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Background: Hepatitis C virus (HCV) of genotype 1b is the most prevalent worldwide, and the least responsive to interferon-based treatments. A combination therapy with two direct-acting antivirals has shown promising results in patients with HCV-1b, but the prevalence of drug-resistant variants before treatment is not known in the Japanese population., Objectives: To detect HCV variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients infected with HCV-1b., Study Design: Drug-resistant mutations were determined in the 362 hepatitis patients infected with HCV-1b who had not received direct-acting antivirals before., Results: Amino-acid substitutions resistant to NS3 inhibitors (V36A, T54S, Q80H and D168E) were detected in 15 of the 307 (4.9%) patients, who had been examined, and T54S (3.3%) predominated over V36A (0.3%), Q80R (0.7%) and D168E (0.7%) in them. Amino-acid substitutions resistant to BMS-790052 (L31M and/or Y93H) were detected in 33 of the 294 (11.2%) patients, and Y93H (8.2%) predominated over L31M (2.7%). One of the 239 (0.4%) patients, who had been examined for amino-acid substitutions in both NS3 and NS5A regions, possessed HCV-1b variants resistant to NS3 inhibitors (T54S) and BMS-790052 (L31M)., Conclusions: Mutations conferring resistance to NS3 inhibitors or BMS-790052 were frequent in our treatment-naive study population, but double mutants with possible resistance to both drugs were rare. Since single mutations did not result in treatment failure in a previous pilot trial combining BMS-790052 and an NS3 inhibitor, larger trials of this drug regimen appear warranted in the Japanese population., (Copyright © 2012 Elsevier B.V. All rights reserved.)

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., (Copyright © 2011 S. Karger AG, Basel.)

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., (Copyright © 2011 S. Karger AG, Basel.)

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., ((c) 2009 Wiley-Liss, Inc.)

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.

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., (Copyright (c) 2008 S. Karger AG, Basel.)

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., ((c) 2007 S. Karger AG, Basel.)

Infection with hepatitis C virus (HCV) is taking an ever increasing role in the development of hepatocellular carcinoma (HCC) over the world. Dynamics of HCV infection were determined by the molecular clock, estimating the dissemination time when HCV entered the country and the "spread time" when it started to grow exponentially on a national scale. A comparison of HCV dynamics in Japan, the United States and Egypt has disclosed different dissemination and spread times among the three countries. Furthermore, they faithfully mirror socioeconomic as well as medical and paramedical events inherent to each country responsible for the wide spread of HCV infection during the past. Epidemic histories of HCV would enable us to predict what is going to happen in the future for HCV infection, in special reference to HCC associated with it. Population dynamics of HCV need to be determined in other countries where HCV prevails and compared with those in the three countries described. These studies should help foresee what will happen in the near future for HCV infection in a given country, time the future development of HCC and take measures for preventing it., (Copyright (c) 2006 S. Karger AG, Basel.)

During the past 30 years, hepatocellular carcinoma (HCC) in Japan has kept linearly increasing from 10 to 30 per 100,000 population per year and is expected to grow further. The increment is attributed to infection with hepatitis C virus (HCV). Hence, there is a pressing need to find subjects with persistent HCV infection in the general population of Japan and take necessary measures to prevent HCC developing in them. As a first approach toward this goal, the sex- and age-specific prevalence of ongoing HCV infection was surveyed in 3,485,648 first-time blood donors during 1995-2000. Taking into account the size of subpopulations with different sex and age in Japan registered at the Census 2000, there are an estimated 884,954 HCV carriers aged from 16 to 69 years, and 759,316 (86%) of them are older than 40 years, with an increased risk for HCC; they are hidden in the society, without overt liver disease. The national 5-year project searching for HCV carriers in the general population was started in April 2002. Subjects are examinees of health check-ups, which they receive every 5 years when reaching the age of 40, as well as those at increased risk for HCV infection. The project detected HCV RNA in 14,672 of the 1,298,746 (1.1%) health check examinees and in 16,721 of the 624,734 (2.7%) high-risk individuals during the first fiscal year. Subjects found with HCV RNA have been referred to clinics and hospitals with expert hepatologists. Hopefully, this project will decrease HCC development in HCV carriers in Japan and be considered in other countries where increases in HCC are predicted from the current age-specific prevalence of anti-HCV., (Copyright (c) 2006 S. Karger AG, Basel.)

Patients on maintenance hemodialysis (HD) are at increased risk of infection with hepatitis C virus (HCV). A prospective follow-up study on HCV infection from November 1999 to February 2003 was conducted in nine hemodialysis (HD) units in Hiroshima. A total of 2,744 HD patients were surveyed regularly for HCV RNA in serum. The prevalence of HCV RNA decreased from 15.7% (262/1,664) on the first survey to 12.9% (242/1,882) in the last one (P<0.05). This decrease may be attributed to the inclusion of patients with a lower prevalence of HCV RNA compared to patients leaving dialysis centers (111/1,080 [10.3%] vs. 132/862 [15.3%], P<0.01). During the 40 months of this study, 16 de novo HCV infections were documented in the nine HD units corresponding to an incidence of 0.33% per year. These cases included eight new HCV infections, three re-infections, and five infections that presumably occured in the window period when tested during the first survey. Our study shows that the annual incidence of de novo HCV infection during HD was 0.33%, and emphasizes the need for frequent serum HCV RNA testing and for stringent disinfection procedures in order to prevent the transmission of HCV in these settings., ((c) 2005 Wiley-Liss, Inc.)

Two chimpanzees were inoculated with hepatitis C virus (HCV) and followed on a daily basis for 12 days. HCV RNA became detectable in their sera on day 5 by polymerase chain reaction with the detection limit of 10(2) copies/ml. Based on an exponential growth observed until 8 or 9 days after inoculation in their sera, the doubling time of HCV in the circulation was estimated at 6.3-8.6 h and log time (time required to grow 10-fold) at 31.3- 42.9 h. The exact doubling time of HCV determined in them would help plan an efficient strategy for screening out blood donors in the window period of infection between the exposure and the development of antibody to HCV in serum., (Copyright (c) 2005 S. Karger AG, Basel.)

Background/aims: The mortality due to hepatocellular carcinoma (HCC) has ranged widely in various areas of Japan since 30 years ago and the incidence was particularly high in once Schistosoma japonicum (Sj)-endemic areas. Our aim was to estimate the spread time of hepatitis C virus (HCV) infection in the past with possible relevance to a higher incidence of HCC in once Sj-endemic than Sj-nonendemic areas., Methods: During 2001, 131 strains of HCV-1b were obtained from patients in three previously Sj-endemic areas, as well as Sj-nonendemic areas in Japan and a cross-sectional study was conducted on them with molecular evolutionary analyses., Results: A phylogenetic tree reconstructed on HCV-1b sequences in the NS5B region disclosed 2 independent clusters for Sj-positive and -negative groups with a high bootstrap value. The estimated effective number of HCV-infections indicated a transition from quiescence to rapid exponential growth in the 1920s among patients with schistosomiasis, which is 20 years earlier than that among patients without schistosomiasis., Conclusions: The estimated spread time in previously Sj-endemic areas in Japan coincides with injection treatment for Sj since 1921. A high incidence of HCC there would be attributed to a long duration of HCV infection since 1920s.

Hepatitis C virus (HCV) infects >10% of the general population in Egypt, in which intravenous injection with an antimony compound for endemic schistosomiasis in the past has been implicated. To simulate the epidemic history of HCV in Egypt, sera were obtained from 3608 blood donors at 13 governorates in or surrounding the Nile valley during 1999. The prevalence of antibody to HCV (anti-HCV) and genotypes was determined in them, and the molecular evolutionary analysis based on the neutral theory was applied to HCV isolates of genotype 4a, which is outstandingly prevalent in Egypt and indigenous there. Of 3608 sera, 317 (8.8%) were positive for anti-HCV. The molecular evolutionary analysis on 47 HCV genotype 4a isolates of carriers from various districts in Egypt indicated that the spread of HCV-4a would have increased exponentially during the 1940s through 1980 when oral medications became available. In conclusion, the estimated spread time is consistent with the duration of intravenous antimony campaigns in Egypt.

Objective: Carriers of hepatitis B virus (HBV) and hepatitis C virus (HCV) in Japan were estimated on a national basis., Methods: Sera from the first-time blood donors aged 16-64 years in eight jurisdictions of the Japanese Red Cross Blood Center during 1995-2000 were tested for hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV). Viremia with HCV was estimated to be present in 70% of donors with anti-HCV., Results: HBsAg was detected in 22,018 of 3,485,648 (0.63%) blood donors including 12,990 of 1,780,149 (0.73%) men and 9,028 of 1,705,499 (0.53%) women, and anti-HCV in 17,010 (0.49%) including 8,504 (0.48%) men and 8,506 (0.50%) women. Multiplying the carrier rate by the population registered in the Census 2000, the total HBV carriers aged 15-65 years were estimated at 967,753 (95% confidence interval 806,760-1,128,745), of whom 571,210 (479,267-663,152) were men and 396,543 (327,494-465,593) were women. Likewise, the total HCV carriers were estimated at 884,954 (95% confidence interval 725,082-1,044,826), of whom 464,363 (377,927-550,799) were men and 420,591 (347,156-494,027) were women., Conclusion: Estimated numbers of HBV and HCV carriers would help plan to prevent the development of hepatocellular carcinoma in Japan., (Copyright 2004 S. Karger AG, Basel)

Objective: To determine the copy number of hepatitis C virus (HCV) RNA, determined by nucleic acid amplification test (NAT) for screening blood units in Japan, that can transmit infection to chimpanzees., Methods: Fresh-frozen plasma with markers of HCV infection, as well as inocula pedigreed from 1 of them, were evaluated for the infectious activity in chimpanzees., Results: One unit each (273-282 ml) of fresh-frozen plasma from 2 blood donors or a pool from 13 donors to make a unit, which contained high-titered antibody to HCV but without HCV RNA detectable by NAT, did not infect any of 3 chimpanzees. Two chimpanzees were infected, however, when they were inoculated with 1 ml of serum from a blood donor in the 'window period' of HCV infection and containing 7.0 x 10(6) copies/ml of HCV RNA. The preacute phase serum from 1 of them harvested 7 weeks after the inoculation was titrated in 2 chimpanzees, and an inoculum containing approximately 2 x 10(1) copies of HCV RNA could transmit infection to both of them., Conclusion: Approximately 20 copies of HCV can transmit infection to recipients, which needs to be taken into consideration in planning the screening of blood units for HCV RNA by NAT. Although the sensitivity of present NAT could be improved further, there would be a limit of it in detecting a low-level HCV RNA in the window period of donors with the infectious capacity in recipients., (Copyright 2004 S. Karger AG, Basel)

The Markov model was introduced to simulate natural histories of hepatitis C virus (HCV) infection in men and women. The data set was constructed on 942 HCV carriers who were examined at least once a year without receiving antiviral therapies. Based on 2,251 patient-year data, the probabilities of transition between any two of the four clinical states, i.e., asymptomatic carrier state, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in 1 year were calculated. Hepatocellular carcinoma was defined as the absorbing state from where no transitions occur. Probability matrices thus obtained on six each subsets of HCV infection (asymptomatic carrier state, chronic hepatitis and liver cirrhosis in men and women) in their forties, fifties, and sixties, were used to simulate long-term outcomes of HCV infection. Male asymptomatic carriers aged 40 years were expected to retain the asymptomatic carrier state in 2.6%, evolve into chronic hepatitis in 48.4%, liver cirrhosis in 14.6% and hepatocellular carcinoma in 34.4% after 30 years when they reached 70 years of age, in contrast to 1.9%, 45.3%, 32.8% and 20.0%, respectively, of female asymptomatic carriers. Likewise, male patients with chronic hepatitis aged 40 years were expected to remain with chronic hepatitis in 43.8%, evolve into liver cirrhosis in 15.0% and hepatocellular carcinoma in 41.1%, contrasting with 38.9%, 32.7% and 22.0%, respectively, of female patients during 30 years. The Markov model could simulate the outcomes of 153 HCV carriers identified among blood donors after 5 years. The Markov simulation would help in assessing the long-term outcome of HCV infection and making decisions in the management of HCV carriers toward prevention of hepatocellular carcinoma., (Copyright 2003 Wiley-Liss, Inc.)

Objective: The role of resolved hepatitis B virus (HBV) infection in promoting hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV) in Japan was evaluated by epidemiological surveys., Methods: Antibody to hepatitis B core (anti-HBc) was determined in age-matched blood donors, and the frequency was compared with that in patients with HCV-associated HCC in Japan., Results: Anti-HBc was detected significantly more frequently in the blood donors with than without antibody to HCV (anti-HCV; 76/135 or 56.3% vs. 65/255 or 25.5%, p < 0.001). In the patients with HCV-associated HCC, anti-HBc was detected in 109 of 202 (54.0%), which was comparable to the frequency in anti-HCV-positive blood donors (56.3%). Among the blood donors with anti-HCV, the prevalence of anti-HBc was no different between those with and without HCV RNA in serum (40/77 or 51.9% vs. 36/58 or 62.1%)., Conclusions: The individuals of an age with high cancer frequency (>or=40 years) in Japan would have been exposed to HBV frequently (>50%), whether or not they have developed HCV-associated HCC. Despite repeated assertions in the literature, no epidemiological evidence was obtained for a role of past HBV infection in hepatocarcinogenesis in patients infected with HCV in Japan., (Copyright 2003 S. Karger AG, Basel)

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 protocolmay minimize the disadvantage ofmedical claim analysis, and is useful for patients, especially asymptomatic carriers and those with CH which had been underestimated in the 2008 Patient Survey. [ABSTRACT FROM AUTHOR]

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 ≥65 years with platelet counts >120×103/mm3 were classified as 120 with aspartate and alanine aminotransferase (ASAT and ALAT) levels ≦40 IU/l (group A) and 212 with either or both levels ≥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 ≦40 IU/l, using antiviral treatments or other agents, in order to prevent cirrhosis and HCC arising in these patients. In view of rare liver-related deaths, aggressive antiviral treatment would not be necessary in the elderly with chronic hepatitis C who have normal transaminase levels. [ABSTRACT FROM AUTHOR]