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Daclatasvir + asunaprevir cures 85% of genotype 1b hepatitis C patients in Japanese study
Liz Highleyman, 2013-11-12 10:30:00
interferon- and ribavirin-free oral regimen of daclatasvir plus asunaprevir
taken for 24 weeks led to sustained virological response (SVR12) in 85% of Japanese
patients with hepatitis C virus subtype 1b, according to findings presented last week at The Liver Meeting 2013, the 64th annual
meeting of the American Association for the Study of Liver Diseases (AASLD), in
The development of
direct-acting antivirals has brought about a revolution in the treatment of
chronic hepatitis C virus (HCV) infection. While the first of these new agents
were initially approved as add-ons to interferon-based therapy, people with
hepatitis C and their care providers are eagerly awaiting all-oral regimens that
avoid the difficult side-effects of interferon.
Chayama of Hiroshima University
presented results from a phase 3 trial testing an interferon-free regimen of Bristol-Myers Squibb's HCV NS5A replication complex inhibitor daclatasvir (formerly
BMS-790052) plus the NS3 protease inhibitor asunaprevir (formerly BMS-650032) for patients who were either
non-responders to prior interferon-based therapy or ineligible for or
intolerant of interferon.
The study enrolled 222
people with chronic hepatitis C subtype 1b, the predominant type in
Japan. In contrast with most US and European studies, two-thirds of
participants were women and the average age was a bit older at 63 years; 40%
were over age 65. Half had the favourable IL28B CC gene variant associated with
interferon responsiveness and 10% had liver cirrhosis.
included 22% prior null responders, 16% prior partial responders, 45% deemed
ineligible to take interferon (for reasons such as pre-existing depression,
anaemia, other co-morbidities or advanced age) and 16% who were interferon
intolerant (previously discontinued interferon before 12 weeks due to
All participants in
this open-label study received 60mg once-daily daclatasvir plus 100mg
twice-daily asunaprevir for 24 weeks. They were followed-up for an additional 24
weeks after finishing treatment to determine sustained virological response
(SVR24), or continued undetectable HCV RNA, which is considered a cure.
The overall SVR24 rate
was 85% in a modified intent-to-treat analysis, broken down to 87% for
people who were interferon ineligible or intolerant and 81% for prior non-responders.
HCV viral load
declined rapidly after starting therapy, with 84% of people who were interferon ineligible/intolerant and 61% of prior non-responders showing rapid virological response at
week 4; 96 and 87%, respectively, had undetectable HCV RNA at the end of
therapy. However, 11 people who were interferon ineligible/intolerant and six prior
non-responders (8%) relapsed during post-treatment follow-up.
response rates were obtained regardless of IL28B status (85% for favourable CC,
85% for intermediate CT and 83% for least favourable TT). Other baseline
factors did not significantly affect response rates. Interestingly, people with
cirrhosis did at least as well as people who did not have cirrhosis (91 and 84%, respectively)
and people aged 65 and older fared slightly better than younger participants
(90 vs 81%).
Daclatasvir plus asunaprevir was generally safe and well-tolerated.
Overall, 6% of participants experienced serious adverse events, 7% developed
grade 3-4 laboratory abnormalities and 5% discontinued due to adverse events,
with all these outcomes being a bit more common among people who were interferon ineligible/intolerant compared to prior non-responders.
The most common adverse
events were upper respiratory infections (30%), elevated ALT or AST liver
enzyme levels (16 and 13%), headache (16%), fever (12%) and diarrhoea (10%);
anaemia was rare (3%). All but one of the 11 people who discontinued treatment early due to side-effects
did so for elevated ALT or AST, which returned to normal after stopping
"[The] all-oral combination of daclatasvir and asunaprevir
achieved high rates of SVR24 in Japanese patients without treatment options and
in patients with no prior response to interferon-based therapy", the
researchers concluded. "This all-oral, interferon-free, ribavirin-free
regimen was well tolerated with low rates of discontinuation, representing a
clinically meaningful improvement in both safety and efficacy compared to
current standard of care."
Based on these
findings, Bristol-Myers Squibb announced during the conference that it has submitted
this first interferon- and ribavirin-free regimen for regulatory approval in
Japan, where an estimated 1.2 million people are living with hepatitis C.
While these are good results for people with HCV
1b, studies have shown that the dual regimen of daclatasvir/asunaprevir is not
as effective against subtype 1a. (Asunaprevir is also not active against HCV
genotypes 2 or 3.) However, as also reported at the Liver
adding a third agent – the non-nucleoside NS5B polymerase inhibitor
BMS-791325 – raised sustained response rates to 91% for people with HCV 1a and
100% for 1b. Bristol-Myers Squibb is working on a fixed-dose combination pill
containing these three drugs.