Kiyomi Yasuda

Precore and core promoter mutations, hepatitis B virus DNA levels and progressive liver injury in chronic hepatitis B

BACKGROUND/AIMS To elucidate the viral factors responsible for progressive liver injury in chronic hepatitis B. METHODS We analyzed 179 persistently infected patients (21 asymptomatic carriers, 126 with chronic hepatitis and 32 with cirrhosis) with genotype C hepatitis B virus (HBV). HBeAg/anti-HBe, levels of HBV DNA, mutations in the basic core promoter (BCP) region at nucleotides 1762/1764 and mutation in the precore (preC) region at nucleotide 1896 were determined. Serial samples from 18 patients also were analyzed. RESULTS HBeAg/anti-HBe and HBV DNA levels per se were not related to liver fibrosis. The frequency of BCP mutations increased with progression of liver fibrosis. Although the preC mutation was detected more often among the LC group, the role of this mutation in progression of fibrosis seems less than that of the BCP mutations. Sequential analysis showed that (1) rapidly progressing cases were positive continuously for double mutations in the BCP with a wild-type precore sequence, and (2) asymptomatic cases with anti-HBe acquired the preC mutation during their clinical course. CONCLUSIONS Double mutations in the BCP region at nucleotide 1762/1764 are closely related to progression of chronic liver disease. Acquisition of mutation in the preC region at nucleotide 1896 may contribute to inactivation of chronic liver disease.

Current State of Interferon Therapy for Chronic Hepatitis C

The current status of interferon (IFN) therapy in chronic hepatitis C is presented, focusing on the results of studies in Japan. Depending on the IFN treatment regimen used in chronic hepatitis C, it is possible to eradicate HCV in a relatively high percentage of patients (about 40%) and to achieve a cure for chronic hepatitis C. The objective of treatment should therefore be the eradication of HCV. The efficacy of IFN in chronic hepatitis C is dependent on the dosage of IFN, duration of treatment, liver histology findings, serum HCV-RNA levels, and HCV genotype. Besides a flu-like syndrome, many adverse reactions are associated with high-dose, long-term IFN treatment. However, as a rule, full recovery or improvement follows prompt withdrawal of IFN. By modification of the IFN, it will be possible to reduce adverse reactions and to create a more effective IFN to further enhance the effect of IFN in chronic hepatitis C.

One-point quantitative determination of pretreatment serum hepatitis C virus RNA predicts long-term responsiveness to high-dose interferon therapy

Abstract We determined quantitative values of serum hepatitis C virus RNA by branched DNA amplification assay in 52 consecutive patients with chronic hepatitis C immediately before high-dose treatment with interferon-alpha. Thirty-four out of 52 patients had >106.3 (≈2 × 106) equivalents/ml of viral genomes. Only three (8.8%) out of these 34 were long-term responders, while 16 (88.9%) out of 18 patients with ≤106.3 equivalents/ml of viral genomes were long-term responders (P 106.3 equivalents/ml was a long-term responder (P

Effect of interferon therapy on RNA of GB virus C in the patients with chronic hepatitis who were co-infected with hepatitis C virus

Abstract Of 112 patients with chronic hepatitis C, 12 (11%) tested positive for RNA of GB virus C (GBV-C) by reverse-transcription polymerase chain reaction with primers deduced from the 5′ untranslated region. RNAs of GBV-C and hepatitis C virus (HCV) were followed in the 12 patients before and after they received 19 trials of interferon (IFN) therapy. GBV-C RNA disappeared from serum in 11 (58%) trials on eight patients. However, it stayed negative at 6 months after IFN only in two patients. One of them regained GBV-C RNA at 12 months and kept it thereafter, while an additional patient who failed to clear it at the completion of IFN turned negative at 24 months after therapy. Thus, two patients (17%) became persistently negative for GBV-C RNA. HCV RNA disappeared from serum at the completion of ten trials (53%) on eight patients, and stayed negative in three patients (25%). Two of them did not lose GBV-C RNA but kept normal transaminase levels. These results indicate that GBV-C is susceptible to IFN with a sensitivity comparable to but independent of HCV, and that GBV-C by itself would not elevate transaminases in hepatitis C patients who respond to IFN.

Intrahepatic hepatitis C virus RNA levels after interferon treatment: eradication of the minus-strand RNA correlates with sustained remission of hepatitis

Abstract The effect of interferon on hepatitis C virus RNA levels in the liver was studied by polymerase chain reaction in chronic hepatitis C patients who were enrolled into a pilot study with short-term interferon treatment. Among 17 patients treated with interferon α or β (168–560 M.U. in total), eight were ‘long-term responders’ as defined by sustained normal serum alanine aminotransferase levels for more than 12 months, while the other nine were ‘nonresponders’ with abnormal alanine aminotransferase levels. In eight ‘long-term responders’, both the plus and minus strands (replicative intermediate) of hepatitis C virus RNA could not be detected in the liver after interferon treatment whereas eight of nine ‘non-responders’ retained the minus strand or both strands of hepatitis C virus RNA in the liver. Serum hepatitis C virus RNA was no longer detected in seven of nine ‘non-responders’ or in all ‘long-term responders’ at the end of treatment, but it reappeared in ‘non-responders’ with the elevation of serum alanine aminotransferase levels, which excluded serum hepatitis C virus RNA as a prognostic marker for sustained alanine aminotransferase normalization after interferon treatment. Our results indicate that the disappearance of hepatitis C virus RNA including the minus strand RNA from the liver is a predictive marker for good prognosis in chronic hepatitis C patients after interferon treatment. It is of great use to determine the levels of hepatitis C virus RNA in the liver to know the prognosis of interferon-treated patients who maintain sustained normal serum alanine aminotransferase levels and undetectable serum hepatitis C virus RNA after interferon treatment.

Interferon Therapy in Chronic Hepatitis C and Liver Histology

The effectiveness of interferon (IFN) in the treatment of chronic hepatitis caused by hepatitis C virus (HCV) has been evaluated by determining serum alanine aminotransferase (ALT) and HCV-RNA levels, but the effects of IFN on the histology of liver have yet to be clarified. We analyzed liver biopsies from 109 patients before and after IFN therapy. With respect to Knodell’s histology activity index (HAI), an improvement of liver histology was observed in 100% of 19 complete responders (those with sustained disappearance of HCV-RNA and normalization of ALT), but in only 8 (42%) of 19 nonresponders. High pretreatment serum levels of HCV-RNA, HCV genotype II (or 1b), and advanced pretreatment disease stage were the major predictors for nonresponsiveness to IFN as seen in liver histology.

Treatment of Chronic Hepatitis C with Interferon-α

Interferon–α (IFN-α) has been indicated to be dramatically effective in some but not all patients with chronic hepatitis C. We investigated retrospectively our patients treated with IFN-α for a better regimen of the therapy and for any effective predictors of responsiveness to the treatment. We found that, sustained normalization of serum alanine aminotransferase levels was more closely associated with high-dose long-term administration of IFN-α, compared with low-dose short-term regimens. Nonresponsiveness to the IFN-α therapy was related to advanced liver histology, high levels of circulating hepatitis C virus (HCV)-RNA, and the HCV genotype II (or 1b).