伽玛干扰+恩曲他滨+左旋氟甲脲嘧啶对乙肝旱獭模型效应

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[B]Combination Treatment with Coviracil (emtricitabine) Plus Clevudine with Interferon Gamma in the Woodchuck Model of Hepatitis B Infection [/B]

New strategies for the treatment of chronic hepatitis B based on multi-drug combinations may be required to clear viral replication. The object of the current study, conducted in France and Germany, was to evaluate in woodchucks (Marmota Monax) chronically infected with the hepatitis B virus (WHV), combination treatment with two reverse transcriptase inhibitors: Coviracil (emtricitabine; FTC) and clevudine (L-FMAU) with adenovirus-driven delivery of recombinant interferon gamma.

Seventeen captive-born woodchucks experimentally infected with WHV were entered into the protocol. During the three-month treatment-period, six woodchucks received Clevudine (10 mg/kg) plus FTC (30 mg/kg) intraperitonealy every other day for 8 weeks. Six received the same treatment associated with intravenous injections of 1010 particles of recombinant woodchuck IFN gamma-adenovirus vector (Ad-IFN) at week 4 and week 8.

Five controls were included in the study, two received Ad-IFN alone, two received adenovirus vector expressing the reporter gene GFP (Ad GFP) and one was untreated. Liver wedge biopsies were performed prior to therapy, at week 5 and at week 9. The viremia was quantified, from blood samples collected every two days, by dot-blot and real time PCR assays. Intrahepatic viral DNA was analyzed by Southern blot hybridization.

In less than 2 weeks, woodchucks which received clevudine plus Coviracil showed a rapid and marked drop in viremia with a 4 to 5 log10 average drop to the limit of detection (6.107 copies/mL) of the dot blot assay. The viral load was further analyzed using a WHV-specific real time PCR assay (limit of detection 100 copies/mL).

Results from the WHV real time PCR assay showed an additional 3-log10 drop in WHV DNA during the treatment period to reach the lowest average value of 9.104 copies/mL. Moreover, viremia remained suppressed for several months following end of treatment.

Rebounds of viral replication were observed in two of the treated woodchucks at week 30 and viremia was still undetectable by dot-blot at week 31. A marked decrease in intrahepatic viral DNA, extracted from the wedge biopsies, was observed in the clevudine + Coviracil treated-groups. Replicative intermediates decreased to undetectable levels.

Intrahepatic covalently closed circular (CCC) DNA levels persisted with a decrease ranging from 24 to 47% compared to pretreatment values. Injection of Ad-IFN alone did not induce a significant decrease in viremia or in intrahepatic viral DNA. However, histology examination of liver sections showed that Ad-IFN in combination with clevudine + Coviracil resulted in an increased inflammation in the liver.

Four of the six woodchucks in this group had lobular lesions similar to those described in acute lobular hepatitis, whereas woodchucks treated with clevudine + Coviracil alone or with Ad-IFN alone had a normal background.

Conclusions: These results indicate that therapy combining clevudine plus Coviracil resulted in a pronounced antiviral effect and represent a potent antihepadnaviral treatment in the woodchuck model.

This study did not show any added benefit of Ad-IFN on the clevudine + Coviracil combination. The clevudine + Coviracil combination should be considered as a new approach for therapy against chronic HBV infection.

Editor's Note: Both Coviracil (emtricitabine) and clevudine were developed by Triangle Pharmaceuticals, which recently was acquired by Gilead Sciences. Coviracil is now under review by the US FDA for approval as a treatment (in combination with other antiretrovirals) for HIV infection. RB

• Triangle Pharmaceuticals Submits New Drug Application for Coviracil (Emtricitabine) for Treatment of HIV

• Gilead Sciences Buys Triangle for $464 Million

01/22/03

Reference
A C Jacquard and others. EVALUATION OF A COMBINATION OF CLEVUDINE AND EMTRICITABINE WITH ADENOVIRUS MEDIATED DELIVERY OF INTERFERON GAMMA IN THE WOODCHUCK MODEL OF HBV INFECTION. Abstract 844. 53rd AASLD. November 1-5, 2002. Boston, MA. Hepatology 2002: Vol 36 No 4, Pt 2 of 2.