Alpha-fetoprotein and des-gamma-carboxy-prothrombin at twenty-four weeks after interferon-based therapy predict hepatocellular carcinoma development.

AIM: To investigate risk factors for development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus-related liver cirrhosis (LC-C). METHODS: To evaluate the relationship between clinical factors including virological response and the development of HCC in patients with LC-C treated with interferon (IFN) and ribavirin, we conducted a multicenter, retrospective study in 14 hospitals in Japan. All patients had compensated LC-C with clinical or histological data available. HCC was diagnosed by the presence of typical hypervascular characteristics on computed tomography and/or magnetic resonance imaging. RESULTS: HCC was diagnosis in 50 (21.6%) of 231 LC-C patients during a median observation period of 3.8 years after IFN and ribavirin therapy. Patients who developed HCC were older (P = 0.018) and had higher serum levels of pretreatment alpha-fetoprotein (AFP) (P = 0.038). Multivariate analysis revealed the following independent risk factors for HCC development: history of treatment for HCC [P < 0.001, odds ratio (OR) = 15.27, 95%CI: 4.98-59.51], AFP levels of ≥ 10 ng/mL (P = 0.009, OR = 3.89, 95%CI: 1.38-11.94), and des-γ-carboxy prothrombin (DCP) levels of ≥ 40 mAU/mL at 24 wk after the completion of IFN and ribavirin therapy (P < 0.001, OR = 24.43, 95%CI: 4.11-238.67). CONCLUSION: We suggested that the elevation of AFP and DCP levels at 24 wk after the completion of IFN and ribavirin therapy were strongly associated with the incidence of HCC irrespective of virological response among Japanese LC-C patients.

Interleukin 28B polymorphism predicts interferon plus ribavirin treatment outcome in patients with hepatitis C virus-related liver cirrhosis: A multicenter retrospective study in Japan.

AIM: This study evaluated the efficacy of interferon plus ribavirin and examined whether interleukin 28B (IL28B) polymorphism influenced treatment outcome in Japanese patients with hepatitis C virus (HCV)-related liver cirrhosis (LC). METHODS: Fourteen collaborating centers provided details of 261 patients with HCV-related LC undergoing treatment with interferon plus ribavirin. Univariate and multivariate analyses were used to establish which factors predicted treatment outcome. RESULTS: Eighty-four patients (32.2%) achieved a sustained virological response (SVR). SVR rates were 21.6% (41/190) in patients with HCV genotype 1 with high viral load (G1H) and 60.6% (43/71) in patients with non-G1H. In patients with non-G1H, treatment outcome was effective irrespective of IL28B polymorphism. In those with G1H, SVR was achieved in 27.1% of patients with the IL28B rs8099917 TT allele compared with 8.8% of those with the TG/GG alleles (P = 0.004). In patients with G1H having TT allele, treatments longer than 48 weeks achieved significantly higher SVR rates than treatments less than 48 weeks (34.6% vs 16.4%, P = 0.042). In patients with G1H having TG/GG alleles, treatments longer than 72 weeks achieved significantly higher SVR rates than treatments less than 72 weeks (37.5% vs 4.1%, P = 0.010). CONCLUSION: Interferon plus ribavirin treatment in Japanese patients with non-G1H HCV-related LC was more effective than those with G1H and not influenced by IL28B polymorphism. In those with G1H, IL28B polymorphism may predict SVR and guide treatment duration: SVR rates were higher in those with the TT allele treated for more than 48 weeks and those with the TG/GG alleles treated for more than 72 weeks.

Inhibition of hepatocellular carcinoma by PegIFNα-2a in patients with chronic hepatitis C: a nationwide multicenter cooperative study.

BACKGROUND: We investigated whether the administration of maintenance doses of interferon prevented hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. METHODS: Study 1: A multicenter, retrospective, cooperative study was carried out to determine whether long-term administration of low-dose peginterferon alpha-2a (PegIFNα-2a) prevented HCC development in patients with chronic hepatitis C. In total, 594 chronic hepatitis C patients without a history of HCC were enrolled and treated with 90 µg PegIFNα-2a administered weekly or bi-weekly for at least 1 year. Study 2: HCC developed in 16 of 99 additional patients without PegIFNα-2a treatment during 3.8 years of observation. A propensity-matched control study was then carried out to compare the incidence of HCC between the 59 patients who received low-dose PegIFNα-2a (PegIFNα-2a group) and 59 patients who did not receive PegIFNα-2a treatment (control group), matched for sex, age, platelet count, and total bilirubin levels. RESULTS: Study 1: HCC developed in 49 patients. The risk of HCC was lower in patients with undetectable hepatitis C virus RNA, ≤40 IU/L alanine aminotransferase (ALT), or ≤10 ng/L alpha-fetoprotein (AFP) 24 weeks after the start of therapy. Study 2: The incidence of HCC was significantly lower in the PegIFNα-2a group than in the control group. CONCLUSIONS: Low-dose and long-term maintenance administration of PegIFNα-2a decreased the incidence of HCC in patients with normalized ALT and AFP levels at 24 weeks compared with patients without normal ALT and AFP levels.

Mechanical properties of hard resins for crowns and bridges.

PURPOSE: Hard resins for crowns and bridges are widely used for esthetic restorations. The objective of this study was to evaluate the mechanical properties of new commercial hard resins and to compare the results with those of the other hard resins previously investigated. METHODS: Dentin and enamel made with two new hard resins (Epricord: EP, Kuraray, Co., Ltd., Osaka, Japan and Prossimo: PR, GC, Co., Ltd., Tokyo, Japan) were used in this study. Regarding the fundamental characteristics, the thermal expansion/shrinkage coefficient, the filler content, the polymerization shrinkage, and the wear were examined. Regarding the strength of resin, the bending strength, hardness, compression strength, elastic modulus, and fracture strength of a jacket crown were measured. RESULTS: These resins showed comparatively lower levels than the other hard resins regarding the bending strength, hardness, compression strength, and fracture strength of the jacket crown. The total filler content rate and wear amount of these resins exhibited similar values to those of the other resins. The thermal expansion/ shrinkage coefficients of these resins exhibited higher values than those of the other resins. EP showed a different tendency from PR about the compression strength, elastic modulus, and polymerization shrinkage. CONCLUSIONS: PR and EP did not show dramatically better physical properties. However, the results of each examination in this study may be acceptable clinically. The results of each investigation changed according to the products used, and proper use for each case and application was suggested.

Efficacy and safety of entecavir in lamivudine-refractory patients with chronic hepatitis B: randomized controlled trial in Japanese patients.

BACKGROUND AND AIM: Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection. METHODS: Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks. RESULTS: The proportions of patients achieving the primary end-point (>or=2 log(10) reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [<400 copies/mL] at week 48) were 90% and 93% for entecavir 0.5 mg and 1 mg, respectively, with 33% of patients in each dosing group achieving <400 copies/mL. The mean reduction in HBV-DNA from baseline was 3.58 and 3.75 log(10) copies/mL for entecavir 0.5 mg and 1 mg, respectively. High proportions of patients achieved alanine aminotransferase normalization at week 48 (0.5 mg 86%, 1 mg 78%). Histological improvement was observed in most patients (0.5 mg 52%, 1 mg 60%). Virological breakthrough (increase in HBV-DNA of >or=1 log(10) copies/mL from nadir) was observed in one patient but was not associated with selection of entecavir-associated resistance substitutions. Entecavir was well tolerated, with no patients discontinuing study drug due to adverse events. CONCLUSIONS: These findings indicate that entecavir is safe and effective for the treatment of Japanese adults with lamivudine-refractory chronic hepatitis B.

Spatial and chronological differences in hepatitis B virus genotypes from patients with acute hepatitis B in Japan.

Genotypes of hepatitis B virus (HBV) were determined in 485 patients with acute hepatitis B from all over Japan. They were A in 92 (19%), Ba in 26 (5%), Bj in 32 (7%), C in 330 (68%) and D in 5 (1%). Sexual contacts were the main route of transmission in them. Overall, HBV persisted in only 5 of the 464 (1%) followed patients. Genotypes C accounted for more than 68% in northern as well as southern areas, contrasting with genotype A accounting for 34% in and around the Metropolitan areas. During 24 years from 1982 to 2005, genotype A increased from 5% to 33%, while genotype B gradually decreased from 26% to 8%. Fulminant hepatitis was significantly more frequent in infection with genotype Bj (41%) than those with the other genotypes (p<0.01). The core-promoter double mutation (T1762/A1764) and precore stop-codon mutation (A1896) were more frequent in patients with fulminant than acute self-limited hepatitis (57% versus 15% and 58% versus 10%, respectively, p<0.01 for both). In conclusion, genotype A distributes unevenly over Japan, prevails in younger patients through sexual transmission and has increased with years. Furthermore, fulminant outcome was more frequent in patients with genotype Bj than those with the other genotypes.

Distinct geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan.

Genotypes of hepatitis B virus (HBV) were determined in 145 patients with acute hepatitis B from various districts in Japan to establish their geographic distribution and evaluating the influence on the clinical illness and outcome. Genotypes were A in 27 (19%) patients, B in 8 (5%), C in 109 (75%) and mixed with B and C in the remaining one (1%). Genotype A was more frequent in metropolitan than the other areas (21/69 (30%) vs. 6/76 (8%), P < 0.001). On phylogenetic analysis, seven of the nine (78%) HBV/A isolates selected at random clustered with those from Europe and the United States, while the remaining two with those of subgroup A' prevalent in Asia and Africa. Maximum ALT levels were lower (2069 +/- 1075 vs. 2889 +/- 1867 IU/L, P = 0.03) and baseline HBV DNA titers were higher (5.90 +/- 1.45 vs. 5.13 +/- 1.36 log genome equivalents (LGE)/ml, P = 0.002) in patients infected with genotype A than C. Hepatitis B surface antigen persisted longer in patients infected with genotype A than C (1.95 +/- 1.09 vs. 1.28 +/- 1.42 months, P = 0.02). HBV infection became chronic in one (4%) patient with genotype A and one (1%) with genotype C infection. Fulminant hepatic failure developed in none of the patients with genotype A, one (13%) with genotype B and five (5%) with genotype C. The point mutation in the precore region (A1896) or the double mutations in the basic core promoter (BCP) region (T1762/A1764) were detected in none of the patients with genotype A, two (25%) with genotype B and 27 (26%) with genotype C. In conclusion, genotype A is frequent in patients with acute hepatitis B in metropolitan areas of Japan, probably reflecting particular transmission routes, and associated with longer and milder clinical course than genotype C.

Precore and core promoter mutations, hepatitis B virus DNA levels and progressive liver injury in chronic hepatitis B.

BACKGROUND/AIMS: To elucidate the viral factors responsible for progressive liver injury in chronic hepatitis B. METHODS: We analyzed 179 persistently infected patients (21 asymptomatic carriers, 126 with chronic hepatitis and 32 with cirrhosis) with genotype C hepatitis B virus (HBV). HBeAg/anti-HBe, levels of HBV DNA, mutations in the basic core promoter (BCP) region at nucleotides 1762/1764 and mutation in the precore (preC) region at nucleotide 1896 were determined. Serial samples from 18 patients also were analyzed. RESULTS: HBeAg/anti-HBe and HBV DNA levels per se were not related to liver fibrosis. The frequency of BCP mutations increased with progression of liver fibrosis. Although the preC mutation was detected more often among the LC group, the role of this mutation in progression of fibrosis seems less than that of the BCP mutations. Sequential analysis showed that (1) rapidly progressing cases were positive continuously for double mutations in the BCP with a wild-type precore sequence, and (2) asymptomatic cases with anti-HBe acquired the preC mutation during their clinical course. CONCLUSIONS: Double mutations in the BCP region at nucleotide 1762/1764 are closely related to progression of chronic liver disease. Acquisition of mutation in the preC region at nucleotide 1896 may contribute to inactivation of chronic liver disease.