Alpha- and gamma-interferon versus alpha-interferon alone in chronic hepatitis B. A randomized controlled study.

Thirty-two patients with chronic hepatitis B were randomly assigned to two groups. Sixteen patients received 10 million units of alpha-interferon per square meter of body surface (MU/m2), three times weekly for 4 months. Sixteen patients were treated simultaneously with gamma-interferon at a dose of 2 MU/m2, and 10 MU/m2 of alpha-interferon. At the end of the study (13th month), hepatitis B virus DNA was negative in 50% of the patients treated with alpha-interferon and in only 25% of those treated with alpha- and gamma-interferon. A similar trend was observed with respect to the hepatitis B e antigen negativization (31% and 19% of HBeAg negativization in patients treated with alpha- and gamma-interferon, respectively). In summary, these data demonstrate that, at the doses used in this study, the combination of alpha- and gamma-interferon does not give better results than the administration of alpha-interferon alone. The tolerance to simultaneous alpha- and gamma-interferons is poor and may decompensate the liver disease.

[Reactivation of hepatitis B virus in chronic carriers with anti-HBe]. / Reactivación del virus B de la hepatitis en portadores crónicos con anti-HBe.

Thirty-eight hepatitis B virus (HBV) carriers, AgHBs and anti-HBe positive, with histologic diagnosis of chronic hepatitis have been periodically revised for three years. Three of them were homosexuals. Fourteen patients presented reactivation of viral replication characterized by the appearance in serum of HBV-DNA and an increase in transaminase levels. Only 7/27 (26%) presented spontaneous reactivation in contrast with 7/11 (64%) patients who had been treated with immunosuppression (p less than 0.05). Furthermore, in 3 cases free AgHBe was temporarily detected during reactivation. Histologic diagnosis and Knodell index were basically similar in reactivated patients and the rest. However, those who presented spontaneous reactivation presented a higher number of AgHB positive cells in liver tissue, both in nucleus and cytoplasm, than patients without reactivation, although, there were no significant differences in relation to the type of reactivation. In summary, this study suggests that immunosuppressants should not be given to HBV carriers with anti-HBe, since this would facilitate the reactivation of viral replication.

Analysis of serum pre-S antigens in chronic hepatitis B virus infection in relation to the expression pattern of hepatitis B virus DNA in the liver.

Pre-S antigens have been analyzed in the serum of patients with chronic hepatitis B virus (HBV) infection according to the expression pattern of HBV DNA in the liver. Pre-S1 and pre-S2 have been identified (1) in all viremic cases with free replicative forms of viral DNA irrespective of the simultaneous detection of integrated sequences; (2) in 2 out of 3 patients with only integrated HBV DNA, and (3) in 19 patients who lacked viral DNA sequences detectable in the host genome. The amounts of hepatitis B surface and pre-S antigens were significantly higher in high-viremic versus low-viremic patients and correlated with the hepatocellular expression of HBV DNA. Conversely, the pre-S-to-hepatitis B surface antigen ratios were lower in the presence of viral DNA sequences in the liver. In summary, detection and level of pre-S antigens are closely related to the hepatocellular expression of viral DNA and seem to reflect reliably different stages of the virus life cycle during the course of HBV infection.

[A controlled study of treatment with recombinant interferon alpha of chronic hepatitis due to the B virus in childhood]. / Estudio controlado de tratamiento con interferon alfa recombinante en la hepatitis crónica por virus B en la infancia.

The natural history of chronic hepatitis B virus (HBV) infection in children may lead to hepatic cirrhosis and hepatoma. Since the antiviral effect of recombinant interferon alpha (rIFN-alpha) in the treatment of chronic hepatitis in adults has been proven, a controlled study of therapy using rIFN-alpha in children chronic hepatitis due to HBV has been carried out. Twenty-four children (4-14 years old) HBsAg, HBeAg and HBV-DNA positive were randomly allocated to one of three groups: 1) n = 8, control; II) n = 8, who received 10 MU/m2 of rIFN-alpha (Boehringer Ingelheim)/m2 body surface, I.M., twice a week for six months and III) n = 8, treated with 7.5 MU/m2 under the same conditions. No basal differences between the three groups were observed. No intolerable toxicity was observed and all children completed the treatment period. At the end of the therapy, 5 patients in groups I (1 case), II (2 cases) and III (2 cases), had lost circulating HBV-DNA. With respect to HBeAg, 3 patients (one from each group) were negative by the sixth month, developing anti-HBe. Decreases in ALT levels among rIFN-alpha responder patients were observed, while no changes occurred in the rest. A significant decrease in the percentage of HBcAg positive hepatocytes was detected only among treated patients, when comparing the basal and final liver biopsies. In summary, rIFN-alpha therapy in children is well tolerated. In addition, these results suggest that rIFN-alpha has an antiviral effect.

Changes in anti-idiotype antibodies against anti-HBs during recombinant interferon treatment of chronic hepatitis B.

To determine the possible changes in the presence and level of anti-idiotype (anti-Id) antibodies against anti-HBs induced by recombinant interferon (rIFN) therapy in chronic hepatitis B virus (HBV) infection, a study of patients under rIFN treatment has been carried out. A total of 62 (38 treated and 24 controls), HBeAg and HBV-DNA positive HBsAg carriers were tested serially for the presence of IgG and IgM anti-Id antibodies. According to serological evolution, treated patients were divided in responders (HBeAg and HBV-DNA became negative) (n = 18) and nonresponders (n = 20). Control patients were also classified as having spontaneous seroconversion (n = 11) and without changes (n = 13). Basally all patients had IgG and IgM anti-Id. At the end of the follow-up period (15th month), a significant decrease was observed in the percentage of cases positive to anti-Id among rIFN-responders (IgG, 67%, p less than 0.01; IgM, 44%, p less than 0.001). In contrast, only one nonresponder lost IgM anti-Id during the study. Among controls, only one with spontaneous loss of HBV-DNA and HBeAg clearance became negative to both IgG and IgM anti-Id. In addition, in the basal sample, the rIFN-responders had significantly lower anti-Id levels than the nonresponders (p less than 0.05). Similar results were obtained when comparing the controls with or without spontaneous response (p less than 0.05). Furthermore, a significant decrease in the anti-Id levels among the rIFN responders at the 9th month was detected (p less than 0.01). In summary, the anti-Id antibodies decreased significantly in patients who became HBV-DNA negative following rIFN administration. This result confirms the close relationship between HBV replication and the anti-idiotype against anti-HBs.

Presence of HBV-DNA in peripheral blood mononuclear cells from anti-HIV symptomless carriers.

The presence of hepatitis B virus DNA (HBV-DNA) in the peripheral blood mononuclear cells (PBMC) of 29 anti-HIV symptomless carriers (eleven HBeAg positive, eleven anti-HBe positive and seven HBsAg negative) and of 40 anti-human immunodeficiency virus (HIV)-negative patients (15 HBeAg positive, 15 anti-HBe positive and ten HBsAg negative) has been studied by dot-blot and Southern blot hybridization. HBV-DNA has been found in similar proportions in both anti-HIV-positive and negative patients (36% and 46%, respectively, in the HBeAg positive group and 27% and 37% in the anti-HBe positive group). No HBV-DNA was detected in the PBMC of the HBsAg-negative patients. No relation has been observed between the presence of HBV-DNA in the PBMC of the anti-HIV-positive patients and the detection of HIV antigen (HIV Ag), number of CD4 cells or the CD4/CD8 ratio. In summary, the presence of HBV-DNA in the PBMC of anti-HIV symptomless carriers does not seem to imply that the patient's clinical state has worsened.

Virus-like particles associated with reverse transcriptase activity in acute sporadic non-A,non-B hepatitis.

Reverse transcriptase activity was tested in 65 patients with non-A,non-B hepatitis, with positive results in 2 acute sporadic cases with favorable outcome. Virus-like particles were observed in ultra-thin sections of successive serum samples from one of the reverse transcriptase activity-positive patients by electron microscopy. These results suggest that some non-A,non-B hepatitis types could be related to a virus-like agent associated with a reverse transcriptase activity.

Receptors for polymerized human serum albumin and other hepatitis B virus markers during acute hepatitis B--predictive value of the outcome of the disease.

Polymerized human serum albumin virus receptors (pHSA-R) HBsAg, HBeAg, antiHBc-IgM, hepatitis B virus (HBV) DNA polymerase activity and HBV-DNA were studied in 47 acute hepatitis B patients, divided into three groups: 26 HBeAg(+) initially, with favorable outcome; 4 HBeAg (+), with chronic outcome; and 17 antiHBe (+), with favorable outcome. In the basal sample only 2 and 8 patients in Group I were HBV-DNAp and HBV-DNA positive, respectively, and became negative during the follow-up. In contrast all patients in Group II remained positive to both HBV-markers. After a one-month follow-up 100% of the patients in Group II were positive for pHSA-R and HBeAg, in contrast to 25% among those with a favorable outcome in Group I (p less than 0.005). Meanwhile, only 6 out of 17 patients in Group III remained positive for pHSA-R. A significant decrease in pHSA-R and HBsAg concentrations was observed in patients from Group I (p less than 0.005 and p less than 0.05, respectively) 15 days after the onset of the disease, while concentrations of both parameters did not vary in Group II. A significant decrease in HBsAg and pHSA-R concentrations was found in patients from Group III after 15 days (p less than 0.05) and one month follow-up (p less than 0.05), respectively. As a result, pHSA-R and HBeAg are the best prognostic indicators in acute hepatitis B. A decrease in HBsAg and pHSA-R concentrations two weeks after the onset may have predictive value.