AbbVie's 3D regimen (newly
named Viekirax + Exviera)
demonstrated a sustained
virological response rate of 97% for people with HCV genotype 1 recurrence after liver transplantation
who had not yet developed advanced liver fibrosis or cirrhosis, according to
results from the CORAL-I study presented at the American Association for the
Study of Liver Diseases (AASLD) Liver Meeting this month in Boston, United
States, and published simultaneously in the New England
Journal of Medicine.
Hepatitis C virus
(HCV) almost always re-infects the new liver after transplantation, often
resulting in rapid progression to severe fibrosis or cirrhosis and potential
graft loss. Liver transplant recipients have historically been difficult to
treat because they do not respond as well to interferon-based therapy and many cannot
tolerate its side-effects or effects on immunosuppressant drugs used to prevent
organ rejection. But now new direct-acting antiviral agents (DAAs) can be
combined in interferon-free regimens that produce high cure rates and are very
well-tolerated.
Parvez Mantry from the Liver
Institute at Methodist Dallas presented findings from CORAL-I, an ongoing phase
2 trial evaluating AbbVie's all-oral 3D regimen for liver transplant
recipients with recurrent HCV genotype 1 infection and mild-to-moderate liver
fibrosis.
Glossary
- erythropoietin
-
A natural hormone made in the kidneys to stimulate the production of red blood cells by the bone marrow.
- 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.
The 3D regimen consists of the HCV protease inhibitor
paritaprevir (ABT-450), NS5A inhibitor ombitasvir (ABT-267) and a ritonavir booster
in a once-daily co-formulation, taken with the twice-daily non-nucleoside HCV
polymerase inhibitor dasabuvir (ABT-333).
The study included 34 participants. About 80% were men
and the mean age was 60 years. Most (85%) had harder to treat HCV subtype 1a,
the rest 1b. Three-quarters had unfavourable IL28B gene variants. Liver
biopsies showed that 18% had no fibrosis (Metavir stage F0), 38% had mild
fibrosis (stage F1) and 44% had moderate fibrosis (stage F2). The median time
between transplantation and treatment was 40 months. None had received prior
treatment since transplantation, but some had previously been treated with
pegylated interferon/ribavirin.
All patients in this open-label study received the 3D
regimen plus ribavirin for 24 weeks. Ribavirin dosing was managed by study
investigators based on tolerability. A prior drug-drug interaction study showed
that combining the 3D regimen with immunosuppressants led to increased levels
of tacrolimus (7-fold) and ciclosporine (3-fold), so their doses were adjusted
accordingly.
At 12 and 24 weeks
post-treatment, 97% of participants achieved sustained virological response
(SVR12 and SVR24), or continued undetectable HCV viral load.
The one patient
without SVR experienced early viral relapse three days after finishing
treatment. Testing at that time revealed emergent resistance-associated
variants that were not present at baseline.
Treatment was
generally safe and well-tolerated. Two patients had serious adverse events and
one person discontinued early due to adverse events but still went on to
achieve SVR12. The most frequently reported side-effects were fatigue (50%),
headache (44%), cough (32%), anaemia (29%), diarrhoea (27%), insomnia (27%),
weakness (24%) and nausea (24%).
Most anaemia was mild
to moderate and no one stopped treatment for this reason, though five patients
received erythropoietin. Everyone who reduced their ribavirin dose went on to
achieve SVR. Two people had grade 3/4 bilirubin elevations, consistent with
paritaprevir's known effect on bilirubin transporter proteins.
There were no episodes of acute
or chronic rejection, no graft loss and no deaths. Tacrolimus and ciclosporine
concentrations
remained generally stable while taking the 3D regimen. Two patients experienced creatinine increases
after tacrolimus dosing errors, which normalised when dosing was corrected.
"This
multi-targeted, interferon-free regimen of ABT-450/ritonavir/ombitasvir,
dasabuvir, and ribavirin achieved high response rates in immunosuppressed liver
transplant recipients with recurrent HCV genotype 1 infection," the
investigators concluded. "This phase 2 study in liver transplant
recipients with mild to moderate liver disease shows that antiviral therapy may
offer clinical benefit before the acceleration of fibrosis to advanced liver
disease and its associated complications in this patient population."
Session moderator Anna Lok said that these results are "very
impressive", but raise the question of whether the addition of ribavirin
and such a long treatment duration are needed for patients with early fibrosis,
given that the 3D regimen taken for 12 weeks has produced similarly high SVR12
rates in non-transplant studies.
Mantry
noted that the CORAL study protocol is now being amended to include patients
with more advanced fibrosis and cirrhosis, and will also test the 3D regimen
without ribavirin for transplant recipients with early HCV recurrence.