Shiomi Aimitsu

IL-28B predicts response to chronic hepatitis C therapy ― fine-mapping and replication study in Asian populations

Type I interferon (IFN) is used for the treatment of chronic hepatitis C virus (HCV) infection. Despite advances in antiviral therapy, a large proportion of patients remain infected following current therapies. Through a genome-wide scan, we found two variants (rs8099917 and rs12979860) in the IL-28B locus that affect the outcome of PEG-IFN and ribavirin combination therapy, consistent with recent studies (P = 6.52×10(-8); odds ratio 2.46 and P = 8.63×10(-8), odds ratio 2.40, respectively). Significant associations were also observed in the case of IFN monotherapy for HCV genotypes 1b and 2a. With rs8099917, HCV genotype 1b patients had a significantly lower frequency of the favourable genotype (86.6 %) compared with healthy controls (91.7 %), and HCV genotype 2a patients had an intermediate frequency (89.9 %). Similar results were found for rs12979860. Fine-mapping analysis revealed that rs8099917 had the strongest association with treatment outcome and 14 others, including four novel single nucleotide polymorphisms, had comparable associations. Haplotype analysis revealed that none of the haplotypes showed stronger association than any single marker. Early non-responders who could not achieve 2 log viral decline during the first 12 weeks of treatment had higher odds ratios for these two variants. The favourable allele of rs8099917 is also associated with initial viral decline at 2 and 4 weeks following the start of therapy. Multivariate analysis of PEG-IFN and ribavirin-treated patients showed that rs8099917 genotype, viral load, fibrosis and age were significant predictors of response to therapy. Common variation at the IL-28B locus is predictive of various IFN-based therapies for HCV independent of regimen or HCV genotype.

Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine

Lamivudine (LAM) is a nucleoside analogue widely used for the treatment of chronic hepatitis B virus (HBV) infection. Emergence of resistant strains with amino acid substitutions in the tyrosine‐methionine‐aspartate‐aspartate (YMDD) motif of reverse transcriptase is a serious problem in patients on LAM therapy. The amount of covalently closed circular DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants. However, there is no useful serum marker that can predict early emergence of mutants during LAM therapy. Analysis of patients who were treated with entecavir (n = 7) and LAM (n = 36) showed some patients had high serum levels of HBV RNA. Median serum levels of HBV RNA were significantly higher in patients in whom the YMDD mutant had emerged within 1 year (n = 6, 1.688 log copies/ml) than in those in whom the YMDD mutant emerged more than 1 year after treatment (n = 12, 0.456 log copies/ml, P = 0.0125) or in whom the YMDD mutant never emerged (n = 18, 0.688 log copies/ml, P = 0.039). Our results suggest that HBV RNA is a valuable predictor of early occurrence of viral mutation during LAM therapy. (HEPATOLOGY 2007;45:1179–1186.)

Effect of vitamin D supplementation on pegylated interferon/ribavirin therapy for chronic hepatitis C genotype 1b : A randomized controlled trial

Chronic HCV–infected patients tend to have vitamin D deficiency, suggesting that vitamin D supplementation may enhance the efficacy of treatment with pegylated interferon (PEG‐IFN) and ribavirin (RBV). We therefore assessed the effects of vitamin D supplementation on viral response to PEG‐IFN/RBV. Eighty‐four patients with HCV genotype 1b were randomized, 42 to oral vitamin D supplementation (1000 IU/day) and 42 to nonsupplementation (control), from week 8 to the end of PEG‐IFN/RBV therapy. The primary end point was undetectable HCV RNA at week 24 (viral response [VR]). VR rate at week 24 was significantly higher in the vitamin D than in the control group (78.6% vs 54.8% P = 0.037). Adverse events were similar in both groups. When patients were subdivided by IL28B SNP rs8099917 genotype, those with the TT genotype group showed a significantly higher VR rate at week 24 with than without vitamin D supplementation (86.2% vs 63.3% vs P = 0.044). Although patients with the TG/GG genotype, who were relatively resistant to PEG‐IFN treatment, had similar VR rates at week 24 with and without vitamin D supplementation, the decline in viral load from week 8 to week 24 was significantly greater with than without vitamin D supplementation. Multivariate analysis showed that rs8099917 genotype and vitamin D supplementation contributed significantly to VR at week 24. SVR rates were similar in the vitamin D and control groups [64.3% (27/42) vs 50% (21/42), P = 0.19]. Vitamin D supplementation may enhance the effects of PEG‐IFN/RBV in HCV genotype 1b–infected patients.

Liver disease in hepatitis C virus carriers identified at blood donation and their outcomes with or without interferon treatment: Study on 1019 carriers followed for 5-10 years.

Aim:  To portray liver disease and project outcomes in carriers of hepatitis C virus (HCV) in the general population.

Eicosapentaenoic Acid Could Permit Maintenance of the Original Ribavirin Dose in Chronic Hepatitis C Virus Patients during the First 12 Weeks of Combination Therapy with Pegylated Interferon-α and Ribavirin

Objective: To evaluate the efficacy of eicosapentaenoic acid (EPA) against ribavirin (RBV)-associated hemolytic anemia during the first 12 weeks in chronic hepatitis C virus (HCV) combination therapy. Methods: This study was a prospective open-label, randomized controlled trial. 100 HCV patients were randomized to either the EPA group (n = 49) or non-EPA group (n = 51) who received combination therapy with or without EPA. We compared the changes in hemoglobin level and RBV plasma concentrations at week 12 in each group with RBV dose reduction rate and performed multivariate analysis to identify independent variables associated with RBV dose reduction. Results: 8 patients (17%) in the EPA group and 20 patients (29%) in the non-EPA group required RBV dose reduction, respectively. The cumulative RBV reduction rate was significantly lower in the EPA group than in the non-EPA group (p = 0.017), while the decrease of hemoglobin and RBV plasma concentrations from baseline was not significantly different. However, in the multivariate analysis, treatment with EPA showed significant variables for the reduction of RBV dose (odds ratio 3.235, p = 0.023). Conclusion: EPA could prevent the RBV dose reduction during the first 12 weeks in combination therapy, although further large-scale double-blind randomized controlled trials are required.

Dose comparison study of pegylated interferon-α-2b plus ribavirin in naïve Japanese patients with hepatitis C virus genotype 2: A randomized clinical trial

Background and Aim:  To compare the efficacy and safety of pegylated interferon (PEG‐I) at 1 and 1.5 µg/kg, and in combination with ribavirin (RBV) for 24 weeks in naïve Japanese patients infected with hepatitis C virus genotype 2.

Prospective study of short‐term peginterferon‐α‐2a monotherapy in patients who had a virological response at 2 weeks after initiation of interferon therapy

Background and Aims:  Long‐term interferon (IFN) therapy is effective in eliminating hepatitis C virus (HCV). However, it carries the risk of adverse effects and reduced quality of life. To assess whether short‐term IFN therapy effectively eliminates HCV, we performed a prospective pilot study of pegylated (peg)IFN‐α‐2a therapy for 8 or 24 weeks.

Follow up of the 987 blood donors found with hepatitis C virus infection over 9–18 years

Aim:  To follow up blood donors found with hepatitis C virus (HCV) infection, to improve the outcome by antiviral treatments.

Impact of ribavirin dose reduction on the efficacy of pegylated interferon plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads

Aim:  To examine the impact of ribavirin dose reduction on the efficacy of pegylated interferon (PEG IFN) plus ribavirin combination therapy for elderly patients infected with genotype 1b and high viral loads.

Prolonged Negative HCV-RNA Status Led to a Good Outcome in Chronic Hepatitis C Patients with Genotype 1b and Super-High Viral Load

Objective: We examined whether a sustained negative HCV-RNA status for 48 weeks affects the outcome in patients with genotype 1b and super-high viral load, and also investigated whether the outcome is affected by the induction therapy of twice-daily pre-administrated interferon (IFN)-β. Methods: 78 eligible patients were divided into four groups. 40 were patients assigned to the short treatment protocol. 13 patients received 3 MU IFN-β twice daily for 2 weeks followed by IFN-α2b+ribavirin for 22 weeks (β-induction group: group 1). 27 patients received IFN-α2b+ribavirin for 24 weeks (standard combination group: group 2). 38 patients were assigned to the maintenance treatment protocol. All of the 13 in the β-induction group (group 3) and 21 of 25 patients in the standard combination group (group 4) who were negative HCV-RNA PCR at week 24 had IFN monotherapy to maintain a negative HCV-RNA result for 48 weeks. Results: An HCV-RNA-negative status at week 24 was observed in 96% (25/26) of groups 1 and 3 versus in 79% (41/52) of groups 2 and 4 (p < 0.01). The sustained virological response (SVR) was 38% (5/13) in group 1 and 11% (3/27) in group 2 (p < 0.05). In the maintenance treatment, SVR was observed in 46% (6/13) of group 3 and 32% (8/25) of group 4 (NS). Conclusions: A sustained negative HCV-RNA status for 48 weeks might be associated with viral elimination in patients with genotype 1 and super-high viral load.