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K Yoshioka,
M Kobayashi,
E Orito,
K Watanabe,
M Yano,
Y Sameshima,
A Kusakabe,
H Hirofuji,
A Fuji,
J Kuriki,
M Arao, K Murase,
M Mizokami,
S Kakumu
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ABSTRACT: Biochemical responders maintain normal alanine aminotransferase levels after interferon (IFN) therapy despite persistent presence of hepatitis C virus (HCV) RNA in their sera. There have been few reports on predictive factors for biochemical response. A region associated with sensitivity to IFN was identified in the nonstructural protein 5 A of genotype 1b [aa 2209-2248; IFN sensitivity-determining region (ISDR)]. The substitutions in ISDR correlate with sustained response to IFN. In this report, we assessed the association of ISDR with biochemical response. The sequences of ISDR were determined in 62 patients with HCV genotype 1b treated by IFN in two randomized controlled trials. 30 patients had wild ISDR (identical to HCV-J), 20 intermediate ISDR (1-3 amino acid substitutions compared with HCV-J), and 12 mutant ISDR (four or more amino acid substitutions). All 12 patients with mutant ISDR had a sustained response, while only one of those with wild or intermediate ISDR had a sustained response (P < 0.0001). In the 49 patients other than sustained responders, the patients with intermediate ISDR obtained biochemical response significantly more frequently (52.6%, 10/19) than those with wild-type ISDR (20.0%, 6/30) (P < 0.05). Multivariate analysis indicated the number of substitutions in ISDR as the most important predictor for biochemical response (discriminant coefficient=1.08, P < 0.05) and sustained response (discriminant coefficient=6.13, P < 0.0001). In phylogenetic analysis, clustering of sustained responders and biochemical responders was observed. These results demonstrate that the substitutions in ISDR are the most important predictor for biochemical response to IFN in patients infected with genotype 1b as well as for sustained response.
Journal of Viral Hepatitis 12/2001; 8(6):421-9. · 4.09 Impact Factor
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K. Yoshioka,
M. Kobayashi,
E. Orito,
K. Watanabe,
M. Yano,
Y. Sameshima,
A. Kusakabe,
H. Hirofuji,
A. Fuji,
J. Kuriki,
M. Arao, K. Murase,
M. Mizokami,
S. Kakumu
[show abstract]
[hide abstract]
ABSTRACT: Biochemical responders maintain normal alanine aminotransferase levels after interferon (IFN) therapy despite persistent presence of hepatitis C virus (HCV) RNA in their sera. There have been few reports on predictive factors for biochemical response. A region associated with sensitivity to IFN was identified in the nonstructural protein 5 A of genotype 1b [aa 2209–2248; IFN sensitivity-determining region (ISDR)]. The substitutions in ISDR correlate with sustained response to IFN. In this report, we assessed the association of ISDR with biochemical response. The sequences of ISDR were determined in 62 patients with HCV genotype 1b treated by IFN in two randomized controlled trials. 30 patients had wild ISDR (identical to HCV-J), 20 intermediate ISDR (1–3 amino acid substitutions compared with HCV-J), and 12 mutant ISDR (four or more amino acid substitutions). All 12 patients with mutant ISDR had a sustained response, while only one of those with wild or intermediate ISDR had a sustained response (P < 0.0001). In the 49 patients other than sustained responders, the patients with intermediate ISDR obtained biochemical response significantly more frequently (52.6%, 10/19) than those with wild-type ISDR (20.0%, 6/30) (P < 0.05). Multivariate analysis indicated the number of substitutions in ISDR as the most important predictor for biochemical response (discriminant coefficient=1.08, P < 0.05) and sustained response (discriminant coefficient=6.13, P < 0.0001). In phylogenetic analysis, clustering of sustained responders and biochemical responders was observed. These results demonstrate that the substitutions in ISDR are the most important predictor for biochemical response to IFN in patients infected with genotype 1b as well as for sustained response.
Journal of Viral Hepatitis 10/2001; 8(6):421 - 429. · 4.09 Impact Factor
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ABSTRACT: We conducted a randomized controlled trial to compare the efficacy of two different dosages of lymphoblastoid interferon alpha (IFN) for the treatment of chronic hepatitis C.
Eighty-four patients with chronic hepatitis C were enrolled and randomly assigned into the two groups; group A was treated with 6 million units (MU) and group B with 9 MU daily for the first 2 wk, and then thrice weekly for an additional 14 or 22 wk.
Eighty patients were evaluated (39 patients in group A and 41 in group B); 14 patients in group A (35.9%) and 15 in group B (36.6%) obtained sustained response. The percentages of patients who became negative for HCV RNA at the end of the second wk differed slightly between the groups, without statistical significance (56.4% and 68.3%). When assessed in detail, patients with genotype 1 and < 1 Meq/ml of viral load became negative for HCV RNA significantly more frequently in group B (eight of eight) than in group A (three of seven) (p < 0.05) at the end of the second week, whereas the sustained response rate was similar between the groups (five of eight and four of seven). Predictors of sustained response by multivariate analysis were low viral load (< 1.0 Meq/ml) and negativity of HCV RNA at the end of the second wk of IFN.
The results indicated that there was no difference in sustained response rate between the 6-MU and 9-MU doses. The earlier disappearance of HCV RNA, at the end of the second wk or at least by the end of the fourth week, is an essential condition for sustained response.
The American Journal of Gastroenterology 02/1999; 94(1):164-8. · 7.28 Impact Factor
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ABSTRACT: Studies were undertaken to clarify the immunological mechanism in patients with chronic hepatitis C compared with chronic hepatitis B. Phenotypic study by flow cytometry showed that CD8+ T cells and HLA-DR+ cells isolated from liver biopsy specimen were significantly increased in their proportions as compared with those in peripheral blood, while intrahepatic CD4+ T cells were significantly lower than peripheral blood CD4+ T cells in both types of patients with chronic active hepatitis (CAH). Furthermore two-color analysis revealed that CD8+ CD11- and CD3+ HLA-DR+ cells were significantly elevated in liver tissue than in peripheral blood in both patients groups. In in vitro tests, mononuclear cells obtained from the liver of type B and type C CAH had a reduced capacity to produce IFN-gamma in response to pokeweed mitogen, while they produced equal amounts of IFN-alpha under stimulation with Newcastle disease virus as compared with control peripheral blood mononuclear cells. In contrast, spontaneous productions of both IFNs were greater in liver infiltrates of the two patients groups. These results indicate that functionally activated T cells are distributed in a similar manner in the liver of both chronic hepatitis B and C, suggesting that cytotoxic T cell plays a major role in the hepatocellular injury of both groups of patients.
Journal of clinical & laboratory immunology 10/1990; 33(1):1-6.
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ABSTRACT: Recombinant human alpha-interferon was administered to 15 patients with chronic non-A, non-B hepatitis as a part of a pilot study. Patients received injections of 2 million units per day of interferon three times weekly for 16 wk. The treatment schedule was completed in all but one, whose serum aminotransferase levels were continuously elevated during treatment. In seven of the 15 patients, elevated serum aminotransferase levels decreased rapidly during therapy and eventually fell into the normal or nearly normal range. However, once the therapy was stopped, a prompt return of aminotransferase levels to pretreatment values usually was observed. After 3 months of follow-up, aminotransferase activities remained normal in only two patients in whom liver histology showed marked improvement in intralobular degeneration and focal necrosis of hepatocytes. Anti-interferon antibody was detected in four patients at the end of therapy, and decreased 2',5'-oligoadenylate synthetase activity occurred in two patients and in another with relapsed aminotransferase level. Whether alpha-interferon therapy could control the disease activity in patients with chronic non-A, non-B hepatitis deserves further evaluation in a prospective controlled trial.
The American Journal of Gastroenterology 02/1989; 84(1):40-5. · 7.28 Impact Factor
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Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 07/1987; 84(6):1251-7.
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ABSTRACT: Proliferation and IgG synthesis of peripheral blood mononuclear cells (PBMC) in response to stimulation with recombinant interleukin 2 (IL-2) and Staphylococcus aureus Cowan 1 (SAC) were evaluated in 32 patients with chronic persistent hepatitis (CPH), chronic active hepatitis (CAH) and liver cirrhosis (LC). Eleven patients had serum HBe antigen, 10 presented with HBe antibody and 11 had non-A, non-B hepatitis. IgG synthesis of PBMC induced with the two stimuli was significantly decreased in patients with CAH and LC when compared with that of controls. However, the generated amounts of IgG were not associated with the HB virus carrier state. B cells and T4+ cells were responsible for the diminished IgG synthesis in patients with CAH and LC when assessed by coculture experiments. On the other hand, proliferative response of PBMC to IL-2 and SAC were similar in controls and patient groups. These findings indicate that IgG production level of PBMC stimulated with IL-2 and SAC can reflect the severity of the underlying disease in chronic hepatitis patients.
Gastroenterologia Japonica 07/1987; 22(3):337-43.
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ABSTRACT: Natural killer (NK) and activated killer (AK) cells appear to be important in immunoregulation, elimination of virus-infected cells and resistance to tumours. NK activity against K 562 and AK activity against FL target cells of peripheral blood mononuclear cells (PBMC) from patients with chronic persistent hepatitis (CPH), chronic active hepatitis (CAH), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) were investigated using 51Cr release assay. Spontaneous NK activity of patients with LC (P less than 0.05) and HCC (P less than 0.001) was decreased when compared to that of controls. The sera and PBMC from patients with low NK activity had no inhibitory effect on the NK activity of normal subjects. Indomethacin treatment significantly enhanced the NK activity of controls (P less than 0.05), whereas the drug did not affect that of patients with low NK activity. The percentages of PBMC that reacted with monoclonal antibodies anti-Leu-7 and anti-Leu-11a were similar in controls and patients. However, a Leu-11a+/Leu-7+ ratio, and NK activity of Leu-11+ and Leu-7+ cell-rich populations were significantly decreased in cirrhotic and HCC patients when compared to controls. Interleukin 2 boosted both NK and AK activities of patients, but to a lesser degree in comparison with those of controls when similarly stimulated. gamma-Interferon also significantly augmented NK and AK activities of patients, but the levels of cytotoxicity were lower in HCC patients (P less than 0.05) than those of controls. These findings suggest that the decreased NK and AK activities in chronic liver disease and HCC are due to an altered subpopulation ratio of NK cells and a functional defect of effector cells.
Clinical & Experimental Immunology 06/1987; 68(2):348-56. · 3.36 Impact Factor
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ABSTRACT: An enzyme-linked immunosorbent assay was developed to detect serum antibody binding to liver membrane antigen derived from human hepatoma cell line SK-Hep-1. When we tested sera from 214 patients with this assay, IgM antibodies were detected in 100% of patients with acute type A, but not with type B or non-A, non-B hepatitis. IgM antibodies were also found in highest frequency (76%) and titer in patients with autoimmune chronic active hepatitis (CAH) among chronic liver disease groups. IgG antibodies occurred in over 50% of patients with acute type A hepatitis, type B chronic active liver disease (CALD), and autoimmune CAH. IgA antibodies were present in 43% of the patients with alcoholic liver disease, but were also seen in other patient groups. When freshly isolated rat hepatocytes were used as target cells, prevalences and titers similar to those obtained with SK-Hep-1 were found. The levels of serum membrane binding antibody were significantly reduced by the addition of human liver-specific membrane lipoprotein in all patient groups. In particular, IgM antibodies became negative in over 50% of patients with CALD (both type B and non-A, non-B) and autoimmune CAH, whereas in acute hepatitis over 50% lost their positivity for IgG antibody. These results indicate that circulating liver membrane binding autoantibodies are heterogeneous, occurring in hepatitis virus-induced acute and chronic liver disease as well as in autoimmune CAH.
Clinical Immunology and Immunopathology 05/1987; 43(1):9-22.
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ABSTRACT: We investigated the role of the interferon system in the pathogenesis of chronic liver disease. Interferon-gamma production by peripheral blood mononuclear cells was measured with an ELISA. While concanavalin A-stimulated and recombinant interleukin 2-stimulated production of interferon-gamma in patients with chronic active hepatitis and liver cirrhosis was significantly decreased when compared with that of controls (518 +/- 189 and 729 +/- 195 units per ml, mean +/- S.D.), there was also a lot of overlap. Addition of indomethacin to the cultures partially restored interferon-gamma production in patients with chronic active hepatitis and liver cirrhosis, indicating that suppressor function of monocytes was, in part, responsible for the diminished interferon-gamma production. Serial studies showed that interferon-gamma production rose during acute deterioration of illness, during treatment with interleukin 2 and with the improvement of clinical course. Interferon-gamma production was not different among hepatitis B e antigen or antibody positive, and non-A, non-B patients with chronic active hepatitis and liver cirrhosis. Our findings suggest that diminished interferon-gamma production is associated with disease severity in chronic liver disease, irrespective of the hepatitis B virus carrier state. It would be interesting to compare the efficacy of treatment with interferon-gamma or interferon-gamma inducers such as interleukin 2 in chronic hepatitis B patients with and without decreased in vitro interferon-gamma production.
Hepatology 7(3):577-81. · 11.66 Impact Factor
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ABSTRACT: Recombinant human interleukin 2 was administered to 10 patients with chronic type B hepatitis as a part of a pilot study to evaluate its antiviral activity. Patients received 1 to 3 x 10(5) units per day of interleukin 2 for 21 to 28 days, and all completed the treatment schedule. During therapy, serum values of DNA polymerase decreased in 6 and became negative in four patients. However, when therapy was discontinued, DNA polymerase levels increased to pretreatment levels in most cases. Serum HBeAg levels did not change during treatment. Serum aminotransferase levels transiently increased in 6 of the 10 patients during therapy; but once therapy was stopped, levels fell markedly. Side effects of interleukin 2 therapy included fever, chills, anorexia and fatigue. After 1 year of follow-up, three treated patients had lost HBeAg and had marked improvement in aminotransferase levels. These serologic and biochemical improvements occurred 1.5 to 11 months after therapy was stopped. Whether a 3- to 4-week course of interleukin 2 therapy leads to an increased rate of seroconversion from HBeAg to antibody in chronic type B hepatitis deserves further evaluation in prospectively randomized, controlled trials.
Hepatology 8(3):487-92. · 11.66 Impact Factor
