Hironori Tanimoto

Short-term interferon-alfa therapy for acute hepatitis C : a randomized controlled trial

Acute hepatitis C often progresses to chronic infection. We undertook a randomized controlled trial to determine whether short‐term therapy with interferon (IFN) during acute hepatitis C is effective in preventing the development of chronic hepatitis. Thirty patients with acute hepatitis C were randomized into 1 of 2 treatment groups. IFN therapy was initiated 8 weeks after the onset of acute hepatitis in the early‐intervention group and after 1 year of observation in the late‐intervention group. Short‐term therapy consisted of natural IFN‐alfa (6 million units) administered on consecutive days for a period of 4 weeks. Any signs of recrudescence of disease were immediately followed by interval IFN therapy (3 times weekly for 20 weeks). In the early‐intervention group, short‐term therapy was associated with a sustained virological response in 13 of 15 patients (87%). Follow‐up treatment was associated with a sustained virological response in both of the remaining 2 patients (100%). The sustained virological response rate was significantly higher in the early‐intervention group (87%, 13 of 15 patients after short‐term therapy alone, and 100%, 15 of 15 patients after short‐term with or without follow‐up therapy) than in the late‐intervention group (40%, 6 of 15 patients after short‐term therapy alone, and 53%, 8 of 15 patients after short‐term therapy with or without follow‐up therapy, P = .021 and P = .006, respectively). In conclusion, short‐term (4 weeks) IFN treatment of patients with acute hepatitis C may be associated with satisfactory results, if initiated at an early stage of the disease. (HEPATOLOGY 2004;39:1213–1219.)

Factors contributing to ribavirin-induced anemia.

Background and Aim:  Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin‐induced anemia.

Efficacy of low dose long‐term interferon monotherapy in aged patients with chronic hepatitis C genotype 1 and its relation to alpha‐fetoprotein: A pilot study

Aim:  The objective of this study was to examine the efficacy and safety of low dose long‐term interferon (IFN) therapy in aged patients with chronic hepatitis C genotype 1.

Promiscuous T cells selected by Escherichia coli: OGDC-E2 in primary biliary cirrhosis.

The etiology of primary biliary cirrhosis (PBC) remains enigmatic. One theory that has attracted attention proposes that PBC is induced via molecular mimicry with Escherichia coli. If molecular mimicry is responsible for the immunogenic response in PBC, then T cell clones specific for E. coli antigens should stimulate and be cross-reactive with peptides specific for the human immunodominant autoepitopes. To address this issue, we developed T cell clones specific for E. coli OGDC-E2 peptide. Importantly, we demonstrate the presence of T cell clones specific for E. coli OGDC-E2 that react promiscuously with the human mitochondrial equivalents. Indeed, there was a significant increase in the liver derived T cell precursor frequency of such reactivity and such liver clones were only found in patients with PBC. In conclusion, these data suggest that PBC is a multi-hit disease involving a genetic predisposition, a mucosal response, and activation of promiscuous T cells; such activation may occur either directly from bacterial antigens, or indirectly through chemically-modified bacterial antigens. Dissection of the mechanisms involved will lead not only to understanding the immunogenetic basis of PBC, but likely its pathogenic etiology.

Occurrence of clinical depression during combination therapy with pegylated interferon alpha or natural human interferon beta plus ribavirin

Aim:  The onset of depression symptoms during pegylated interferon α plus ribavirin (PEG‐IFN/RBV) combination therapy has led to treatment discontinuation in some cases. In the present study, we conducted a questionnaire survey during treatment to determine whether natural human interferon β plus ribavirin (IFNβ/RBV) therapy is associated with a lower incidence of depression symptom onset compared with PEG‐IFN/RBV therapy.

Pilot study of prolonged interferon-α retreatment in chronic hepatitis C patients with genotype 1b

OBJECTIVES: To investigate the efficacy of prolonged IFN retreatment for 3 years in chronic hepatitis C patients with high viral load and IFN treatment-resistant genotype 1b. PATIENTS AND METHODS: The study was conducted in 12 patients, not HCV RNA-negative after completion of the initial treatment. Retreatment consisted of administration of 6 million international units (MIU) of natural interferon-alpha, two or three times a week for 3 years. RESULTS: One patient was withdrawn for personal reasons. All other 11 patients completed treatment without any serious adverse reactions and were followed for 3 years. Of the patients, 4 (36%) showed a sustained virological response, 5 (45%) showed a biochemical response, and 2 (18%) relapsed after retreatment. All patients with a sustained response had a transient response to initial therapy. Patients showing a sustained response tested negative for HCV RNA within the first 6 months of retreatment. CONCLUSIONS: After prolonged IFN retreatment, a significant number of patients showed a sustained response for the first time and long-term improvement in ALT level.

Interferon-beta plus ribavirin therapy can be safely and effectively administered to elderly patients with chronic hepatitis C

AIM This study aims to evaluate the efficacy and safety of interferon-beta plus ribavirin therapy in older Japanese patients. PATIENTS AND METHODS This study enrolled 132 older patients (age, ≥65 years) with chronic hepatitis C who received 24-48 weeks of interferon-beta plus ribavirin (FR; n = 66) or pegylated interferon-alpha plus ribavirin (PR; n = 66) therapy. RESULTS Patients with the ITPA genotype (CA/AA) in the PR group had significantly greater decreases in hemoglobin levels than those in the FR group at or after week 8. The proportions of patients with a dose reduction of interferon-beta and ribavirin in the FR group were significantly lower than those in the PR group. A significantly higher proportion of patients completed treatment in the FR group than in the PR group. The sustained virological response (intention-to-treat analysis) rate of naïve patients with genotype 1 was 29% (6 of 21) in the PR group and 29% (6 of 21) in the FR group. The sustained virological response (intention-to-treat) rate of those with genotype 2 was 67% (12 of 18) in the PR group and 72% (13 of 18) in the FR group. CONCLUSION Interferon-beta plus ribavirin therapy was safe in elderly patients, with lower proportions of patients with a dose reduction of interferon-beta or ribavirin and treatment discontinuation. In treatment-naïve patients, the sustained virological response rate was similar between interferon-beta plus ribavirin therapy and pegylated interferon-alpha plus ribavirin therapy, regardless of whether the patients had hepatitis C virus genotype 1 or 2.

Interferon-α-Induced Changes to Natural Killer Cells Are Associated with the Treatment Outcomes in Patients with HCV Infections

Aim. We analyzed the pretreatment natural killer (NK) cell functions with the aim of predicting the sustained virological response (SVR) or the interleukin (IL) 28B polymorphism that is strongly associated with the treatment response. Methods. The peripheral NK cells from chronic hepatitis patients with HCV genotype 1 and high virus titers were activated using a Toll-like receptor (TLR) 4 ligand and IFN-α. The cell surface markers were evaluated using a flow cytometric analysis, and IFN-γ production was evaluated using an enzyme-linked immunosorbent assay (ELISA). The genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on the DNA collected from each patient. Results. The production of IFN-γ was significantly higher in the SVR patients compared with the no-response (NR) patients, whereas the cell surface markers were similar between the SVR and the NR patients. There were no significant differences found in the IL28B genotype distribution associated with the production of IFN-γ. Conclusion. Differences in the NK cell functions were observed between the SVR patients and the NR patients, suggesting that NK cells play a potential role in the treatment response independent of the IL28B genotype.

[Hypoxemia due to pulmonary tumor microembolisms from a hepatocellular carcinoma: a case report].

We report a case of pulmonary tumor embolism due to hepatocellular carcinoma (HCC). A woman in her 60s was treated with sorafenib 800 mg daily for HCC with lymph node metastasis. Approximately 50 days after taking sorafenib, she experienced dyspnea and was admitted to the hospital on account of hypoxia. Although her oxygen saturation levels deteriorated, we could find no obvious cause for the hypoxia; despite artificial respiration and oxygenation, she died of respiratory failure on the fourth day of admission. Tissue samples revealed that the HCC cells had infiltrated her lung arterioles; therefore, we concluded that multiple tumor microembolisms from the HCC to the lungs had caused death via respiratory failure. Cases of hypoxia caused by multiple invisible embolisms from HCCs are rarely reported. We believe that infiltration into the lymphatic system may have been related to the development of pulmonary tumor microembolisms.