Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy.
OBJECTIVE
Patients with high titer (>/=100 kIU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve highly sustained virological response rates to combination therapy with interferon plus ribavirin. Non-virological responders (NVRs, namely ultimate resistant cases) who do not achieve HCV-RNA negativity during treatment are also encountered. We investigated the pretreatment virological features of NVRs.


METHODS
We evaluated 50 consecutive Japanese adults with high titer of HCV genotype 1b who received combination therapy for 48 weeks. We investigated the pretreatment substitution patterns in amino acids 1-191 of the core region and amino acids 2209-2248 of NS5A, and early viral kinetics.


RESULTS
Overall, a non-virological response was noted in 12 (24%) patients. Multivariate analysis identified serum albumin <3.9 g/dl, substitutions of amino acid 70 in the core region, and substitutions of amino acid 91 as independent and significant factors associated with a non-virological response. Especially, substitutions of arginine (R) by glutamine (Q) at amino acid 70, and/or leucine (L) by methionine (M) at amino acid 91 were significantly more common in NVRs. The falls in HCV-RNA levels during treatment in patients with specific substitutions in the core region were significantly less than in those without such substitutions.


CONCLUSIONS
Our results suggest that serum albumin and amino acid substitution patterns in the core region in patients with high titers of HCV genotype 1b may have an effect on combination therapy in NVRs. Further large-scale studies are required to examine the role of amino acid substitutions specific to a non-virological response to combination therapy.
Akuta
Norio
N
Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. akuta-gi@umin.ac.jp
Suzuki
Fumitaka
F
Sezaki
Hitomi
H
Suzuki
Yoshiyuki
Y
Hosaka
Tetsuya
T
Someya
Takashi
T
Kobayashi
Masahiro
M
Saitoh
Satoshi
S
Watahiki
Sachiyo
S
Sato
Junko
J
Matsuda
Marie
M
Kobayashi
Mariko
M
Arase
Yasuji
Y
Ikeda
Kenji
K
Kumada
Hiromitsu
H
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000145:classification / Q000235:genetics* / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D007372:Interferons / Q000494:pharmacology / Q000627:therapeutic use*; D007564:Japan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D012367:RNA, Viral / Q000097:blood; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use*; D012709:Serum Albumin / Q000032:analysis; D014758:Viral Core Proteins / Q000737:chemistry* / Q000235:genetics; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D007372:Interferons; D012367:RNA, Viral; D012254:Ribavirin; D012709:Serum Albumin; D014758:Viral Core Proteins; D017361:Viral Nonstructural Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase