Hepatitis: Miyakawa Y

Miyakawa Y, Yoshizawa H. · Miyakawa Memorial Research Foundation, Minami-Aoyama 2-19-8, Minato-Ku, Tokyo 107-0062, Japan. · Hepatol Res. · Pubmed #17092770 No free full text.

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Miyakawa Y, Iino S. · No affiliation provided · J Gastroenterol Hepatol. · Pubmed #11446875 No free full text.

This publication has no abstract.

Miyakawa Y, Mizokami M. · Miyakawa Memorial Research Foundation, Minami-Aoyama 2-19-8, Minato-ku, Tokyo 107-0062, Japan. · Intervirology. · Pubmed #14688448 No free full text.

Abstract: In 1988, hepatitis B virus (HBV) was classified into four genotypes by a sequence divergence in the entire genome exceeding 8%, and designated by capital letters of the alphabet from A to D. There are seven genotypes of HBV (A-G) at present, and an eighth is on the horizon. They have an uneven geographical distribution, and only a few of them are prevalent in a given area of the world. Thus genotype A is frequent in northwest Europe, Sub-Saharan Africa, India and the North, Central and South America, B as well as C are common in Southeast Asia and Oceania, and D is prevalent in the Mediterranean area, Central Asia and South America. Genotype E is restricted to West Africa, and F is localized in Central and South America. The distribution of genotype G added to the alphabet list very recently has yet to be determined. Coinfection with HBV of distinct genotypes is not infrequent and found in about 10% of infected individuals, and is responsible for intertypic recombination of HBV genomes. The mutation for a stop codon in the precore region (G1896A) for aborting the translation of hepatitis B e antigen (HBeAg) is prohibited in HBV genomes of genotype A, as well as some of genotypes C and F, because they possess C at position 1858 that makes a Watson-Crick pair with G at position 1896. Hence, seroconversion to antibody to HBeAg is forbidden or delayed in individuals who carry them. Evidence is accumulating as regards the influence of HBV genotypes on the progression of chronic hepatitis B and response to antiviral therapies. HBV isolates even of the same genotype can differ in virological and clinical characteristics, and therefore, the genotype needs to be classified further into subtypes, especially if they are clinically relevant.

Kidd-Ljunggren K, Miyakawa Y, Kidd AH. · Department of Infectious Diseases, University of Lund, SE-221 85, Lund, Sweden. · J Gen Virol. · Pubmed #12029141 links to  free full text

Abstract: In 1988, it was reported that the full nucleotide sequences of 18 hepatitis B virus (HBV) strains clustered into four genetic groups (A to D) with more than 8% divergence between the groups. This classification of strains in terms of genome sequence has since proven to be an important tool in the understanding of HBV epidemiology and evolution and has been expanded to include three more genotypes. In parallel with the HBV genotypes described in humans, HBV strains isolated from different primates and hepadnaviruses found in woodchucks, ground squirrels, ducks and herons have been studied. Sequence differences between HBV genotypes can lead to structural differences at the level of the pregenome and can also lead to dramatic differences at the translational level when specific and commonly occurring mutations occur. There is increasing evidence that the clinical picture, the response to treatment and the long-term prognosis may differ depending on which genotype has infected the patient. The consideration of traditional serological patterns in a patient must therefore take the genotype of the infecting strain into account. Nucleotide variability between HBV strains has been used in several studies to trace routes of transmission and, since it is becoming increasingly clear that the differences between HBV genotypes are important, the need for reliable and easy methods of differentiating HBV genotypes has arisen. This review summarizes the knowledge of HBV genotypes with regard to their genetic, structural and clinically significant differences and their origin and evolution in the context of the hepadnaviruses in general.

Miyakawa Y, Yoshizawa H. · Miyakawa Memorial Research Foundation, Tokyo 107-0062, Japan. · Indian J Gastroenterol. · Pubmed #11293191 No free full text.

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Kobayashi M, Suzuki F, Akuta N, Hosaka T, Sezaki H, Yatsuji H, Yatsuji H, Kobayashi M, Suzuki Y, Arase Y, Ikeda K, Watahiki S, Iwasaki S, Miyakawa Y, Kumada H. · Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan. · J Med Virol. · Pubmed #17705186 No free full text.

Abstract: Although loss of hepatitis B e antigen (HBeAg) from the serum is sought by treatment with lamivudine, clearance of hepatitis B surface antigen (HBsAg) is the eventual goal of any antiviral therapy. In a single hepatology center in the Metropolitan Tokyo, 486 patients with chronic hepatitis B were followed up for longer than 3 years after they started treatment with lamivudine. HBsAg disappeared from the serum in 17 (3.5%). Age >or=50 years and low HBsAg levels (hemagglutination titer <or=2(7)) at the start of lamivudine were significantly more frequent in the patients who did than did not lose HBsAg from the serum. Except for these two factors, there were no differences between the two groups of patients in the prevalence of HBeAg and HBV DNA levels at the baseline, as well as the development of YMDD mutants and breakthrough hepatitis during lamivudine treatment. Using multivariate analysis, age >or=50 years at the start of lamivudine was the only factor predicting the loss of HBsAg (hazard ratio: 2.96 [95% confidence interval: 1.14-7.68], P = 0.028). By the method of Kaplan-Meier performed on the 486 patients, the loss of HBsAg was estimated to occur in 3% and 13% of patients, respectively, who had received lamivudine therapy for 5 and 10 years. These results indicate that loss of HBsAg occurs in a minority (3.5%) of patients with chronic hepatitis B who receive lamivudine therapy and more frequently in those with lower HBsAg titers and older ages at the start of treatment.

Kobayashi M, Suzuki F, Akuta N, Suzuki Y, Arase Y, Ikeda K, Hosaka T, Sezaki H, Kobayashi M, Iwasaki S, Sato J, Watahiki S, Miyakawa Y, Kumada H. · Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan. · J Med Virol. · Pubmed #16927289 No free full text.

Abstract: Response to lamivudine treatment longer than 1 year was compared in 15 patients persistently infected with hepatitis B virus (HBV) genotype A, 38 with genotype B, and 449 with genotype C. Patients with genotype A were younger (median age 37 [range 24-49] vs. 47 [24-67] or 44 [18-73], P = 0.015), possessed hepatitis B e antigen (HBeAg) more frequently (73% vs. 21% or 56%, P < 0.001) and HBV DNA in higher levels (8.6 [6.1-8.7] vs. 6.5 [<3.7-8.7] or 6.5 [<3.7-8.7] log genome equivalents (LGE)/ml, P = 0.024) than those with genotype B or C. During lamivudine, YMDD mutants (89% vs. 53% or 42%, P = 0.0001) and breakthrough hepatitis developed more often (47% vs. 21% or 29%, P = 0.023) in patients with genotype A than B or C. YMDD mutants elicited more frequently in patients with genotype A than B or C who were positive (82% [9/11] vs. 25% [2/8] or 48% [117/245], P = 0.037) or negative for HBeAg (75% [3/4] vs. 30% [9/30] or 33% [68/204], P = 0.003). HBeAg (hazard ratio 2.1 [95% confidence interval 1.53-2.92], P < 0.001) and genotype A (2.78 [1.08-7.12], P = 0.034) enhanced the emergence of YMDD mutants by the Cox proportional hazard model. The risk for breakthrough hepatitis was increased by the baseline alanine aminotransferase level <500 IU/L (2.56 [1.82-5.50], P = 0.018), HBeAg (2.11 [1.40-3.16], P < 0.001), cirrhosis (1.92 [1.24-2.97], P = 0.004) and HBV DNA > or =8.0 LGE/ml (1.57 [1.04-2.36], P = 0.03); it was influenced by genotypes only in patients with HBeAg. In conclusion, HBV genotypes help in predicting response to long-term lamivudine treatment and development of YMDD mutants in patients with chronic hepatitis B.

Suzuki Y, Arase Y, Ikeda K, Saitoh S, Tsubota A, Suzuki F, Kobayashi M, Akuta N, Someya T, Miyakawa Y, Kumada H. · Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan. · Intervirology. · Pubmed #12867754 No free full text.

Abstract: OBJECTIVE: The long-term effects of lamivudine and the influence of YMDD mutants on the histology of chronic hepatitis B are not known. METHODS: 3-year lamivudine therapy was given to 16 patients with chronic hepatitis B. YMDD mutants did not develop in 9 patients (group A), while they appeared in the remaining 7 patients (group B). RESULTS: Biochemical and virological responses were invariably achieved in the 9 patients without YMDD mutants, while virological breakthroughs with or without biochemical relapses occurred in all 7 patients with such mutants. All 16 patients accomplished histological improvement, with the total histology activity index (HAI) score decreasing from 11.3 +/- 3.0 to 4.1 +/- 1.7 (p < 0.001). The total HAI score decreased from 11.6 +/- 3.8 to 3.4 +/- 1.3 in the 9 patients in group A (p < 0.001). Although to a significantly lesser extent (p < 0.02), the total HAI score also decreased in the 7 patients in group B from 10.9 +/- 1.0 to 5.0 +/- 1.7 (p < 0.001). CONCLUSION: The results obtained indicate that 3-year lamivudine therapy can induce histological improvements, regardless of the appearance of YMDD mutants accompanied by virological breakthroughs and biochemical relapses.

Suzuki F, Tsubota A, Akuta N, Someya T, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Miyakawa Y, Kumada H. · Research Institute for Department of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. · J Gastroenterol. · Pubmed #12483247 No free full text.

Abstract: BACKGROUND: We aimed to treat patients with chronic hepatitis B on long-term treatment with lamivudine who developed lamivudine-resistant hepatitis B virus (HBV) mutants along with clinical relapses. METHODS: Of 217 patients with chronic hepatitis B who had been treated with lamivudine for 1-6 years, 23 (11%) developed lamivudine-resistant hepatitis B virus (HBV) mutants. Seven of them, including 1 whose case was previously reported, received interferon (IFN) daily for 4 weeks and then two or three times a week thereafter to cope with exacerbation of hepatitis. We investigated the efficacy of this IFN therapy in 6 patients, excluding the 1 previously reported. RESULTS: In 4 patients, HBV DNA decreased to below the detectable limit of the branched DNA assay (<0.7 MEq/ml) accompanied by normalization of transaminase levels. During IFN therapy, 2 patients seroconverted to antibody to hepatitis B e antigen (HBeAg) and showed normalized transaminase levels. Interferon was required in 7 of the 111 (6%) patients with chronic hepatitis B who were positive for HBeAg, but in none of the 106 who were positive for antibody to HBeAg ( P = 0.014). CONCLUSIONS: The efficacy of IFN in controlling virological breakthroughs and exacerbation of hepatitis by infection with lamivudine-resistant HBV mutants in patients with HBeAg-positive chronic hepatitis B could enhance the versatility of lamivudine, which may have to be given to them indefinitely.

Itoh K, Hirakawa K, Okamoto H, Ukita M, Tanaka H, Sawada N, Tsuda F, Miyakawa Y, Mayumi M. · Japanese Red Cross Yamaguchi Blood Center, Yamaguchi. · Transfusion. · Pubmed #10336003 No free full text.

Abstract: BACKGROUND: An unenveloped, single-stranded DNA virus named TT virus has been found in association with elevated alanine aminotransferase (ALT) levels in recipients of transfusions and has been detected frequently in patients with acute or chronic hepatitis of non-A to -G etiology in Japan. DNA of the TT virus was searched for in blood donors with or without elevated ALT levels. STUDY DESIGN AND METHODS: A total of 861 blood donors without previous transfusions and who were negative for markers of hepatitis B or C virus infection were tested. DNA of the TT virus was detected by polymerize chain reaction with hemi-nested primers. RESULTS: TT virus DNA was detected in 62 of 280 (22.1% [95% CI: 18.1-26.6]) donors with elevated ALT levels (mean +/- SD, 89.3 +/- 36.4 U/L; range, 61-301 U/L), which is significantly more frequently (p<0.02) than its detection in 91 of 581 (15.7% [95% CI: 13.2-18.4]) donors with normal ALT (< or = 45 U/L).The frequency of TT virus DNA increased with age, in donors with and without elevated ALT. CONCLUSION: The detection of TT virus DNA, at a frequency higher in donors with elevated ALT than in those without, strengthens the association of TT virus with non-A to -G hepatitis.

Kusakabe A, Tanaka Y, Mochida S, Nakayama N, Inoue K, Sata M, Isoda N, Kang JH, Sumino Y, Yatsuhashi H, Takikawa Y, Kaneko S, Yamada G, Karino Y, Tanaka E, Kato J, Sakaida I, Izumi N, Sugauchi F, Nojiri S, Joh T, Miyakawa Y, Mizokami M. · Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. · Hepatol Res. · Pubmed #19456899 No free full text.

Abstract: Background: Host and viral factors can promote the development of fulminant hepatitis B (FHB), but there have been no case-control studies for figuring out virological parameters that can distinguish FHB. Methods: In a case-control study, virological factors associated with the development of FHB were sought in 50 patients with FH developed by transient hepatitis B virus (HBV) infection (FH-T) and 50 with acute self-limited hepatitis B (AHB) who were matched for sex and age. In addition, 12 patients with FH developed by acute exacerbation (AE) of asymptomatic HBV carrier (ASC) (FH-C) were also compared with 12 patients without FH by AE of chronic hepatitis B (AE-C). Results: Higher HBV DNA levels, subgenotype B1/Bj, A1762T/G1764A, G1896A, G1899A and A2339G mutation were significantly more frequent (P < 0.05), while hepatitis B e-antigen was less frequent in the FH-T patients than AHB. In multivariate analysis, G1896A mutation (odds ratio [OR], 13.53; 95% confidence interval [CI], 2.75-66.64), serum HBV DNA more than 5.23 log copies/mL (OR, 5.14; 95% CI, 1.10-24.15) and total bilirubin more than 10.35 mg/mL (OR, 7.81; 95% CI, 1.77-34.51) were independently associated with a fulminant outcome by transient HBV infection. On the other hand, in comparison with the patients between FH-C and AE-C groups, there was no significant difference of virological factors associated with the development of FHB. Conclusion: A number of virological factors have been defined that may distinguish FH-T from AHB in a case-control study. The pathogenic mechanism of FHB between transient HBV infection and AE of ASC would be different.

Takahashi K, Okamoto H, Abe N, Kawakami M, Matsuda H, Mochida S, Sakugawa H, Suginoshita Y, Watanabe S, Yamamoto K, Miyakawa Y, Mishiro S. · Toshiba General Hospital, Tokyo, Japan. · Emerg Infect Dis. · Pubmed #19402955 links to  free full text

Abstract: 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.

Sezaki H, Suzuki F, Akuta N, Yatsuji H, Hosaka T, Kobayashi M, Suzuki Y, Arase Y, Ikeda K, Miyakawa Y, Kumada H. · Department of Hepatology, Toranomon Hospital, Tokyo, Japan. · Intervirology. · Pubmed #19372703 No free full text.

Abstract: 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.

Matsuura K, Tanaka Y, Hige S, Yamada G, Murawaki Y, Komatsu M, Kuramitsu T, Kawata S, Tanaka E, Izumi N, Okuse C, Kakumu S, Okanoue T, Hino K, Hiasa Y, Sata M, Maeshiro T, Sugauchi F, Nojiri S, Joh T, Miyakawa Y, Mizokami M. · Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya, Japan. · J Clin Microbiol. · Pubmed #19297602 No free full text.

Abstract: 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.

Inokuchi M, Ito T, Uchikoshi M, Shimozuma Y, Morikawa K, Nozawa H, Shimazaki T, Hiroishi K, Miyakawa Y, Imawari M. · Department of Gastroenterology, Showa University School of Medicine, Tokyo, Japan. · J Med Virol. · Pubmed #19235854 No free full text.

Abstract: 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.

Suzuki Y, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Hosaka T, Akuta N, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Miyakawa Y, Kumada H. · Department of Hepatology, Toranomon Hospital, Takatsu-ku, Kawasaki City, Japan. · J Gastroenterol Hepatol. · Pubmed #19226381 No free full text.

Abstract: BACKGROUND AND AIMS: Long-term lamivudine therapy is required for patients with chronic hepatitis B, because hepatitis reappears frequently after it has withdrawn. However, hepatitis B virus (HBV) mutants resistant to lamivudine emerge frequently accompanied by breakthrough hepatitis. METHODS: Effects of entecavir were evaluated in 19 patients who had developed breakthrough hepatitis during lamivudine therapy for longer than 5 years. This study is a subgroup analysis of a previously reported study. Entecavir, in either 0.5 or 1.0 mg/day doses, was given to 10 and nine patients for 52 weeks, respectively, and then all received 1.0 mg/day entecavir for an additional 68-92 weeks. RESULTS: There were no differences in biochemical and virological responses in the two groups of patients with respect to the two different initial doses of entecavir. Serum levels of alanine aminotransferase were normalized in 17 (90%) patients, and hepatitis B e antigen (HBeAg) disappeared from the serum in two (14%) of the 14 patients who were HBeAg-positive before. Furthermore, a decrease in histological activity index score greater than 2 points was achieved in nine of the 11 (82%) patients in whom annual liver biopsies were performed during 3 years while they received entecavir. HBV mutants resistant to entecavir emerged in five of the 19 (26%) patients, and hepatitis flare occurred in two of them (40%). CONCLUSION: Entecavir in the long term would be useful for histological improvement of breakthrough hepatitis induced by lamivudine-resistant HBV mutants in patients with chronic hepatitis B. However, the relatively high rate of entecavir resistance is a concern, and other strategies need to be considered when available.

Tabuchi A, Tanaka J, Katayama K, Mizui M, Matsukura H, Yugi H, Shimada T, Miyakawa Y, Yoshizawa H. · Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. · J Med Virol. · Pubmed #19040280 No free full text.

Abstract: Studies of hepatitis B virus (HBV) infection in non-human primates such as chimpanzees are no longer possible due to ethical considerations and the endangered status of chimpanzees since April 2007 in Japan. A human hepatocyte transplanted chimeric mouse was used to characterize HBV infectivity in serial stages of acute infection. Chimeric mice were inoculated intravenously with serum samples obtained from an experimentally infected chimpanzee with HBV. Sera from the pre-acute phases (i.e., rump-up viremia prior to anti-HBc) and late acute phases (i.e., declining phase of HBsAg and anti-HBcAb positive) were collected from the chimpanzees 57 and 244 days after inoculation. These sera contained 2.6 x 10(6) and 2.8 x 10(6) copies/ml of HBV DNA, respectively. Three chimeric mice inoculated intravenously with 100 microl of pre-acute serum (equivalent to 10(0) copy of HBV DNA) developed an HBV infection. The three chimeric mice that received 100 microl of pre-acute serum (equivalent to 10(1) copies of HBV DNA), developed high levels of serum HBV DNA. None of the three chimeric mice inoculated with 100 microl of 1:10(4) dilution (equivalent to 10(1) copies of HBV DNA) of late-acute serum was infected, while only one of three chimeric mice inoculated with 100 microl of 1:10(3) dilution (equivalent to 10(2) copies of HBV DNA) of late-acute serum developed an HBV infection. Based on these results, chimeric mice can be used as animal models for the study of HBV infectivity, pathogenesis and control. The results show that pre-acute phase HBV serum is about 100-times more infectious than late acute phase serum.

Sezaki H, Suzuki F, Kawamura Y, Yatsuji H, Hosaka T, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Miyakawa Y, Kumada H. · Department of Hepatology, Toranomon Hospital, Tokyo, Japan. · Dig Dis Sci. · Pubmed #18958621 No free full text.

Abstract: BACKGROUND: Response to treatment in patients with chronic hepatitis C, with reference to age and gender, has not been examined fully. AIM: The influence of gender and age on treatment with pegylated interferon (PEG-IFN) and ribavirin was evaluated in a retrospective study. METHODS: PEG-IFN and ribavirin were given for 48 weeks to 179 men and 121 women infected with hepatitis C virus (HCV) of genotype 1b in high viral loads (>100 kIU/ml). RESULTS: Sustained virological response at 24 weeks after treatment was poorer in women than men who were aged >or=50 years (22% vs 53%, P < 0.001). Among the patients aged >or=50 years who had received >or=80% of the doses of PEG-IFN, ribavirin, or both, women responded less often than men (26% vs 64%, P < 0.001; 33% vs 61%, P = 0.022; and 32% vs 63%, P = 0.016; respectively). In multivariate analysis, male gender, retention of indocyanine green, ribavirin dose and compliance with therapy increased sustained virological response. CONCLUSIONS: Response to combined PEG-IFN and ribavirin is poorer in female than male patients with hepatitis C who are aged >or=50 years, irrespective of compliance with treatment. Low estrogen levels in older women could be responsible for their impaired response to PEG-IFN and ribavirin.

Kobayashi M, Ikeda K, Arase Y, Suzuki F, Akuta N, Hosaka T, Sezaki H, Yatsuji H, Kobayashi M, Suzuki Y, Watahiki S, Mineta R, Iwasaki S, Miyakawa Y, Kumada H. · Research Institute for Hepatology, Toranomon Hospital, Tokyo, Japan. · J Med Virol. · Pubmed #18814241 No free full text.

Abstract: During 35 years from 1971 to 2005, 153 patients with acute and 4,277 with chronic HBV infection visited the Toranomon Hospital in Tokyo, Japan. They were grouped into seven 5-year periods, and HBV genotypes/subgenotypes were determined. Patients with acute HBV infection were younger (P = 0.046), predominantly male (P = 0.004), possessed higher alanine aminotransferase levels (P < 0.001), positive more frequently for HBeAg (P < 0.001), and had lower HBV DNA loads (P = 0.014) than those with chronic infection. Sexual transmission was more frequent in patients with acute than chronic HBV infection (67% vs. 3%, P < 0.001). The number of patients with acute infection increased throughout 1971-2005. Patients with chronic infection increased since 1971, peaked in 1986-1990 and then decreased. The number of patients increased since 1990-2000 again, however, reflecting recent boost of acute HBV infection. The distribution of HBV genotypes was considerably different between patients with acute and chronic infections (A, B, and C: 28.6%, 10.3%, and 59.5% vs. 3.0%, 12.3%, and 84.5%, respectively, P < 0.001). Since 1991, genotype A foreign to Japan started to increase sharply in patients with acute infection, and gradually in those with chronic infection. There was a trend for the foreign subgenotype B2/Ba to increase recently (P < 0.05). Despite immunoprophylaxis of high-risk babies born to carrier mothers with hepatitis B e antigen, implemented nationally since 1986, acute and chronic infections with HBV have been increasing in Japan. Based on genotypes/subgenotypes changing with time, the resurgence of hepatitis B could be attributed to infections, with foreign HBV genotypes/subgenotypes, spreading swiftly by sexual contact.

Yamane A, Nakamura T, Suzuki H, Ito M, Ohnishi Y, Ikeda Y, Miyakawa Y. · Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. · Blood. · Pubmed #18523149 links to  free full text

Abstract: Human interferon (IFN)-alpha is the standard therapy for chronic hepatitis C to prevent its progression to liver cirrhosis and hepatocellular carcinoma. Thrombocytopenia is one of the major adverse effects of IFN-alpha and often leads to dose reduction or treatment discontinuation. However, there is little information on how IFN-alpha inhibits human megakaryopoiesis. In this study, we demonstrated that IFN-alpha did not inhibit colony formation of megakaryocytes from human CD34(+) hematopoietic stem cells. IFN-alpha did not inhibit endomitosis but did inhibit cytoplasmic maturation of megakaryocytes and platelet production in vitro. IFN-alpha suppressed the expression of transcription factors regulating late-stage megakaryopoiesis, such as GATA-1, p45(NF-E2), MafG. IFN-alpha also significantly reduced the number of human platelets but not megakaryocytes, and did not inhibit endomitosis of human megakaryocytes in immunodeficient NOD/Shi-scid/IL-2R gamma(null) (NOG) mice transplanted with human CD34(+) cells (hu-NOG). We also demonstrated that a novel thrombopoietin mimetic, NIP-004, was effective for treating IFN-alpha-induced thrombocytopenia in hu-NOG mice. From ultrastructural study, IFN-alpha inhibited the maturation of demarcation membranes in megakaryocytes, although NIP-004 prevented the inhibitory effects of IFN-alpha. These results defined the pathogenesis of IFN-alpha-induced thrombocytopenia and suggested possible future clinical applications for thrombopoietin mimetics.

Kusumoto K, Yatsuhashi H, Nakao R, Hamada R, Fukuda M, Tamada Y, Taura N, Komori A, Daikoku M, Hamasaki K, Nakao K, Ishibashi H, Miyakawa Y, Eguchi K. · First Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan. · J Gastroenterol Hepatol. · Pubmed #18410611 No free full text.

Abstract: BACKGROUND AND AIM: Acute exacerbation of chronic hepatitis B has to be distinguished from acute hepatitis, because treatment strategies differ between them. METHODS: Mutations in the core promoter and precore region of hepatitis B virus (HBV) were determined in 36 patients with acute exacerbation of chronic hepatitis B, in whom alanine aminotransferase (ALT) increased above 500 IU/L, as well as the 36 patients with acute hepatitis. RESULTS: Mutations in the core promoter (A1762T/G1764A) and precore region (G1896A) were more frequent in patients with acute exacerbation of chronic hepatitis than acute hepatitis (81% vs 19%; P < 0.0001 and 58% vs 6%; P < 0.0001, respectively). Of the 19 patients with mutations in both the core promoter and precore region, 17 (89%) had acute exacerbation of chronic hepatitis. In contrast, among the 32 patients with the wild-type for both the core promoter and precore region, 29 (89%) developed acute hepatitis. By multivariate analysis, the double mutation in the core promoter was predictive of acute exacerbation in chronic hepatitis with the highest odds ratio at 26.4. CONCLUSIONS: In patients with hepatitis B having ALT levels >500 IU/L, mutations in the core promoter and precore region are useful in distinguishing acute exacerbation of chronic from acute HBV infection. Detection of these mutations would be useful for commencing prompt antiviral treatments on patients with acute exacerbation of chronic hepatitis for a better prognosis.

Tanaka J, Mizui M, Nagakami H, Katayama K, Tabuchi A, Komiya Y, Miyakawa Y, Yoshizawa H. · Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. · Intervirology. · Pubmed #18309247 No free full text.

Abstract: OBJECTIVE: Although prevalence rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have kept decreasing in blood donors, there is little information on incidence rates of these hepatitis viruses in Japan. METHODS: During 10 years from June 1994 through April 2004, 418,269 inhabitants of Hiroshima, Japan, donated blood (1,409,465 units in total). They were screened for serum markers of HBV and HCV infections, and individuals who developed de novo infections were identified. RESULTS: Infection with HBV occurred at a rate of 2.78 per 100,000 person-years (95% confidence interval: 1.78-4.14/100,000 person-years) and that with HCV at a rate of 1.86 per 100,000 person-years (95% confidence interval: 1.06-3.01/100,000 person-years). Residual risks of transmission by transfusions, based on the relationship risk [window period (estimated at 0.15 and 0.03 years in chimpanzees inoculated with minimum infectious doses for HBV and HCV, respectively) x incidence], were 1/243,000 for HBV and 1/1,960,000 for HCV infections. CONCLUSION: At present, incidence rates of HBV and HCV infections are extremely low in Japan.

Komiya Y, Katayama K, Yugi H, Mizui M, Matsukura H, Tomoguri T, Miyakawa Y, Tabuchi A, Tanaka J, Yoshizawa H. · Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan. · Transfusion. · Pubmed #18028278 No free full text.

Abstract: BACKGROUND: In planning optimal hepatitis B virus (HBV) blood screening strategies, the minimum infectious dose and early dynamics of HBV need to be determined for defining the window period for HBV DNA as well as for hepatitis B surface antigen (HBsAg). STUDY DESIGN AND METHODS: Pairs of chimpanzees were inoculated with preacute-phase inocula containing HBV of genotype A or genotype C to determine the minimum infectious dose, and two pairs of chimps infected with the lowest infectious dose of genotypes A and C were followed for HBV markers. RESULTS: The minimum 50 percent chimpanzee infectious dose (CID50) was estimated to be approximately 10 copies for genotype A and for genotype C. In the two chimps inoculated with the lowest infectious dose, the HBV DNA window was 55 to 76 days for genotype A and 35 to 50 days for genotype C, respectively. The HBsAg window was 69 to 97 days for genotype A and 50 to 64 days for genotype C, respectively. The doubling times of HBV DNA were 3.4 days (95% confidence interval [CI], 2.6-4.9 days) for genotype A and 1.9 days (95% CI, 1.6-2.3 days) for genotype C. When comparing the replication velocity of HBV DNA between the two genotypes, the doubling time of genotype C was significantly shorter than that of HBV genotype A (p < 0.01). CONCLUSION: Although the CID50 of approximately 10 copies was similar for the two HBV genotypes, the doubling time and pre-HBV nucleic acid amplification technology (<100 copies/mL) window period in chimps infected with the lowest infectious dose seemed to be shorter for genotype C than for genotype A.

Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Miyakawa Y, Kumada H. · Department of Hepatology, Toranomon Hospital, Tokyo, Japan. · Intervirology. · Pubmed #17728547 No free full text.

Abstract: OBJECTIVE: To evaluate power of amino acid polymorphisms in core protein of hepatitis C virus (HCV) for predicting sustained virological response (SVR) to pegylated interferon (Peg-IFN)/ribavirin, when they were combined with virological response. METHODS: Peg-IFN/ribavirin was given to 118 patients infected with HCV genotype 1b in high viral loads. Amino acid polymorphisms (Arg70 vs. Gln70 and Leu91 vs. Met91) in combination with on-treatment virological responses were correlated with SVR. RESULTS: End-of-treatment response (ETR) was achieved in 71% and SVR in 47% of the 118 patients. In multivariate analysis, Arg70 and Leu91, and higher ribavirin dose were independently associated with ETR. In patients with Gln70 and/or Met91, SVR was more frequent in those with than without prompt virological response (PVR) for a decrease in viral load >or=1.0 log by 48 h. Specificity in predicting patients without ETR and SVR, in combination with core polymorphisms, was not different between PVR and early virological response at 12 weeks. CONCLUSION: Core polymorphisms combined with PVR would be useful in promptly identifying the patients who will not respond to Peg-IFN/ribavirin, thereby avoiding unrewarding side effects and high costs.

Mizui M, Tanaka J, Katayama K, Nakanishi T, Obayashi M, Aimitsu S, Yoshida T, Inoue J, Yokoyama T, Tsuji K, Arataki K, Yamaguchi S, Miura T, Kitamoto M, Takezaki E, Orimen S, Sakata T, Kamada K, Maruhashi A, Tamura T, Nakamura T, Ishida K, Teramen K, Miyakawa Y, Yoshizawa H. · Department of Laboratory Medicine, Japanese Red Cross, Hiroshima Blood Center, Hiroshima, Japan. · Hepatol Res. · Pubmed #17627620 No free full text.

Abstract: Aim: To portray liver disease and project outcomes in carriers of hepatitis C virus (HCV) in the general population. Methods: Liver disease was evaluated in 1019 individuals who were found with HCV infection at blood donation, and they were followed for 5-10 years with or without receiving interferon (IFN). Results: At baseline, chronic hepatitis was detected in 529 (51.9%) HCV carriers and more frequently in men than in women (62.6% [299/478]vs 42.5% [230/541], P < 0.01); cirrhosis was diagnosed in five (0.5% [three men included]) and hepatocellular carcinoma (HCC) in one (0.1% [man]). Of the carriers who were followed for 5 years or longer, loss of HCV-RNA from serum was achieved in 61 (31.0%) of the 197 treated with interferon (IFN) and only one of the 211 (0.5%) without IFN (P < 0.0001). HCC developed in 14 carriers including six ofthe 211 (2.8%) without IFN and eight of the 197 (4.1%) with IFN (six non-responders included). Follow ups of the 949 carriers identified age (P < 0.002), male gender (P < 0.01) and cirrhosis at the baseline (P < 0.0001) as factors contributing to the development of HCC. Cumulative incidence rates of HCC during 10 years among carriers found with chronic hepatitis increased in parallel with the age at the baseline. Conclusion: Identification of HCV carriers in the general population and treating those indicated with IFN would help decrease the development of HCC and lift its medical, as well as economic, burdens off society.