Effects of pyrimidine and purine analog combinations in the duck hepatitis B virus infection model.
To design new strategies of antiviral therapy for chronic hepatitis B, we have evaluated the antiviral activity of the combination of amdoxovir (DAPD), emtricitabine [(-)FTC], and clevudine (L-FMAU) in the duck hepatitis B virus (DHBV) model. Using their triphosphate (TP) derivatives in a cell-free system expressing a wild-type active DHBV reverse transcriptase (RT), the three dual combinations exhibited a greater additive inhibitory effect on viral minus-strand DNA synthesis than the single drugs, according to the Bliss independence model. Both dual combinations with DAPD TP were the most efficient while the triple combination increased the inhibitory effect on the DHBV RT activity in comparison with the dual association, however, without additive effect. Postinoculation treatment of experimentally infected primary duck hepatocytes showed that dual and triple combinations potently inhibited viral DNA synthesis during treatment but did not inhibit the reinitiation of viral DNA synthesis after treatment cessation. Preinoculation treatment with the same combinations exhibited antiviral effects on intracellular viral DNA replication, but it was unable to prevent the initial covalently closed circular DNA (cccDNA) formation. Short-term in vivo treatment in acutely infected ducklings showed that the dual combinations were more-potent inhibitors of virus production than the single treatments, with the L-FMAU and FTC combination being the most potent. A longer administration of L-FMAU and FTC for 4 weeks efficiently suppressed viremia and viral replication. However, no viral clearance from the liver was observed, suggesting that the enhanced antiviral effect of this combination was not sufficient for cccDNA suppression and HBV eradication from infected cells.
Seignères
Béatrice
B
INSERM Unit 271, 69003 Lyon, France.
Martin
Perrine
P
Werle
Bettina
B
Schorr
Olivier
O
Jamard
Catherine
C
Rimsky
Laurence
L
Trépo
Christian
C
Zoulim
Fabien
F
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D015139:Blotting, Southern; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D004148:Dioxolanes / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004372:Ducks; D000068679:Emtricitabine; D018347:Hepadnaviridae Infections / Q000188:drug therapy*; D015611:Hepatitis B Virus, Duck / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006524:Hepatitis, Viral, Animal / Q000188:drug therapy*; D022781:Hepatocytes / Q000821:virology; D016133:Polymerase Chain Reaction; D011684:Purine Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004148:Dioxolanes; D011684:Purine Nucleosides; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; D001086:Arabinofuranosyluracil; C098393:amdoxovir; D000068679:Emtricitabine; C034935:clevudine