Retreatment with interferon in patients with chronic hepatitis C.
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Chronic Disease↗
Biomedical subjects
S Kakumu
Publications and source records attributed to S Kakumu.
[Genomic changes in the E2/NS1 region of HCV before and after IFN therapy in relation to clinical course].
To estimate the relationship between genomic change in the E2/NS1 region and clinical feature, we made a pairwise comparison in the nucleotide and deduced amino acid sequences for multiple recombinant clones of the E2/NS1 region, which derived from blood samples taken from four patients (three treated by IFN) at different stages. Sequence heterogeneities among the clones were generally high but they appeared to be significantly lowered after cessation of therapy. Our results showed, through IFN therapy, a few clones were selected and survived, although many clones disappeared. After discontinuation of the drug, three patients became carrier state, normal ALT levels with viremia. Evolution of defective viruses was seen in most of the cases. These features of HCV genome suggest that the virus could circulate as an extremely heterogeneous population including defective virus, and that this heterogeneity lend itself to selection pressures including interferon therapy and host immune response.
Aged↗
[Predicting factors for the response to interferon therapy against hepatitis C virus infection: HCV genotyping].
The predictive factors in the efficacy of interferon therapy were analyzed on the patients with chronic hepatitis C by multivariate analysis, and HCV genotype and histological diagnosis were found useful for predicting the response to interferon therapy. Of the patients, 57% were found to be infected with HCV II, 27% were with HCV III, and 3% were with HCV IV. HCV I was not found in our patients. The complete response rate of the patients with HCV II (21%) was significantly lower than that of HCV III (63%). The concentration of HCV RNA was significantly larger in the patients with HCV II than in those with HCV III. When the patients with equal concentrations of HCV RNA were compared, the complete response rate was also significantly lower in the patients with HCV II than in those with HCV III. On histological diagnosis, the patients with mild disease were significantly more responsive than those with severe disease. The complete response rate of the patients with HCV II who have severe histological lesions (severe CAH) was 7%. On the other hand, the complete response rate of the patients with HCV III and a histological diagnosis of mild disease (CPH or mild CAH) was 80%. Our findings suggest that the outcome of interferon therapy can be predicted to some degree from the pretreatment data.
Base Sequence↗
Interferon-gamma production specific for hepatitis B virus antigen by intrahepatic T lymphocytes in patients with acute and chronic hepatitis B.
OBJECTIVES: Studies were undertaken to determine whether intrahepatic lymphocytes have a greater cellular immune response specific for hepatitis B virus (HBV) antigen than peripheral blood lymphocytes in HBV-infected man. METHODS: HB nucleocapsid antigen-stimulated interferon-gamma (IFN-gamma) production of lymphocytes was measured in acute self-limited hepatitis (AH) (eight cases) and chronic hepatitis (CH) (14 cases). RESULTS: In both patient groups, basal IFN-gamma levels without any stimulation were higher in the hepatic T cells than in the peripheral T cells. The values in cultures from blood and liver were larger in AH than in CH. Alternatively, IFN-gamma response to HBcAg and HBeAg was less in hepatic T cells than in the corresponding blood cultures; T cell response was HLA class II restricted. Cell flow cytometry study showed that in all patient groups, percentages of CD3+, CD8+, and HLA-DR+ cells were significantly greater in liver than in peripheral blood, whereas the proportion of hepatic CD4+ cells was decreased, compared with that in peripheral CD4+ cells. CONCLUSIONS: These findings suggest that liver infiltrates are already activated in vivo to produce IFN-gamma, particularly in patients with AH. The changes in the proportion of lymphocyte subsets may be responsible for the altered IFN-gamma response of hepatic T cells.
Acute Disease↗
Long-term carriage of hepatitis C virus with normal aminotransferase after interferon treatment in patients with chronic hepatitis C.
Studies were undertaken to investigate whether interferon therapy could induce hepatitis C virus (HCV) carriage with normal serum alanine aminotransferase (ALT) values using an assay that combined reverse transcription and polymerase chain reaction. The subjects studied were 53 patients with chronic active hepatitis C who received interferon (alpha, 33 cases; beta, 20 cases) therapy. All were seropositive for HCV RNA prior to therapy. In all 22 complete responders, whose ALT levels fell to normal during therapy and for at least 24 weeks after therapy, HCV RNA became persistently negative except in two cases. The two had sustained viremia on treatment and for 1.0-1.5 years of follow-up, although their biochemical tests were normal. In 15 patients with a transient response in whom the disease recurred when interferon was stopped, HCV RNA was undetectable in 80% of the cases at the end of therapy, but the virus reappeared with subsequent elevation of ALT in all patients. However, 3 patients in this group had normal enzyme levels with viremia for 2.1-2.8 years of follow-up after acute deterioration of illness. In 16 patients who did not respond to interferon, HCV RNA was persistently positive during and after therapy. These findings suggest that interferon therapy induces a long-term carrier state of HCV infection with normal ALT levels in some patients.
Adult↗
Comparison of envelope and precore/core variants of hepatitis B virus (HBV) during chronic HBV infection.
We analyzed entire pre-C/C and pre-S/S coding genes of hepatitis B virus (HBV) in serial serum samples from four chronic HBV carriers with 4-5 years of follow-up. Two patients with chronic active hepatitis became seronegative for HB e antigen (HBeAg), but the hepatitis did not subside, while the other two were persistent asymptomatic carriers with normal aminotransferase values. DNAs amplified by PCR were cloned and sequenced (subtype adr). After HBeAg became negative, one patient had 96-183 bp deletions in 4/6 clones for C gene. In addition, both patients had 129-183 bp deletions in 3/6 and 2/5 clones for pre-S1 gene, respectively. Divergence rate of deduced amino acid for both pre-C/C and pre-S/S regions from the adr subtype was significantly higher in patients with chronic hepatitis than in asymptomatic carriers. Furthermore, the divergence rate for pre-S/S region was usually greater in asymptomatic carriers as well as chronic hepatitis patients compared with that for pre-C/C region. However, no significant difference was found in the rate of amino acid divergence for the entire HBV genes between the serial samples in all patients studied here. These results suggest that active hepatitis induces variation of HBV gene and defective virus is often selected along with the disappearance of HBeAg. In addition, the fact that patients with active liver disease possess greater numbers of mutant clones than asymptomatic carriers suggests that viral mutants are being immune-selected.
Adult↗
Dynamics of genome change in the E2/NS1 region of hepatitis C virus in vivo.
To substantiate and extend the quasispecies model of hepatitis C virus (HCV), we made a pairwise comparison in the nucleotide and deduced amino acid sequences for multiple recombinant clones of the E2/NS1 region, which derived from each blood sample taken from five patients of subtype II or subtype III infection at different stages. Sequence heterogeneity among the clones was generally high. The heterogeneity, however, changed temporally and appeared to be significantly lowered after interferon therapy. The temporal fluctuation involved selection of particular amino acids at particular positions, which had represented only a minor fraction or had been absent in the previous clones. Evolution of defective viruses was featured by most of the cases, the proportion of which also fluctuated temporally and was extremely high at a certain stage in one of the patients. A comparison was also made among the clones from different stages of each patient and revealed highly divergent clones. An extreme case of subtype III infection showed sequence differences well beyond those among chronologically and geographically different isolates of subtype I or subtype II, which were defined by the same calculation of available sequence data. These features of HCV genome suggest that the virus could circulate as an extremely heterogeneous population including defective viruses and that this heterogeneity lends itself to selection pressures including interferon therapy and host immune response. Our results also indicate an absolute need of population based approach in HCV genetics.
Aged↗
Hemangiopericytomatous meningioma metastasized to the liver: report of a case and review of the literature.
A 54-year-old male was admitted to our hospital for treatment of a liver tumor which was pointed out by screening ultrasonography. Computed tomography revealed a tumor in the right lobe of the liver measuring 7 cm in diameter. Angiography revealed a hypervascular tumor. A hepatocellular carcinoma or hypervascular metastatic tumor was suspected. A right hepatic lobectomy was performed. The patient had previously undergone operations for a hemangiopericytomatous meningioma in the occipital fossa in 1972 and 1977. The histological findings of the liver tumor were identical to those for hemangiopericytomatous meningioma, so the etiology was considered to be liver metastasis from the previous meningioma. Nineteen cases of extracranial metastasis of hemangiopericytomatous meningioma have been reported in the literature, but hepatic resections of this metastasizing tumor have been very rare.
Brain Neoplasms↗
Interleukin 6 production by peripheral blood mononuclear cells in patients with chronic hepatitis B virus infection and primary biliary cirrhosis.
IL-6 production by peripheral blood mononuclear cells (PBMC) was studied in patients with chronic hepatitis B virus (HBV) infection and primary biliary cirrhosis (PBC) using the ELISA method. Spontaneous production of IL-6 was significantly increased in patients with HBeAg+ chronic hepatitis (CH). The cultures stimulated with lipopolysaccharide and lectin-free interleukin-2 (IL-2) showed enhanced IL-6 production both in controls and all patient groups compared with culture without any stimulation. IL-6 production in response to IL-2 was higher in patients with HBeAg+ CH and PBC than in controls. In PBMC with increased IL-6 production, monocyte function was increased in patients with HBeAg+ CH and PBC, while B cells from PBC showed elevated response to Staphylococcus aureus Cowan 1. IL-6 production in the presence of HBeAg was greater in anti-HBe+ patients than in HBeAg+ ones. These results suggest that IL-6 response is involved in the immune response in patients with chronic liver disease.
Adult↗
Cytotoxic T lymphocyte activity and HB virus mutant in chronic HB virus carriers.
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Adult↗
Cytotoxic T lymphocyte activity to hepatitis B virus DNA-transfected HepG2 cells in patients with chronic hepatitis B.
Cytotoxic T lymphocyte (CTL) activity for hepatitis B virus (HBV) DNA-transfected HepG2 cells (designated HB3-5), which secrete HBsAg, HBeAg and HBV particles, was investigated in 31 patients with chronic HBV infection (18 chronic hepatitis and 13 asymptomatic carriers). 51Cr-labeled HB3-5 with A2 as a major HLA class I antigen served as target cells and T cells from peripheral blood mononuclear cells as effector cells. The CTL activity was measured by a 51Cr release assay. Patients were divided into two groups, the A2 group bearing HLA-A2 and the non-A2 group not bearing HLA-A2. Chronic hepatitis patients in the A2 group showed increased HBV Ag-specific cytotoxicity compared with that seen in the non-A2 group (5.2 +/- 3.1% vs. 0.9 +/- 1.4%; means +/- SD, P < 0.01). In the A2 group with chronic hepatitis, the cytotoxicity was greater in anti-HBe positive patients than in HBeAg positive patients (8.6 +/- 1.9% vs. 3.4 +/- 2.0%, P < 0.01), and asymptomatic carriers showed less cytotoxicity (0.35 +/- 0.31%, P < 0.001) compared with chronic hepatitis patients. In the non-A2 group, HBV Ag-specific CTL activity was negligible in most patients and thus no differences were found among all patient groups. The HBV Ag-specific cytotoxicity was inhibited by antibodies to CD3, HLA class I and hepatitis B nucleocapsid antigens. Removal of CD8+ cells also resulted in marked decrease in the cytotoxicity. These findings indicate that HBV Ag-specific cytotoxicity reflects liver cell damage and HBeAg/anti-HBe status. Furthermore, our assay system appears to be useful to assess CTL response in patients with chronic HBV infection.
Adult↗
A pilot study of ribavirin and interferon beta for the treatment of chronic hepatitis C.
BACKGROUND: Chronic hepatitis C is a common and often progressive liver disease for which interferon alfa therapy widely spreads, but the beneficial response is frequently transient. Ribavirin is a nucleoside analog with a broad spectrum of antiviral action, and we investigated the efficacy of it in patients with chronic active hepatitis C. METHODS: We conducted a pilot study of oral ribavirin in patients with chronic active hepatitis C. Twenty-seven patients with hepatitis C virus RNA were randomly assigned to receive either 0.8-1.0 g of ribavirin daily or 3 MU of interferon beta three times weekly or combination of the two for 24 weeks. RESULTS: Ribavirin was tolerated well, and all completed the treatment schedule. Ribavirin decreased aminotransferase levels in all instances, and the mean value at termination decreased to half of the baseline level (P < 0.01), but the enzyme level increased after cessation of therapy in most cases. Ribavirin suppressed amounts of hepatitis C virus RNA in 4 of 9 patients, and 1 became negative during follow-up. Interferon alone (P < 0.05) or with ribavirin (P < 0.01) significantly decreased the viral population, resulting in sustained loss of viremia with normal enzyme levels in 2 of 9 and 3 of 9 patients, respectively, in each therapy during follow-up. CONCLUSIONS: These results indicate that ribavirin has a beneficial effect in some patients with chronic hepatitis C, although the antiviral effect is less than interferon beta. Large-scale trials are needed to determine whether the combination of interferon and ribavirin is of more benefit than interferon alone.
Adult↗
Effect of recombinant human transforming growth factor beta 1 on immune responses in patients with chronic hepatitis B.
Studies were undertaken to examine the effect of recombinant human transforming growth factor beta 1 (rTGF-beta 1) on cellular and humoral immune responses of peripheral blood mononuclear cells (PBMC) from patients with chronic hepatitis B. The addition of TGF-beta 1 caused a significant dose-dependent inhibition of hepatitis B (HB) core Ag-stimulated interferon-gamma and antibody to HB core Ag production and proliferation of PBMC from chronic hepatitis patients and HB-immune donors. TGF-beta 1 also induced a significant reduction in pokeweed mitogen-stimulated IgG and IgM production, as well as phytohemagglutinin p-stimulated proliferative response of PBMC. The degree of inhibition of TGF-beta 1 did not differ between antigen-specific and -nonspecific cellular and humoral immune responses, and between control individuals and patients. Pretreatment study with TGF-beta 1 showed that the activities of T cells, B cells and monocytes were similarly inhibited. Further, TGF-beta 1 inhibited activities of HLA class I antigen-matched cytotoxic T cells from patients with chronic hepatitis B for HBV DNA-transfected HepG2 cells in a 51Cr release assay. The results suggest that TGF-beta 1 may play a role in the regulation of antigen-dependent and -independent immune responses in patients with chronic hepatitis B.
Adult↗
Effects of interferon-alpha treatment on hepatitis B virus antigen-specific immunologic responses in patients with chronic hepatitis B.
Studies were undertaken to evaluate the relationship between the immune responses and the effectiveness of interferon-alpha treatment in 21 patients with HBeAg-positive chronic active hepatitis. Peripheral blood mononuclear cells (PBMC), obtained on four occasions during an 8-week course of IFN-alpha therapy, were cultured with recombinant HBcAg, purified HBeAg or pokeweed mitogen (PWM). During follow-up for 6 months after therapy, clearance of serum HBeAg was observed in eight patients designated as responders. Immunological responses of PBMC obtained before treatment did not differ between responders and non-responders. In responders, IFN-gamma and anti-HBc production was depressed during therapy, but recovered to above the pretreatment level at the end of and/or after cessation of therapy, while lymphocyte proliferation was enhanced during therapy with a subsequent decline to baseline value. In non-responders, such changes were modest throughout the study, and anti-HBc response remained decreased even after cessation of therapy. These results indicate that PBMC of responders have immunologically different responses to IFN-alpha therapy when compared with non-responders.
Adolescent↗
Relative immunogenicity of hepatitis B virus-encoded antigens as targets for cytotoxic T-cell response.
To analyse the immunological mechanism of hepatocellular injury in hepatitis B virus (HBV) infection, the immunoreactivity of HBV-encoded antigens as a target for cytotoxic T lymphocyte (CTL) response was examined using recombinant vaccinia virus (RVV) expressing surface protein (S), precore/core protein (PC), and core protein (C) of HBV. C3H/He mice (H-2k) were inoculated with each RVV. Their spleen cells were then harvested and stimulated in vitro with the histocompatible transfectant, which stably expressed hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and hepatitis B core antigen (HBcAg), and used as effectors. As the targets, L cells (H-2k) infected with individual RVV were used. Cytotoxic test was performed with various combinations and ratios of effectors and targets. The reactivity of PC-primed effectors against PC-expressing targets was greatest with 71.4% specific lysis on average at an effector/target ratio of 12.5:1 among all the combinations. C-primed effectors against C-expressing target also revealed rather high cytotoxicity (specific lysis, 40.6% at an E/T ratio of 12.5:1). Furthermore, PC-primed and C-primed effectors showed a cross-reactivity to the targets expressing other nucleocapsid antigen, respectively. S-primed effectors showed less lytic activity against S-expressing targets (specific lysis, 18.4% at an E/T ratio of 12.5:1). The CTL responses were blocked by anti-CD8 and anti-major histocompatibility complex (MHC) class I antibodies, but not by anti-CD4 or anti-MHC class II. These findings suggest that endogenously synthesized nucleocapsid antigen, especially PC, is a dominant target for the MHC class I-restricted CTL in H-2k mice and that this system may work as an efficient model to study immunopathogenesis of HBV infection.
Animals↗
Pilot study of ribavirin and interferon-beta for chronic hepatitis B.
Ribavirin is a nucleoside analog that inhibits the replication of many DNA and RNA viruses. To evaluate the efficacy of oral ribavirin, we randomly assigned 24 HBeAg-positive patients with chronic active hepatitis to a 12-wk course of treatment with 0.8 to 1.0 gm/ribavirin day, 3 mU interferon-beta three times a week intravenously or a combination of those drugs. Ribavirin, alone and in combination with interferon-beta, decreased hepatitis B virus levels in most patients, and mean serum hepatitis B virus DNA and DNA polymerase levels at the end of treatment were approximately half of baseline levels (p < 0.05). Interferon alone exerted the most inhibitory effect on hepatitis B virus activity (p < 0.01). During ribavirin treatment, changes in serum aminotransferase values varied considerably and the mean values did not change significantly, although interferon alone and the combination of interferon and ribavirin were associated with significant reductions in serum aminotransferase activities. Ribavirin was well tolerated, but we transiently reduced the dosage in two cases because of mild hemolytic anemia, although all patients completed the treatment schedule. The combination of interferon and ribavirin did not appear to result in greater toxicity. During the follow-up period (6 to 9 mo), HBeAg and hepatitis B virus DNA disappeared in one patient treated with ribavirin, in two treated with interferon and in two given the combination. These results indicate that ribavirin suppresses hepatitis B virus replication, although its effect is less than that of interferon, and that it may be useful as adjunctive therapy for chronic hepatitis B.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Defective short variants of S region in chronic HBV carriers].
We analyzed the pre-S and S region of hepatitis B virus by polymerase chain reaction in 60 chronic carriers. In 10 hepatitis B e antigen-positive chronic carriers, a single DNA band was detected at the expected size, whereas additional shorter DNA bands were observed in some cases with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The smaller-sized DNA bands from chronic hepatitis patients had the deletion of 183 bp in the pre-S gene, and the deletion of 492 bp in S gene. The reasons of the appearance of these mutants are unknown, but it may be interesting to study in relationship to the mechanism of host immune response.
Adult↗
Detection of hepatitis C virus by polymerase chain reaction and response to interferon-alpha therapy: relationship to genotypes of hepatitis C virus.
To investigate the relationship between genotypes of hepatitis C virus and response to interferon-alpha therapy, hepatitis C virus RNA was assayed by polymerase chain reaction with three sets of primers and probes in 70 patients with non-A, non-B chronic hepatitis who received interferon-alpha. Twenty-four patients sustained long-term remissions (complete responders). Polymerase chain reaction for 5'-terminal noncoding region detected hepatitis C virus RNA in 94.3% (66 of 70) of the patients. Polymerase chain reaction for nonstructural region 3, in which primers and a probe were synthesized to be identical to hepatitis C virus-J, detected hepatitis C virus RNA in 40 patients. Polymerase chain reaction for nonstructural region 5-in which sequences of primers and a probe were derived from hepatitis C virus-K2, a genotype different from hepatitis C virus-J--detected hepatitis C virus RNA in 17 patients. Only one patient was positive on both nonstructural region 3 and nonstructural region 5 polymerase chain reaction. Nucleotide sequence of clones obtained from 5' terminal noncoding region polymerase chain reaction products of two patients positive on polymerase chain reaction for nonstructural region 3 and negative on polymerase chain reaction for nonstructural region 5 (group 1) corresponded to that of the hepatitis C virus-J group, and those of clones from two patients negative on polymerase chain reaction for nonstructural region 3 and positive on polymerase chain reaction for nonstructural region 5 (group 2) corresponded to that of hepatitis C virus-K2.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗