Rapid hepatitis C virus clearance by antivirals correlates with immune status of infected patients.

Altered immune parameters associated with hepatitis C virus (HCV) genotype 1b infection and their correlation with virus eradication in direct-acting antivirals (DAA)-treated patients were examined. Thirty-one HCV-infected patients were treated with DAAs for 12 weeks. Pre-DAA-treatment and post-DAA-treatment sera were analyzed for cytokines/chemokines using MILLIPLEX MAP. Serum complement level and antibody neutralization activity were measured separately. Sera from 11 spontaneously cleared HCV subjects were included for comparison. Rapid virological responders (RVR) or end-of-treatment responders (EOTR) were defined as patients with HCV RNA negative at week 4 or positive at week 4 and negative at week 12, respectively. HCV RNA eradication and a decrease in liver fibrosis-related cytokines after treatment were observed when compared with pretreatment sera from RVR and EOTR. In pretreatment sera, interferons and T-helper 1 or 2 cell-associated cytokines/chemokines were significantly higher among RVR as compared with EOTR. Furthermore, serum complement and virus neutralizing antibody levels were higher in pretreatment RVR sera. Eradication of HCV RNA by DAA decreased liver fibrosis-related cytokines. Pretreatment sera from RVR displayed an enhanced cytokine/chemokine, complement and virus neutralizing antibody response as compared with EOTR sera. Our results suggested that enhanced host immune status may play an additive role on HCV RNA clearance by DAA.

Contribution of genome-wide HCV genetic differences to outcome of interferon-based therapy in Caucasian American and African American patients.

BACKGROUND: Hepatitis C virus (HCV) has six major genotypes, and patients infected with genotype 1 respond less well to interferon-based therapy than other genotypes. African American patients respond to interferon alpha-based therapy at about half the rate of Caucasian Americans. The effect of HCV's genetic variation on treatment outcome in both racial groups is poorly understood. METHODOLOGY: We determined the near full-length pre-therapy consensus sequences from 94 patients infected with HCV genotype 1a or 1b undergoing treatment with peginterferon alpha-2a and ribavirin through the Virahep-C study. The sequences were stratified by genotype, race and treatment outcome to identify HCV genetic differences associated with treatment efficacy. PRINCIPAL FINDINGS: HCV sequences from patients who achieved sustained viral response were more diverse than sequences from non-responders. These inter-patient diversity differences were found primarily in the NS5A gene in genotype 1a and in core and NS2 in genotype 1b. These differences could not be explained by host selection pressures. Genotype 1b but not 1a African American patients had viral genetic differences that correlated with treatment outcome. CONCLUSIONS & SIGNIFICANCE: Higher inter-patient viral genetic diversity correlated with successful treatment, implying that there are HCV genotype 1 strains with intrinsic differences in sensitivity to therapy. Core, NS3 and NS5A have interferon-suppressive activities detectable through in vitro assays, and hence these activities also appear to function in human patients. Both preferential infection with relatively resistant HCV variants and host-specific factors appear to contribute to the unusually poor response to therapy in African American patients.

Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy.

Pegylated alpha interferon and ribavirin therapy for hepatitis C virus (HCV) genotype 1 infection fails for half of Caucasian American patients (CA) and more often for African Americans (AA). The reasons for these low response rates are unknown. HCV is highly genetically variable, but it is unknown how this variability affects response to therapy. To assess effects of viral diversity on response to therapy, the complete pretreatment genotype 1 HCV open reading frame was sequenced using samples from 94 participants in the Virahep-C study. Sequences from patients with >3.5 log declines in viral RNA levels by day 28 (marked responders) were more variable than those from patients with declines of <1.4 log (poor responders) in NS3 and NS5A for genotype 1a and in core and NS3 for genotype 1b. These correlations remained when all T-cell epitopes were excluded, indicating that these differences were not due to differential immune selection. When the sequences were compared by race of the patients, higher diversity in CA patients was found in E2 and NS2 but only for genotype 1b. Core, NS3, and NS5A can block the action of alpha interferon in vitro; hence, these genetic patterns are consistent with multiple amino acid variations independently impairing the function of HCV proteins that counteract interferon responses in humans, resulting in HCV strains with variable sensitivity to therapy. No evidence was found for novel HCV strains in the AA population, implying that AA patients may be infected with a higher proportion of the same resistant strains that are found in CA patients.