| Budget Amount *help |
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2010: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2009: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2008: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
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| Research Abstract |
The virological response to pegylated-interferon/ribavirin therapy (PEG-IFN/RBV) for chronic hepatitis C virus (HCV)-1b infection is quite diverse. However, contribution of virological factors in determining early responses as well as the final outcome in association with interleukin 28B (IL28B) single nucleotide polymorphisms (SNPs) is not understood comprehensively. We undertook a retrospective cohort analysis for 124 consecutive HCV-1b Japanese patients treated by PEG-IFN/RBV. After classification of patients by the initial responses at week 12, the pretreatment dominant complete HCV amino acid sequences in those patients were subjected to systematic sliding window analysis in association with IL28B SNPs analyses (rs8099917) to characterize response-specific viral sequences. One hundred three patients were eligible for the study. When complete HCV open reading frames (ORFs) were compared between patients with (n=10) and without (n=93) a rapid viral response (RVR), NS5A aa2224 to 224
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8, a part of interferon sensitivity determining region (ISDR), was extracted as the region most significantly associated with this favorable response (p=4E-04). Between non-end of treatment response (non-EVR) (n=32) and the remainder (n=71), core aa.70 was extracted (p=7.0E-08). IL28B SNP was correlated significantly with the polymorphisms of core 70 (p=3.4E-06). On the other hand, the final sustained virological response (SVR) rate was most significantly correlated with NS5A aa2340 to 2382, almost completely coinciding with the interferon ribavirin response determining region (IRRDR) (p=1.2E-07). In PEG-IFN/RBV therapy, polymorphisms in IL28B, NS5A-ISDR, core, and most importantly, NS5A-IRRDR have a tremendous influence on the treatment response in association with the viral kinetics, resulting in significantly different outcomes in chronic HCV-1b infection.
The association between hepatitis C virus (HCV) sequences along with interleukin 28B (IL28B) SNP in the development of hepatocellular carcinoma (HCC) has not been well clarified. (1) Complete HCV open reading frame sequences were determined in 20 patients developing HCC and 23 non-HCC patients with HCV-1b infection in 2 distant time points. (2) An additional 230 patients were studied for core and NS5A sequences with HCC development. (3) 98 patients were investigated for changes in the viral core sequences over time. (4) IL28B SNP was investigated in 228 patients. (1) During observation period (HCC for 10.8 years, and non-HCC for 11.1 years), changes of core a.a. 70 and three amino acid positions in NS5A were characteristic of the patients developing HCC. (2) In 230 patients, the Q/H:R ratio at core a.a. 70 was significantly higher in the HCC group (HCC group 43:22 vs. non-HCC group 66:99, p=0.001). (3) A change of core R70Q was observed over time in eleven patients associated with a decrease in platelets (p=.005) and albumin over time (p=.005) or with HCC occurrence (6/11, 54.5%), whilst a Q70R change was observed in four patients without associated changes in platelets (n.s.) and albumin (n.s.), or HCC occurrence (0/4, 0%). (4) The IL28B SNP showed significant correlation with the core 70 residue. HCV core a.a.70 residue and its changes over time were associated with HCC development in genotype-1b infection in close correlation with the IL28B SNP.
Protease inhibitor (PI)-resistant hepatitis C virus (HCV) variants may be present in substantial numbers in PI-untreated patients according to recent reports. However, influence of these viruses in the clinical course of chronic hepatitis C has not been well characterized. The dominant HCV nonstructural 3 (NS3) amino acid sequences were determined in 261 HCV genotype 1b-infected Japanese patients before pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, and investigated the patients' clinical characteristics as well as treatment responses including sustained virological response (SVR) rate. HCV-NS3 sequences were also determined in 39 non-SVR patients after completion of the therapy. Four single mutations (T54S, Q80K, I153V and D168E) known to confer PI resistance were found in 35 of 261 patients (13.4%), and double mutations (I153V+T54S/D168E) were found in 6 patients (2.3%). Responses to PEG-IFN/RBV therapy did not differ between patients with and without PI-resistance mutations (mutation group, SVR 48% ; wild-type group, SVR 40% ; P=0.38). On the other hand, 2 mutations appeared in 2 non-SVR patients after PEG-IFN/RBV therapy (I153V and E168D, 5.1%). PI resistance-associated NS3 mutations exist in a substantial proportion of untreated HCV-1b-infected patients. The impact of these mutations in the treatment of PIs is unclear, but clinicians should pay attention to avoid further development of PI resistance.
A proportion of patients infected with genotype 2a hepatitis C virus (HCV) cannot achieve a sustained virological response (SVR) to pegylated-interferon plus ribavirin therapy (PEG-IFN /RBV) but the reason remains unclear. The present study aimed to clarify the possible correlation between viral sequence variations and final outcome. The pretreatment complete open reading frame (ORF) sequences of genotype 2a HCV were determined by direct sequencing for two independent groups of patients (43 patients as test ; group 1 and 35 as validation ; group 2), and the correlation with the final outcome was explored. Patients with SVR (n=58) and with non-SVR (n=20) differed significantly in pretreatment HCV RNA level (p=0.002), fibrosis score (p=0.047), and cumulative ribavirin dosage (p=0.003). By comparison of all amino acid positions in the complete HCV ORFs, threonine at amino acid (aa) 110 in the core region was remarkably frequent in SVR (p=0.01 for group 1, p=0.004 for group 2, and p=5E-05 for combined). A sliding window analysis revealed that the total numbers of amino acid variations within the NS5A aa 2258 to 2306 region were significantly high in SVR compared to non-SVR patients (p=0.01 for group 1, p=0.006 for group 2, and p=0.0006 for combined). Multivariate analyses revealed that core aa 110 (p=0.02), NS5A aa 2258-2306 (p=0.03), and cumulative ribavirin dosage (p=0.02) were identified as independent variables associated with the final outcome. The outcome of PEG-IFN/RBV therapy is significantly influenced by variation in the core and NS5A regions in genotype 2a HCV infection. Less
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