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Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovir in vitro
Author(s) -
Colledge D,
Locarnini S,
Shaw T
Publication year - 1997
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510260129
Subject(s) - lamivudine , duck hepatitis b virus , virology , penciclovir , nucleoside , hepatitis b virus , nucleoside analogue , in vivo , biology , hepatitis b , pharmacology , cccdna , deoxyguanosine , viral replication , woodchuck hepatitis virus , in vitro , hepadnaviridae , virus , dna , biochemistry , hbsag , microbiology and biotechnology , herpes simplex virus
Lamivudine ([‐]‐β‐ L ‐2′,3′‐dideoxy‐3′‐thiacytidine [3TC]) and penciclovir (9‐[2‐hydroxy‐1‐(hydroxymethyl)ethoxymethyl]guanine [PCV]) are potent inhibitors of hepatitis B virus (HBV) replication. Both drugs have entered phase III clinical trials for treatment of chronic HBV infection. 3TC and PCV are deoxycytidine and deoxyguanosine analogs, respectively, and their modes of action and how they interact are matters of both theoretical and practical interest. We compared the antiviral activities of 3TC and PCV alone and in combination in primary duck hepatocyte (PDH) cultures derived from ducklings congenitally infected with the duck hepatitis B virus (DHBV). 3TC and PCV inhibited DHBV replication to a comparable extent when used alone (50% inhibitory concentrations with 95% confidence intervals were 0.55 [0.50‐0.59] μmol/L for 3TC and 0.35 [0.27‐0.43] μmol/L for PCV), and in combination, the two nucleoside analogs acted synergistically over a wide range of clinically relevant concentrations. Synergy between PCV and 3TC was also observed in acutely infected cells and in “washout” experiments designed to assess the persistence of antiviral activity after drug removal. Furthermore, the combination was more effective in reducing the normally recalcitrant viral covalently closed circular (CCC) DNA form of DHBV than either drug alone. These results suggest that combinations of 3TC and PCV may act synergistically against HBV in vivo .