Impact of NS5A sequences of Hepatitis C virus genotype 1a on early viral kinetics during treatment with peginterferon- alpha 2a plus ribavirin.
BACKGROUND. Hepatitis C virus (HCV) genotype 1 is the most prevalent genotype in Western countries, and treatment with pegylated interferon (pegIFN) plus ribavirin fails in 50%-60% of patients. Genetic variability within the NS5A dsRNA-dependent protein kinase binding domain (PKRbd) of HCV-1b has been associated with responsiveness to IFN- alpha . Little is known about NS5A sequences of HCV-1a. We investigated whether genetic variability of HCV-1a NS5A correlates with the early HCV kinetics during treatment.


METHODS
Twenty-four treatment-naive, HCV-1a-infected patients were treated with standard doses of pegIFN- alpha 2a plus ribavirin. HCV viremia was quantitated at days 0, 1, 2, and 3 and weeks 1, 2, 4, 8, and 12 of treatment. According to HCV kinetics, patients were classified as early rapid responders, early moderate responders, or early slow responders. The full-length HCV NS5A was sequenced at baseline and at week 1.


RESULTS
At baseline, variability of the NS5A C terminus (concentrated in the PKRbd) is associated with interferon efficacy but not with the second phase of the early viral decline that has been associated with a sustained virologic response. Comparisons between baseline and week-1 full-length sequences did not show significant increases in mutations.


CONCLUSIONS
Genetic variability of HCV-1a NS5A does not predict responsiveness to IFN- alpha . Differences in early kinetics during combination therapy are not due to selection of IFN-resistant HCV strains.
Dal Pero
Francesca
F
Venetian Institute for Molecular Medicine, Padova, 35129, Italy. francesca.dalpero@unipd.it
Tang
Kwok H
KH
Gerotto
Martina
M
Bortoletto
Gladis
G
Paulon
Emma
E
Herrmann
Eva
E
Zeuzem
Stefan
S
Alberti
Alfredo
A
Naoumov
Nikolai V
NV
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000145:classification / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D008954:Models, Biological; D008969:Molecular Sequence Data; D010802:Phylogeny; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; 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