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- 现金
- 62111 元
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- 30437
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- 2009-10-5
- 最后登录
- 2022-12-28
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414
Promising Antiviral Combination Therapy
Targeting HBV Eradication with Nucleoside
Analogue, Interferon, Statin, and a Novel
Compound Derived from Spice
Kazuya Okushin1,2, Hidetaka Fujinaga2, Takeya Tsutsumi3,
Kazuhiko Ikeuchi4,5, Akira Kado2, Kenichiro Enooku2,
Hiroshi Yotsuyanagi4, Kazuhiko Koike6 and Kyoji Moriya1,5,
(1)Department of Infection Control and Prevention, The
University of Tokyo, (2)Department of Gastroenterology,
The University of Tokyo, (3)Division of Infectious Diseases,
Advanced Clinical Research Center, The Institute of Medical
Science, the University of Tokyo, (4)Division of Infectious
Diseases, Advanced Clinical Research Center, the Institute of
Medical Science, The University of Tokyo, (5)Department of
Infectious Diseases, The University of Tokyo, (6)Department
of Gastroenterology, The University of Tokyo Graduate School
of Medicine
Background: A remarkable advance has been made in
the research and treatments of hepatitis B virus (HBV).
Nucleos(t)ide analogues efficiently suppress HBV replication
and prolong survival of HBV infected patients. However, no
existing nucleos(t)ide analogues could eradicate HBV from
hepatocyte, chiefly because of the residue of covalently closed
circular DNA (cccDNA). Consequently, novel therapeutic
strategies targeting HBV eradication are urgently needed.
We found a promising compound harboring anti-HBV effects
using HBV-replicating cells. In this study, we examined the
efficacy of combination therapies with this novel compound
(called compound F, applying for patent) using HBV-infected
humanized mice.Methods: Fifteen-week-old male mice
possessing transplanted human hepatocytes (PXB-mice)
were inoculated with HBV genotype C (1.0 x 107 HBV-DNA
copies/mouse). Seven weeks after HBV inoculation, mice
were separated into 3 groups. In group A (n=4), mice were
inoculated subcutaneously with pegylated interferon (Peg-
IFN)-2a (100 μg/kg) twice a week, together with daily oral
administration of entecavir (30 μg/kg), fluvastatin (10 mg/
kg), and compound F (100 μg/kg) for 8 weeks. In group B
(n=3), mice were treated with Peg-IFN-2a (30 μg/kg) similarly
with group A, together with daily fluvastatin (10 mg/kg) and
lamivudine (15 mg/kg). In a previous experiment, we confirmed
lamivudine and entecavir presented a similar antiviral efficacy
in these mice. In group C (n=3), no treatment was performed.
Serological and viral parameters were monitored once every
2 weeks throughout the follow-up period. We also evaluated
the concentration of cccDNA in the liver at the end of the
observation period.Results: In group A, cccDNA in the liver
significantly decreased to 198 ± 132.6 copies/100ngDNA
(mean ± SD, p < 0.05 compared with both group B and
group C). HBV-DNA and HBsAg continuously decreased and
reached to 1362.5 ± 1144.1 copies/mL and 177.0 ± 134.0 IU/
mL at day 56, respectively (p < 0.05 compared with group
C). Concerning the tolerability of the treatment, no major
complication and death were observed in all of the groups,
but transient elevations of liver enzymes were observed in
group A from day 14 to 28, but decreased to the same levels
of group B and group C at day 42. Conclusion: An additional
administration of compound F presented remarkable antiviral
efficacy, especially on intrahepatic cccDNA, compared with
an existing antiviral treatment. These results suggest a
possibility of HBV eradication by the new therapeutic regimen.
Compound F is a derivative of spice and its safety to human
is secured, although the initial elevation of transaminases
may be monitored. Further studies prefiguring the antiviral
mechanism of compound F and confirming the efficacy and
safety of long-term administration are necessary, but we
expect the combination therapy with compound F should be
a promising candidate for therapeutic strategies in clinical
practice.
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发表于 2018-10-18 13:49