An all-oral regimen containing three next-generation
antivirals taken for either 12 or 24 weeks produced sustained virological response
in more than 90% of previously untreated genotype 1 chronic hepatitis C
patients in a phase 2a study, according to interim findings presented last week
at the 48th International Liver Congress (EASL 2013) in Amsterdam.
The advent of direct-acting antivirals (DAAs) has
changed the treatment paradigm for chronic hepatitis C. Although several DAAs
have been shown to improve treatment response when added to pegylated
interferon and ribavirin, many patients and clinicians are awaiting all-oral
regimens that avoid interferon and its difficult side-effects.
Gregory Everson from the University of Colorado and colleagues
conducted an open-label trial comparing interferon- and ribavirin-sparing regimens
containing the HCV NS5A replication complex inhibitor daclatasvir (formerly BMS-790062), the NS3 protease
inhibitor asunaprevir (formerly BMS-650032) and Bristol-Myers
Squibb's non-nucleoside NS5B polymerase inhibitor BMS-791325.
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
This open-label study enrolled 66 treatment-naive
chronic hepatitis C patients without liver cirrhosis. Overall about 60% were
men (ranging from 44 to 72% in the different treatment arms), about 80% were
white, about 20% were black and the median age was 50 years. Three-quarters had
harder-to-treat HCV subtype 1a, the rest 1b. About one-third had the favourable
IL28B CC gene pattern which predicts good interferon responsiveness.
All participants received a three-drug combination containing
60mg once-daily daclatasvir, 200mg twice-daily asunaprevir and BMS-791325. Initially,
32 participants were randomly assigned to receive BMS-791325 at a
dose of 75mg twice daily for either 24 or 12 weeks.
After favourable safety assessment, another 34
patients were randomised to receive 150mg BMS-791325 twice daily
for 24 or 12 weeks. Because patients started treatment at different times, researchers
reported varying durations of sustained virological response (SVR, considered a cure), or
continued undetectable HCV RNA after finishing therapy:
- Group 1 (n=16): Daclatasvir
+ asunaprevir + 75mg BMS-791325 for 24 weeks: SVR24.
- Group 2 (n=16): Daclatasvir
+ asunaprevir + 75mg BMS-791325 for 12 weeks: SVR36.
- Group 3 (n=16): Daclatasvir
+ asunaprevir + 150mg BMS-791325 for 24 weeks: SVR4.
- Group 4 (n=18): Daclatasvir + asunaprevir + 150mg BMS-791325 for 12
Viral decline was rapid using both dosing regimens. By week 4 of
treatment 100% of participants in Groups 1, 2 and 3, and 89% in Group 4 had
rapid virological response, and most still had undetectable viral load at the
end of treatment.
Four weeks post-treatment, SVR rates were 94, 94, 94 and 89% in
Groups 1, 2, 3 and 4, respectively, in a modified intention-to-treat analysis.
Sustained response rates remained the same at post-treatment week 12 for Groups
1, 2 and 4, with Group 3 not having reached this endpoint. SVR24 rates for
Group 1 and 2 were 88 and 94%, respectively. Finally, an SVR36 of 88% was
reported for Group 2.
All treatment 'failures' in Groups 1 and 2 were due to missing
data from participants who had previously reached undetectable viral load but
did not return for further testing. Group 3 included one participant who experienced
viral breakthrough at week 6 of therapy. Treatment was intensified by adding
pegylated interferon/ribavirin, but the patient discontinued due to an adverse
Group 4 included one person who experienced viral breakthrough at week 8
of therapy and also intensified treatment (follow-up ongoing). In addition, one
other patient experienced early relapse between the end of treatment and
post-treatment week 4. Drug resistance mutations were detected in both Group 4
patients with treatment failure. No relapses have been observed so far after
SVR4 in any group.
Treatment was equally effective regardless of whether the 75mg or 150mg
dose of BMS-791325 was used or whether the duration of therapy was 12 or 24
weeks. The researchers did not report a breakdown of results by HCV subtype or
IL28B status in this interim analysis.
The three-drug regimen was generally safe and well tolerated, again
regardless of BMS-791325 dose or treatment duration. There were two serious adverse
events, both considered unrelated to the DAAs under study, and no participants
stopped treatment for this reason (except for the interferon intensification case
The most frequently reported side-effects were headache, weakness,
diarrhoea and nausea, with abdominal pain being more common at the higher dose. No serious
changes in liver enzymes (ALT or AST), bilirubin or blood cell counts were
all-oral, interferon-free, ribavirin-free, ritonavir-free combination [of
daclatasvir, asunaprevir, and BMS-791325 at 75mg or 150 mg twice daily] achieved
> 90% SVR4 (61/66) and SVR12 (30/32) by modified intent-to-treat analysis in
predominantly genotype 1a patients, IL-28Bnon-CC patients," the researchers concluded.
High rates of
SVR appear to be similar with either 12 or 24 weeks of treatment and with
either the 75mg or 150mg dose of BMS-791325, and treatment was "highly
tolerable at either dose level," with similar adverse
event rates regardless of dose or treatment duration, they added.
Bristol-Myers Squibb indicated in a press release that
it plans to start a phase 3 study of daclatasvir,
asunaprevir and BMS-791325 in a fixed-dose
coformulation by the end of the year. The poster noted that daclatasvir is also being
studied in other all-oral, ribavirin-free regimens in combination with simeprevir
(formerly TMC435), sofosbuvir (formerly GS-7977) or VX-135.