Pegylated Interferon and Ribavirin Promote Early Evolution of Nonstructural 5A Protein in Individuals with Hepatitis C Who Demonstrate a Response to Treatment

Abstract

Background Hepatitis C virus (HCV) quasispecies diversity is more likely to affect early viral decline during treatment of hepatitis C than is having human immunodeficiency virus (HIV) infection. We evaluated the influence of HCV therapy on changes in the nonstructural 5A (NS5A) protein. Methods Fifteen patients with HCV genotype 1 infection with or without HIV infection were recruited for the present study, and the decrease in the HCV RNA level was measured at early time points. The evolution of HCV NS5A quasispecies within the first week was analyzed by comparing the clones observed at later times in the study with the baseline consensus sequence of individual patients. The response to therapy was defined as an early response (ER; ie, an HCV RNA level <615 IU/mL at week 4) or a slow response (SR; ie, a detectable HCV RNA level at week 4). Results HIV infection did not affect early viral kinetics. At baseline, lower diversity was seen in NS5A and in the amino and carboxyl termini of patients with an ER, compared with those with an SR. Rapid evolution of the NS5A genetic region occurred in patients with an ER (P =.01) but not in those with an SR (P =.73). The evolution was the result of an increase in the number of amino acid substitutions in the carboxyl region (P = .02) in patients with an ER. Conclusions Selective pressure appears to result in more-marked changes in individuals with an ER than in those with an SR. The carboxyl terminus was subject to the most change and may be an important determinant of phenotypic resistance to interferon-based therapy.

Analysis of HCV quasispecies dynamic under selective pressure of combined therapy

“…Our findings are consistent with previous observations made on patients undergoing anti-HCV therapy that less complexity and lower diversity of HCV quasispecies at the baseline is associated with viral clearance [19,21,37-39]. Therefore, high genetic variability of HCV could be related to the low efficiency of anti-HCV treatment [22].…”

“…Therefore, high genetic variability of HCV could be related to the low efficiency of anti-HCV treatment [22]. Jain et al observed that the initial anti-viral effect of interferon is influenced by the quasispecies composition at the time of treatment initiation, and patients who demonstrated high viral diversity were less likely to respond to treatment [21]. In agreement with the genetic distance and entropy results, the number of viral strains at baseline was lower for SVR patients than NR and ETR patients, showing that quasispecies composition was more homogeneous than other groups of responses.…”

Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes

“…However, studies on HCV dynamics typically include a small number of patients. 11,21,27,30,33,34,37,[39][40][41][42][52][53][54][55][56][57][58] Despite this limitation, we identified a delayed early HCV kinetics pattern in LT patients that should be further investigated in larger studies before drawing any definitive conclusion.…”

A single nucleotide polymorphism in IL28B affects viral evolution of hepatitis C quasispecies after pegylated interferon and ribavirin therapy

“…However, no study has examined the difference in viral sequence diversity between patients with different IL28B SNP polymorphism. In a prior study, more patients with lower baseline sequence diversity in HCV NS5A region were able to achieve early viral response [Jain et al, 2009]. In this study, patients with the favorable CC polymorphism at rs12979860 were hypothesized to have lower sequence diversity.…”

“…Patients were recruited prospectively from the HIV and Liver Clinics at Parkland Health and Hospital Systems, a teaching hospital associated with UT Southwestern Medical Center. Patient selection criteria have been described previously [Jain et al, 2009]. All patients signed an informed consent, and were anti‐HCV positive, aged 18–65, and had HCV genotype 1 with serum HCV RNA> 1,000 IU/ml by either polymerase chain reaction (PCR) or branched DNA (bDNA) assays.…”