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Antimicrobial Agents and Chemotherapy, March 2000, p. 551-560, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Vitro Antihepadnaviral Activities of Combinations of Penciclovir, Lamivudine, and Adefovir

Danni Colledge, Gilda Civitico, Stephen Locarnini, and Tim Shaw*

Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, 3051, Australia

Received 7 June 1999/Returned for modification 27 August 1999/Accepted 7 December 1999

Penciclovir {9-[2-hydroxy-1-(hydroxymethyl)-ethoxymethyl]guanine [PCV]}, lamivudine ([-]-beta -L-2',3'-dideoxy-3'-thiacytidine [3TC]), and adefovir (9-[2-phosphonylmethoxyethyl]-adenine [PMEA]) are potent inhibitors of hepatitis B virus (HBV) replication. Lamivudine has recently received approval for clinical use against chronic human HBV infection, and both PCV and PMEA have undergone clinical trials against HBV in their respective prodrug forms {famciclovir and adefovir dipivoxil [bis-(POM)-PMEA]}. Since multidrug combinations are likely to be used to control HBV infection, investigation of potential interactions between PCV, 3TC, and PMEA is important. Primary duck hepatocyte cultures which were either acutely or congenitally infected with the duck hepatitis B virus (DHBV) were used to investigate in vitro interactions between PCV, 3TC, and PMEA. Here we show that the anti-DHBV effects of all the combinations containing PCV, 3TC, and PMEA are greater than that of each of the individual components and that their combined activities are approximately additive or synergistic. These results may underestimate the potential in vivo usefulness of PMEA-containing combinations, since there is evidence that PMEA has immunomodulatory activity and, at least in the duck model of chronic HBV infection, is capable of inhibiting DHBV replication in cells other than hepatocytes, the latter being unaffected by treatment with either PCV or 3TC. Further investigation of the antiviral activities of these drug combinations is therefore required, particularly since each of the component drugs is already in clinical use.

* Corresponding author. Mailing address: Victorian Infectious Diseases Reference Laboratory, Locked Bag 815, Carlton South, Victoria, 3053, Australia. Phone: 61 3 9342 2615. Fax: 61 3 9342 2666. E-mail: Tim.Shaw{at}nwhcn.org.au.

Antimicrobial Agents and Chemotherapy, March 2000, p. 551-560, Vol. 44, No. 3
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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