Naturally occurring dominant resistance mutations to HCV protease and polymerase inhibitors in treatment-naïve patients

• Published in: Hepatology (Baltimore, Md.) Vol. 48; no. 6; pp. 1769 - 1778
• Main Authors: Kuntzen, Thomas, Timm, Joerg, Berical, Andrew, Lennon, Niall, Berlin, Aaron M., Young, Sarah K., Lee, Bongshin, Heckerman, David, Carlson, Jonathan, Reyor, Laura L., Kleyman, Marianna, McMahon, Cory M., Birch, Christopher, Wiesch, Julian Schulze zur, Ledlie, Timothy, Koehrsen, Michael, Kodira, Chinnappa, Roberts, Andrew D., Lauer, Georg M., Rosen, Hugo R., Bihl, Florian, Cerny, Andreas, Spengler, Ulrich, Liu, Zhimin, Kim, Arthur Y., Xing, Yanming, Schneidewind, Arne, Madey, Margaret A., Fleckenstein, Jaquelyn F., Park, Vicki M., Galagan, James E., Nusbaum, Chad, Walker, Bruce D., Lake-Bakaar, Gerond V., Daar, Eric S., Jacobson, Ira M., Gomperts, Edward D., Edlin, Brian R., Donfield, Sharyne M., Chung, Raymond T., Talal, Andrew H., Marion, Tony, Birren, Bruce W., Henn, Matthew R., Allen, Todd M.
• Format: Journal Article
• Language: English
• Published: 01-12-2008
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.22549

Resistance mutations to HCV NS3 protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness
in vitro
. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant STAT-C resistance mutations in the population we analyzed HCV genome sequences from 507 treatment-naïve HCV genotype 1 infected patients from the US, Germany and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication competent, drug resistant viral strains in the population and to infer the consequences of these mutations upon viral replication
in vivo
. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir, the NS5B polymerase inhibitor AG-021541, and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multi-drug resistance. Collectively, however, 8.6% of the genotype 1a and 1.4% of the genotype 1b infected patients carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug resistant viral strains might achieve replication levels comparable to non-resistant viruses
in vivo
.
Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in HCV genotype 1 infected treatment-naïve patients. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous non-response to peginterferon and ribavirin.