Genetic polymorphisms of IL-28B are associated with sustained virologic response in patients with chronic hepatitis C / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To explore the relationship between polymorphism in the interleukin (IL)-28B gene and sustained virologic response (SVR) in chronic hepatitis C (CHC) patients.</p><p><b>METHODS</b>A total of 220 patients with CHC were prospectively treated with pegylated-interferon (peg-IFN) in combination with ribavirin (RBV) for 48 weeks, and followed-up for an additional 24 weeks. All patients were genotyped for the rs8099917 polymorphism and correlations with antiviral efficacy were determined by statistical analysis.</p><p><b>RESULTS</b>One-hundred-and-eighty-two (82.7%) of the patients achieved end-of-treatment virological response (ETVR). Significantly more patients in the ETVR group carried the rs8099917 genotypes of TT (93.5%) and GT+GG (68.8%), compared to the patients who did not achieve ETVR (X2=23.287, P less than 0.01). In addition, the patients who achieved SVR also represented significantly higher rates of both genotypes (TT: 86.2% and GT+GG: 60.6%; X2=15.531, P less than 0.01). In the SVR group: TT vs. GT+GG: odds ratio (OR)=4.063, 95% confidence interval (CI): 1.972-8.369; X2=15.531, P less than 0.01. In the RP group: TT vs. GT+GG: OR=0.246, 95% CI: 0.119-0.507; X2=15.531, P less than 0.01).</p><p><b>CONCLUSION</b>The IL-28B rs8099917 genotype is closely related to antiviral response of patients with chronic hepatitis C. Compared to carriers of the GT and GG genotypes, carriers of the TT genotype have higher SVR rates and lower RP rates. The TT genotype may be an important predictor of antiviral efficacy.</p>

Dynamics of serum HBV DNA levels during the terminal phases of acute-on-chronic hepatitis B liver failure with different HBeAg status / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the dynamics and clinical significance of serum hepatitis B virus (HBV) DNA levels during the terminal phase of acute-on-chronic liver failure (ACLF) with different hepatitis B e antigen (HBeAg) status.</p><p><b>METHODS</b>One-hundred-and-seven patients with terminal ACLF were tested for HBeAg status by electrochemiluminescence immunoassay and serum HBV DNA levels by real-time PCR at three chronological time ranges, representing increasing severity of disease phases prior to death (day 0): 29-56 d, 15-28 d, and 0-14 d.</p><p><b>RESULTS</b>In the 37 HBeAg(+) patients, HBV DNA levels at above-mentioned phases were 6.10+/-1.63, 5.61+/-1.50, and 5.29+/-1.96 log10 copies/mL. In the 70 anti-HBe(+) patients, HBV DNA levels were 4.63+/-1.82, 5.81+/-1.78, and 4.93+/-1.73 log10 copies/mL. Phase to phase comparisons revealed that the HBV DNA level in the HBeAg(+) group was significantly higher than that in the anti-HBe(+) group at 29-56 d (P less than 0.05), and that 15-28 d and 0-14 d were not significantly different (P more than 0.05). Intragroup comparisons of phases revealed no significant differences in the HBeAg(+) group (P more than 0.05), but a significant difference between 15-28 d and 0-14 d (P less than 0.05) for the anti-HBe(+) group.</p><p><b>CONCLUSION</b>Serum levels of HBV DNA in patients with HBeAg positivity are higher than those in patients with anti-HBe positivity as the disease phase of ACLF nears fatality. Following the deterioration to liver failure, the HBV DNA load in HBeAg(+) patients remains stable while that in anti-HBe(+) patients decreases.</p>

Relationship between the genetic variation in interleukin 28B and response to antiviral therapy in patients with chronic hepatitis C / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Genetic variations at the interleukin 28B (IL-28B) locus are important in predicting outcome following therapy for chronic hepatitis C virus (HCV) infection. The aim of this research was to evaluate the role of IL-28B single nucleotide polymorphism (SNP) variations in Chinese patients undergoing pegylated interferon-α plus ribavirin (PEG-IFN-α/RBV) treatment.</p><p><b>METHODS</b>To determine the effect of IL-28B variation on the response to HCV therapy, these variants were genotyped in a cohort of 220 patients who were chronically infected with HCV and received combined PEG-IFN-α/RBV therapy.</p><p><b>RESULTS</b>The proportions of rs12979860 CC, CT, and TT genotypes were 71.4%, 25.0%, and 3.6% respectively, in the sustained virological response (SVR) group; 15.8%, 60.5%, and 23.7% respectively, in the null virological response (NVR) group; and 38.1%, 52.4%, and 9.5% respectively, in the relapse (Rel) group (P < 0.05). Logistic regression analysis showed that, compared to those having the CC genotype, CT heterozygotes had an increased risk of NVR and Rel (OR = 10.95, 95%CI = 4.12-29.11, P = 1.5×10(-7) and OR = 3.93, 95%CI = 1.86-8.32, P = 2.1×10(-4) respectively). The RNA quantification assay showed that patients with genotype CC exhibited much higher levels of IL-28 expression than those with genotype CT or TT (P < 0.001).</p><p><b>CONCLUSIONS</b>The IL-28B SNP rs12979860 genotype was related to the effectiveness of HCV therapy: patients with the CC rs12979860 genotype had higher rates of SVR than those with the CT or TT genotype, and the CC genotype revealed a significantly higher level of IL-28 mRNA expression.</p>

Genetic variation of IL-28B is associated with treatment response of patients with chronic hepatitis C / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To explore the effect of IL-28B variation on the response of patients with chronic hepatitis C virus (HCV) infection to therapy.</p><p><b>METHODS</b>A total of 220 patients with chronic hepatitis C (CHC) were prospectively treated with pegilated interferon (peg-IFN) in combination with ribavirin (RBV) for 48 weeks. After completing the therapy, the patients were followed-up for 24 weeks and the therapeutic effectiveness was evaluated. The rs8099917 was identified from each cohort. The IL28B genotype was compared in hepatitis C patients to assess the effect of single nucleotide polymorphism (SNP) on different treatment response.</p><p><b>RESULT</b>The proportion of the rs8099917 TT, TG, and GG genotypes was 71.4%, 25.0%, and 3.6% in sustained viral response (SVR) group; 15.8%, 60.5%, 23.7% in null response (NR) group; 38.1%, 52.3%, 9.6% in relapse (RP) group. There was a statistically significant difference in the genotype among SVR, NR and RP groups (P < 0.001, Chi-square test). NR vs. SVR (TG vs. TT: OR = 7.67, 95% CI: 2.91-20.56, P < 0.001). RP vs. SVR (TG vs. TT: OR = 3.10, 95% CI: 1.14-6.36, P < 0.01).</p><p><b>CONCLUSIONS</b>The genotypes of IL-28 B (rs8099917) is closely related to the effectiveness of peg-IFN-alpha/RBV therapy, and it is an important predictive factor before treatment in patients with chronic hepatitis C.</p>

Study on HBV antigens and IL-12 affecting T cell-mediated immunity in HBsAg carriers / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To investigate the effect of HBV antigens and pathological mechanism of chronic HBV infection by analyzing the cellular immune function of peripheral blood mononuclear cells (PBMCs) from HBsAg carriers.</p><p><b>METHODS</b>PBMCs were prepared from individuals with chronic asymptomatic HBV infection and cultured in the presence of different antigens and/ or cytokines. The levels of cytokines in culture supernatants were detected by ELISA method. The phenotype of the cells was detected by FACS.</p><p><b>RESULTS</b>The levels of IFN y secreted by PBMCs from HBsAg carriers were (48.3+/-19.8) pg/ml, significantly lower than that from healthy controls (t = 3.023, P less than 0.05); The IFN y produced by PBMCs from HBeAg positive patients due to HBsAg and HBcAg stimulation were (50.4+/-51.6) pg/ml and (63.2+/-36.9) pg/ml, significantly lower than that of HBeAg negative patients (t = 2.468 and 3.184, P less than 0.05, respectively). The IL-12p70 secreted by PBMCs from HBeAg positive patients was also significantly lower than that of HBeAg negative patients (P less than 0.05); Exogenous IL-12 promoted significantly PBMCs to secrete IFN y (P less than 0.01) and IL-12 combined with HBV antigens activated CD8+CD45RA+CCR7+ and CD8+CD45RA-CD62L+ cells. IL-12 secreted by PBMCs decreased in HBeAg positive patients, which may be the crucial reason of viral persistence in chronic HBV carriers. Exogenous IL-12 combined with specific HBV antigen could promote the central memory CD8+ T cells to produce IFN y.</p>

Programmed death-1 (PD-1) and PD-L1 expression during antiviral treatment of chronic hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study PD-1 and PD-L1 expressions during 24 weeks telbivudine antiviral treatment in patients with chronic hepatitis B (CHB) and to explore the relationship between PD-1 expression and HBeAg/HBeAb seroconversion.</p><p><b>METHODS</b>Ten CHB cases with HLA-A2 and HBeAg positive were treated with telbivudine 600 mg/d orally for 24 weeks. Fresh blood samples were collected at week 0, 12 and 24 after treatment. HBV-specific CD8+ T cells were expanded in vitro. Cell culture medium were collected for interferon gamma (IFNgamma) detection. Flow cytometry was used to detect the HLA-A type, PD-1, PD-L1 and HBV specific CD8+ T cells. The expressions of PD-1 and PD-L1, the counts of HBV-specific CD8+ T cells in circulating CD8+ lymphocytes, and IFNgamma concentration in culture medium were evaluated during antiviral treatment.</p><p><b>RESULTS</b>At week 0, 12 and 24 after telbivudine treatment, 7 of 10 patients were HBV DNA undetectable, 2 were HBeAg seroconversion and 2 were HBeAg lose but anti-HBe negative. The frequency of PD-1-positive PBMCs were 52.1%+/-17.0%, 39.1%+/-18.2% and 23.4%+/-16.3% (week 24 vs week 0, P < 0.01) respectively; PD-L1 positive PBMCs were 45.6%+/-15.4%, 34.6%+/-16.2% and 20.9%+/-9.5% respectively(week 24 vs week 0, P < 0.01; week 24 vs week 12, P < 0.05). The frequency of PD-1-positive CD8+ T cells were 76.2%+/-10.4%, 66.5%+/-15.4% and 49.5%+/-25.3% respectively (week 24 vs week 0, P < 0.01; week 12 vs week 0, P < 0.05; week 24 vs week 12, P < 0.05); HBV-specific CD8 cells were 1.3%+/-0.5%, 1.5%+/-1.0% and 2.2%+/-1.5%; IFNgamma levels in cell culture medium were (91.7+/-82.1) pg/ml, (99.4+/-93.5) pg/ml and (109.5+/-86.6) pg/ml. A remarkable decrease of PD-1 and PD-L1 expressions and increase of HBV-specific CD8+ T cells were observed in patients who had HBeAg/HBeAb seroconversion at week 24.</p><p><b>CONCLUSIONS</b>Direct suppression of HBV replication by telbivudine in CHB patients can decrease PD-1 and PD-L1 expressions and restore HBV-specific CD8+T cells. The relationship between the changes of PD-1 expression and HBeAg/HBeAb seroconversion during antiviral therapy in HBeAg-positive patients need to confirm by future study.</p>

The predictive value of ALT, HBeAg and HBV DNA levels at baseline and the degree of HBV suppression at week 12 adefovir dipivoxil treatment to the efficacy of it at week 52 in patients with HBeAg-positive chronic hepatitis B / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the predictive value of ALT, HBeAg and HBV DNA levels at baseline and HBV DNA levels at week 12 adefovir dipivoxil (ADV) treatment to the efficacy of it at week 52 in patients with HBeAg-positive chronic hepatitis B (CHB).</p><p><b>METHODS</b>Ninety-eight HBeAg-positive CHB patients with serum HBV DNA>or=1x10(6) copies/ml and ALT levels between 1.5 to 10 times of upper limits of normal (ULN) were enrolled in the study. Ten mg/d of ADV was administered for 52 weeks. Line serum samples were collected for measuring HBV DNA and HBV markers. The efficacy of the treatment at week 52 was evaluated in patients with different ALT, HBeAg and HBV DNA levels at baseline and HBV DNA levels at week 12 after treatment.</p><p><b>RESULTS</b>At week 52 of ADV treatment, the rates of HBV DNA<10(3) were 72.7%, 66.7% and 53.0% respectively in patients with ALT>5xULN, HBeAg<or=350 s/co and HBV DNA<or=10(8) copies/ml. Significant differences were found between them and patients with ALT<2xULN (38.0%, P<0.05), HBeAg>350 s/co (30.2%, P<0.01) and HBV DNA>10(8) copies/ml (34.4%, P<0.05) at baseline. HBeAg seroconversion rates were 42.2% and 7.5% (P<0.01) in patients with HBeAg titer<or=350 and >350 S/co at baseline. In patients with HBV DNA<10(3), 10(3)-10(5) and >10(5) copies/ml at week 12, the ratios of them with HBV DNA<10(3) less than 1000 copies/ml at week 52 were 82.6%, 57.1% and 17.5% and significant differences were found between these groups (P<0.05); HBeAg seroconversion rates were 52.2%, 25.7% and 5.0% (P<0.05); ALT normalization rates were 100%, 83% and 75%, significantly higher in patients with HBV DNA<10(3) copies/ml than those with HBV DNA>10(5) copies/ml (P<0.05) at week 12. HBV DNA and HBeAg seroconversion at week 52 correlated with HBV DNA levels at week 12 (r=0.6 and r=0.5 respectively, P<0.01).</p><p><b>CONCLUSIONS</b>In HBeAg-positive CHB patients treated with adefovir dipivoxil, HBV DNA levels at week 12 can be used to predict the efficacy at week 52. HBV DNA<10(3) copies/ml at week 12 predict a better treatment result at week 52.</p>

Specific T cell immune response in chronic hepatitis B patients treated with different doses of recombinant hepatitis B vaccine / 中华实验和临床病毒学杂志

<p><b>OBJECTIVE</b>To study the specific cellular immunoresponse of peripheral blood lymphocytes in the chronic hepatitis B patients treated with different doses of recombinant hepatitis B vaccine.</p><p><b>METHODS</b>Seventy-two chronic hepatitis B patients who did not use any anti-HBV drugs within 6 months were randomized into 3 groups (90 micrograms, 60 micrograms, and placebo) in a ratio of 1:1:1. The patients in different groups were treated with different doses of recombinant hepatitis B vaccine in combination with IFN alpha 1b 50 micrograms with 3 times a week for 24 weeks. All patients were followed up for 24 weeks (W24). HBV DNA, HBeAg and liver functions were detected at different time points, and the number of cells that secrete IFN-gamma were detected by ELISPOT.</p><p><b>RESULTS</b>There were no significant difference in ELISPOT positive ratio among the 3 groups on baseline detection. At W24, 12 cases, 12 cases, and 7 cases showed ELISPOT positive in the group of 90 micrograms, 60 micrograms, and placebo. The proportion of patients who were ELISPOT positive was higher in the groups treated with recombinant hepatitis B vaccine (including the dose of 90 micrograms and 60 micrograms) than that in the placebo group (P=0.0446). HBV DNA turned negative in 6/24 of the patients treated with recombinant hepatitis B vaccine (at both the doses of 90 micrograms and 60 micrograms), and HBeAg/Anti-HBe seroconversion or HBeAg became negative in 7/24 of them. In the placebo group, none of the patients showed undetectable HBV DNA, HBeAg/Anti-HBe seroconversion or HBeAg disappearance. At the 24W of follow up, in the patients who were ELISPOT positive, HBV DNA became undetectable in 4 of the patients treated with recombinant hepatitis B vaccine (at doses of 90 micrograms and 60 micrograms), and HBeAg/Anti-HBe seroconversion or HBeAg disappearance were found in 9 of the cases. In the placebo group, none of the cases showed undetectable HBV DNA, and only 1 case had HBeAg/Anti-HBe seroconversion.</p><p><b>CONCLUSION</b>The recombinant hepatitis B vaccine may increase the function of specific T lymphocytes in patients with chronic hepatitis B. There were no significant differences between the patients treated with the dose of 90 micrograms and 60 micrograms hepatitis B vaccine.</p>

The change of HBV nucleotide sequence during Adefovir dipivoxil treatment / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To study the change of HBV nucleotide sequence during Adefovir dipivoxil treatment.</p><p><b>METHODS</b>Serum samples were collected from 4 patients (numbers 228, 229, 230 and 233) with chronic hepatitis B (CHB) treated with PMEA. PCR amplification of full-length genomes, total genome clone, and sequencing and linkage of the HBV viruses were done with the serum samples collected before the therapy, and again on the 28th week, 52nd week and on the 92nd week of the therapy. Gene types and serum types were studied according to the HBV DNA sequence. The related biological information was analyzed, including the homogeneity and heterogeneity of the HBV DNA sequence before and during PMEA therapy, and variance of amino acids coded by HBV sequence.</p><p><b>RESULTS</b>The gene types and serum types of HBV of the 4 patients were determined. Patient 228 was gene type C/serum type adrq+. Patient 229 was complex gene type B and C/complex serum type adw2 and adrq+. Patients 230 and 233 were both serum type adw2. The homogeneity of total gene sequence was 97.5% - 99.8% in one group of patients and 90.6% - 100% between groups in variant patients. The base mutation quantity of 52W was significantly higher than that of 28W and 92W. There was a common site of hotspot congregating mutation that existed in the P region. The target of PMEA was located in the P region encoding reverse transcriptase, which was generally very conservative. Therefore the mutations in this region were very significant. This might affect the activity of reverse transcriptase, leading to resistance to PMEA.</p><p><b>CONCLUSION</b>We discovered some unusual aminophenol variations in the HBV genomes, which most probably are related to the HBV mutation that resulted in the developing resistance to PMEA.</p>

Efficacy and safety in chronic hepatitis B adolescent patients with lamivudine therapy / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To analysis the efficacy and safety of lamivudine (made in China) therapy for 52 weeks in adolescent patients with chronic hepatitis B (CHB).</p><p><b>METHODS</b>One hundred and five teenage CHB patients were treated with lamivudine 100 mg once daily for 52 weeks. Patients with elevated ALT at baseline were in group 1 and those with normal ALT were in group 2. The changes of HBV DNA, HBV seromarkers and ALT at the end of 12, 24 and 52 weeks after lamivudine therapy were compared with those at baseline. Adverse events were recorded and evaluated.</p><p><b>RESULTS</b>At the end of 52 weeks of lamivudine therapy, HBV DNA-ve, HBeAg loss and anti-HBe seroconversion were observed in 92.0%, 24.4% and 22.0% in group 1 patients and 76.1%, 14.2% and 14.2% in group 2 patients respectively. No significant differences were found between two groups. At 12, 24 and 52 weeks, normalization rates of ALT were 59.0%, 66.7% and 76.0%, normal ALT with undetectable HBV DNA were 44.9%, 64.1% and 70.7% at the same time. During 52 weeks lamivudine treatment 26 mild adverse events were observed in 18 patients.</p><p><b>CONCLUSION</b>Lamivudine can inhibit HBV replication rapidly and normalize ALT in majority adolescent CHB patients. HBeAg loss or seroconversion of anti-HBe was observed in some of these patients. All patients in this study were safety and well tolerated.</p>