Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients.

UNLABELLED: Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (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 resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, 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 multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b 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 nonresistant viruses in vivo. CONCLUSION: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. 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 nonresponse to peginterferon and ribavirin.

Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response.

BACKGROUND: African Americans with genotype 1 chronic hepatitis C attain a sustained virologic response (SVR) at only approximately one-half the rate of whites after peginterferon and ribavirin treatment. The serum concentration of 25-hydroxyvitamin D [25(OH)D] has recently been established as a predictor of treatment response. Therefore, the low serum concentrations of 25(OH)D found among African Americans may contribute to the low response rate; however, to our knowledge, none of the studies of vitamin D in chronic hepatitis C treatment have included a significant number of black patients. OBJECTIVE: The objective was to compare the relation between the 25(OH)D concentration and genotype 1 chronic hepatitis C treatment response in African Americans with that in whites. DESIGN: This cross-sectional analysis included 106 African American and 65 white patients with genotype 1 chronic hepatitis C. RESULTS: Consistent with previous studies, we found that the SVR rate in the white patients increased significantly with an increasing serum concentration of 25(OH)D [SVR rates were 20%, 46%, and 70% for 25(OH)D serum concentrations <20, 20-35, and >35 ng/mL, respectively; P-trend = 0.008]; however, there was no relation between the SVR rate and 25(OH)D serum concentration in the African American patients [SVR rates were 32%, 28%, and 33% for 25(OH)D serum concentrations <20, 20-35, and >35 ng/mL, respectively; P-trend = 0.832]. We also found an analogous racial difference in the relation between the extent of liver fibrosis and the 25(OH)D concentration. CONCLUSION: Racial differences in vitamin D physiology or race-specific factors that modify the effects of vitamin D may affect the immune response to genotype 1 hepatitis C virus.

The induction of type I interferon production in hepatitis C-infected patients.

Chronic infection with hepatitis C virus (HCV) is a major global health problem. One way HCV may evade the host immune response is by inhibiting the production of type I interferon (IFN). In addition, the standard treatment for chronic HCV infection involves treatment with IFN-alpha (or its pegylated derivative), alone or in combination with ribavirin. Therefore, it is believed that an important reason that most HCV-infected individuals progress from acute to chronic infection is due to a defect in the host response. In this study, we examined the host response to HCV infection in a cohort of patients enrolled in the UTHSC Cooperative HCV Research Center by determining levels of biologically active IFN in the sera of patients. We found that 15 of 35 enrolled HCV-infected patients show serum levels of IFN (ranging from 2 to 40 IU/mL) before initiation of therapy. Uninfected individuals do not have circulating levels of IFN. Basal IFN levels do not correlate with the clinical response to therapy, nor do they reflect the age, sex, or race of patients. These results suggest that the differential response of patients most likely reflects a defect in the later stages of the host innate immune response, such as the cellular response to endogenous or exogenous IFN. In contrast, the early stage of the host immune response in vivo of many HCV-infected patients (approximately 40%) is intact as determined by IFN production.