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.

Incidence rates of hepatitis B and C virus infections among blood donors in Hiroshima, Japan, during 10 years from 1994 to 2004.

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.

Minimum infectious dose of hepatitis B virus in chimpanzees and difference in the dynamics of viremia between genotype A and genotype C.

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.

Hepatitis C virus infection in 2,744 hemodialysis patients followed regularly at nine centers in Hiroshima during November 1999 through February 2003.

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.

Early dynamics of hepatitis C virus in the circulation of chimpanzees with experimental infection.

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.

Sex- and age-specific carriers of hepatitis B and C viruses in Japan estimated by the prevalence in the 3,485,648 first-time blood donors during 1995-2000.

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.

Titration of hepatitis C virus in chimpanzees for determining the copy number required for transmission.

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.

Lack of epidemiological evidence for a role of resolved hepatitis B virus infection in hepatocarcinogenesis in patients infected with hepatitis C virus in Japan.

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.

Natural histories of hepatitis C virus infection in men and women simulated by the Markov model.

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.

High incidence of extrahepatic manifestations in an HCV hyperendemic area.

We previously investigated the incidence of extrahepatic manifestations including oral precancerous disease among the inhabitants in a hepatitis C virus (HCV) hyperendemic area in Fukuoka in Japan. The present study design was based on a prospective cohort at the other HCV hyperendemic area. One oral surgeon examined the oral lesions of 59 adult inhabitants (21 men, 38 women; mean age of 70.7 years), of a hyperendemic area of HCV infection. Furthermore, all subjects were interviewed regarding the natural history of extrahepatic manifestations. All sera were examined for antibodies to HCV (anti-HCV), serum HCV RNA, HCV genotype, antinuclear antibody (ANA), rheumatoid factor (RF) activity, and anti-SS-A and-B antibodies. Anti-HCV or HCV RNA was detected in sera from 59 (100%) or 57 (96.7%) of all subjects. Oral lichen planus (OLP), leukoplakia with leukoedema, or only leukoedema was observed in 8 (8.5%), 1 (1.7%), or 2 (3.4%) subjects, respectively. The incidence of all subjects with one or more HCV-related extrahepatic manifestation was 66.1% (39/59). The subjects with dry mouth were 25.4% (15/59). There was no relation among these autoantibodies, symptoms of dry mouth, or prevalence of HCV-associated extrahepatic manifestations. These findings demonstrate that the inhabitants with HCV infection showed various extrahepatic manifestations, and was not always limited to specific HCV areas.