Although an interferon-free combination of
antiviral drugs developed by Bristol-Myers Squibb to treat hepatitis C was
highly effective in curing the infection in previous null responders to
treatment with HCV genotype 1b infection, some new antiviral drugs may still
need to be administered with interferon in harder-to-treat patients with HCV
genotype 1a, researchers reported on Sunday at The Liver Meeting 2012, the 63rd meeting of
the American Association for the Study of Liver Diseases (AASLD), in Boston.
The study found a very high rate of
sustained virologic response (SVR12) in people with HCV genotype
1a amongst patients who received new direct-acting antivirals with pegylated
interferon and ribavirin.
The findings came from a phase 2a study of
asunaprevir, an HCV protease inhibitor, combined with daclatasvir, an inhibitor
of the HCV NS5A protein. The drugs are being developed by Bristol-Myers Squibb, potentially for use in combination. The study was designed to evaluate once- and
twice-daily dosing of asunaprevir in combination with daclatasvir, with or
without pegylated interferon and ribavirin.
Like a number of other studies presented at
this meeting, the trial was designed to give a preliminary picture of the
potential of these agents to cure hepatitis C infection when used without
interferon or ribavirin. The side-effects of interferon, and the fact that some
people fail to respond to interferon due to genetic characteristics or due to
resistance induced by prior treatment, make the identification of
interferon-free regimens essential for people who have failed to respond to a
previous interferon-containing regimen.
Interferon-free treatment will also be
highly attractive for anyone needing treatment for the first time, because it
is likely to come with fewer side-effects, and treatment may be completed in
six or even three months.
However, research studies are also
evaluating the use of new regimens with and without ribavirin, because this
drug causes anaemia, causing treatment regimens to be terminated prematurely
owing to poor tolerance.
The randomised study was open-label and
involved people with genotype 1 HCV infection. This study excluded patients
with cirrhosis. All had previously received standard therapy with pegylated
interferon and ribavirin but were classified as null responders, having failed
to achieve a sustained virological response (SVR).
A total of 101 people were recruited to
the study. There was a high prevalence of factors associated with a poorer
response to treatment in the study population. Over 95% of participants lacked the
IL28B 'CC' mutation, which predicts a favourable response to interferon
treatment, and 89% had a hepatitis C viral load above 10 million IU/ml.
Participants with HCV genotype 1b infection
were randomised to one of four treatment arms, consisting of 24 weeks of
the HCV protease inhibitor daclatasvir
(60mg once daily) plus:
- asunaprevir (200mg twice daily) (n=18, restricted to
participants with genotype 1b).
- asunaprevir (200mg once daily) (n=20, restricted to
participants with genotype 1b).
- asunaprevir (200mg twice daily) plus pegylated interferon and
- asunaprevir (200mg once daily) plus pegylated interferon and
with HCV genotype 1a infection were randomised to receive one of the two
pegylated interferon-containing regimens, due to the higher risk of viral
breakthrough and consequent null response in this group of patients.
fifth treatment group (daclatasvir 60mg qd plus asunaprevir [200mg twice daily] plus ribavirin [n=22]) was recruited separately and
consisted of participants with genotype 1a or 1b infection.
Ninety-five per cent of participants who
received the four-drug, interferon-containing regimens achieved an HCV viral load
below the lower limit of quantification (LLOQ, 25 iu/ml) at week 4 of
treatment and all participants had HCV RNA < LLOQ at week 12.
Ninety-five per cent of participants (39 of 41)
had a sustained virologic response twelve weeks after the completion of
treatment (SVR12), suggesting
that these interferon-containing regimens are highly effective and comparable
in efficacy to other regimens that have tested a combination of new antiviral
drugs in combination with pegylated interferon and ribavirin.
Only two cases of post-treatment
virological relapse were observed, one at week 4 and one at week 12 after
completion of treatment.
The vast majority of participants (36 of 41)
receiving interferon-containing regimens had HCV genotype 1a infection.
In the dual-treatment group (genotype 1b
only), 78% of participants receiving asunaprevir twice daily and 65% receiving
asunaprevir once daily achieved a sustained virologic response (SVR12).
Eight cases of viral breakthrough occurred; HCV RNA was re-suppressed with the
addition of pegylated interferon and ribavirin in all cases. In five cases,
naturally existing HCV variants with resistance to daclatasvir were found to
have been present prior to treatment.
study found that, in the triple-therapy arm, 56% of participants with genotype 1a
infection experienced viral breakthrough in the absence of interferon, compared
with none of the genotype 1b patients. This result confirmed the findings of a
previous study, which also found a higher rate of viral breakthrough in
participants with genotype 1a who received daclatasvir and asunaprevir without
findings led the investigators to conclude that the interferon-free combination
of daclatasvir and asunaprevir with ribavirin should not be pursued in
harder-to-treat genotype 1a null responders.
“These data suggest that interferon-free
treatment regimens for genotype 1 patients may need to be tailored according to
subgenotype,” Dr Anna Lok told the meeting.
No participant stopped taking either
daclatasvir or asunaprevir because of side-efects.
The most common side-effects among people taking the dual combination of daclatasvir and asunaprevir were headache,
diarrhoea, weakness and nausea. These side-effects were also observed in
participants taking the four-drug regimen, among whom hair loss and irritability
were also common.
The authors concluded that the four-drug
combination of daclatasvir and asunaprevir with pegylated interferon and ribavirin
is highly effective for patients with either genotype 1a or genotype 1b who did
not respond to earlier treatment with pegylated interferon and ribavirin.
Preliminary data also suggested that treatment with daclatasvir/asunaprevir
alone was effective, but only in people with genotype 1b infection.