Naturally Occurring Resistance to HCV Protease and Polymerase Inhibitors in Trea

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Naturally Occurring Resistance to HCV Protease and Polymerase Inhibitors in Treatment-naive Hepatitis C Patients By Liz Highleyman

Given the suboptimal response rates and difficult side effects of interferon-based therapy for chronic hepatitis C, researchers have explored various agents that act at various steps of the HCV lifecycle, collectively known as specifically targeted antiviral therapy for HCV, or "STAT-C."

While studies of STAT-C agents -- including HCV protease inhibitors and polymerase inhibitors -- have produced promising results, the drawback of this approach is the emergence of drug-resistant virus.

As is the case with antiretroviral therapy for HIV, some individuals have natural pre-existing viral mutations than confer drug resistance. T. Kuntzen of Harvard Medical School and colleagues conducted a study to characterize such mutations in people with chronic hepatitis C. Results were reported in the December 2008 issue of Hepatology and at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008).Resistance mutations to HCV NS3 protease inhibitors in less than 1% of an individuals' viral quasispecies may still allow for a greater than 1000-fold reduction in HCV RNA, consistent with their reported reduced replicative fitness in vitro, the researchers noted as background. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naive individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against STAT-C agents in the population, the investigators analyzed HCV genome sequences from 507 treatment-naive patients with HCV genotype 1 from the U.S., Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent drug-resistant HCV strains in the population, and to estimate the consequences of these mutations on viral replication. Results

The researchers detected mutations reported to confer resistance to the HCV protease inhibitors telaprevir (VX-950), ITMN-191, boceprevir (SCH503034), SCH6, and BILN2061 (discontinued due to toxicity); the NS5B polymerase inhibitor AG-021541; and the NS4A antagonist ACH-806. These mutations were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% of the population. 2 patients were found to have possible multidrug resistance. Collectively, 8.6% of the patients with HCV genotype 1a and 1.4% of those with genotype 1b carried at least 1 dominant resistance mutation. HCV viral loads were high in a majority of these patients, suggesting that drug-resistant viral strains may replicate at levels comparable to those of non-resistant (wild type) virus.

Based on these findings, the researchers concluded, "Naturally occurring dominant STAT-C resistance mutations are common in treatment-naive patients infected with HCV genotype 1."They continued that the effect of these resistant viruses on treatment outcomes "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 nonresponse to peginterferon and ribavirin."Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.1/09/09