Stephen Shafran from the University of Alberta and
fellow investigators with the COMMAND GT 2/3 study
evaluated the safety and efficacy of 12 or 16 weeks of 60mg once-daily daclatasvir
(an HCV NS5A inhibitor, formerly BMS-790052) plus pegylated interferon alfa-2a (Pegasys) and 800mg ribavirin in treatment-naive hepatitis C patients with HCV genotypes 2 or 3.
People who did not
experience adequate early response stopped daclatasvir and continued on
pegylated interferon/ribavirin through to 24 weeks. The control group received the
standard of care for these genotypes, pegylated interferon/ribavirin alone for
included 151 treatment-naive chronic hepatitis C patients, 47% with genotype 2
and 53% with genotype 3. The genotype 2 group was just over half men with a median
age of approximately 53 years; about 30% had the favourable IL28B CC gene variant
and only one person had liver cirrhosis. The genotype 3 group included about
70% men with a median age of about 45 years; about 41% had the CC variant and
nearly one-quarter had cirrhosis.
Most people (83%)
with either genotype 2 or 3 experienced protocol-defined early response and
were eligible for shorter therapy. People taking the triple regimen for 12 or
16 weeks were less likely to stop treatment early for any reason than those on
standard therapy (10, 12 and 18%, respectively).
HCV genotypes 2 and
3 have traditionally been considered 'easier-to-treat' relative to genotypes 1
and 4, but recent studies have shown that genotype 3 is harder to cure. This
study reported efficacy results for the two genotypes separately.
Amongst people with
genotype 2, rates of sustained virological response (SVR), or undetectable HCV
RNA at 12 weeks after completing therapy (SVR12), were 88% in the 12-week daclatasvir
arm and 83% in the 16-week arm, compared with 71% in the standard therapy arm
(modified intent-to-treat, missing=failure analysis).
After 12 more weeks of post-treatment follow-up,
SVR24 rates were 83% in both daclatasvir arms and 63% in the standard therapy
arm. SVR24 rates were 80, 100 and 83%, respectively, for genotype 2 patients
with the IL28B CC variant compared with 85, 75 and 56% for those with non-CC
Amongst genotype 3 patients, 69% in the 12-week daclatasvir
arm and 78% in the 16-week arm achieved SVR12, compared with 52% in the
standard therapy arm. Corresponding SVR24 rates were 69, 67 and 59%,
respectively. SVR24 rates for IL28B CC patients were 50, 75 and 64%, compared
with 81, 64 and 56% for those with non-CC variants.
SVR24 was traditionally considered the criteria for
a cure for hepatitis C. Regulatory authorities in the US and Europe now accept
SVR12, but these findings show that relapses may still occur between 12 and 24
weeks of post-treatment follow-up.
Genotype 3 patients were more likely to experience
virological failure – mostly post-treatment relapses – than those with
genotype 2. Relapse was associated with baseline drug-resistance mutations and
cirrhosis, but not with IL28B status.
Daclatasvir plus interferon/ribavirin was generally
safe and well tolerated. Four people taking the 12-week daclatasvir regimen,
none taking the 16-week regimen and two taking standard therapy experienced
serious adverse events; four, three and two people, respectively, stopped due
to adverse events. About one-quarter of participants in all arms reported rash
and itching. Neutropenia was also common (20, 24 and 31%, respectively) but
anaemia was uncommon (8, 6 and 10%).
concluded that daclatasvir triple therapy for 12 or 16 weeks "achieved
numerically higher SVR24 rates" than pegylated interferon/ribavirin. Genotype
2 patients had higher response rates than genotype 3 patients with all three
responses were similar for genotype 2 and 3 patients taking daclatasvir, but
relapse was more frequent for genotype 3, they added. Within genotype groups, however,
SVR24 rates were statistically similar with 12 or 16 weeks of treatment.