Juan Carlos Porres

High doses of recombinant alpha-interferon or gamma-interferon for chronic hepatitis C: a randomized, controlled trial.

Chronic hepatitis C is often a progressive liver disease for which there is no satisfactory treatment. We studied the efficacy of recombinant alpha-interferon or gamma-interferon in the treatment of this disease in comparison with a control group. Thirty patients were randomly assigned to three groups. Ten patients received 7.5 MU alpha-interferon/m2 body surface three times weekly for 3 mo, then 5 MU/m2 for 3 mo and 2.5 MU/m2 for 6 mo. Ten patients were treated with gamma-interferon at a dose of 2 MU/m2 for 6 mo and the other 10 served as controls without treatment. The mean serum ALT levels and liver histological findings improved significantly only in the patients treated with alpha-interferon. No changes were observed in patients treated with gamma-interferon or in controls. Five of 10 patients treated with alpha-interferon had complete responses (mean ALT normal during therapy). After treatment ALT returned to pretreatment levels in two of 5 patients. The long-term response rate after alpha-interferon therapy was 30% at 18 mo. We conclude that alpha-interferon is effective in controlling disease activity in a portion of patients with chronic hepatitis C. High doses of alpha-interferon do not appear to add further benefit in the response rate or relapse rate. gamma-Interferon therapy is ineffective.

A Controlled Trial of Recombinant Interferon-Alpha in Caucasian Children with Chronic Hepatitis B

Twenty-four children with chronic active hepatitis due to hepatitis B virus (HBV) infection, who were positive for HBeAg and had increased levels of transaminases, were included in a controlled study of treatment using recombinant interferon-alpha (rIFN-alpha), 10 MU/m2 body surface, intramuscularly, 3 times a week over a period of 3 months. During therapy, a significant decrease in HBV-DNAp was observed in the 12 patients treated. By the end of therapy, the HBV-DNA had disappeared in 3 children, the same occurring in 1 child (33% overall) during the course of the 4th month. By this time, all the controls remained with HBV replication markers (p less than 0.05). The 4 treated patients who responded became HBeAg-negative, developing anti-HBe during the first 12 months after therapy. In the control group, the HBV-DNA disappeared in 3 children in the 7th month of follow-up. All of the children remained HBsAg-positive. The therapy with rIFN-alpha was well tolerated, secondary effects consisting of a flu-like syndrome and a slight decrease in leukocytes and platelets. At the second biopsy, 15 months after the beginning of therapy, a significant decrease in Knodells index of histological activity was observed in the responders. In the light of these results and since treated children lost viral replication markers in a shorter period of time than the controls, who seroconverted spontaneously, we consider that rIFN-alpha may be useful in the treatment of chronic hepatitis B in childhood.

Treatment of chronic delta infection with recombinant human interferon alpha 2c at high doses

Superinfection by hepatitis delta virus (HDV) in hepatitis B virus chronic carriers is normally associated with a progressive liver injury. For this reason, the aim of the present study was to determine the efficacy of recombinant interferon alpha (rIFN-alpha) treatment of chronic delta hepatitis, by giving high doses of rIFN-alpha 2c during a prolonged period. A total of 20 HBsAg, anti-HD carriers with a chronic active hepatitis were randomly allocated in two groups: (I) n = 10, control and (II) n = 10, treated with 10 MU/m2 body surface of rIFN-alpha, twice weekly, intramuscularly (im) during 6 months. Basally, all patients presented HDAg in the liver and serum IgM anti-HD. Serum HDV-RNA was positive in 8 and 7 patients from groups I and II, respectively. The interferon therapy was well tolerated and all patients finished the treatment period. During the first 6 months, a decrease in ALT levels among treated patients (255 +/- 98 vs. 193 +/- 117) was observed. In addition, a transient drop in HDV-RNA levels was also observed. No changes in anti-HD titer, IgM anti-HD and HBsAg concentration were detected. At the end of the follow-up period (15 months) two treated patients had lost IgM anti-HD. In addition, another two patients were HDV-RNA negative. In conclusion, no permanent antiviral effects of rIFN-alpha 2c in chronic delta hepatitis, using this schedule, was achieved.

Changes of hepatitis B virus (HBV) markers during prolonged recombinant interferon alpha-2A treatment of chronic HBV infection

Eleven HBsAg chronic carriers were treated with recombinant-interferon (rIFN)-alpha-2A with either 20 X 10(6) (n = 6) or 10 X 10(6) IU/m2 body surface (n = 5), i.m. twice weekly for 6 months. HBV-markers were tested monthly for 15 months. Throughout the follow-up, 6 patients (54%) became HBeAg, HBV-DNAp and HBV-DNA negative (responders). In addition, 8 were HBcAg-negative, 10 anti-HBc-IgM-negative and 2 HBsAg/IgM complexes negative. All patients gave polymerized human serum albumin receptors and HBsAg-positive results. The low rIFN dose seems to be more efficient for clearing HBV-markers than the high dose. Responder patients already showed lower (P less than 0.05) HBsAg concentration and HBsAg/IgM complexes levels in their basal samples as compared to non-responders, and exhibited under rIFN treatment significant decreases (P less than 0.05) in all HBV-markers studied. In conclusion, the most reliable HBV-markers to be assayed in the evaluation of antiviral therapy are HBV-DNA, HBV-DNAp or HBcAg. The testing of pHSA-R, HBsAg/IgM complexes and anti-HBc-IgM does not seem to be very useful.

Hepatitis Delta Virus RNA Detection in Chronic HBsAg Carriers with and without HIV Infection

Hepatitis delta virus (HDV) RNA detection was carried out, using a full-length HDV RNA probe, in serum of 43 patients with chronic HDV infection. Among them, 30 cases (70%) were HDV RNA-positive. With respect to other HDV markers, serum HDAg (detected by immunoblot) was found in 33 patients (77%) and IgM anti-HD in 29 (67%). A similar percentage of HDV RNA-positive patients with and without circulating hepatitis B virus (HBV) DNA (32.5 vs. 37%, respectively) was found. Antibodies against the human immunodeficiency virus (HIV) were detected in 15/43 subjects studied. The presence of HDV RNA was significantly higher (p less than 0.05) in anti-HIV-seropositive cases (93%) than in the HIV-seronegative ones (57%). Moreover, simultaneous HDV and HBV replication was found more frequently (60 vs. 18%, p less than 0.05) and at higher levels among the anti-HIV-positive patients than in the rest. In addition, in most of the anti-HIV-positive subjects, HDV RNA and HBV DNA were constantly positive during a whole year of follow-up.

Hepatitis B virus DNA in liver and peripheral blood mononuclear cells during reduction in virus replication.

Changes in hepatitis B virus DNA in blood cells and liver were studied in 34 patients (12 controls, 22 under therapy). There were no basal differences in the presence of the viral genome in blood cells between treated and control patients. A significant decrease in the percentage of patients with viral genome in blood cells was observed in patients who lost this marker in serum. Replicative intermediates of the viral genome were observed in the basal liver samples from all patients. In patients who lost the viral DNA in serum, hepatitis B virus genome became undetectable in the second liver sample in all but two patients who had viral sequences integrated in the host genome. Replicative intermediates were found in all patients with serum viral DNA. The results of this study suggest that there may be a relation between the disappearance of hepatitis B virus DNA in liver and blood cells.

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 patients 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.

Detection of Antibody to Calmodulin in Chronic Viral Hepatitis: Lack of Correlation with Virus Replication and Hepatocellular Damage

We have analyzed the presence of IgG and IgM anti-calmodulin antibodies (anti-CaM) by ELISA in patients with chronic hepatitis due to B, delta and C viruses as well as in patients with other liver diseases. The specificity of the assay was demonstrated by preadsorption of positive serum with calmodulin (CaM) but not with myosin light chain. Among 164 patients with chronic viral hepatitis (B, delta and C) and 50 with non-viral hepatitis, 27 and 26%, respectively, had auto antibodies against CaM. There was a significantly increased frequency (37%) of these auto-antibodies in chronic delta infection as compared to that (21%) of patients with chronic B hepatitis (p less than 0.05). An intermediate incidence of anti-CaM, (24%) was found in chronic C infection. The frequency of anti-CaM was not related to the level of hepatitis B virus (HBV) or hepatitis delta virus (HDV) replication. A high occurrence of anti-CaM in the presence of liver membrane antibody (p less than 0.03) was observed. During follow-up of patients with chronic delta-hepatitis, the presence of anti-CaM was consistently observed, when the isotype was IgM, but transiently when it was IgG. The occurrence of anti-CaM correlated neither with ALT levels nor with histological diagnosis. Antibodies to CaM, are present in liver diseases especially in chronic delta-hepatitis, and do not play a pathogenic role on hepatocellular damage.

Receptors for polymerized human serum albumin in plasma derived hepatitis B vaccines

The presence of polymerized human serum albumin receptors (pHSA-R) in two hepatitis B virus (HBV) plasma derived vaccines (HB-Vax, Merck Sharp and Dohme; Hevac-B, Pasteur) was detected by three methods, using pHSA polystyrene coated beads and 125I-anti-HBs (method 1) and polyclonal (method 2) or monoclonal (method 3) peroxidase conjugated anti-HBs. Only a very weak reaction was found for pHSA-R in HB-Vax vaccine when the tests were performed in undiluted vaccine. No reactivity in 1/100 dilution (normally used to test pHSA-R in serum samples) was observed. In contrast, Hevac-B vaccine contained pHSA-R activity in 1/100 dilution as tested by any of the three methods. Furthermore, the level of pHSA-R detected in Hevac-B vaccine is similar to that observed in asymptomatic HBsAg carriers with the same HBsAg concentration. In summary, Hevac-B vaccine contains pHSA-R, whilst HB-Vax shows only weakly reacting pHSA-R, probably insufficient to develop anti-pHSA-R antibodies.