Efficacy and Changes of the Nonstructural 5A GENE by Prolonged Interferon Therapy for Patients with Hepatitis C Virus genotype 1b and a High Level of Serum HCV-RNA.

Arase, Yasuji; Ikeda, Kenji; Chayama, Kazuaki; Matsumoto, Naoya; Tsubota, Akihito; Suzuki, Yoshiyuki; Saitoh, Satoshi; Kobayashi, Masahiro; Kobayashi, Mariko; Kobayashi, Mizuho; Kumada, Hiromitsu

doi:10.2169/internalmedicine.38.461

Cited by 14 publications

(10 citation statements)

References 24 publications

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“…This sequence has been termed the interferon sensitivity-determining region (ISDR). These results were then confirmed by other Japanese studies [11][12][13][14][15] , but were never in accordance with most Western European [16][17][18][19][20] and American studies [21][22][23] , in which most of the ISDR sequences harbored an intermediate profile.…”

Section: Introductionsupporting

confidence: 65%

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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AIM:To evaluate the implication of substitutions in the hepatitis C virus (HCV) non-structural 5A (NS5A) protein in the resistance of HCV during mono-interferon (IFN) or combined IFN-ribavirin (IFN-R) therapy. Although NS5A has been reported to interact with the HCV RNAdependent RNA polymerase, NS5B, as well as with many cellular proteins, the function of NS5A in the life cycle of HCV remains unclear.METHODS: HCV quasispecies were studied by cloning and sequencing of sequential isolates from patients infected by HCV genotype 1b. Patients were treated by IFN-α2b for 3 mo followed by IFN-α2b alone or combined IFN-R therapy for 9 additional months. Patients were categorized intro two groups based on their response to the treatments: 7 with sustained virological response (SVR) (quasispecies = 150) and 3 non-responders (NR) to IFN-R (quasispecies = 106). RESULTS:Prior to treatment, SVR patients displayed a lower complexity of quasispecies than NR patients. Most patients had a decrease in the complexity of quasispecies during therapy. Analysis of amino acids substitutions showed that the degree of the complexity of the interferon sensitivity-determining region (ISDR) and the V3 domain of NS5A protein was able to discriminate the two groups of patients. Moreover, SVR patients displayed more variability in the NS5A region than NR patients. CONCLUSION:These results suggest that detailed molecular analysis of the NS5A region may be important for understanding its function in IFN response during HCV 1b infection.

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Section: Introductionsupporting

confidence: 65%

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Veillon

Payan²,

Guillou‐Guillemette³

et al. 2007

WJG

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“…Of these 11 substitutions, only R2234Q is unique to IFN-sensitive ISDRs. The R2234Q substitution is also lacking in the ISDR sequences of all other IFN-resistant viruses published to date but not included in the database [Rispeter et al, 1998;Ibarrola et al, 1999;Mihm et al, 1999;Arase et al, 1999;Sakuma et al, 1999]. The observation that substitutions in IFN-sensitive viruses are not less conservative than substitutions in the IFN-resistant viruses suggests that the general integrity of the NS5A protein is maintained in IFNsensitive viruses.…”

Section: Analysis Of Individual Substitutions In the Isdrmentioning

confidence: 99%

“…Of the 25 studies that have published ISDR sequences from IFN resistant and IFNsensitive viruses, nine support the Enomoto model and conclude that, at the 5% significance level, the data provide sufficient evidence that IFN-response and substitutions in the ISDR are dependent [Enomoto et al, 1995[Enomoto et al, , 1996Chayama et al, 1997;Kurosaki et al, 1997;Fukuda et al, 1998;Saiz et al, 1998;Murashima et al, 1999;Sarrazin et al 1999;Sakuma et al, 1999]. The other 16 studies were unable to conclude that there is a correlation [Hofgartner et al, 1997;Khorsi et al, 1997;Squadrito et al, 1997;Zeuzem et al, 1997;Duverlie et al, 1998;Franguel et al, 1998;Odeberg et al, 1998;Pawlotsky et al, 1998;Polyak et al, 1998;Rispeter et al, 1998;Chung et al, 1999;Sarrazin et al 1999;Squadrito et al, 1999;Ibarrola et al, 1999;Mihm et al, 1999;Arase et al, 1999].…”

Section: Introductionmentioning

confidence: 98%

Statistical analysis of combined substitutions in nonstructural 5A region of hepatitis C virus and interferon response

Witherell¹,

Beineke²

2000

J. Med. Virol.

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Interferon (IFN) therapy (+/- ribavirin) is the only currently available treatment for chronic hepatitis C virus (HCV), but is not effective for a majority of patients. Several studies have correlated IFN response with substitutions in a small region of the nonstructural 5A (NS5A) gene product of HCV, termed the interferon sensitivity determining region (ISDR). Many other studies, however, have been unable to verify this correlation. To address this issue, available data from published studies was used to create a database of 675 individual ISDR sequences. The database was used to analyze substitutions in the ISDR with regard to IFN response. Combined data was analyzed by the chi-square independence test and by logistic regression analysis. Each statistical analysis demonstrated a strong correlation between IFN response and substitutions in the ISDR. A statistically significant correlation was also found between IFN-response and substitutions in ISDRs of combined studies that independently were unable to detect a correlation. The failure of these individual studies to verify a correlation seems to be at least partially due to inadequate sample size. A new model for chi-square analysis is proposed that could allow a correlation between IFN-response and ISDR sequence to be detected for data sets with less statistical power than that required for the current model. The ISDR database was also used to analyze individual substitutions in the ISDR. The results show that IFN-sensitive viruses contain a larger number and more diverse collection of substitutions than IFN-resistant viruses. Substitutions that are most likely to be tolerated or detrimental to NS5A function in the IFN-response mechanism were identified as a first step toward site directed mutagenesis of the ISDR.

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“…To enhance the response rate, prolonged IFN therapy, [12][13][14] or combination therapy with other drugs (e.g., ribavirin) has been reported recently. 6,7 However, irrespective of the treatment strategy, the viral clearance rate remained at 20%-30%, at most, in patients with HCVgenotype 1b and an HCV-RNA level of more than 1 Meq/ml.…”

Section: Factors Determining Cr By Logistic Regression Analysismentioning

confidence: 99%

“…To reduce the relapse rate and improve the response rate, various approaches have been used, including the administration of IFN with other agents, [5][6][7][8][9][10] and prolongation of and/or higher dose/ higher frequency of IFN therapy. [11][12][13][14] For the treatment of chronic hepatitis B, several studies have suggested that the serum level of hepatitis B virus decreases after acute exacerbation. 15,16 Similarly, in patients with chronic hepatitis C, the serum HCV-RNA level may decrease at the recovery stage of alanine aminotransferase (ALT) relapse.…”

Section: Introductionmentioning

confidence: 99%

Increased response rate to interferon therapy after a second course in hepatitis C patients who show relapse after the initial course

Arase

Ikeda

Chayama

et al. 2000

Journal of Gastroenterology

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Some patients with chronic hepatitis C become HCV-RNA seronegative during interferon (IFN) therapy. However, about one-half of these patients show a relapse, evident by high serum alanine aminotransferase (ALT) level. In some patients with biochemical relapse, the serum HCV-RNA level becomes low immediately after the ALT relapse. Here, we assessed the changes in serum HCV-RNA level in patients with ALT relapse after IFN therapy, and evaluated the efficacy of a second course of IFN, started at the recovery stage after ALT relapse. Two hundred and seventy-seven patients who showed HCV-RNA seronegativity by reverse transcription nested-polymerase chain reaction (RT nested-PCR) and normalization of ALT during the initial IFN therapy, and had positive HCV-RNA with ALT relapse (> 100 IU/l) within 3 months after completion of the initial IFN course were enrolled in this retrospective study. Two hundred and sixty patients were followed-up without further IFN retreatment after the ALT relapse (group 1), and 17 patients received another 6-month course of IFN after the ALT relapse (group 2). The median level of serum HCV-RNA, determined with a branched DNA probe assay (version 1; Chiron-Dai-ichi Kagaku Tokyo, Japan), in group 1 was 3.1 Meq/ml before IFN therapy, 1.3 Meq/ml at the time point of the ALT peak after the completion of IFN therapy, and 0.7 and 2.6 Meq/ml at 2-4 and 6-8 weeks after the ALT peak, respectively. The serum HCV-RNA level at 2-4 weeks after the ALT peak was lower than that before IFN therapy. The eradication rate of HCV-RNA (complete response; CR) in group 2 (47.1%; 8/17) was significantly higher than that in group 1 (1.5%; 4/260; P < 0.001). In conclusion, our data suggested that: (1) patients who showed biochemical relapse after initial IFN therapy had a significantly lower serum HCV-RNA level at recovery after ALT relapse compared with that before initial IFN therapy. (2) A high response rate was noted after a second course of IFN administered at the recovery stage of the ALT relapse, compared with patients without IFN retreatment.

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Efficacy and Changes of the Nonstructural 5A GENE by Prolonged Interferon Therapy for Patients with Hepatitis C Virus genotype 1b and a High Level of Serum HCV-RNA.

Cited by 14 publications

References 24 publications

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Quasispecies evolution in NS5A region of hepatitis C virus genotype 1b during interferon or combined interferon-ribavirin therapy

Statistical analysis of combined substitutions in nonstructural 5A region of hepatitis C virus and interferon response

Increased response rate to interferon therapy after a second course in hepatitis C patients who show relapse after the initial course

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