EZETIMIBE IMPROVES EFFICACY OF PEGIFN AND RIBAVIRIN
THERAPY VIA ACCELERATION OF IFN-MEDIATED ISG15
M. Nakamuta1, M. Yada2, K. Notsumata3, N. Tanaka3, R. Yada1,
M. Kohjima1, K. Gotoh1, T. Yoshimoto1, N. Fukushima1,
K. Fukuizumi1, K. Kawabe1, T. Mizutani1, N. Harada1, S. Morizono4,
N. Sakamoto5, M. Enjoji6. 1Gastroenterology, Clinical Research
Center, Kyushu Medical Center, National Hospital Organization,
Fukuoka, 2Hepatology, Aso Iizuka Hospital, Iizuka, 3Internal Medicine,
Fukui-ken Saiseikai Hospital, Fukui, 4Internal Medicine, Saiseikai
Fukuoka Hospital, Fukuoka, 5Gastroenterology and Hepatology, Tokyo
Medical and Dental University, Tokyo, 6Clinical Pharmacology, Faculty
of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
Background and Aim: Lipid metabolism in the liver reportedly
affects innate immunity and hepatitis C virus (HCV) replication.
Ezetimibe, an HMG-CoA reductase inhibitor, is used as an adjuvant
to PegIFN and ribavirin therapy. It inhibits Nieman-Pick-C1-like-1,
which is abundantly expressed in the liver. Here, we investigated
ezetimibe’s effect on subgenomic HCV replication, and its efﬁcacy
when co-administered with PegIFN and ribavirin therapy.
Method: Samples from 334 HCV-1 high-titer patients treated with
PegIFN/RBV, of whom 44 received ezetimibe and 290 did not,
were used to study ezetimibe’s efﬁcacy as an adjuvant. Patients’
HCV RNA-negativity (deﬁned as early viral response [EVR]: less
than 50 IU/ml by Amplicore method) was tracked from the start of
treatment to the 12th week.
We also studied Huh7/Rep-Feo, an HCV-replicon cell line
expressing a selectable chimeric reporter protein of ﬁreﬂy luciferase
and neomycin, which was cultured with ezetimibe and IFNa.
Reporter protein expression was measured by luciferase assay;
expression levels of related genes were measured by quantitative
Results: In the clinical study, EVR occurred in 65.9% of patients
receiving ezetimibe, but only 45.2% of patients who did not
(P = 0.002). In the Huh7 cells, ezetimibe suppressed luciferase
activity in a dose-dependent manner, while enhancing IFNa’s
repression of HCV replication. To study this repressive mechanism,
we measured expression of several genes related to innate
immunity. Interferon singly induced ISG15, activating enzyme
Ube1L and conjugating enzyme UbcH8. Ezetimibe enhanced ISG15
expression singly and in combination with IFNa. Reportedly,
IFN-mediated ISGylation of HCV-NS5A inhibits HCV replication in
subgenomic replicon cells. These results suggest that ezetimibe may
accelerate the IFN-mediated ISG15 conjugation system.
Conclusions: Ezetimibe shows synergistic anti-HCV effect with
IFNa in subgenomic system by accelerating the IFN-mediated ISG15
conjugation system. Ezetimibe may be a promising adjuvant for
PegIFN and ribavirin therapy against chronic HCV infection.