D. Colledge et al., In vitro antihepadnaviral activities of combinations of penciclovir, lamivudine, and adefovir, ANTIM AG CH, 44(3), 2000, pp. 551-560
Penciclovir {9-[2-hydroxy-1-(hydroxymethyl)-ethoxymethyl]guanine [PCV]}, la
mivudine ([-]-beta-L-2',3'-dideoxy-3' -thiacytidine [3TC]), and adefovir (9
-[2-phosphonylmethoxyethyl]-adenine [PMEA]) are potent inhibitors of hepati
tis B virus (HBV) replication. Lamivudine has recently received approval fo
r clinical use against chronic human HBV infection, and both PCV and PMEA h
ave undergone clinical trials against HBV in their respective prodrug forms
{famciclovir and adefovir dipivoxil [bis-(POM)-PMEA]}. Since multidrug com
binations are likely to be used to control HBV infection, investigation of
potential interactions between PCV, 3TC, and PMEA is important. Primary duc
k hepatocyte cultures which were either acutely or congenitally infected wi
th the duck hepatitis B virus (DHBV) were used to investigate in vitro inte
ractions between PCV, 3TC, and PMEA. Here we show that the anti-DHBV effect
s of all the combinations containing PCV, 3TC, and PMEA are greater than th
at 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 the
re is evidence that PMEA has immunomodulatory activity and, at least in the
duck model of chronic HBV infection, is capable of inhibiting DHBV replica
tion in cells other than hepatocytes, the latter being unaffected by treatm
ent with either PCV or 3TC. Further investigation of the antiviral activiti
es of these drug combinations is therefore required, particularly since eac
h of the component drugs is already in clinical use.