Estimated numbers of patients with liver disease related to hepatitis B or C virus infection based on the database reconstructed from medical claims from 2008 to 2010 in Japan.

AIM: To estimate the number of patients with liver-related diseases classified by hepatitis viruses (HBV, HCV) based on the information from re-coded medical claims including several diagnosed diseases. METHODS: We analyzed reimbursement data provided by health insurance societies for 2.1 million individuals during 2008-2010. Database information of employees and their families aged under 65 years employees with hepatitis-related disease was extracted, the 1-year period prevalence was calculated, and then number of patients with liver disease related to HBV and HCV by sex and age groups, respectively, was estimated. RESULTS: The estimated number of patients were almost equivalent during 2008-2010. As for HBV and HCV, the estimated numbers of patients with chronic hepatitis (CH) in a year ranged 192 641-226 601 and 282 438-306 877, respectively. CONCLUSION: In the 2008 Patient Survey in Japan, the number of patients was estimated by the main disease in one patient, even though the patient was diagnosed with several diseases. Based on the database with hepatitis-related diseases after evaluating several diagnosed diseases from medical claims, the estimation method and protocol may minimize the disadvantage of medical claim analysis, and is useful for patients, especially asymptomatic carriers and those with CH which had been underestimated in the 2008 Patient Survey.

High prevalences of hepatitis B and C virus infections among adults living in Binh Thuan province, Vietnam.

AIM: Vietnam is one of the countries with the highest mortality from liver cancer, which is mostly attributed to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. For planning preventive strategies against these infections, we investigated prevalences of HBV and HCV infections among adults living in Binh Thuan, Vietnam. METHODS: Our study consisted of a serological survey for HBV and HCV infections and a questionnaire survey on their risk factors. The sample size was calculated based on anticipated rate of hepatitis B surface antigen (HBsAg). Subjects were randomly sampled using a multistage method. Confirmation and family-tree surveys were conducted to examine persistent HBV infection and intrafamilial HBV transmission, respectively. RESULTS: A total of 509 adults, comprised of 230 men (45.2%) and 279 women (54.8%), were enrolled. Prevalences of HBsAg, hepatitis B surface antibody and hepatitis B core antibody were 15.3%, 60.3% and 71.7%, respectively. Most HBV DNA positive sera were classified as genotype B (75.3%) and C (11.7%). Of HBsAg positive subjects, 96.7% were persistently infected and one acutely HBV infected person was identified. Family-tree surveys suggested that horizontal extrafamilial HBV transmission might have been frequent. Prevalences of anti-HCV and HCV RNA were 3.3% and 1.8%, respectively. HCV genotype 6a was prominent (55.6%). CONCLUSION: In Binh Thuan, prevalences of HBV and HCV infections are high, HBV genotype B and HCV genotype 6a are predominant, and horizontal HBV transmission may still occur. Therefore, raising the coverage of a universal HBV vaccination program may be an effective liver cancer control in Vietnam.

Hepatitis B virus infection in hemodialysis patients in Japan: Prevalence, incidence and occult hepatitis B virus infection.

AIM: A survey of hepatitis B virus (HBV) infection in hemodialysis (HD) patients was conducted to determine the burden and risk of infection and to suggest preventive measures against HBV infection among HD patients at nine hospitals in Hiroshima, Japan, from 1999 to 2003. METHODS: HBV markers were investigated for 1860 HD patients. The prevalence, incidence of HBV and prevalence of occult HBV were calculated. RESULTS: The prevalence of hepatitis B surface antigen (HBsAg) was 2.6%, the positive rate of anti-hepatitis B core (HBc) was 20.6% and that of anti-hepatitis B surface (HBs) was 11.7%. Among 1372 patients who started HD after the approval of erythropoietin in Japan in 1991, the prevalence of HBsAg was 2.1%. The incidence rate of HBsAg positivity was 0/1000 person-years and the incidence of anti-HBc was 0.3/1000 person-years. Among 1812 HBsAg negative patients HBV DNA was detected in two: one case was negative for anti-HBc and anti-HBs, and the other was only positive for anti-HBc. Prevalence of occult HBV was 0.11%. CONCLUSION: The incidence rate of HBV was much lower than that of hepatitis C virus (HCV) in the same cohort. We supposed that the discrepancy between incidence rate of HBV and that of HCV was caused by the difference of their carrier rates and of their characteristics for persistent infection. So, we concluded that it is prerequisite to grasp the burden of HBV carriers in the group to prevent new HBV infections in HD patients.

Seroprevalence, genotypic distribution and potential risk factors of hepatitis B and C virus infections among adults in Siem Reap, Cambodia.

AIM: We investigated hepatitis B virus (HBV) and hepatitis C virus (HCV) infections among adults in Siem Reap, Cambodia, to consider the prevention strategy in cooperation with the Ministry of Health in Cambodia. METHODS: Serological tests for determining HBV and HCV infections and questionnaires were performed from 2010 to 2012 among the general population in the province of Siem Reap. Multivariate logistic regression analysis was conducted to clarify the factors related to HBV and HCV infections. RESULTS: There were 483 participants, comprising 194 men and 289 women (age range, 18-89 years). The prevalence of hepatitis B surface antigen was not very high at 4.6%, while anti-hepatitis B core (anti-HBc) was high at 38.5%. All HBV DNA samples were classified as genotype C. Anti-HBc showed the trend that the older the age, the higher the positive rate (P = 0.0002). The prevalence of HCV RNA and anti-HCV were 2.3% and 5.8%, respectively. HCV RNA was detected in 39.3% of anti-HCV positive samples and most of them were classified as genotype 6 (54.5%) and 1 (27.3%). Remarkably, in multivariate logistic regression analysis, history of operation and blood transfusion were significantly associated with the positivity for HBV infection and HCV RNA, respectively. CONCLUSION: Our results showed that operation and blood transfusion were potential risk factors for HBV and HCV infection, respectively, and supposed that horizontal HBV transmission may be frequent in adults in Cambodia. Hence, for reducing HBV and HCV infections, it is necessary to improve the safety of blood and medical treatment.

Validation and limitation of age-period-cohort model in simulating mortality due to hepatocellular carcinoma from 1940 to 2010 in Japan.

AIM: We aimed to simulate the mortality due to hepatocellular carcinoma (HCC) by the age-period-cohort (APC) model with use of sex- and age-specific mortality data, for the purpose of validating the utility and assessing the limitation of this model. METHODS: Age-specific mortality due to HCC was gleaned from people aged 20-84 years during 1940 through 2010 in Japan. RESULTS: The APC model had a high performance in reproducing HCC mortality (modified determination coefficient R(2) COR ≥ 0.99). Risk of HCC increased with age in both sexes, while risk of period barely changed in both sexes. The birth cohort factor in the APC model in males highlighted the maximum point within birth years 1931-1935. The observed HCC mortality in 2010 in males (19 444) was lower than the predicted, and corresponded to 72.3% of the predicted 26 883.4, and in all age groups by 5-year increments (55.6-90.9%). In females, the observed mortality was lower than that predicted in those aged 64 years or less, but not in those aged 65 years or more. CONCLUSION: We applied the APC model to predict HCC mortality rate, and it reproduced the observed mortality rate faithfully. However, in the recent past, the observed morality rate in males was only 72.3% that of the predicted. Such differences would be attributed to combined effects of medical interventions, such as antiviral treatments and screening for hepatitis viruses implemented in the early 1990s in Japan.

Estimating numbers of persons with persistent hepatitis B virus infection transmitted vertically and horizontally in the birth cohort during 1950-1985 in Japan.

AIM: We estimated numbers of persons, born between 1950 and 1985 in Japan, who were persistently infected with hepatitis B virus (HBV) through vertical and horizontal infections. METHODS: HBV carrier rates with vertical and horizontal infections were computed using sex- and age-specific prevalence rates of hepatitis B surface antigen (HBsAg) and hepatitis B e-antigen (HBeAg) by mathematical model. Probabilities of vertical HBV transmission in babies born to carrier mothers with and without HBeAg were presumed to be 90% and 10%, respectively. RESULTS: HBV carrier rates with vertical infection stayed contrast at approximately 0.3% in birth cohorts through 36 years (1950-1985), both in men and women. By a remarkable constant, HBV carrier rates with horizontal infection decreased steadily from 1.43% to 0.10% in men and from 0.95% to 0.03% in women. The estimated total number of HBV carriers born between 1950 and 1985 was 522 500 (355 488-693 606). Of them, the numbers of HBV carriers with vertical and horizontal infections were 197 574 (149 505-288 709) and 324 926 (205 983-404 896); they accounted for 37.81% and 62.19%, respectively, with a ratio of 1:1.64. The ratio between vertical and horizontal infections was 1:2.20 in men and 1:1.06 in women. CONCLUSION: Vertical HBV infection had stayed constant until immunoprophylaxis of mother-to-baby transmission was implemented in 1986 in Japan. In contrast, horizontal HBV infection decreased over years. The decrease would be due to many factors, including improved socioeconomic environments, advanced medical maneuvers and equipment, and careful vaccination procedures.

High levels of hepatitis B virus after the onset of disease lead to chronic infection in patients with acute hepatitis B.

BACKGROUND: Some patients with acute hepatitis B virus (HBV) infection develop chronic infection. However, the method for identifying these patients has not been established. METHODS: We followed 215 Japanese patients with acute HBV infection until the clearance of hepatitis B surface antigen (HBsAg) or the development of chronic infection. Levels of HBsAg and HBV DNA were serially monitored from the onset. RESULTS: Of the 215 patients, 113 (52.5%) possessed HBV genotype A, 26 (12.0%) genotype B, and 73 (34.0%) genotype C. Twenty-one of the 215 (9.8%) developed chronic infection, with the persistence of HBsAg for >6 months. The rate of chronicity of genotype A, B, and C was 12.4%, 3.8%, and 8.2%. Of the 21 patients, only 6 (2.8%) patients, including 5 with genotype A, failed to clear HBsAg within 12 months. Levels of HBsAg at 12 weeks and HBV DNA at 4 weeks were useful for distinguishing the patients who became chronic from those who did not (P < .001 and P < .001, respectively). Likewise, the levels of HBsAg at 12 weeks and HBV DNA at 8 weeks were useful for discriminating between the patients who lost HBsAg within 12 months and those who did not (P < .01 and P < .05, respectively). CONCLUSIONS: In acute HBV infection, clearance of HBV may happen between 6 and 12 months from the onset. Only those who fail to clear HBV within 12 months from the onset may develop chronic infection.

Hepatitis B virus strains of subgenotype A2 with an identical sequence spreading rapidly from the capital region to all over Japan in patients with acute hepatitis B.

OBJECTIVE: To examine recent trends of acute infection with hepatitis B virus (HBV) in Japan by nationwide surveillance and phylogenetic analyses. METHODS: During 1991 through 2009, a sentinel surveillance was conducted in 28 national hospitals in a prospective cohort study. Genotypes of HBV were determined in 547 patients with acute hepatitis B. Nucleotide sequences in the preS1/S2/S gene of genotype A and B isolates were determined for phylogenetic analyses. RESULTS: HBV genotype A was detected in 137 (25% (accompanied by genotype G in one)) patients, B in 48 (9%), C in 359 (66%), and other genotypes in the remaining three (0.5%). HBV persisted in five with genotype A including the one accompanied by genotype G; another was co-infected with HIV type 1. The genotype was A in 4.8% of patients during 1991-1996, 29.3% during 1997-2002, and 50.0% during 2003-2008 in the capital region, as against 6.5%, 8.5% and 33.1%, respectively, in other regions. Of the 114 genotype A isolates, 13 (11.4%) were subgenotype A1, and 101 (88.6%) were A2, whereas of the 43 genotype B isolates, 10 (23.3%) were subgenotype B1, 28 (65.1%) were B2, two (4.7%) were B3, and three (7.0%) were B4. Sequences of 65 (64%) isolates of A2 were identical, as were three (23%) of A1, and five (18%) of B2, but none of the B1, B3 and B4 isolates shared a sequence. CONCLUSIONS: Acute infection with HBV of genotype A, subgenotype A2 in particular, appear to be increasing, mainly through sexual contact, and spreading from the capital region to other regions in Japan nationwide. Infection persisted in 4% of the patients with genotype A, and HBV strains with an identical sequence prevailed in subgenotype A2 infections. This study indicates the need for universal vaccination of young people to prevent increases in HBV infection in Japan.

Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir.

UNLABELLED: Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (-1.63 ± 0.92 vs. -0.48 ± 0.75 g/dL, P = 0.001) and week 4 (-3.5 ± 1.1 vs. -2.2 ± 0.96, P = 0.001), as well as at the end of treatment (-2.9 ± 1.1 vs. -2.0 ± 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 ± 14% vs. 65 ± 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 ± 17% and 54 ± 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). CONCLUSION: ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes.

Prediction of early HBeAg seroconversion by decreased titers of HBeAg in the serum combined with increased grades of lobular inflammation in the liver.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is an important hallmark in the natural course of chronic hepatitis B. This study was designed to predict early HBeAg seroconversion within 1 year, by not only biochemical and virological markers, but also pathological parameters in patients with chronic hepatitis B. MATERIAL/METHODS: In a retrospective cohort study, 234 patients with HBeAg were reviewed for demographic, biochemical, virological and pathological data at the time of liver biopsy. Then, the patients who accomplished HBeAg seroconversion within 1 year thereafter were compared with those who did not, for sorting out factors predictive of early HBeAg seroconversion. RESULTS: Early HBeAg seroconversion occurred in 58 (24.8%) patients. In univariate analysis, factors predictive of early HBeAg seroconversion were: alanine aminotransferase (ALT) (p=0.002), IP-10 (p=0.029), HBsAg (p=0.003), HBeAg (p<0.001), HBV DNA (p=0.001), HBcrAg (p=0.001), core-promoter mutations (p=0.040), fibrosis (p=0.033) and lobular inflammation (p=0.002). In multivariate analysis, only serum HBeAg levels <100 Paul Ehrlich Institute (PEI) U/ml and grades of lobular inflammation ≥2 were independent factors for early HBeAg seroconversion (odds ratio 8.430 [95% confidence interval 4.173-17.032], p<0.001; and 4.330 [2.009-9.331], p<0.001; respectively). CONCLUSIONS: HBeAg levels < 100 PEIU/ml combined with grades of lobular inflammation ≥2 are useful for predicting early HBeAg seroconversion. In patients without liver biopsies, high ALT levels (≥200 IU/L) can substitute for lobular inflammation (grades ≥2).

Interferon alone or combined with ribavirin for acute prolonged infection with hepatitis C virus in chimpanzees.

Infection with hepatitis C virus (HCV) persisted for longer than 29 weeks in 2 chimpanzees after they had been inoculated with it experimentally. One of them (C-210) received short-term subcutaneous interferon-α (IFN-α) 6 million units (MU) daily for 7 days at week 29. He cleared HCV RNA from the serum and remained negative for it during 25 weeks after the withdrawal of IFN. The other (C-224) did not respond to 2 courses of a short-term IFN monotherapy at weeks 20 and 23. Twelve weeks thereafter, he received IFN-α 3 MU daily for 2 weeks and then 3 times a week for 14 weeks combined with oral ribavirin 600 mg daily during 16 weeks. HCV RNA disappeared from the serum and stayed negative until the last follow-up 24 weeks after the completion of combination therapy.

Total numbers of undiagnosed carriers of hepatitis C and B viruses in Japan estimated by age- and area-specific prevalence on the national scale.

OBJECTIVE: To estimate total numbers of undiagnosed carriers of hepatitis C virus (HCV) and hepatitis B virus (HBV) in Japan. METHODS: Area- and age-specific prevalence of HCV as well as HBV was determined in the first-time blood donors [20-39 years (n = 2,429,364)] and examinees of periodical health check-ups [40-74 years (6,204,968 for HCV and 6,228,967 for HBV)] in Japan. Prevalence in adolescents [5-19 years (79,256 for HCV and 68,792 for HBV)] was determined in a single prefecture, and that of HCV in the elderly (≥ 75 years) was estimated by the exponential model. HBV infection was determined by the detection of hepatitis B surface antigen, and HCV infection by either the algorithm or assuming persistent infection in 70% of the individuals with antibody to HCV. RESULTS: Of the total population of 127,285,653 in 2005, 807,903 (95% CI 679,886-974,292) were estimated to be infected with HCV at a carrier rate of 0.63%, and 903,145 (837,189-969,572) with HBV at that of 0.71%. CONCLUSION: Accurate estimation of undiagnosed HCV and HBV carriers in the general population would help to predict the future burden of liver disease, and take appropriate measures for improving healthcare.

A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J.

Hepatitis B virus (HBV) of a novel genotype (J) was recovered from an 88-year-old Japanese patient with hepatocellular carcinoma who had a history of residing in Borneo during the World War II. It was divergent from eight human (A to H) and four ape (chimpanzee, gorilla, gibbon, and orangutan) HBV genotypes, as well as from a recently proposed ninth human genotype I, by 9.9 to 16.5% of the entire genomic sequence and did not have evidence of recombination with any of the nine human genotypes and four nonhuman genotypes. Based on a comparison of the entire nucleotide sequence against 1,440 HBV isolates reported, HBV/J was nearest to the gibbon and orangutan genotypes (mean divergences of 10.9 and 10.7%, respectively). Based on a comparison of four open reading frames, HBV/J was closer to gibbon/orangutan genotypes than to human genotypes in the P and large S genes and closest to Australian aboriginal strains (HBV/C4) and orangutan-derived strains in the S gene, whereas it was closer to human than ape genotypes in the C gene. HBV/J shared a deletion of 33 nucleotides at the start of preS1 region with C4 and gibbon genotypes, had an S-gene sequence similar to that of C4, and expressed the ayw subtype. Efficient infection, replication, and antigen expression by HBV/J were experimentally established in two chimeric mice with the liver repopulated for human hepatocytes. The HBV DNA sequence recovered from infected mice was identical to that in the inoculum. Since HBV/J is positioned phylogenetically in between human and ape genotypes, it may help to trace the origin of HBV and merits further epidemiological surveys.

Influence of amino-acid polymorphism in the core protein on progression of liver disease in patients infected with hepatitis C virus genotype 1b.

The substitution of amino acid (aa) 70 of arginine for glutamine and/or that of aa91 of leucine for methionine in the core protein in patients infected with hepatitis C virus (HCV) genotype 1b is associated with a poor response to pegylated interferon and ribavirin. Factors influencing these substitutions were sought in 1,097 patients infected with HCV-1b who had not received antiviral treatment. HCV variants with Arg70 and Leu91 (wild-type) decreased, while those with Gln70 and/or Met91 (mutant types) increased with age (P < 0.001). Of the 1,097 patients, 464 (42.3%) were infected with the Gln70 variant and the remaining 633 patients with the Arg70 variant. The proportion of patients with the Gln70 variant increased with the severity of liver disease (P < 0.001), elevated gamma-glutamyl transpeptidase (gamma-GTP) levels (P < 0.001) and a decrease in platelet count (P = 0.008). In univariate analysis patients with hepatocellular carcinoma, elevated aspartate aminotransferase (AST > or = 58 IU/L) and gamma-GTP (> or =61 IU/L), and decreased albumin levels (<3.9 g/dl) were more frequent in the patients with the Gln70 variant than the Arg70 variant (P = 0.003, 0.005, <0.001, and 0.031, respectively). In multivariate analysis HCC (odds ratio 1.829 [95% confidence interval 1.147-2.917]) and gamma-GTP > or =61 IU/L (1.647 [1.268-2.139]) increased the risk for the Gln70 variant. In conclusion, the substitution of amino aa70 of Arg for Gln in patients infected with HCV-1b increases with age, and it is associated with severe liver disease accompanied by elevated AST and gamma-GTP levels, as well as the development of hepatocellular carcinoma.

Association of HLA-DR14 with the treatment response in Japanese patients with autoimmune hepatitis.

BACKGROUND: Influence of human lymphocyte antigen (HLA) on the therapeutic response in autoimmune hepatitis (AIH) is not known. AIMS: To evaluate if HLA-DR types influence biological and histological responses to corticosteroids in patients with AIH. METHODS: During 28 years from 1979 through 2007, 48 patients with definite diagnosis of AIH received long-term corticosteroid therapy (median 9 years [range: 5-28 years]) in a single Japanese center. They were followed for transaminase levels and received liver biopsy before and after the treatment. RESULTS: DR4 was detected in 32 and DR14 in 11 patients; seven possessed both DR4 and DR14. DR4 was more frequent in AIH patients than in the general population (67% vs. 22%), while DR14 was comparably frequent between them (23% vs. 17%). Overall, biochemical response was achieved in 43 (90%) of the 48 patients. The sustained biochemical response to a maintenance prednisolone dose < 10 mg was gained more frequently in the patients with than without DR14 (10/11 [91%] vs. 10/37 [27%], P < 0.001). Marked histological improvement with a decrease in histology activity index (HAI) score by > 2 points was achieved in 31 of the 32 (97%) biochemical responders. Histological aggravation with an increase in HAI score occurred in 4 of the 16 (25%) patients without biochemical response (non-responders and relapsers combined), but in none of the 32 responders. CONCLUSION: Long-term immunosuppressive treatment can improve the outcome of Japanese patients with AIH, and DR14 is associated with excellent biochemical response.

Virulent strain of hepatitis E virus genotype 3, Japan.

Hepatitis E virus (HEV) genotype 3, which usually causes asymptomatic infection in Japan, induced severe hepatitis in 8 patients. To better understand genetic features of HEV associated with increased virulence, we determined the complete or near-complete nucleotide sequences of HEV from these 8 patients and from 5 swine infected with genotype 3 strain swJ19. Phylogenetic analysis showed that the isolates from the 8 patients and the 5 swine grouped separately from the other genotype 3 isolates to create a unique cluster, designated JIO. The human JIO-related viruses encoded 18 amino acids different from those of the other HEV genotype 3 strains. One substitution common to almost all human HEV strains in the JIO cluster was located in the helicase domain (V239A) and may be associated with increased virulence. A zoonotic origin of JIO-related viruses is suspected because the isolates from the 5 swine also possessed the signature V239A substitution in helicase.

Distribution of hepatitis B virus genotypes among patients with chronic infection in Japan shifting toward an increase of genotype A.

Acute hepatitis B virus (HBV) infection has been increasing through promiscuous sexual contacts, and HBV genotype A (HBV/A) is frequent in patients with acute hepatitis B (AHB) in Japan. To compare the geographic distribution of HBV genotypes in patients with chronic hepatitis B (CHB) in Japan between 2005 and 2006 and between 2000 and 2001, with special attention to changes in the proportion of HBV/A, a cohort study was performed to survey changes in genotypes of CHB patients at 16 hospitals throughout Japan. Furthermore, we investigated the clinical characteristics of each genotype and examined the genomic characteristics of HBV/A isolates by molecular evolutionary analyses. Of the 1,271 patients, 3.5%, 14.1%, and 82.3% were infected with HBV/A, -B, and -C, respectively. In comparison with our previous survey during 2000 and 2001, HBV/A was twice as frequent (3.5% versus 1.7%; P = 0.02). The mean age was lower in the patients with HBV/A than in those with HBV/B or -C. Based on phylogenetic analyses of 11 full-length genomes and 29 pre-S2/S region sequences from patients, HBV/A isolates were imported from Europe and the United States, as well as the Philippines and India. They clustered with HBV/A from AHB patients and have spread throughout Japan. HBV/A has been increasing in CHB patients in Japan as a consequence of AHB spreading in the younger generation through promiscuous sexual contacts, aided by a tendency of HBV/A to induce chronic hepatitis. The spread of HBV/A infection in Japan should be prevented by universal vaccination programs.

Infection of B cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C.

Infection with hepatitis C virus (HCV) is associated with lymphoproliferative disorders, represented by essential mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma, but the pathogenic mechanism remains obscure. HCV may infect B cells or interact with their cell surface receptors, and induce lymphoproliferation. The influence of HCV infection of B cells on the development of lymphoproliferative disorders was evaluated in 75 patients with persistent HCV infection. HCV infection was more prevalent (63% vs. 16%, 14%, or 17% P < 0.05 for each), and HCV RNA levels were higher (3.35 +/- 3.85 vs. 1.75 +/- 2.52, 2.15 +/- 2.94 or 2.10 +/- 2.90 log copies/100 ng, P < 0.01 for each) in B cells than CD4(+), CD8(+) T cells or other cells. Negative-strand HCV RNA, as a marker of viral replication, was detected in B cells from four of the 75 (5%) patients. Markers for lymphoproliferative disorders were more frequent in the 50 patients with chronic hepatitis C than the 32 with chronic hepatitis B, including cryoglobulinemia (26% vs. 0%, P < 0.001), low CH(50) levels (48% vs. 3%, P = 0.012), and the clonality of B cells (12% vs. 0%, P < 0.01). By multivariate analysis, HCV RNA in B cells was an independent factor associated with the presence of at least one marker for lymphoproliferation (odds ratio: 1.98 [95% confidence interval: 1.36-7.24], P = 0.027). Based on the results obtained, the infection of B cells with HCV would play an important role in the development of lymphoproliferative disorders.

An open pilot study exploring the efficacy of fluvastatin, pegylated interferon and ribavirin in patients with hepatitis C virus genotype 1b in high viral loads.

OBJECTIVE: Response to pegylated (PEG) interferon (IFN) and ribavirin is achieved only in 40-50% of patients infected with hepatitis C virus (HCV) of genotype 1 in high viral loads, which needs to be improved. METHODS: In an open-label pilot study, fluvastatin (HMG-CoA reductase inhibitor), 20 mg daily, was given along with PEG-IFN/ribavirin to 21 patients with chronic hepatitis C. They were followed for HCV RNA in serum. RESULTS: During treatment for 48 weeks, HCV RNA was lost from serum in 93% of the patients. In the 15 patients who received 48-week therapy, a sustained virological response (SVR) with loss of HCV RNA 24 weeks after completion was achieved in 10 (67%), including 7 of the 9 (78%) male and 3 of the 6 (50%) female patients. In the remaining 6 patients who received 72-week therapy, SVR was gained in 4 (67%), including 1 of the 2 male and 3 of the 4 female patients aged 56, 58 and 62 years, respectively. CONCLUSION: Fluvastatin could be used safely to increase the response to PEG-IFN and ribavirin, especially in aged women who respond poorly to combined PEG-IFN/ribavirin.

Development of hepatocellular carcinoma in elderly patients with chronic hepatitis C with or without elevated aspartate and alanine aminotransferase levels.

OBJECTIVE: Hepatocellular carcinoma (HCC) in the elderly infected with hepatitis C virus (HCV) is expected to increase globally within the next two decades. The purpose of the study was to define the natural history of elderly patients with chronic hepatitis C needs in order to prevent HCC from arising in these patients. MATERIAL AND METHODS: Treatment-naive patients aged >or=65 years with platelet counts >120 x 10(3)/mm(3) were classified as 120 with aspartate and alanine aminotransferase (ASAT and ALAT) levels or=41 (group B) and followed-up for 3 years or longer without antiviral treatment. RESULTS: Cirrhosis and HCC developed more frequently in group B than in group A (p<0.001 for both). In particular, of the patients aged 65-69 years at entry, cirrhosis and HCC developed more frequently in group B than in group A (p<0.001 and p=0.001, respectively). Liver-related causes of death were more common in group B than in group A (20/34 (59%) versus 1/9 (11%), p=0.021). HCC developed more frequently in men than in women (p=0.033). CONCLUSIONS: In elderly patients with chronic hepatitis C, cirrhosis and HCC develop more frequently in those with elevated transaminase levels than in those without elevated transaminase levels. Therefore, transaminase levels need to be suppressed below