Pegylated interferon and ribavirin promote early evolution of nonstructural 5A protein in individuals with hepatitis C who demonstrate a response to treatment.
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.
Jain
Mamta K
MK
Department of Internal Medicine, University of Texas Southwestern Medical Center, 4323 Harry Hines Boulevard, Dallas, TX 75390, USA. mamta.jain@utsouthwestern.edu
Yuan
He-Jun
HJ
Adams-Huet
Beverley
B
Reeck
Amanda
A
Shelton
Janel
J
Attar
Nahid
N
Zhang
Song
S
Neumann
Avidan U
AU
Carney
David S
DS
Gale
Michael
M
Lee
William M
WM
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D019143:Evolution, Molecular; D015658:HIV Infections / Q000150:complications; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010802:Phylogeny; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D012367:RNA, Viral / Q000235:genetics; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use*; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C100416:peginterferon alfa-2a