Activity
of PMEO against Wild-type and Drug-resistant HBV
Various
antiviral agents are active against hepatitis B
virus (HBV), but treatment is hampered by the development of drug-resistant
virus. Successive therapy with nucleoside analogs including lamivudine
(Epivir-HBV), adefovir (Hepsera),
and entecavir (Baraclude) can
lead to the emergence of resistant virus strains harboring complex patterns of
mutations within the HBV polymerase gene.
At the annual meeting of the
American Association for the Study of Liver Diseases (AASLD)
last month in Boston, researchers presented data from a study of 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine
(PMEO), a novel acyclic pyrimidine nucleoside analog.
In past laboratory
studies, PMEO demonstrated an anti-HBV effect comparable to that of adefovir in
hepatoma cells expressing wild-type or lamivudine-resistant HBV. In the present
study, the researchers investigated the cross-resistance profile of multidrug-resistant
HBV strains against PMEO in comparison to lamivudine, adefovir, entecavir, and
tenofovir (not yet approved for
HBV, but marketed as Viread for HIV).
The
anti-HBV activity of the various agents was evaluated after transfection of Huh7
cells with HBV genomes cloned in a pTriex-HBV vector. These genomes were derived
from laboratory HBV strains, the viral quasispecies of a chronically infected
patient failing successive therapy with lamivudine and lamivudine plus adefovir,
and a chronically infected patient failing successive therapy with lamivudine
and entecavir. Drugs were administrated daily from Day 4 through Day 9 after transfection.
Cells were lysed at Day 9 for analysis of intracellular viral DNA.
Results
The in vitro drug potency in inhibiting wild-type HBV replication, whatever
the origin of the strain, was ranked in the following order:
For laboratory strains and virus from the second patient, PMEO similarly inhibited
the replication of wild-type and mutant HBV strains, whereas the activity of adefovir
and tenofovir was decreased against strains resistant to adefovir or lamivudine
plus adefovir.
The mutation M204V led to a loss of susceptibility to entecavir and resistance
to lamivudine.
For the first patient, all mutant strains were resistant to lamivudine, sensitive
to tenofovir, and retained susceptibility to PMEO.
The V173L/L180M/A181V/N236T mutant displayed the highest fold resistance to PMEO
(IC50= 28.6 ± 5.34 mcM).
Conclusion
"The antiviral potency and the cross-resistance
profile of PMEO suggest that it represents a new candidate for the treatment of
chronic HBV carriers who have developed resistance to currently approved drug
regimen, and for the design of combination therapy to delay the emergence of resistance,"
the researchers concluded. "PMEO warrants further evaluation in animal models
and clinical trials."
INSERM U271, Lyon, France; Rega institute
for Medical Research, Leuven, Belgium.
11/14/06
Reference F
Zoulim, M Brunelle, J Lucifora, and others. Inhibitory activity of the 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]-pyrimidine
(PMEO) against wild type and drug resistant mutants of HBV. 57th AASLD. Boston,
MA. October 27-31, 2006. Abstract 94.
The in vitro drug potency in inhibiting wild-type HBV replication, whatever
the origin of the strain, was ranked in the following order: 
