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.

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.

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.

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.

Seroclearance rate of hepatitis B surface antigen in 2,112 patients with chronic hepatitis in Japan during long-term follow-up.

BACKGROUND: Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years. METHODS: Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10(3)/mm(3); HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan-Meier life table method. RESULTS: The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p < 0.001)], and HBeAg-negative status [RR 3.75 (p < 0.001)] significantly influenced HBsAg seroclearance. CONCLUSIONS: In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.

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.

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).

Prevalence of hepatitis C virus variants resistant to NS3 protease inhibitors or the NS5A inhibitor (BMS-790052) in hepatitis patients with genotype 1b.

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.

Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus.

BACKGROUND: Two nucleotide polymorphisms of the interleukin-28B (IL28B) gene, at rs8099917 and rs12979860, influence the response to interferon (IFN)-based therapies in patients infected with hepatitis C virus (HCV) of genotype 1. We aimed to investigate whether these polymorphisms showed complete linkage in Japanese patients. METHODS: A total of 1,518 Japanese patients infected with HCV were genotyped for the two IL28B loci, and the two sets of genotypes were compared. RESULTS: TT at rs8099917 and CC at rs12979860 were detected in 77.7 and 76.8%, respectively, of the 1,518 patients and TG/GG and CT/TT were detected in 22.3 and 23.2%. These two sets of IL28B genotype stood in strong linkage disequilibrium (r (2) = 0.98). Discordance between the two IL28B polymorphisms occurred in 16 (1.1%) patients, and 13 (0.9%) of them possessed IFN-sensitive TT at rs8099917 and IFN-resistant CT at rs12979860. Three of these 13 patients had HCV of genotype 1b and had received pegylated-interferon and ribavirin, and none of them gained a sustained virological response. At rs8099917, IFN-resistant TG/GG were more frequent in patients infected with HCV of genotype 1 than in those infected with HCV of genotype 2 [258/1,046 (24.7%) vs. 75/441 (17.0%), p = 0.001]. The response to pegylated-interferon/ribavirin in 279 patients who were infected with HCV-1 and the response to IFN monotherapy in 361 patients who were infected with HCV-1 , was higher in those with TT than in those with TG/GG at rs8099917, as well as being higher in those with CC than in those with CT/TT at rs12979860 (p < 0.001). CONCLUSIONS: Linkage disequilibrium between two IL28B polymorphisms at rs8099917 and rs12979860 is strong in Japanese HCV patients, but there are some discrepancies between the two sets of genotypes.

Follow up of the 987 blood donors found with hepatitis C virus infection over 9-18 years.

AIM: To follow up blood donors found with hepatitis C virus (HCV) infection, to improve the outcome by antiviral treatments. METHODS: Between 1991 and 2001, 3377 of the 1 925 860 donors (0.18%) were found to have HCV infection at the Hiroshima Red Cross Blood Center in Japan. Of them, 987 were able to be followed regularly over 9-18 years until 2009, and received antiviral treatments as required. RESULTS: At the start, chronic hepatitis was diagnosed in 541 (54.8%), cirrhosis in five (0.5%) and hepatocellular carcinoma (HCC) in one (0.1%), whereas the remaining 439 (44.5%) had persistently normal aminotransferase levels (PNAL). Hospital visits were terminated voluntarily in 24.3% within the first year, 46.8% by 10 years and 50.9% by 17 years. Liver disease improved in 178 (18.0%), remained stable in 606 (61.4%) and aggravated in 170 (17.2%). Of the 541 donors with chronic hepatitis, HCC developed in 28 (5.2%) and cirrhosis in 11 (2.0%), whereas HCV infection was cleared in 107 (19.8%) by antiviral treatments. In addition, HCV infection resolved in 54 of the 439 donors (12.3%) with PNAL after they had developed chronic hepatitis and received treatments. In donors with chronic hepatitis, the cumulative incidence of HCC was 4.1% at 10 years. By multivariate analysis, age and diagnosis of chronic hepatitis at the entry were found to be independent risk factors for the development of HCC. CONCLUSION: Individuals with undiagnosed HCV infection need to be identified and receive medical care. They have to be motivated to merit from this health-care program.

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.

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.

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.

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.

Alpha-fetoprotein above normal levels as a risk factor for the development of hepatocellular carcinoma in patients infected with hepatitis C virus.

BACKGROUND: Noninvasive risk factors are required for predicting the development of hepatocellular carcinoma (HCC) not only in patients with cirrhosis but also in those with chronic hepatitis who are infected with hepatitis C virus (HCV). METHODS: A total of 707 patients with chronic HCV infection without other risks were evaluated for the predictive value of noninvasive risk factors for HCC, including age, sex, viral load, genotype, fibrosis stage, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count, and alpha-fetoprotein (AFP) at entry to the study, as well as interferon (IFN) therapy they received. RESULTS: The ten-year cumulative incidence rates of HCC for patients with fibrosis stages F0/F1, F2, F3, and F4 were 2.5, 12.8, 19.3, and 55.9%, respectively. Multivariate analysis identified age ≥57 years [hazard ratio (HR) 2.026, P = 0.004], fibrosis stage F4 (HR 3.957, P < 0.001), and AFP 6-20 ng/mL (HR 1.942, P = 0.030) and ≥20 ng/mL (HR 3.884, P < 0.001), as well as the response to IFN [relative risk (RR) 0.099, P < 0.001], as independent risk factors for the development of HCC. The ten-year cumulative incidence rates of HCC in the patients with AFP levels of <6, 6-20, and ≥20 ng/mL at entry were 6.0, 24.6, and 47.3%, respectively. CONCLUSIONS: Not only high (>20 ng/mL), but also even slightly elevated (6-20 ng/mL) AFP levels, could serve as a risk factor for HCC to complement the fibrosis stage. In contrast, AFP levels <6 ng/mL indicate a low risk of HCC development in patients infected with HCV, irrespective of the fibrosis stage.

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.

Development of HCC in patients receiving adefovir dipivoxil for lamivudine-resistant hepatitis B virus mutants.

AIM: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add-on lamivudine for treatment of lamivudine-resistant hepatitis B virus (HBV) mutants. METHODS: A total of 247 patients who developed lamivudine-resistant HBV mutants, with an increase of HBV DNA >/= 1 log copies/mL, received adefovir dipivoxil 10 mg add-on lamivudine 100 mg daily during a median of 115 weeks (range: 25-282 weeks). They were followed for the development of HCC by imaging modalities every 3-6 months. RESULTS: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and alpha-fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan-Meier analysis, AST levels >/= 70 IU/L, YIDD mutants, cirrhosis and age >/= 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). CONCLUSION: HCC can develop in cirrhotic patients receiving adefovir add-on lamivudine. Hence, the patients with baseline AST >/= 70 IU/L and YIDD mutants would need to be monitored closely for HCC.

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.