Hepatitis C Virus Resistance In a plenary lecture, Ralf Bartenschlager, from
Heidelberg, Germany, reviewed the basics for the development of drug resistance
in HCV and the steps recently made to assess it.[10] HCV comprises a group of
positive-strand RNA viruses that, together with the flaviviruses and the
pestiviruses, belong to the Flaviviridae family. Chronic hepatitis C affects 175
million people worldwide, and nearly one quarter of HIV-infected patients are
coinfected with HCV. The viral genome was first molecularly cloned in 1988. The
3-dimensional structure has been solved for several viral enzymes that are prime
targets for antiviral therapy. However, a major hurdle in unraveling the HCV
life cycle has been the difficulty in propagating the virus in cell culture. A
first step to overcome this barrier was the establishment of subgenomic
replicons that self-amplify to high levels in the human hepatoma cell line
Huh-7. Subsequent studies led to the identification of
more efficient HCV replicons for different genotypes and cell lines. In spite
of this remarkable progress, the replicon system is limited because only the
intracellular steps of the HCV life cycle could be studied. This limitation was
recently overcome with the molecular cloning of a novel HCV isolate, JFH-1, that
was found in a Japanese patient who developed fulminant hepatitis. It replicates
to very high levels in cell culture, and virus particles are released from
infected cells.[11] JFH-1 genomes with reporter genes such as luciferase or
green fluorescent protein have been developed. Of importance, assays using these
genomes make it possible to quantify HCV production in the presence of
investigational inhibitors.
The first proof-of-concept that specific HCV inhibitors could be used to treat
patients with chronic hepatitis C came from studies of BILN-2061, a protease
inhibitor developed by Boehringer-Ingelheim.[12] There is now enormous
enthusiasm and effort in this field. Table 3 shows some of the HCV inhibitors
currently under development, which target the HCV protease, polymerase, and
helicase enzymes. One intriguing aspect is that while most protease inhibitors
directed against HCV have shown robust antiviral properties, the in vivo
inhibitory effects of most polymerase inhibitors, either nucleosides or
nonnucleoside analogs, have been much more modest. In this conference,
investigators from Merck reported that this might be just a matter of dose,
since potent suppression of viral replication was achieved in a dose-dependent
manner using MK-0608, a nucleoside inhibitor of the HCV NS5B polymerase.[13]
Table 3. New Anti-HCV Compounds in the Pipeline Modified Interferons
Polymerase Inhibitors Protease Inhibitors Nucleoside analogs Nonnucleoside
analogs
Albuferon
Consensus interferon

NM-283
R126
MK-0608

HCV-796
BI-2071
A-848837

VX-950
SCH-3034
BMS-5339
GS-9132
BI-1335
BI-1230
As in HIV, almost all of these antivirals can select for resistance mutations
and some of these changes may cause cross-resistance. So far, it seems that most
of these compounds show a low genetic barrier to resistance and, therefore,
combination therapy will be preferred in most instances. A further limitation of
many of these drugs will be that they are relatively specific for distinct HCV
genotypes and therefore will not work against other HCV genotypes.
References
Locarnini S. HBV drug resistance. Abstracts of the XV International Drug
Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract P2.
Locarnini S. Molecular virology and the development of resistant mutants:
implications for therapy. Semin Liver Dis. 2005;25(suppl 1):9-19. Abstract
Johnson V, Hazelwood J, Andersen J, et al. TDF and ADV are effective in
chronic HBV infection in subjects who are coinfected with HIV: HBV and HIV drug
resistance results of ACTG A5127. Abstracts of the XV International Drug
Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 9.
Sheldon J, Camino N, Rodes B, et al. Selection of hepatitis B virus
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Abstract
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phenotyping test to evaluate the drug susceptibility of HBV strains isolated
from patients: Phenoscript HBV. Abstracts of the XV International Drug
Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract 7.
Bartenschlager R. New achievements in hepatitis C virus research and their
implications for antiviral therapy. Abstracts of the XV International Drug
Resistance Workshop; June 13-17, 2006; Sitges, Spain. Abstract P1.
Wakita T, Pietschumann T, Kato T, et al. Production of infectious hepatitis C
virus in tissue culture from a cloned viral genome. Nat Med. 2005;11:791-796.
Abstract
Hinrichsen H, Benhamou Y, Wedemeyer H, et al. Short-term antiviral efficacy
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genotype 1 patients. Gastroenterology. 2004;127:1347-1355. Abstract
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