Effect of a combination of clevudine and emtricitabine with adenovirus-mediated delivery of gamma interferon in the woodchuck model of hepatitis B virus infection.
Our aim was to evaluate the antiviral effect of a combination of two nucleoside reverse transcriptase inhibitors, emtricitabine (FTC) and clevudine (L-FMAU), with the addition of an adenovirus-driven delivery of recombinant gamma interferon (IFN-gamma) in the woodchuck model of hepatitis B virus infection. Six woodchuck hepatitis virus (WHV)-infected woodchucks received L-FMAU (10 mg/kg) plus FTC (30 mg/kg) intraperitoneally for 8 weeks; six other animals received in addition an intravenous injection of a recombinant adenovirus vector expressing woodchuck IFN-gamma (Ad-IFN) at weeks 4 and 8. In the control group, two animals received Ad-IFN alone, two received adenovirus vector expressing the green fluorescent protein reporter gene, and one remained untreated. In less than 2 weeks, all woodchucks that received L-FMAU plus FTC showed a rapid and marked inhibition of viral replication, with a 4-log(10) drop in serum WHV DNA. In two animals, viremia remained suppressed for several months after the end of treatment. Similarly, a dramatic decrease in intrahepatic replicative intermediates of viral DNA was observed in the L-FMAU/FTC-treated groups. The additional administration of Ad-IFN led to increased inflammation in the liver but did not enhance the antiviral effect of the L-FMAU/FTC combination. In conclusion, therapies combining L-FMAU and FTC in WHV-infected woodchucks resulted in a potent and sustained antihepadnaviral effect both in the liver and in the blood circulation. However, no extra benefit of adding IFN-gamma gene transduction to the L-FMAU/FTC combination could be detected.
Jacquard
A C
AC
INSERM U271, 151 Cours Albert Thomas, 69003 Lyon, France.
Nassal
M
M
Pichoud
C
C
Ren
S
S
Schultz
U
U
Guerret
S
S
Chevallier
M
M
Werle
B
B
Peyrol
S
S
Jamard
C
C
Rimsky
L T
LT
Trepo
C
C
Zoulim
F
F
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004338:Drug Combinations; D000068679:Emtricitabine; D015316:Genetic Therapy; D006509:Hepatitis B / Q000188:drug therapy / Q000628:therapy*; D006512:Hepatitis B Core Antigens / Q000378:metabolism; D017919:Hepatitis B Virus, Woodchuck; D007371:Interferon-gamma / Q000235:genetics* / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008392:Marmota / Q000502:physiology*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000201:enzymology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014766:Viremia / Q000821:virology; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology
D000998:Antiviral Agents; D004338:Drug Combinations; D006512:Hepatitis B Core Antigens; D018809:Proliferating Cell Nuclear Antigen; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D001086:Arabinofuranosyluracil; D007371:Interferon-gamma; D004259:DNA-Directed DNA Polymerase; D000068679:Emtricitabine; C034935:clevudine