Yoshitaka Etoh

A Relationship between the Evolution of Hepatitis C Virus Variants, Liver Damage, and Hepatocellular Carcinoma in Patients with Hepatitis C Viremia

To clarify the mechanism of liver damage induced by hepatitis C virus (HCV) and to determine whether the damage is related to hepatocellular carcinoma (HCC), HCV RNA levels were measured serially, and HCV genome mutations were analyzed from serum of 274 Japanese patients with chronic HCV viremia during 1993-1998. All patients had alanine aminotransferase (ALT) levels measured during 1986-1998. Patients with consistently normal ALT levels had identical and highly conserved HCV core regions; however, those with consistently abnormal ALT levels had quasi species, and the population of the quasi species changed over time. HCV RNA levels did not change in the 274 patients. HCC developed in 31% of 80 patients with consistently abnormal ALT levels and in 4% of 92 patients with intermittently abnormal ALT levels but never in 102 patients with ALT levels consistently normal during 1993-1998. In patients with chronic HCV viremia, persistent liver damage plays an important role in the development of HCC.

Maintenance hemodialysis decreases serum Hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection

OBJECTIVE:Hepatitis C virus (HCV) infection is a major complication among hemodialysis patients the world over. To determine the natural course of HCV viremic levels in patients on maintenance hemodialysis, we prospectively quantified the HCV RNA levels in serial blood samples from hemodialysis patients and compared them with those in nonuremic subjects.METHODS:The population studied included 98 hemodialysis patients and 228 nonuremic subjects with chronic HCV infection. HCV RNA was detected by polymerase chain reaction (PCR) and the levels were determined by branched DNA probe assay. HCV RNA genotypes were determined by PCR using type-specific primers.RESULTS:HCV RNA levels were significantly lower in hemodialysis patients (median, 0.4 × 106 genome equivalent [Meq;[sol;ml) than in nonuremic subjects (median, 3.0 Meq/ml) (p < 0.05). HCV of genotype 1b was prevalent in the hemodialysis patients (81.6%) and nonuremic subjects (88.6%). HCV RNA levels in 20 hemodialysis patients with genotype 1b were significantly reduced after each hemodialysis procedure (p < 0.05). The 3-yr prospective observation from 1995 to 1998 showed a significant decrease of HCV RNA levels in 47 hemodialysis patients with genotype 1b (median, 1.9–0.9 Meq/ml, p < 0.05), whereas levels in 155 nonuremic subjects with genotype 1b did not decrease (median, 2.6–3.0 Meq/ml). There were no patients or nonuremic subjects with undetectable HCV RNA by a PCR assay during the observation period.CONCLUSIONS:These observations suggest that maintenance hemodialysis decreases the HCV RNA levels in hemodialysis patients with chronic HCV infection, but does not produce clearance of the viremia.

Acute hepatitis C among Japanese hemodialysis patients: a prospective 9-year study.

Abstract OBJECTIVES: The aims of this prospective survey were to determine the incidence and clinical characteristics of newly acquired hepatitis C virus (HCV) infection in hemodialysis patients after the start of antibody to HCV (anti-HCV) screening for blood products in Japan in 1989. METHODS: In serial serum samples from 269 hemodialysis patients who were followed over a mean period of 6.6 yr (± 2.1 yr) from 1990 to 1998, HCV RNA and anti-HCV were detected by reverse transcription-polymerase chain reaction and second generation ELISA, respectively. RESULTS: During the observation period, newly acquired HCV infection was found in 26 (15.4%) of the 169 hemodialysis patients without anti-HCV or HCV RNA at entry, an annual incidence rate of 2.59%. Of these 26, only four had a history of blood transfusion, one of whom had received the blood transfusion after 1992, the year in which screening of blood products for anti-HCV by second-generation ELISA was introduced in Japan. Persistent HCV viremia was found in 17 (65.4%) of the 26 patients; the other nine (34.6%) had transient HCV infection. The mean period of continuous ALT abnormality was significantly longer in the former (12.4 ± 13.6 months) than in the latter (1.9 ± 3.5 months) ( p = 0.0067). However, only three (17.6%) of 17 patients with chronic HCV viremia had continuous ALT abnormality for more than 24 months; in all of them, ALT eventually normalized. CONCLUSIONS: These findings indicate that newly acquired HCV infection has continued to occur in hemodialysis patients after the initiation of anti-HCV screening of blood products and that the abnormal ALT found in these patients is related to HCV chronicity.

Liver damage in hemodialysis patients with hepatitis C virus viremia : A prospective 10-year study

Hepatitis C virus (HCV) infection is a major problem associated with hemodialysis. The extent of liver damage in hemodialysis patients with chronic HCV infection has not been thoroughly documented. The aim of this study was to evaluate liver damage of hemodialysis patients infected with HCV. A total of 233 hemodialysis patients were categorized into two groups at entry: group X, 80 positive for serum HCV RNA, and group Y, 153 negative for serum HCV RNA. All were tested for serum alanine aminotransferase (ALT) serially from 1989 to 1998, and serum hyaluronic acid (HA), serum type-IV collagen (IV-C), platelet counts, and ultrasonographic examination of the liver was done in 1998. In group X, 61.3% had continuously abnormal ALT levels for over six months followed by normal ALT levels. Of the group X patients, 11.3% had abnormal ALT levels in 1998, and in three, hepatocellular carcinoma occurred. Mean HA and IV-C levels in group X (648.8 and 188.7 ng/ml, respectively) were significantly higher than in group Y (213.1 and 165.5 ng/ml, respectively) (P < 0.05). Ultrasonographic findings significantly correlated with serum HA level and platelet counts and showed significantly more abnormalities in group X than in group Y (P < 0.05). From these findings, a combined examination with ultrasonography and serum fibrogenesis markers is useful for detection of liver damage in hemodialysis patients with HCV viremia.

Heterosexual Transmission of GB Virus C/Hepatitis G Virus Infection to Non-Intravenous Drug-Using Female Prostitutes in Fukuoka, Japan

To determine if GB virus C (GBV-C) or hepatitisG (HGV) infection can be transmitted by heterosexualintercourse, we tested serum samples from 234non-drug-injecting female prostitutes for GBV-C/HGV. We used reverse transcription polymerase chainreaction to test for GBV-C/HGV RNA and ELISA forGBV-C/HGV-E2 antibody. The prevalence of total GBV-C/HGVmarker (GBV-C/HGV RNA and/or GBV-C/HGV-E2 antibody) was 58/234 (24.8%) in the prostitutes, and 7/71(8.9%) in matched controls. The GBV-C/HGV RNA andGBV-C/HGV-E2 antibody concurrence rate was 12.5% for theprostitutes, but was nil in matched controls. Total GBV-C/HGV marker was significantly higher inthe prostitutes than in matched controls. Additionally,total GBV-C/HGV marker was associated with the number ofyears engaged in prostitution after adjusting for age. We found hepatitis B virus andhepatitis C virus infections in prostitutes to beassociated with syphilis infection, but GBV-C/HGVinfection was not. Thus, it seems likely that GBV-C/HGVcan be transmitted by heterosexual intercourse, evenin the absence of syphilis.

Double point mutation in the core promoter region of hepatitis B virus (HBV) genotype C may be related to liver deterioration in patients with chronic HBV infection.

Background and Aim:  Hepatitis B virus (HBV) genotype C has a more severe pathogenesis than genotype B in Japan. We retrospectively investigated the relationship between HBV genotype and the core promoter (CP) (nt 1762 and 1764) and precore (PreC) (nt 1896) mutations of the HBV genome.

Seroepidemiology of TT Virus Infection and Relationship Between Genotype and Liver Damage

TT virus (TTV) has been identified in patients with posttransfusion hepatitis of unknown etiology and is thought to be a new hepatitis virus. We determined the extent of TTV infection in the Japanese general population and the relationship between TTV DNA genotype and liver damage. In 1998, we tested 847 serum samples for TTV. TTV DNA was assayed by a nested polymerase chain reaction and classified into three different genotypes and eight subtypes. TTV DNA was detected in 25.3% and 32.4% of the inhabitants of the two areas studied, respectively. The genotype distribution was similar in both areas. G1, G2, and G3 were 60%, 20%, and 5%, respectively. Of the 20 subjects with TTV DNA alone and elevated serum ALT levels, 18 were G1, one was G2, and one was G3. TTV infection is endemic in the Japanese general population studied. The main TTV genotype, G1, may be related to the ensuing liver damage.

Hepatitis C viral RNA status at two weeks of therapy predicts the eventual response.

We investigated the timing of the disappearance and reappearance of serum hepatitis C viral (HCV) RNA in patients with chronic hepatitis C during interferon treatment and follow-up. Serum samples were tested for HCV RNA by polymerase chain reaction in 62 patients with chronic hepatitis C treated with interferon-alpha for 24 weeks. We found that 17 patients obtained complete response, with absence of serum HCV RNA for 6 months after the treatment. Twenty-nine patients had a partial response, with reappearance of serum HCV RNA within 6 months of follow-up, and 16 patients were nonresponders who were positive for serum HCV RNA throughout the observation period. HCV RNA disappeared within 2 weeks of treatment in 31 patients, including all 17 (100%) complete responders and 14 (48.3%) of the 29 partial responders. The patients remaining positive for HCV RNA at the second week were 15 (51.7%) of the 29 partial responders and the 16 nonresponders. In all of the 29 partial responders, viremia recurred within 1 month after the treatment. These results indicate that the status of HCV RNA at the second week of treatment is a useful predictor of effective treatment, whereas status at the first month after cessation of treatment is useful for assessing the effectiveness of interferon itself.

Hepatitis G virus in the general population and in patients on hemodialysis.

To determine the routes of transmission ofhepatitis G virus (HGV) and the relationship between HGVand hepatitis C virus (HCV) infections, we tested forHGV RNA by polymerase chain reaction and antibody to HCV (anti-HCV) in 494 hemodialysis patients,638 inhabitants of two HCV endemic areas, and in 400blood donors in Japan. HGV RNA was detected in 6.9% ofhemodialysis patients, in 1.4% of inhabitants, and in 0.8% of donors, and anti-HCV wasdetected in 39.3%, 12.4%, and 1.8%, respectively. Of HGVRNA-positive hemodialysis patients, and HGV RNA-positiveinhabitants, 64.7% and 11.1%, respectively, had been given blood transfusions. Theprevalences of HGV RNA and anti-HCV significantlyincreased with the duration of hemodialysis. Of all HGVRNA positives, 74.4% were coinfected with HCV andsubjects with HGV RNA alone had normal liver function.In conclusion, HGV is transmitted by blood transfusionand within the hemodialysis unit itself. HGV does notseem to injure hepatocytes.

No Significant Changes in Levels of Hepatitis C Virus (HCV) RNA by HCV Infection Competitive Polymerase Chain Reaction in Blood Samples from Patients with Chronic

To determine if levels of hepatitis C virus(HCV) RNA change over a several-year period, wequantified the amount of HCV RNA by competitivepolymerase chain reaction. The population studiedincluded 44 residents of a rural area with chronic HCVinfection, 39 had chronic hepatitis C and 37 werepatients on hemodialysis. All these Japanese patientshad HCV RNA of genotype II. Blood samples were collected once a year from 1992 to 1995. From 1993 to1995 between the groups, there was no significantdifference in change of HCV RNA levels of 44 residentswith chronic HCV infection, with and without liverdysfunction, nor was there any change in the 31 hemodialysispatients from 1992 to 1995. The HCV RNA levels in the 25with chronic hepatitis who did not respond tointerferon-alpha during 1992-1993 returned topretreatment levels after the cessation of interferontreatment. In two of six hemodialysis patients who wereinfected with HCV during this observation period, HCVRNA was eliminated within one year, and the remaining four became HCV carriers. HCV RNA levels in thelatter rose rapidly after infection and were sustainedat a high level throughout the study period. Thus, HCVRNA level did not change remarkably during a three-year period, a finding which supportsthat it does not correlate with deterioration of liverdamage and aging of HCV carriers.