Kazuhiko Sekiyama

Combined interferon α2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial

Background. Only 15% to 20% of patients with chronic hepatitis C have a sustained virological response to interferon monotherapy. The aim of the present study was to compare the efficacy and safety of interferon, in combination with oral cyclosporin A, with interferon monotherapy in the treatment of chronic hepatitis C. Methods. We assigned 120 patients with chronic hepatitis C to receive the standard Japanese dose of interferon α2b alone for 24 weeks or that dose of interferon α2b in combination with cyclosporin A, at doses of 200 mg daily for the first 4 weeks and 100 mg daily for the following 20 weeks. All patients were assessed for drug safety, tolerance, and efficacy at the end of weeks 4, 12, 24, and 48. Efficacy was assessed by the disappearance of serum hepatitis C virus (HCV)-RNA by polymerase chain reaction and normalization of serum aminotransferase. The primary endpoint was a sustained virological response; i.e., sustained undetectable serum HCV RNA at 48 weeks. Results. The sustained virological response rate was significantly higher in the combination therapy group (42/76) than in the monotherapy group (14/44; P = 0.01). The sustained biochemical response rate was also higher in the combination therapy group (46/76) than in the monotherapy group (17/44; P = 0.017). In patients with genotype 1 and high viral loads, the sustained virological response rate was markedly higher in the combination therapy group (16/38) than in the monotherapy group (1/21; P = 0.006). Side-effect profiles were similar in the two groups. Conclusions. In patients with chronic hepatitis C; combined interferon and cyclosporin A treatment was more effective than interferon monotherapy. The benefit was mostly achieved in patients with a high viral load and HCV genotype 1.

Development of reliable artificial liver support (ALS)--plasma exchange in combination with hemodiafiltration using high-performance membranes.

A new artificial liver support system (ALSS) consisting of plasma exchange (PE) in combination with hemodiafiltration (HDF) using high-performance membranes of polymethyl metacrylate (PMMA) and cellulose triacetate (CTA) was developed to efficiently remove middle molecules from plasma and treat fulminant hepatic failure (FHF) complicated, by the onset of hepatic coma. Twenty-seven patients with FHF due to viral hepatitis, two with type A (HA), nine with type B (HB), and 16 with type non-A, non-B (NANB) underwent therapy with this new ALSS over the last five years. Three patients, with an exacerbation of chronic HB and 15/16 with type NANB hepatitis were treated with interferon (IFN) also. Of these, 25 patients (92.6%), regained consciousness and 15 (55.6%) [1/2 (50%) with type A, 6/9 (66.7%) with type B and 8/16 (50%) with type NANB hepatitis] survived Including four patients who survived with intensive, care and plasma exchange alone, 19/31 (61.3%) patients survived. Because of its biocompatibility, both survivors and nonsurvivors could be sustained with the ALSS without complications for long periods (19.3 days for the survivors and 32.4 days for nonsurvivors). With this ALSS the ability to sustain life for such prolonged periods allows hepatic regeneration to occur and result in patient survival. It is anticipated that this new ALSS will not only be of value in cases of fulminant hepatic failure but that it may also play a role in sustaining life for those, awaiting liver transplantation.

Reactivation of precore mutant hepatitis B virus leading to fulminant hepatic failure following cytotoxic treatment

Three hepatitis B virus carriers who were HBeAg negative and having normal liver function developed fulminant hepatitis with evidence of HBV replication following intensive chemotherapy for non-Hodgkins lymphoma. Each was continuously negative for HBeAg. Analysis of the precore region of HBV isolated from each demonstrated that the HBV of each had a point mutation in the precore region that inhibited the synthesis and the release of hepatitis Be antigen. This observation suggests that all HB carriers receiving either immunosuppressive or cytotoxic therapy should be monitored closely even if standard assays suggest that viral replication is not present. Sudden enhanced replication of a HBV mutant as a result of such therapy can be a cause of either very severe hepatitis or occasionally fulminant hepatitis.

Case Report: Fulminant Hepatitis C Viral Infection After Allogeneic Bone Marrow Transplantation

The authors describe two patients with acute leukemia who died of fulminant hepatitis caused by hepatitis C virus (HCV) after an allogeneic bone marrow transplant, the first such cases reported in Japan. Both had developed posttransfusion hepatitis during chemotherapy to induce remission and for consolidation. Six months after blood transfusion, the blood serum of each patient was positive for HCV antibody and HCV RNA. In each case, there was a transient improvement in liver function after the transplant. However, within 5 months of receiving the transplant and coincident with the withdrawal of cyclosporin A, each patient developed an acute exacerbation of hepatitis. The fulminant hepatitis in our patients may, therefore, have been caused by the reactivation of HCV induced by the immunosuppressive therapy followed by a reconstitution of the immune system.

Prognostic value of hepatic volumetry in fulminant hepatic failure

Serial hepatic volumetry calculated from the liver area on abdominal computed tomography was performed in 19 patients with fulminant hepatic failure to determine a relationship between liver volume and prognosis. All patients received intensified artificial liver support comprised of plasma exchange and hemodiafiltration using high-performance membranes, and 10 patients survived. Liver volume was significantly larger in survivors than in nonsurvivors, both in an initial volumetry performed at the onset of coma and in subsequent volumetry performed 10–20 days after the onset of coma. The difference became more significant in the subsequent volumetry because of the recovery of liver size in some of the survivors and progressive liver shrinkage in all nonsurvivors. All patients with a liver volume greater than 656 ml at 10–20 days after the onset of coma survived, whereas all but one patient with a liver volume less than that died. Multivariate analysis revealed only liver volume in subsequent volumetry had discriminatory power upon prognosis among six prognostic factors. These observations imply that in order to obtain an accurate prediction of fulminant hepatic failure by hepatic volumetry, serial studies at least until 10–20 days after the onset of coma are necessary.

Interferon and cyclosporin A in the treatment of fulminant viral hepatitis

The prognosis of fulminant hepatitis due to non-A, non-B virus infection and acute reactivation of hepatitis B virus in HB carriers is generally poor, and the treatment of choice in Western countries is recognized as liver transplantation. In countries such as Japan where liver transplantation is not readily available, however, these intractable types of fulminant hepatitis have to be treated medically. Based on the assumption that persistent replication of causal viruses and enhanced host immune responses, especially cellular immunity, to eradicate the viruses are the key mechanism in progressive liver cell destruction and the poor prognosis, we attempted a combination treatment with interferon and cyclosporin A for these types of fulminant viral hepatitis. Subjects in the present study consisted of 1 patient with acute severe hepatitis without coma and 13 patients with coma (13 with fulminant hepatic failure) due to non-A, non-B virus and acute reactivation of hepatitis B virus. The patients were given interferon-beta, 300 × 104U daily, and cyclosporin A, at an initial dose of 3 mg/kg, with tapering. Fourteen patients with coma received artificial liver support that we devised. The patient with acute severe hepatitis survived, showing histologically remarkable liver regeneration. Eight of the 14 patients with hepatic coma, all of whom were indications for liver transplantation according to the criteria of the Kings College group, survived. Decreased transaminase level, increased liver volume, and histological liver regeneration were observed in all the survivors. The combination of interferon and cyclosporin A is worth attempting in fulminant hepatitis caused by non-A, non-B virus and acute reactivation of hepatitis B virus in HB carriers.

Chronic hepatitis A with persistent viral replication

Hepatitis A virus (HAV) usually causes an acute self‐limited illness. This report describes a patient with hepatitis A whose serum aminotransferase activities remained above normal and whose serum was persistently positive for immunoglobulin (Ig) M class anti‐hepatitis A 31 months after the onset of hepatitis. Liver biopsy carried out 11 months after the onset of hepatitis showed histological changes consistent with chronic hepatitis of moderate severity. HAV RNA was detected by polymerase chain reaction (PCR) in feces collected at the time of the liver biopsy. Furthermore, the patient developed esophageal varices 25 months after the onset of hepatitis. We believe this to be the first reported case in which persistent replication of HAV is implicated in chronic hepatitis with the potential to develop into liver cirrhosis.

Accurate prediction of fulminant hepatic failure in severe acute viral hepatitis: multicenter study.

Background: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. Methods: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. Results: In the retrospective study, we established the following discrimination equation: Z = −0.89 + 1.74 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. Conclusions: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis.

Clinical and molecular virological differences between fulminant hepatic failures following acute and chronic infection with hepatitis B virus

Clinical and molecular biological characteristics were compared between patients who presented with fulminant hepatic failure following acute infection with hepatitis B virus (HBV) and those who developed hepatic failure during they carried HBV. The 11 patients with acute HBV infection had higher levels of alanine aminotransferase (mean ± SD: 4943 ± 2867 vs. 1157 ± 678 IU/L, P< 0.01), more often with a single peak (91% vs. 0%, P< 0.001), and lower total bilirubin levels (15.3 ± 4.4 vs. 28.1 ± 14.3 mg/100 ml, P< 0.01) than the 13 patients with chronic HBV infection. Hepatitis B surface antigen was detected less often (55% vs. 100%, P< 0.05) and viral DNA polymerase less frequently (0% vs. 46%, P< 0.05) in the patients with acute than chronic HBV infection. Hepatitis B e antigen was detected in one (9%) patient with acute infection, less frequently than in six (46%) patients with chronic infection (P< 0.05). Mutations in the precore region was detected in HBV DNA clones from ten (91%) patients with acute infection and only in those from eight (62%) patients with chronic infection. All HBV DNA clones from the five (38%) patients with chronic infection that did not have precore mutations, however, possessed mutations in the core promoter. These results indicate that HBV mutants incapable of translating hepatitis B e antigen would play a major role in fulminant hepatic failure occurring after acute HBV infection. In contrast, HBV variants with core promoter mutations for reducing the transcription of hepatitis B e antigen would play an additional role in fulminant hepatic failure developing during chronic infection. J. Med. Virol. 55:35–41, 1998.

TT virus infection in patients with fulminant hepatic failure

OBJECTIVE:A new DNA virus, which has been designated the TT virus, was discovered in 1997. It is not clear whether TT virus is a cause of any of the types of hepatitis. We conducted a case-control study to test the hypothesis that the presence of TT virus is a necessary condition for the development of fulminant hepatic failure in people who have non-A, -B, or -C hepatitis.METHODS:We studied 55 patients with fulminant hepatic failure [28 men, 27 women, mean (± SD) age, 47 ± 15 yr], 32 patients with acute hepatitis (18 men, 14 women, mean age, 38 ± 15 yr), and 200 healthy subjects (106 men, 94 women, mean age, 42 ± 14 yr). TT virus DNA was detected in sera by a nested polymerase chain reaction using a primer set for genotype 1.RESULTS:TT virus was more frequently detected in patients with fulminant hepatic failure [in 33 of 55 (60%); 95% confidence interval (CI), 47–73%] than in those with acute hepatitis [in 8 of 32 (25%); 95% CI, 10–40%; p= 0.0016] or in healthy subjects [in 50 of 200 (25%); 95% CI, 19–31%; p < 0.0001]. TT virus was detected at a significantly higher rate in non-A, -B, or -C fulminant hepatic failure [in 18 of 22 (82%); 95% CI, 66–98%] than in fulminant hepatic failure of A, B, or C type [45%, 28–62%, 15/33; p= 0.007] or in non-A, -B, or -C acute hepatitis [24%, 3–44%, 4/17; p= 0.0003]. The logistic regression analysis selected TT virus (p= 0.0009), age (p= 0.0116), and etiology (p= 0.0309) as independent variables associated with fulminant hepatic failure (coefficient of determination, 0.2335).CONCLUSIONS:TT virus comparatively plays a role in the pathogenesis of non-A, -B, or -C fulminant hepatic failure.