Katsuo Uchiumi

Recombinant Leukocyte A Interferon Treatment in Patients With Chronic Hepatitis B Virus Infection: Pharmacokinetics, Tolerance, and Biologic Effects

Large doses of recombinant leukocyte A interferon were administered to 20 patients with deoxyribonucleic acid polymerase- and hepatitis B e antigen-positive chronic hepatitis B to study the maximum tolerated dose, its pharmacokinetics, and its antiviral activity. The first group of 5 patients received a constant dose of 36 X 10(6) U/day for 28 consecutive days. When it was well tolerated, the second, third, and fourth groups (5 patients each) received 50, 72, and 100 X 10(6) U/day, respectively. All 20 patients completed the 28-day treatment. Hourly and daily profile of serum interferon level showed a dose-dependent effect with an increasing dosage, and cumulative effects during the treatment. The mean peak serum interferon concentration ranged from 93 U/ml on day 1 in the first group to 1271 U/ml on day 28 in the fourth group. Inhibition of serum deoxyribonucleic acid polymerase activity and hepatitis B virus-deoxyribonucleic acid during the treatment was compared between the groups with low doses (36 and 50 X 10(6) U) and high doses (72 and 100 X 10(6) U). Low doses of interferon suppressed deoxyribonucleic acid polymerase activity to the same extent as did the high doses. Prednisolone withdrawal was combined with interferon in 5 patients. Three patients treated with such combination became seronegative for hepatitis B e antigen during the treatment, whereas all 15 with interferon alone remained seropositive. These results suggest that a maximum antiviral effect of recombinant leukocyte A interferon is below the maximum tolerated doses.

Combination of short-term prednisolone and adenine arabinoside in the treatment of chronic hepatitis B

The efficacy of adenine arabinoside (Ara-A) alone or in combination with prednisolone utilizing its withdrawal effect was studied in 43 patients with deoxyribonucleic acid polymerase- and hepatitis B e antigen-positive chronic hepatitis. Ten patients were treated with 10 mg/kg body wt of Ara-A alone for 4-8 wk. In 9 cases, prednisolone (40 mg/day) was given at a constant dosage for 4 wk before Ara-A treatment. Fourteen patients received oral prednisolone alone for 4 wk, and 10 patients served as untreated controls. Six of 9 patients (67%) undergoing the combination therapy became seronegative for hepatitis B e antigen, whereas only 4 of 24 patients (17%) treated either with Ara-A alone or prednisolone alone lost the antigen. Two of the 10 untreated patients became seronegative for hepatitis B e antigen during the same follow-up period of 9 mo. This prospective controlled study suggests that the combination of immunomodulation by steroid withdrawal and subsequent Ara-A is more effective in the treatment of patients with chronic liver disease and active hepatitis B virus replication than treatment with Ara-A alone.

Early events in duck hepatitis B virus infection: Sequential appearance of viral deoxyribonucleic acid in the liver, pancreas, kidney, and spleen

Early events in duck hepatitis B virus infection were studied in 1-day-old ducklings following inoculation. Group A ducklings (n = 26) were inoculated intraperitoneally with 10 microliter of infective serum, and group B ducklings (n = 29) were inoculated with 50 microliter. Samples of the serum, liver, pancreas, kidney, and spleen were taken, starting 3 h after inoculation and continuing through the 14th day. In group A, relaxed circular double-stranded deoxyribonucleic acid (DNA) did not appear in serum until day 10, whereas single-stranded DNA, indicative of active replication of the virus, was already demonstrable in the liver on day 6. In group B, single-stranded DNA was first detected in the liver on day 3, and relaxed circular double-stranded DNA became detectable in the liver and serum on day 6. The pancreas started to have single-stranded DNA on day 10 in group A and on day 6 in group B, suggesting active viral replication in this organ soon after it occurred in the liver. In the spleen, relaxed circular double-stranded DNA was detectable when serum became positive for viral DNA, probably due to contamination by serum DNA. However, single-stranded DNA became detectable on day 14 in group A and on day 6 in group B, suggesting a delayed but active viral replication in the constituent tissues of the spleen. These results have demonstrated that active replication of duck hepatitis B virus starts in the liver after infection, and is followed by the pancreas, the kidney, and the spleen. The incubation period is shortened when larger amounts of virus are inoculated, but the sequential occurrence of viral replication in these organs remains the same.

Histological changes of the liver by treatment of chronic non-A, non-B hepatitis with recombinant leukocyte interferon alpha

We have treated 17 patients with non-A, non-B chronic hepatitis by recombinant interferon alpha (0.3–9 megaunits for 4–28 weeks). In six patients, serum aminotransferase levels fell to normal or near-normal range during treatment. The mean levels of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 17 patients fell from 156±80 (mean±sd) and 213±135 at the beginning of treatment to 94±49 and 112±71, respectively, at the end of treatment. In 12 patients, liver biopsies were performed before and after (or during) the treatment, and histological activity indices (HAI) were blindly examined by two independent observers. For comparison, we examined histological changes of pre- and posttreatment liver biopsies of 19 patients who were treated by recombinant interferon for chronic hepatitis B. Mean HAI scores improved from 10.0 to 5.4 after treatment in non-A, non-B chronic hepatitis. The most marked reduction was noted in scores of portal inflammation and hepatocellular degeneration and/or necrosis. No such reduction was observed in B- viral chronic hepatitis. These data indicated that rapid biochemical resolution by the treatment was related to histological improvement of the liver in our patients with non-A, non-B hepatitis.

Correlation of Hepatitis B Virus DNA and Antigens in the Liver A Study in Chronic Liver Disease

Hepatitis B virus deoxyribonucleic acid (DNA) and antigens (HBsAg and HBcAg) were studied in liver biopsy specimens from 105 HBsAg-positive patients with chronic liver diseases. Free or integrated viral DNA, or both, was detected in 83 of 105 (79%) patients, whereas HBsAg and HBcAg were demonstrated immunohistologically in 96 (91%) and 39 (37%), respectively. Of 60 patients with detectable free viral DNA, 38 (63%) were positive for HBcAg, whereas only 1 of 45 (2%) with either integrated viral DNA alone (n = 23) or no detectable viral DNA (n = 22) was positive for HBcAg (p less than 0.001). Furthermore, the amount of HBcAg was positively correlated with the amount of free viral DNA in the liver tissue. In contrast, HBsAg was well expressed not only in the liver with free viral DNA, but also in the liver with integrated DNA. These data suggest that the synthesis of HBcAg is primarily directed by free viral DNA, whereas that of HBsAg may be directed by free as well as integrated viral DNAs.

Combination of prednisolone withdrawal and antiviral agents (adenine arabinoside, interferon) in chronic hepatitis B: A long-term follow-up study*

In 1981, we initiated combination therapy of short-term prednisolone withdrawal and adenine arabinoside (ARA-A) or interferon (IF) for the treatment of chronic hepatitis B. Long-term follow up (range 12-48 months) of 79 HBeAg-positive patients showed that at 24 months serum HBeAg was still positive in 77% of controls, 73% of patients receiving ARA-A or IF alone, 38% of patients receiving prednisolone withdrawal alone, and 25% of those receiving the combination therapy. The long-term follow up study revealed that the combination of an immunomodulating therapy and antiviral agents appears more effective in reducing hepatitis B virus replication than single agent treatment.

High sustained virologic response rate after interferon monotherapy in Japanese hepatitis C patients with a low HCV RNA titer and/or HCV genotype 2. A prospective study.

Objective: Hepatitis C virus (HCV) RNA titer and HCV genotype are considered to be major determinants of the outcome of interferon monotherapy. To clarify whether interferon monotherapy is really effective in patients with the appropriate viral parameters, we prospectively examined these parameters and treated the patients with interferon monotherapy. Methods: Sixty-four patients with an HCV RNA titer <100 kIU/ml and/or HCV genotype 2 were enrolled in the study. Eighteen patients with an HCV RNA titer >100 kIU/ml and genotype 1 were also enrolled as controls. All patients were treated with 10 megaunits of interferon-α2b every day for 2 weeks and then 3 times a week for 24 weeks. Results: Of the 64 patients with either HCV RNA <100 kIU/ml and/or genotype 2, seven dropped out from the study. Of the remaining 57 who completed the treatment, 48 (84%) showed a virologic sustained response. In contrast, only 4 of the 18 patients (22%) with HCV RNA >100 kIU/ml and genotype 1 were virologic sustained responders (p < 0.001). Conclusion: Our current study showed that the patients with HCV RNA <100 kIU/ml and/or HCV genotype 2 are good candidates for interferon monotherapy.

Immuno-electronmicroscopical study of the delta antigen in liver from an HBsAg carrier.

HBs抗原陽性者140名中に発見されたδ抗原陽性2名のうち1例に酵素抗体法にて免疫電顕的検索を行った.δ抗原は肝細胞核内にのみ染色され,核小体を除く核内に比較的び漫性に見い出されるが核によって染色性の強弱は様々であり,その頻度は45個につき陽性核は1個(2.2%)であった.強拡大では雲状の個々の形態不鮮明なものが主であるが,1部に直径10～20nmの境界不鮮明な顆粒状のものが見られるが明確な形態は認められなかった.細胞質では染色されているものはなかった.各阻止試験組み合せの免疫電顕的検索で,核内に陽性に染色されるものはδ抗原であることを確認した.本邦におけるδ抗原についての免疫電顕的検索は最初である.

Immunohistological study of delta-antigen and anti-delta in hepatitis B virus infection.

HBs抗原陽性者におけるδ感染症を検索する為,本邦慢性肝疾患146例,米国慢性肝疾患21例について酵素抗体法を施行した.δ抗原は,核小体を除く肝細胞核内に明瞭に染色された.本邦例においては146例中2例(1.4%)と極めて低い頻度であったが,米国例においては21例中8例(38.1%)と高率に認められた.本邦におけるδ感染症を認めた2例は,いずれも麻薬,覚醒剤の既往はなく,渡航歴のある点が共通しており,1例は輸血歴を有している.また,両者の肝組織,臨床経過は共に良好であった.現在δに関するassayの確立の為にはδ抗原を含む肝組織が多量に必要であり,我が国においては抗原の入手は容易ではない.今回,我々が施行した酵素抗体法は,現時点において本邦におけるδ感染症のスクリーニングに最も有用である.