 78%.
  • There were 6 post-treatment relapses in both daclatasvir arms and 2 in the control arm.
  • In the modified intent-to-treat analysis, SVR12 rates were 69%, 78%, and 52%, respectively.
  • SVR24 rates were 69%, 67%, and 59%.
  • After excluding people with missing data, observed SVR24 rates were 72%, 69% and 70%, or essentially the same in all arms.
  • Nearly 85% of daclatasvir recipients with both genotypes achieved protocol-defined response and were eligible to stop all treatment at week 12 or 16 with no interferon/ribavirin tail.
  • Within this group, 81% and 94% of genotype 2 patients achieved SVR24 with the 12- and 16-week regimens, respectively; among genotype 3 patients, the rate was 73% with either duration.
  • Only 1-3 participants in each genotype/duration arm failed to experience good early response and received extended interferon/ribavirin; their SVR24 rates were 100% and 40% for genotype 2, and 50% and 40% for genotype 3.
  • Among genotype 2 patients with the favorable CC variant, SVR24 rates for the 3 regimens were 80%, 100% and 83%; for those with CT or TT variants, the corresponding rates were 85%, 75% and 56%.
  • Although response rates were lower across the board, the same pattern was seen for genotype 3 patients: among CCs, the longer daclatasvir duration worked best with little difference between the short duration and control regimen (50%, 75%, and 64%), while CT/TTs did better with the shorter daclatasvir course (81%, 64%, and 56%).
  • Further analysis showed that among people with genotype 3, the presence of resistance-association viral mutations at baseline raised the risk of relapse (50% vs 19%), as did presence of cirrhosis (36% vs 21%), but IL28B non-CC gene variants and high baseline viral load did not.
  • Adding daclatasvir to interferon-based therapy was generally safe and well tolerated.
  • 4 people taking the 12-week daclatasvir regimen, none taking the 16-week regimen, and 2 taking standard therapy experienced serious adverse events.
  • 4, 3, and 2, respectively, stopped treatment early due to adverse events.
  • About one-quarter of patients in all arms reported rash and itching, and neutropenia was also common (20%, 24%, and 31% in the 3 arms).

The researchers concluded that daclatasvir triple therapy for 12 or 16 weeks "achieved numerically higher SVR24 rates" than standard interferon/ribavirin for 24 weeks. While end-of-treatment responses were similar in genotype 2 and 3 patients taking daclatasvir, "relapse was more frequent in genotype 3."

There was "no indication of additional benefit" of continuing daclatasvir for 16 vs. 12 weeks," Dore added, and "no clear data" to show that extending treatment duration for patients with rapid response would improve outcomes.



GJ Dore, E Lawitz, C Hezode, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with HCV genotype 2 or 3 infection: COMMAND GT2/3 study. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1418.