Over 79% of previously untreated and null
responder patients with genotype 1a hepatitis infection achieved a sustained
virologic response twelve weeks after completing treatment (SVR12) with an
interferon-free combination of two or three directly-acting antivirals developed
by Abbott, investigators reported on Monday at The Liver Meeting 2012, the 63rd meeting of
the American Association for the Study of Liver Diseases (AASLD) in Boston.
In the group receiving all three drugs plus ribavirin, 96% of participants achieved a sustained virologic response twelve weeks after completing treatment, while only two out of 148 patients with HCV
genotype 1b infection receiving any of the drug combinations tested in the study failed to achieve SVR12.
Investigators previously reported data on
the use of Abbott drugs in interferon-free regimens for untreated patients at
the European Association for the Study of the Liver conference in Barcelona in
April 2012. Those studies looked at combinations of two drugs.
Glossary
- IL28B
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.
- qd
Abbreviation
of a Latin term meaning once every day.
New data were presented today from phase II
studies that recruited non-cirrhotic untreated patients with HCV genotype 1
and previous null responders to pegylated interferon and ribavirin, testing a
combination of two or three direct-acting antivirals with or without
ribavirin in patients with genotype 1 HCV infection.
Dr Kris Kowdley, director of the Liver
Center of Excellence at Virginia Mason Medical Center, Seattle, presented
results from the Aviator study, a phase 2b study designed to identify the
optimal drug combinations for study in phase 3 licensing trials.
Treatment-naive participants received the
HCV protease inhibitor ABT-450 in one of two doses (100mg or 200mg) boosted by
ritonavir (100mg), an inhibitor of the CYP 3A4 enzyme, in order to raise plasma
levels. This was combined with the NS5a inhibitor ABT-267 (25mg qd) and/or
the non-nucleoside polymerase inhibitor ABT-333 (400mg twice daily) with or
without ribavirin for eight or twelve weeks.
Previous null responders were randomised to
one of two arms, a combination of ABT-450/r and ABT-267 with ribavirin, or to
receive all three DAAs in combination with weight-based ribavirin.
Data were reported on SVR12
results in 448 patients. The data were presented by intent to treat, meaning
that all participants who received at least one dose were assessed at each time
point in the study and counted as treatment failures if they dropped out due to
side-effects or missed study visits. This method of analysis is intended to better
approximate the real-world effectiveness of a treatment regimen than an
on-treatment analysis, which only captures those people who stayed on treatment
– by definition, those who did best.
Most participants (358) were taking therapy
for the first time. The remaining 90 had previously been treated with pegylated
interferon and ribavirin. All the participants had genotype 1 infection and none
were cirrhotic.
Most of the participants (56%) were men,
their mean age was 50 years and two-thirds had genotype 1a infection.
In genotype 1a patients the best response
rates were seen in individuals treated with the four-drug combination of
ABT-450 (boosted by ritonavir), with ABT-267, ABT-333 and ribavirin. In total, 97.5% of
treatment-naive participants taking this combination responded to treatment, as did
93% of previously treated patients.
|
Treatment-Naive
|
Null Responders
|
Duration
|
8 weeks
|
12 weeks
|
12 weeks
|
Regimen
|
ABT-450/r
ABT-267
ABT-333
RBV
|
ABT-450/r
ABT-333
RBV
|
ABT-450/r
ABT-267
RBV
|
ABT-450/r
ABT-267
ABT-333
|
ABT-450/r
ABT-267
ABT-333
RBV
|
ABT-450/r
ABT-267
RBV
|
ABT-450/r
ABT-267
ABT-333
RBV
|
SVR12 (ITT) GT1a
|
84%
(47/56)
|
79%
(23/29)
|
85%
(44/52)
|
83%
(43/52)
|
96%
(52/54)
|
81%
(21/26)
|
89%
(25/28)
|
SVR12 (ITT) GT1b
|
96%
(23/24)
|
100%
(12/12)
|
100%
(27/27)
|
96%
(24/25)
|
100%
(25/25)
|
100%
(18/18)
|
100%
(17/17)
|
Larger studies will be required to
determine whether these rates of response can be reproduced in more diverse
populations. Some interferon-free combination studies have seen differences in
response according to IL28b 'CC' gene status, a predictor of response to
interferon, but Dr Kowdley said that no substantial difference in outcomes had been
seen in the Aviator study population.
The consistently high response rates in
patients with HCV genotype 1b suggest that people with this sub-genotype will
be candidates for ribavirin-sparing regimens in the future, said Dr Kowdley.
More research will be needed to determine the characteristics of people with
HCV genotype 1a who are most likely to achieve a sustained virologic response
on a three-drug DAA regimen without ribavirin. (HCV genotype 1a is the
predominant sub-genotype in the United States; 1b predominates in Europe.)
Therapy was well tolerated. Only two
participants (1%) stopped taking their treatment because of side-effects, and in
both cases they subsequently resumed treatment and achieved a sustained
virologic response. There were five serious adverse events, but only one, joint
pain, was possibly treatment-related.
The most common side-effects were tiredness
and headache. Side-effect incidence was similar between the treatment-naive and
treatment-experienced patients, ranging between 27 and 31%.
The investigators were encouraged by these
findings, concluding that the four-drug combination was effective and safe,
regardless of prior treatment history.