An all-oral regimen of daclatasvir, asunaprevir and BMS-791325 – without
interferon or ribavirin – led to sustained response in approximately 90% of people
with hepatitis C virus (HCV) who had not previously taken treatment, most with
hard-to-treat genotype 1a, according to a study presented at the 21st
Conference on Retroviruses and Opportunistic Infections (CROI) this month in
The advent of effective direct-acting antivirals has brought about a revolution
in treatment for chronic hepatitis C. New regimens coming through the pipeline will eliminate
both interferon and ribavirin, both of which often cause difficult side-effects.
Trevor Hawkins from the Southwest CARE Center in New Mexico reported
findings from a trial evaluating an interferon- and ribavirin-free regimen
consisting of Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (formerly BMS-790052), the NS3 protease inhibitor
asunaprevir (formerly BMS-650032)
and the NS5B polymerase inhibitor BMS-791325.
After a pilot
study of the triple combination taken for 12 or 24 weeks showed sustained
virological response rates of around 90% with either duration at 12 and 24
weeks post-treatment (SVR12 and SVR24, respectively), the researchers conducted
an expanded trial to test the 12-week regimens in a larger group of people with
genotype 1 HCV infection, including people with liver cirrhosis.
This analysis included 166 people with chronic hepatitis C who had not
taken treatment before (treatment naive). About two-thirds were men, about 80%
were white and the median age was 54 years. Most (82%) had harder-to-treat HCV
subtype 1a, the rest 1b. One-third had the favourable IL28B CC gene variation
associated with good interferon responsiveness. Although 20% had advanced
fibrosis (stage F3) and 18% had cirrhosis (stage F4) according to the
non-invasive FibroTest biomarker
index, half that many (9%) had biopsy-proven cirrhosis. People with HIV or
hepatitis B co-infection were excluded.
Participants were randomly assigned to receive 30mg daclatasvir, 200mg
asunaprevir, and either 75 or 150mg BMS-791325, all taken twice daily for 12
weeks. Although daclatasvir can be taken once daily, in this trial it was taken
twice daily to support development of a co-formulation with the other drugs. Prior
studies have shown that 60mg once-daily and 30mg twice-daily daclatasvir dosing
are equally effective.
In an intent-to-treat analysis at 12 week post-treatment, 88.8% of participants
in the 75mg BMS-791325 arm and 89.5% in the 150mg arm achieved SVR12. Excluding
three people in the 75mg arm and two in the 150mg arm who had missing data,
observed SVR12 rates were 92.2% and 91.7%, respectively. The differences
between the dose arms were not statistically significant.
In an observed analysis of patient subgroups, cure rates were similarly
high regardless of factors traditionally associated with poor response.
For people with HCV subtype 1a, the SVR12 rate was 91% using either the
75 or 150mg BMS-791325 dose. For people with subtype 1b, SVR12 rates were 100%
and 94%, respectively. For people with the IL28B CC variant the SVR12 rate was
96% with both doses; for those with unfavourable non-CC variants cure rates
were 91% and 89%, respectively.
Looking at people with liver cirrhosis, the observed SVR12 rate was 100%
in the 75mg dose arm, but 71% in the 150mg arm (two people with liver cirrhosis
in this arm ended up adding pegylated interferon/ribavirin, one due to viral
breakthrough and one after stopping BMS-791325). For people who did not have
cirrhosis, cure rates were 91% and 94%, respectively. Overall, 13 out of 15
participants with cirrhosis achieved SVR12.
Six people in the 75mg BMS-791325 arm experienced virological failure (two
viral breakthroughs during treatment and four relapses after completing
therapy), as did five people in the 150mg arm (three breakthroughs and two
relapses). All relapses occurred in participants with HCV 1a and happened
during the first four weeks of post-treatment follow-up. No factors other than
HCV subtype predicted virological failure. Among the 11 people with virological
failure, five had evidence of emergent resistance to daclatasvir and
asunaprevir and six showed resistance to all three drugs.
Triple therapy was generally safe and well-tolerated. A single
participant in each BMS-791325 dose arm discontinued early due to adverse
events. There were a total of three serious adverse events (oesophageal neoplasm; abdominal wall abscess;
pleurisy/chest pain), none deemed related
to the study drugs. The most common side-effects were headache (25%), diarrhoea
(15%), fatigue (11%) and nausea (10%), with no major differences between dose
12-week, interferon- and ribavirin-free, all-oral 3-DAA regimen achieved SVR12
in >90% of patients despite high prevalence of genotype 1a, advanced
fibrosis/cirrhosis, and IL28B
non-CC genotypes," the researchers concluded. They added that this was a
"well tolerated regimen with low rates of adverse events and treatment
discontinuations, regardless of BMS-791325 dose."
regimen is now being studied in the phase III UNITY-1 and UNITY-2 trials,
testing a twice-daily fixed-dose co-formulation of all three drugs, using the
75mg dose of BMS-791325. UNITY-1 is looking at people who do not have
cirrhosis and UNITY-2 at people with compensated cirrhosis.
Daclatasvir is also currently being tested in people
with HIV/HCV co-infection. All three drugs in this combination are CYP3A4
substrates. Drug-drug interaction studies have shown that daclatasvir can be
combined with several antiretroviral drugs, in some cases with dose
adjustments. Asunaprevir can also be used with several antiretrovirals,
excluding HIV protease inhibitors; interaction studies are underway for