All-oral regimens consisting of the HCV protease
inhibitor ABT-450, a non-nucleoside polymerase inhibitor and ribavirin led to
sustained response for more than 90% of previously untreated hepatitis C patients – including those with unfavourable IL28B gene
patterns – but only about
half of prior non-responders, researchers reported earlier this month at the 20th Conference
on Retroviruses and Opportunistic Infections (CROI
2013) in Atlanta.
Direct-acting antiviral agents that target
various steps of the hepatitis C virus (HCV) lifecycle have brought about a new
treatment paradigm for chronic hepatitis C, and many patients and clinicians
are eagerly awaiting all-oral regimens without interferon.
Eric Lawitz from the
University of Texas Health Science Center and colleagues compared various
interferon-free combinations of direct-acting drugs being developed by AbbVie, formerly
All 12-week regimens
included the once-daily HCV NS3/4A protease inhibitor ABT-450, boosted with
ritonavir (Norvir) to achieve adequate levels in the body (ABT-450/r). They
also included a non-nucleoside HCV NS5B polymerase inhibitor – either ABT-072 taken once daily or ABT-333 taken
twice daily – and 1000 to 1200mg/day weight-based ribavirin.
combined data from four cohorts in two studies:
- Cohort 1 (n=11): 150/100mg ABT 450/r + 400mg
ABT-072 + ribavirin in treatment-naive patients.
- Cohort 2 (n=19): 250/100mg ABT-450/r + 100mg
ABT-333 + ribavirin in treatment-naive patients.
- Cohort 3 (n=14): 150/100mg ABT-450/r + 100mg
ABT-333 + ribavirin in treatment-naive patients.
- Cohort 4 (n=17): 150/100mg ABT-450/r + 100mg
ABT-333 + ribavirin in prior partial or null responders.
About 70% of
participants overall were men (though this varied from about one-half to 100%
in different treatment arms), about 80% were white and the average age was
approximately 53 years. About 80% had more difficult-to-treat HCV sub-type 1a.
In Cohort 4, about 60% were prior partial responders (still-detectable HCV RNA
at the end of previous interferon-based therapy) and the rest null responders
(less than a 2-log10 decline in HCV RNA).
Enrolment in Cohort 1
was restricted to patients with the favourable IL28B CC gene pattern, which is
associated with good interferon response; its role in interferon-free therapy
is not yet clear. In Cohort 2 half had the CC pattern, about one-third had the
CT (intermediate) pattern and about 10% were TT (least favourable). In Cohort 3
the CC and CT proportions were reversed. In Cohort 4 no one had the CC pattern (typical
of non-responders) whilst about 70% were CT and 30% TT. People with HIV and hepatitis B co-infection
In Cohort 1 – the sole arm testing ABT-072 – 91% of patients achieved sustained virological
response, or undetectable HCV RNA at 24 weeks post-treatment (SVR24) whilst two
people (18%) relapsed, one early and one late.
In Cohort 2 (250/100mg
ABT-450/r) and Cohort 3 (150/100mg ABT-450/r), SVR24 rates were 95 and 86%,
respectively. Cohort 3 included one person who had sustained response at week
12 (SVR12) but relapsed before week 24.
For the more challenging
treatment-experienced participants in Cohort 4, the SVR24 rate fell to just
47%. Looking further out at 48 weeks post-treatment (SVR48), six people
experienced viral breakthrough while on therapy and three relapsed after
Breaking out the results
by IL28B pattern, amongst the treatment-naive participants, SVR24 rates were 85%
for people with the CC pattern and 100% for those with either CT or TT,
demonstrating that IL28B has no impact on these interferon-free regimens. For
non-responders, SVR24 rates were 50% for those with the CT pattern and 40% for
those with TT.
Further analysis found
that most people with virological failure showed evidence of two-class
resistance. One person who experienced viral breakthrough had a resistance
mutation at NS3 protease position D168 at baseline, and almost everyone else
with on-treatment breakthrough or post-treatment relapse showed such mutations
at the time of failure. NS5B polymerase mutations were more variable, many
involving positions G554 or S556.
Turning to safety, all
combinations were generally safe and well tolerated. The most common
side-effects were fatigue, nausea, headache and dizziness. About 13% had
elevated bilirubin, which Lawitz explained was due to a known effect of ABT-450
on a bilirubin-transporter protein in the liver. There were no serious adverse
events or deaths, and just one person in Cohort 2 stopped treatment early due
to side-effects. Efficacy and side-effects did not differ significantly between
the 150mg and 250mg ABT-450 doses.
in a state of a paradigm shift to the era of direct-acting antivirals,"
Lawitz said at an accompanying CROI press conference. "For those with mild-to-moderate disease, as
timelines for approval [of direct-acting drugs] firm up, we're using interferon
less and putting more people in the warehouse" to wait for interferon-free treatment.