Relationship between Human Leukocyte Antigen Determinants and Courses of Hepatitis B Virus Infection in Caucasian Patients with End-Stage Renal Disease

Background: Divergent results have been reported with regard to the relationship between the course of hepatitis B virus (HBV) infection and the human leukocyte antigen (HLA) determinants. The aim of the present study was to investigate the phenotype frequencies of HLA class-I and -II alleles in Caucasians with and without HBV infection. Methods: Fifty-eight patients with persistent HBV infection (group 1), 119 patients with resolved HBV infection (group 2), and 106 patients neither infected by HBV nor vaccinated against HBV (group 3) were analyzed. All patients had end-stage renal disease. HLA class-I antigens were serologically determined. For HLA class-II typing we performed DRB1, DQA1, and DQB1 genotyping using a polymerase chain reaction-sequence-specific oligonucleotide procedure. Results: Compared with group 2, group 1 showed increased frequencies of HLA-B8, DR3 (P < 0.05), A30, DQA1^*0501 (P < 0.01), and a decreased frequency of HLA-B12 (P < 0.05). Decreased frequencies of HLA-B27, B40, DR13, and DQ1^*0604 (P < 0.05) and an increased frequency of HLA-B35 (P < 0.05) were found in groups 1 and 2 compared with controls (group 3). None of the differences detected in the phenotype frequencies of HLA alleles were statistically significant after correction. Conclusions: We conclude that the susceptibility to HBV infection and the different courses of HBV infection are not strongly related to HLA status in Caucasians.     

Hepatitis C Virus Infection among Patients with Chronic Liver Disease in an Area Hyperendemic for Hepatitis B

Tsai J-F, Jeng J-E, Chang W-Y, Lin Z-Y, Tsai J-H. Hepatitis C virus infection among patients with chronic liver disease in an area hyperendemic for hepatitis B. Scand J Gastroenterol 1994;29:550-552.

Background: The prevalence of hepatitis C virus (HCV) infection was assessed in patients with nonalcoholic chronic liver disease (CLD).

Methods: Antibody levels to HCV (anti-HCV) were assessed in 100 pairs of CLD patients and healthy controls.

Results: The prevalence of anti-HCV was higher in patients (26.0%) than in controls (2.0% p = 0.0001). The patient group with anti-HCV was older (p equals; 0.0001) and had more smokers (p equals; 0.034), fewer hepatitis B surface antigen carriers (p equals; 0.0001), and more patients with active liver disease (p equals; 0.023) and a history of blood transfusion (p equals; 0.026). Multivariate analysis showed that anti-HCV (odds ratio, 8.1; 95% confidence intervals, 3.7-17.6) was strongly associated with CLD.

Conclusions: HCV infection is a risk factor of non-alcoholic CLD, and HCV causes more severe hepatocellular damage than HBV.     

Clinical Characteristics of Patients with Hepatitis C Virus-Related Chronic Liver Disease Seropositive for Anticentromere Antibody

The association between anticentromere antibody (ACA) and hepatitis C virus (HCV) infection remains unclear. We subjected eight patients with HCV-related chronic liver disease (CLD) seropositive for ACA to a battery of clinical and laboratory tests. The patient cohort was dominated by females, and four of the eight (50%) patients had a concomitant autoimmune disease. All of the patients had high titers of ACA (≥1:320). The histological activity index scores in chronic hepatitis C (CH-C) patients with ACA were significantly higher than those in CH-C patients without antinuclear antibody (ANA) (12.8 ± 1.8 vs. 8.3 ± 4.5, P = 0.0372). The frequency of human leukocyte antigen (HLA) DR-8 in patients with HCV-related CLD seropositive for ACA was significantly higher than that in patients with CH-C seronegative for ANA (71 vs. 18%, P = 0.0108). These findings suggest that ACA is induced by chronic HCV infection in association with HLA DR-8, and that CH-C patients with ACA exhibit more severe hepatic fibrosis and inflammation than CH-C patients without ANA.     

Celiac Disease and Non-organ-specific Autoantibodies in Patients with Chronic Hepatitis C Virus Infection

OBJECTIVE: Considering that celiac disease (CD) is an autoimmune-based entity and the hepatitis C virus is suspected of being able to trigging autoimmune reactions, it has been hypothesized that hepatitis C virus infection might predispose to CD. The aim of this study was to investigate CD-related antibodies in a large series of hepatitis C virus-infected subjects that were also tested for non-organ-specific autoantibodies (NOSA) as indirect marker of autoimmune disorders. METHODS: Two hundred and forty-four patients with chronic hepatitis C virus infection (HCV-patients) and 121 patients with HCV-negative liver disease (non-HCV-patients) underwent NOSA determination and celiac serology (firstly, anti-tissue transglutaminase antibodies, then the cases which tested positive were subsequently evaluated for the presence of antiendomysial antibodies). Serum samples from 42 of the HCV-patients who underwent interferon-alpha therapy after enrollment were tested for celiac antibodies and NOSA even after stopping treatment. Additionally, sera from 1,230 blood donors were assayed for celiac serology as healthy control population. RESULTS: Positive anti-endomysial antibodies (AEA) were found in 5/244 (2%) HCV-patients, 1/121 (0.8%) non-HCV-patients and 2/1,230 (0.16%) blood donors, with a significant difference between HCV-patients and blood donors (P = 0.02; Odds ratio 12.8; 95% Confidence Interval 2.4-66). NOSA were found in 51 HCV-patients but only one of them had positive AEA. Eight out of 42 HCV-patients treated with interferon-alpha developed NOSA under therapy and none of them had CD antibodies. CONCLUSIONS: AEA occur in 2% of HCV-patients and their presence is independent of other patterns of autoimmunity.     

Ethnicity and route of HCV infection can influence the associations of HLA with viral clearance in an ethnically heterogeneous population

Approximately 20% of hepatitis C virus (HCV) infected individuals clear the virus. Host factors that influence the course of HCV infection are still under investigation, and the data on the association of human leukocyte antigen (HLA) alleles and HCV clearance are scarce and controversial. The aims of this study were to investigate whether HLA alleles are associated with clearance of HCV infection in a highly admixed Brazilian population and whether these associations could be influenced by ethnicity and route of infection. HLA-A, -B, -C, -DRB1 and -DQB1 genotyping were performed in 135 HCV-infected Brazilian patients among which 45 cleared HCV infection (cases) and 90 had persistent viral infection (controls). Controls were matched by sex, ethnicity (withes and non-whites) and route of infection (high infectious dose or low infectious dose). No significant association was identified between HLA alleles and the outcome of HCV infection when analyzing the sample as a single group. However, a new protective association of HLA-DQB1*04 (P = 0.006; P(c) = 0.030) and a rarely described association of HLA-DRB1*08 (P = 0.004; P(c) = 0.048) were found only among white patients. The DRB1*11 allele, previously reported in homogeneous population, was associated with HCV clearance (P = 0.020) only among patients with expected high-dose exposure. These findings confirm the influence of ethnicity on the associations of HLA with spontaneous viral clearance of HCV infection and emphasize the possible influence of route of infection in this process.     

Persistence of Hepatitis C Virus in Peripheral Blood Mononuclear Cells of Sustained Viral Responders to Pegylated Interferon and Ribavirin Therapy

The aim of this paper was to assess the persistence of hepatitis C virus (HCV) among patients successfully treated with peginterferon and ribavirin. The persistence of viral RNA was evaluated in the serum and peripheral blood mononuclear cells (PBMCs) of 25 chronic hepatitis C patients with sustained viral response to peginterferon and ribavirin treatment up to 56 months after the completion of therapy. Viral RNA was detected in the peripheral blood mononuclear cell cultures of five patients (20%), but none had detectable serum HCV RNA. At present, the clinical relevance of this finding is unclear. It is possible that viral persistence and, specifically, the presence of HCV RNA in PBMCs may lead to HCV reactivation under special circumstances, such as immunosuppression.     

Hepatitis C Virus Infection in Institutionalized Psychiatric Patients

The objective of this study was to determine if HCV can be transmitted from patient to patient in psychiatric institutions and to determine possible routes of infection. We did a cross-sectional survey of 196 Japanese psychiatric patients tested for HCV and HBV markers and 400 age- and sex-matched controls. Anti-HCV was detected in 10.2% and antibody to hepatitis B core antigen was detected in 44.4% of the patients, a significantly higher prevalence than found among matched controls. A multiple regression logistic analysis was used to identify risk factors that could indicate the route of infection by HCV. Duration of hospitalization, age, razor sharing, and history of surgery proved to be statistically significant independent risk factors associated with positive anti-HCV results [odds ratio (OR), 4.00; 95% confidence interval (CI), CI, 1.74–9.19; OR, 2.19; 95% CI, 1.27–1.3.77; OR, 4.90; 95% CI, 1.29–18.86; OR, 3.35; 95% CI, 0.997–11.3, respectively]. These observations suggest that razor sharing played an important role in the spread of the HCV infection in the institutionalized psychiatric patients we studied.     

Hepatitis C virus clearance is prominent in women in an endemic area

BACKGROUND: The clinical and virological backgrounds of cases with previous hepatitis C virus (HCV) infection (positive for HCV antibody (anti-HCV) and HCV-RNA negative) in an HCV endemic area were examined to identify factors related to the clearance of HCV. METHODS: The study population comprised 3117 inhabitants, 1037 male and 2080 female, from an HCV endemic area. Hepatitis C virus antibody was detected by a passive haemagglutination test. The HCV-RNA and the HCV genotype were detected by using the polymerase chain reaction method. The HCV serotype was determined by enzyme immunoassay by using the peptides of the core region. RESULTS: Twenty-two per cent of the inhabitants were positive for anti-HCV, with males and the elderly having a significantly higher antibody titre (P < 0.01) than youths and females. Hepatitis C virus-RNA was detected in 78% of the HCV antibody-positive cases. The rate of HCV-RNA positivity was significantly higher in males than in females (P < 0.01). No relationship was found between HCV-RNA positivity and age. The HCV genotype 1b was the predominant genotype among the HCV-RNA-positive cases. Mixed genotypes (1b + 2a) were observed in 12% of cases, primarily in elderly males and females. In cases with previous HCV infection, serotype 1 was the most common serotype, and there appeared to be no relationship between the distribution of HCV serotypes and age and gender. There was a female predominance with regard to previous HCV infection, but not to being HCV carriers (P < 0.01). CONCLUSIONS: Gender, not HCV genotype, is the primary factor influencing HCV clearance.     

Prevalence and Significance of Hepatitis GB Virus-C/Hepatitis G Virus Viremia in a Large Cohort of Patients with Chronic Hepatitis B Infection, with Chronic Hepatitis C Infection, and on Renal Replacement Therapy in Hong Kong

A total of 455 patients were recruited to study the prevalence of hepatitis GB virus-C/hepatitis G virus viremia in Hong Kong. There was no significant increase in the prevalence of hepatitis GB virus-C viremia in asymptomatic hepatitis B virus- and hepatitis C virus-infected patients compared to that of controls (1.56% and 7.14%, respectively, vs 3.85%, both P = NS). Renal patients as a whole had a significantly higher prevalence of hepatitis GB virus-C viremia compared to that of controls (13.95% vs 3.85%, P = 0.0271). The duration of the replacement therapy, especially for patients with peritoneal dialysis was associated with a higher chance of hepatitis GB virus-C viremia. Among renal patients, renal transplanted patients had the highest prevalence of hepatitis GB virus-C viraemia (19.1%) probably because of a higher susceptibility as a result of immunosuppression. However, hepatitis GB virus-C viraemia did not cause liver biochemistry derangement in renal transplanted patients.     

Management of Hepatitis C in Patients with End-stage Renal Disease

Hepatitis C virus infection is more prevalent in patients with chronic kidney disease on hemodialysis than in the general population. Moreover, chronic hepatitis C virus infection in hemodialysis patients and renal transplant recipients is associated with significant morbidity and even mortality, including de novo diabetes mellitus, sepsis, and glomerulonephritis posttransplantation. Strategies to treat patients on hemodialysis and in the post-renal transplant setting are limited by drug-related toxicity, particularly ribavirin-related anemia, and induction of graft rejection. However, in hemodialysis patients who are candidates for renal transplantation, treatment with interferon or pegylated-interferon results in better sustained virologic responses (SVR) than those achieved in the general population (3%–41% and 31%–37%, respectively). Moreover, SVR is maintained posttransplantation and is associated with superior graft function and prevention of de novo glomerulonephritis. Encouraging results with low doses of ribavirin have been reported in recent small studies, but monitoring of ribavirin plasma concentrations is recommended. In the kidney transplant recipient, treatment with interferon is precluded except for severe cholestatic disease.     

Hepatitis C virus genotypes in chronic hepatitis C of children

SUMMARY. Several hepatitis C virus (HCV) genotypes have been recently identified and genotype 1b has been correlated with severe liver disease and a poor response to interferon therapy. HCV infection in children is an interesting model for evaluation of the relationship between HCV genotypes and liver disease, because of its relatively short duration and the infrequent association with confounding cofactors. We have investigated HCV genotypes, using a dot-blot hybridization assay with genotype-specific probes, in 36 Italian children with chronic hepatitis C who were otherwise well and had no other underlying disease. Only four patients were symptomatic; liver histology, obtained in 3 3 patients, showed minimal hepatitis in 17 and mild chronic hepatitis in 16. Infection with HCV genotype Ib was found in 55.5% of patients, with a peak prevalence of 83% in children from southern Italy (P < 0.05 vs other regions). The remaining children were infected with HCV genotype la (16.6%), genotype 2 (11.1%). and mixed (10.9%) or undetermined (2.7%) genotypes. In one patient, HCV viraemia was never detected. There was no statistically significant correlation between genotype and age, sex, source of infection, alanine aminotransferase pattern and histological activity index. These results indicate that genotype 1b is widespread among Italian children with chronic hepatitis C, although with significant geographical variations. It is not associated with a more severe liver disease, therefore suggesting that the greater severity of liver disease recently reported in adults could reflect the cumulative effects of disease duration and of interfering cofactors.     

Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

Lower Hepatitis G Virus Infection Prevalence Compared to Hepatitis B and C Virus Infection Prevalences

To more accurately determine the seroprevalence of hepatitis G virus (HGV) infection, we surveyed antibody to HGV (anti-E2) by enzyme-linked immunosorbent assay (ELISA) and HGV RNA by nested polymerase chain reaction (PCR) in 298 residents of a hepatitis C virus (HCV)-endemic area of Japan and in 225 hemodialysis patients. We then compared these findings with known HCV and hepatitis B virus (HBV) infection prevalences. Anti-E2 and HGV RNA prevalences were 32 (10.7%) and 5 (1.7%) in the residents and 24 (10.7%) and 10 (4.4%) in the hemodialysis patients, respectively. Anti-E2 and HGV RNA concurrence was found in two of the hemodialysis patients. Total HGV marker (anti-E2 and/or HGV RNA) prevalences [37 (12.4%) in residents and 32 (14.2%) in hemodialysis patients], were significantly lower than the prevalences of antibody to HCV (anti-HCV) by ELISA [59 (19.8%) and 96 (42.7%)], and antibody to hepatitis B core antigen (anti-HBc) by radioimmunoassay (RIA) [87 (29.2%) and 101 (44.9%)] (P < 0.05). The anti-HCV prevalence in subjects with total HGV marker was significantly higher than in those without total HGV marker. There was no significant difference in anti-HBc prevalence between those with and without total HGV marker. The viremic rate was highest in HCV infection (HCV RNA by PCR/anti-HCV) (83.2%), with HGV infection (HGV RNA/total HGV marker) (21.7%) intermediate, and HBV infection (hepatitis B surface antigen by RIA/anti-HBc) (5.3%) lowest (P < 0.05). These findings indicate that HGV infection was less endemic than HCV and HBV. HGV was eliminated naturally more frequently than HCV infection and less frequently than HBV infection.     

Significance of Prior Hepatitis B Virus Infection in the Development of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

To clarify the clinical significance of prior hepatitis B virus (HBV) infection in the development of C-viral hepatocellular carcinoma (HCC), we conducted two studies: (1) Two hundred thirty-four patients with C-viral HCC and 320 patients with C-viral chronic liver disease without HCC admitted to our hospital between 1990 and 1994 were analyzed for the association of hepatitis B core antibody (HBcAb) positivity with HCC by multivariate logistic regression analysis, and this revealed HBcAb positivity as an independent risk factor for development of HCC adjusted for age and sex. (2) Four hundred fifty-nine patients with biopsy-proven hepatitis C virus-related chronic liver disease between 1986 and 1998 were enrolled in the cohort study and followed for the development of HCC. During an average follow-up of 6.6 ± 3.3 years, HCC developed in 63 patients, 37 of 160 patients positive for HBcAb and 26 of 299 patients negative for HBcAb. Multivariate Cox proportional regression analysis showed that the incidence of HCC increased by age, advanced stage of liver fibrosis, mean alanine aminotransferase value of more than 80 IU/liter, and positivity of HBcAb. Sustained virological responders after interferon therapy revealed a reduced risk for HCC development. In conclusion, prior HBV infection was shown to be one of the independent risk factors for development of HCC in C-viral chronic liver disease.     

Discrepant Diagnostic Results of Nested Polymerase Chain Reaction-based Genotyping in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection

Accurate genotyping is important to improve the treatment of hepatitis C virus (HCV) infection. We herein report a 44-year-old Japanese man with hemophilia A and coinfection of HCV and human immunodeficiency virus (HIV) who was diagnosed with HCV genotype 4 by direct sequencing. Two genotyping tests based on the nested polymerase chain reaction method that we used misdiagnosed his genotype as 2b and 1b. Although several HCV genotyping tests are available in Japan, it is important to recognize that some cannot detect genotype 4. Care should be taken when genotyping HCV patients who have received non-heated coagulation factor preparations or were infected abroad.     

Antibodies to Hepatitis E and A Viruses among Patients with Non-Alcoholic Chronic Liver Disease in Taiwan

Tsai J-F, Jeng J-E, Chang W-Y, Lin Z-Y, Tsai J-H. Antibodies to hepatitis E and A viruses among patients with non-alcoholic chronic liver disease in Taiwan. Scand J Gastroenterol 1994;29:651-654

Background: The prevalence of hepatitis E virus (HEV) and hepatitis A virus (HAV) infection in patients with non-alcoholic chronic liver disease (CLD) was assessed.

Methods: Antibody levels to HEV (anti-HEV) and HAV (anti-HAV) were evaluated in 100 pairs of CLD patients and healthy controls.

Results: The prevalence of anti-HEV was higher in patients (10.0%) than in controls (0%; p = 0.0001). There was no difference in anti-HAV positivity between patients (95%) and controls (93%). The patient group with anti-HEV was older (p equals; 0.024) and had more smokers (p equals; 0.03), having a higher prevalence of antibodies to hepatitis C virus (p equals; 0.02). Patients with anti-HAV were older than patients without (p equals; 0.0001). The prevalence of anti-HAV in patients more than 30 years old was higher than younger patients (95.1% versus 73.6%, p equals; 0.011). Conclusion: HEV may superinfect on chronic liver disease in an area hyperendemic for hepatitis A and B.     

Hepatitis C infection in hemodialysis patients: A review

Hepatitis C virus(HCV)-related liver disease is a significant cause of morbidity and mortality in patients with end-stage renal disease(ESRD) who is treated with dialysis or kidney transplantation(KT). The survival rate for HCV-infected renal transplant recipients is better than that for HCV-infected hemodialysis patients on transplant waiting lists. Early diagnosis and treatment HCV infection prior to KT prevents complications posttransplantation and reduces mortality. In addition to screening for anti-HCV antibodies and detecting HCV RNA, percutaneous liver biopsy is particularly valuable for assessing the stage of liver damage in HCV-infected patients, because the stage of fibrosis is importantdetermining optimal treatment for HCV. Studies have been demonstrated that with conventional interferon(IFN) monotherapy or pegylated IFN monotherapy are similar efficacy and safety in HCV-infected hemodialysis patients. Sustained viral responses(SVRs) with these monotherapies have ranged approximately 30% to 40%. Limited reports support the use of IFN and ribavirin combination therapy as antiviral treatment for ESRD patients or patients on hemodialysis. Ribavirin can be started at low dose and careful monitoring for side effects. Patients that show SVR after treatment are strong candidates for KT. It is also generally accepted that ESRD patients with decompensated cirrhosis and portal hypertension should be referred to the liver transplant team for consideration of combined liver-KT.     

巨细胞病毒与乙肝病毒持续感染的关系

对感染乙型肝炎病毒(HBV)的个体中巨细胞病毒(CMV)感染的情况进行研究。选取HBV慢性感染或携带者99例,康复组121例,健康对照组60例。分别测定血清CMV-IgG抗体、尿中CMV-DNA及各组相关的生化指标。结果:持续感染组ALT、AST、TBA、Glob高于康复组和正常对照组(P<0．01)。其它指标各组间差异均不显著;三组CMV-IgG阳性率均在95％以上,无显著差异。取对照组中CMV-IgG阳性者的OD均值0．3做为强阳性的cut-off值,三组的CMV-IgG强阳性率分别是65％、51％和40％,持续感染组高于康复组和对照组;三组CMV-DNA扩增结果分别为3例、2例和1例,差别不显著。在受检对象中,按CMV-IgG强阳性与否分组,对HBV的持续感染率进行统计,HBV的持续感染率CMV-IgG强阳性组43％,显著高于非强阳性组27％(P< 0．01)。提示CMV-IgG强阳性是HBV持续感染的危险因素。     

Hepatitis C Virus and Inflammatory Bowel Disease

Gastroenterologists frequently treat patients with complex illnesses such as chronic hepatitis C infections and inflammatory bowel disease (IBD). Occasionally, a patient will present with these two diseases which behave very differently and the treatment for one may potentially exacerbate the other. The purpose of this article is to review the current literature regarding hepatitis C virus therapy in the setting of IBD as well as the effects of common IBD therapies on the hepatitis C virus. Based on limited data, anti-viral therapy is probably safe in patients with well-controlled IBD, but there might be a risk of causing new onset of IBD. Also, it does not appear that the commonly used medications for IBD have much of an effect on the hepatitis C virus (HCV) or its course.