No abstract

Alpha-fetoprotein (AFP) is a marker of the presence of hepatocellular carcinoma (HCC), but is also elevated in advanced chronic hepatitis B. The detection and usage of AFP tests need to be improved. A cohort of 101 patients with advanced chronic hepatitis B and elevated AFP values was treated with entecavir (ETV) or peginterferon-alpha2a. ETV was more effective in reducing AFP levels; mean time to AFP normalization was 11.9 weeks after ETV treatment initiation vs 22.3 weeks in peginterferon treated patients (P = 0.000). An additional cohort of 93 hepatitis B virus (HBV) cirrhotic patients with elevated AFP were treated with ETV prospectively and maintained under intensive surveillance. HCC developed in 16 (17.2%) patients in whom the strongest independent predictor was a continued AFP rise in spite of ongoing treatment. In this context, nodules of sizes 10-14 mm and 15-20 mm were detected in 40% of patients each. In conclusion, HBV cirrhotic patients with rising AFP levels were at very high risk of HCC development. Early detection of minute lesions may be possible by monitoring AFP levels, whilst patients are on treatment in conjunction with enhanced computed tomography examination.

The biological implications of substitutions L60V and I97L in the core (c) gene of hepatitis B virus (HBV) were investigated in order to determine whether they could change the immunogenicity of HBcAg or influence the immune response in mice. Three strains of recombinant adenoviruses--AdHBV-WT, AdHBV-L60V and AdHBV-I97L--containing wild-type or mutant HBV genomes were constructed using the AdEasy system and used to infect BALB/c mice intranasally. Infected mice produced anti-HBc efficiently to comparable levels. IgG1 and IgG2a specific for HBcAg were present in mice sera, and the response was dominated by IgG2a. The lymphocyte proliferative response specific for HBcAg was assessed by [3H]-thymidine uptake. We found that AdHBV-WT induced a stronger T-cell proliferation response than AdHBV-L60V and AdHBV-I97L. In conclusion, the L60V and I97L substitutions had no influence on humoral immune responses, but could downregulate T-cell responses to HBcAg, suggesting that L60V and I97L were immune escape mutants.

Context: One approach to protect against liver fibrosis is the use of herb-derived natural compounds, such as hydroxysafflor yellow A (HSYA). The antifibrosis effect of HYSA against liver fibrosis has been investigated; however, its mechanisms have not yet been entirely revealed. Objectives: To study the protective effects of HSYA on liver fibrosis induced by carbon tetrachloride (CCl 4 ) and a high-fat diet (HFD), and to determine the mechanism of action of HSYA. Materials and methods: CCl 4 and HFD were used to mimic liver fibrosis in rats, and serum biochemical indicators were determined. The antifibrosis effects of HSYA were evaluated and its mechanisms were investigated by histopathological analysis, immunohistochemical staining, enzyme-linked immunosorbent assays, real-time-PCR, and western blotting. Results: HSYA reduced CCl 4 -and HFD-mediated liver fibrosis and ameliorated serum biochemical indicator, downregulated the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) (0.31 ± 0.03 protein, 0.59 ± 0.02 mRNA) and transformin growth factor-b1 (TGF-b1) (0.81 ± 0.02 protein, 0.58 ± 0.04 mRNA), and upregulated the expression of peroxisome proliferator-activated receptor-g (PPAR-g) (1.57 ± 0.13 protein, 2.48 ± 0.19 mRNA) and matrix metallopeptidases-2 (MMP-2) (2.31 ± 0.16 protein, 2.79 ± 0.22 mRNA) (p50.01, versus model group). These effects were significantly attenuated by PPAR-g antagonist GW9662 via blocking the phosphorylation of p38 MAPK. Discussion and conclusion: These data demonstrate a novel role for HSYA in inhibiting CCl 4 -and HFD-mediated liver fibrosis, and reveal that PPAR-g and p38 MAPK signaling play pivotal roles in the prevention of liver fibrosis induced by CCl 4 and HFD.

Hepatitis B virus (HBV) genotypes B and C are most prevalent in China and genotype B is found exclusively in recombination with the pre-C/C gene of genotype C. We investigated whether there is a difference in clinical relevance between the two genotypes sharing the same pre-C/C gene. Thus, we determined the genotype of HBV among consecutive HBeAg-positive patients with tailored interferon-alpha (IFN-alpha) therapy, and the demographic, baseline clinical characteristics and treatment results were compared between them. The median values of alanine transaminase (ALT) were 4.5 and 5.0 times the upper limit of normal (P = 0.419), HBV-DNA levels were 1.4 x 10(7) and 1.5 x 10(7)copies/mL (P = 0.829), mean scores of necroinflammatory histological activity 9.8 and 10.44 (P = 0.105) and fibrotic activity 2.64 and 2.86 (P = 0.227) in genotype B and C patients, respectively. The end-of-treatment response was 42.7% and 39.0% (P = 0.531) with mean tailored treatment months of 8.28 and 9.34 (P = 0.160), and the sustained response 43.4% and 37.5% (P = 0.31) at the end of a 12-month follow-up period in genotype B and C patients, respectively. These results remained similar when follow-up was extended to nearly 3 years. In conclusion, no significant differences in clinical characteristics and response to IFN-alpha between genotypes B and C were found, probably, because both types shared a common pre-C/C encoding region.

No abstract

Monitoring longitudinal nonadvanced fibrosis is a more common scenario in management of chronic hepatitis B (CHB), for which, however, current evaluation methods generally lack sufficient performance. We conducted a proof-of-concept study to evaluate the performance of quantitative fibrous collagen parameters (q-FP) in the assessment. Data sets from a prior CHB trial (NCT00962533) with mostly mild-to-moderate fibrosis participants were used for this study. 301 subjects with paired liver biopsies were consecutively included. Of these, 139 subjects were used to establish the test and the rest for internal validation. Fibrosis change between baseline and week 104 of treatment was blindly assessed with q-FP and was compared with Ishak fibrosis staging. There were 70% and 93% subjects with Ishak F0-2 at baseline and week 104, respectively. For the test of the subjects, q-FP and Ishak staging showed no difference in determining the incidence of fibrosis regression (68% vs 67%; difference = 0.7%, P = 1.00). Q-FP demonstrated that the regression was independently associated with the antiviral efficacy endpoint (OR 3.0, 95% CI 1.4-6.5, P = .005), but Ishak failed the detection (OR 0.6, 95% CI 0.3-1.3, P = .24). Moreover, q-FP directly revealed a higher fibrosis-resistance to antiviral treatment in virus genotypes C vs B and in males vs females. These results were confirmed in the validation subjects. Additionally, a functional model built on the test subjects showed an accuracy of 82% in stratifying fibrosis reversibility of the validation subjects. In conclusion, q-FP could have improved efficiency and accuracy in the longitudinal assessment of mild-to-moderate CHB fibrosis, indicating a potential alternative to current evaluation methodologies.

The response to interferon-alpha treatment of patients with chronic hepatitis B under the current protocol is not satisfactory. The aim of this study was to try an alternative approach to improve treatment outcome. Of 374 HBeAg-positive patients, 127 of them received 5 million units of interferon-alpha thrice weekly for 6 months and constituted the control group, while 247 in the study group received the same dosage but the duration of treatment was tailored. The study protocol provided for continuation of treatment if HBV DNA levels were continuously decreasing. The treatment ended when viral, antigenic and biochemical endpoints were reached or when HBV DNA levels were no longer decreasing. The median length of tailored treatment was 10 (range 6-24) months. The end-of-treatment response rates were 39.3% and 23.6% (P = 0.002), and after 12-month, follow-up, the sustained response rates were 40.5% and 28.3% (P = 0.013) in the study and control groups, respectively. Excluding the patients who dropped out, 228 and 115 completed a median of 40- and 44-month-long follow-up; the long-term response was thus 45.3% and 33.1% (P = 0.014) in the respective groups. Interferon-alpha treatment tailored in length demonstrated significantly increased efficacy in patients with chronic hepatitis B.