Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.

BACKGROUND & AIMS: Interferon therapy has been associated with a number of severe side effects when administered to patients with decompensated cirrhosis caused by chronic hepatitis B. The safety and potential efficacy of a low-dose, titratable regimen of interferon alfa-2b in patients with decompensated liver disease caused by chronic hepatitis B virus infection were studied. METHODS: Twenty-six patients were treated at five medical centers. Five patients had Child's class A status, 15 had Child's B status, and 6 had Child's C status. Treatment was continued for 24 weeks whenever possible. Dose adjustments were made according to predefined safety criteria. RESULTS: All patients with Child's A status responded with a sustained loss of serum hepatitis B virus DNA, reduction in aminotransferase activity, and clinical stabilization. Only 5 patients with Child's B (33%) and no patients with Child's C status reached similar end points. The probability of survival was greater in responders than in nonresponders (P = 0.017). Three patients each developed serious infections or greater than twofold increases in serum aminotransferase levels during therapy. CONCLUSIONS: Low-dose, titratable interferon therapy is safer than previously reported regimens. Nonetheless, serious infections were observed relatively frequently, and this therapy should be reserved for individuals with mild to moderate hepatic decompensation, preferably patients with Child's A status.

Genomic variations in the hepatitis B core gene: a possible factor influencing response to interferon alfa treatment.

BACKGROUND/AIMS: Interferon treatment causes a sustained loss of virus replication only in a proportion of patients with chronic hepatitis B. This study investigated whether genomic variations in the precore/core gene of hepatitis B virus affect the response to interferon alfa. METHODS: The precore/core region was sequenced in 46 serum samples obtained before, during, and after interferon treatment of 12 patients. RESULTS: In 23 samples from 7 responders (group A), there were 24 missense mutations, whereas in 23 samples from 5 patients who did not respond or relapsed after treatment (group B), there were 141 missense mutations (P < 0.001). All group B patients had cirrhosis, but only 2 of 7 patients in group A had cirrhosis (P = 0.026). Substitutions in amino acids 21-27 of the core protein, known to diminish HLA-A2-restricted cytotoxic T-cell function, were found in all nonresponders but in none of the responders. No significant changes occurred in the precore/core region in responders after seroconversion to antibody to hepatitis B e antigen, but multiple variations persisted in group B during treatment and new mutations appeared with the relapse of hepatitis. CONCLUSIONS: Specific mutations in the core protein that can interfere with T-cell function occur frequently in patients with advanced chronic hepatitis B and may affect the response to interferon.

HLA class I antigen expression as a measure of response to antiviral therapy of chronic hepatitis B.

HLA class I antigen expression on peripheral blood mononuclear cells was evaluated by flow cytometry in 21 HBeAg-positive patients with chronic hepatitis B. Measurements were made before, during or after treatment with recombinant interferon-alpha-2b, either given alone or after a 6 wk course of prednisone. Immunohistochemical staining for human leukocyte class I antigen was also evaluated in 28 percutaneous liver biopsy specimens either obtained before or after therapy (N = 27) and during therapy in one instance. The amount of HLA class I antigen on peripheral blood mononuclear cells varied markedly among individual patients, but the overall results indicated that the level of inducible antigen did not correlate with increments of ALT during therapy or with a virological response to therapy. Hepatocyte staining for HLA class I antigen was observed in a minority of biopsy specimens (29%) and also did not appear to predict a response or correlate with the severity of histological disease. These data do not support current theories concerning pathogenetic mechanisms in chronic hepatitis B nor do they suggest that spontaneous display of HLA class I antigen on hepatocytes or interferon-induced expression of these antigens on peripheral blood mononuclear cells is a critical determinant for a response to therapy.

Prednisone withdrawal followed by recombinant alpha interferon in the treatment of chronic type B hepatitis. A randomized, controlled trial.

STUDY OBJECTIVE: To determine the efficacy of a short course of prednisone followed by recombinant interferon treatment in patients with chronic type B hepatitis. DESIGN: Randomized, controlled trial with a 5-month treatment phase and a 9-month observation period after treatment. SETTING: Two referral-based university-affiliated medical centers. PATIENTS: Thirty-nine clinically stable patients with chronic type B hepatitis, all of whom were positive for hepatitis B antigen, hepatitis B virus-associated-DNA (HBV-DNA), and DNA polymerase for at least 6 months before entry. Patients included 20 heterosexuals and 19 male homosexuals. INTERVENTIONS: Eighteen patients were treated with a 6-week tapered regimen of prednisone, followed by 90 days treatment with recombinant interferon alpha-2b; 21 patients were untreated controls. Paired liver biopsy specimens of 27 patients (pretreatment and 9 months after treatment) were blindly evaluated. MEASUREMENTS AND MAIN RESULTS: Nine treated patients had a sustained loss of HBV-DNA. In addition, eight treated patients lost hepatitis B e antigen and four became negative for hepatitis B surface antigen (HBsAg). When compared with controls the differences were statistically significant for clearance of HBV-DNA and HBsAg (P = 0.035 and 0.037, respectively). Treated patients who had a sustained loss of HBV-DNA had higher initial alanine aminotransferase lower initial DNA and DNA polymerase levels, and were more frequently heterosexual. Patients who responded to treatment with the disappearance of hepatitis B e antigen and HBV-DNA had normal liver function tests and markedly improved liver histology during follow-up. CONCLUSIONS: The immunologic priming provided by a short course of prednisone used with alpha interferon may be an effective treatment for selected patients with chronic type B hepatitis.

Comparative efficacy of adenine arabinoside 5' monophosphate and prednisone withdrawal followed by adenine arabinoside 5' monophosphate in the treatment of chronic active hepatitis type B.

Thirty-eight patients with chronic active hepatitis type B received antiviral therapy. In one trial, 22 patients were randomized to either no treatment or treatment with a 28-day cycle of adenine arabinoside 5' monophosphate (ARA-AMP); in a second trial, 13 patients were randomized to no treatment or treatment with two 28-day cycles of ARA-AMP separated by a 4-wk rest interval; during a third trial, 11 individuals were treated with 8 wk of prednisone therapy followed by 28 days of ARA-AMP therapy. The response rate (73%) to the regimen with prednisone was significantly greater than that achieved in the first or second trial (0% and 15%, respectively). The data indicate that the combination of short-term prednisone and ARA-AMP therapy may offer more promise for successful treatment of chronic active hepatitis type B than does ARA-AMP alone. Synergism may possibly occur by the combined effects of immune rebound provided by corticosteroid withdrawal and the inhibition of viral proliferation by ARA-AMP.

Clinical and immunologic features of chronic dialysis patients who fail to respond to hepatitis B vaccine.

Eighteen patients on chronic dialysis (15 haemodialysis, three peritoneal) were evaluated to determine whether certain clinical features and/or in vitro indicators of immune function correlated with the response to hepatitis B vaccine. Only 44% of patients developed antibody to hepatitis B surface antigen (anti-HBS) following vaccination and neither duration of dialysis, history of renal transplant, peripheral T cell numbers, T4/T8 ratios, nor mitogen induced lymphocyte proliferation correlated with response to vaccination. Advanced age, history of multiple blood transfusions and depressed levels of IgM may be associated with a poor antibody response to the vaccine. Future studies need to consider these variables when evaluating immunogenicity of new hepatitis B vaccine preparations.

Survey of hepatitis B viral markers at a public day school and a residential institution sharing mentally handicapped students.

The prevalence of hepatitis B virus markers was studied among employees and clients at a nonresidential public school for the mentally handicapped and at a privately operated residential facility. In the residential institution, 73 (80%) of 91 clients and 15 (16%) of 92 workers had positive tests for hepatitis B virus markers. Twenty-three clients, including six carriers of hepatitis B surface antigen (subtype ayw), received their education their education at the public school. Only two students (4%) who did not live at the residential institution and one employee (2%) had positive tests for hepatitis B virus markers. One of these students had acute hepatitis B infection, with hepatitis B surface antigen subtype ayw; the subtyping suggested that he had acquired the infection from one of the six carriers from the residential institution. Testing for IgM antibody to hepatitis B core antigen in single serum samples facilitated the identification of acute and chronic hepatitis B infection in children and staff of both facilities. The results show hepatitis B can be transmitted in this setting, and vaccination may be warranted for susceptible students and staff.

Spontaneous clearance and reactivation of hepatitis B virus infection among male homosexuals with chronic type B hepatitis.

Abrupt increases of alanine transaminase were observed in 6 of 23 non-treated, male homosexuals with chronic hepatitis associated with hepatitis B virus. Before this occurrence, all subjects had hepatitis B e antigen (HBeAg) and elevated DNA polymerase activity. Within 3 months, HBeAg was nondetectable in 3 subjects and elevated DNA polymerase disappeared in 4. These serologic events were not always sustained, however. In 3 subjects, reactivation of hepatitis B virus infection occurred within the subsequent 6-month period. Serologic testing for cytomegalovirus, Epstein-Barr virus, delta agent, and hepatitis B surface antigen (HBsAg) subtype showed that episodes of clearance and reactivation were not explainable by secondary infection with these agents or infection with a different HBsAg subtype. Spontaneous clearance and reactivation of hepatitis B virus infection may commonly occur among male homosexuals with chronic type B hepatitis. These phenomena should be considered when evaluating the need for treatment or interpreting the results of investigations that use anti-viral therapy.

Immune globulin and hepatitis B immune globulin. Prophylactic measures for intimate contacts exposed to acute type B hepatitis.

We studied the relative prophylactic efficacies of recently derived immune globulin containing antibody to hepatitis B surface antigen (anti-HBs) and hepatitis B immune globulin in 60 intimate contacts exposed to acute type B hepatitis. Forty susceptible contacts were randomly assigned to treatment with either a single intramuscular dose of immune globulin or hepatitis B immune globulin (0.06 mL/kg of body weight), following which observation was maintained over a 12-month period. Twenty additional contacts received the equivalent of twice the dose of immune globulin given to the first group, and follow-up was maintained for six months. Neither the hepatitis B virus (HBV) attack rates (11% to 19%) nor the frequency of clinical illness (0% to 4.8%) was substantially different in the three groups. When compared with average frequencies reported in the literature, significantly lower illness rates were noted for immune globulin recipients. These data indicate that currently derived immune globulin as well as hepatitis B immune globulin may confer protection from illness (le, passive-active immunity) in the setting of intimate exposure to HBV.

Use of conventional and IgM-specific radioimmunoassays for anti-hepatitis A antibody in an outbreak of hepatitis A.

During a common source outbreak of hepatitis A, we studied the characteristics and utility of commercially available radioimmunoassays for total and IgM-specific antibody to hepatitis A virus. IgM hepatitis A antibody was detectable in all serum specimens obtained up to 119 days following onset from the seven persons with hepatitis A, and as long as 347 days in one person. Acute infection could also be documented by a four-fold or greater increase in titers of hepatitis A antibody, although as long as nine weeks was required between the times acute and convalescent specimens were obtained. The radioimmunoassay for IgM-specific hepatitis A antibody had greater specificity (99 percent versus 84 percent) and a higher positive prediction value (88 percent versus 23 percent) for the diagnosis of acute hepatitis A than did the radioimmunoassy for hepatitis A antibody. Uses of the radioimmunoassay for IgM-specific hepatitis A antibody include rapid diagnosis of acute hepatitis A, differentiation between recent and past hepatitis A infection, and screening for recent hepatitis A infection in epidemiologic investigation.