替比夫定治疗慢性乙型肝炎的临床疗效分析

我国为乙型肝炎病毒感染的高发地区，目前在慢性乙肝的治疗方面已明确了抗病毒治疗的重要性，抗病毒治疗延缓了慢性乙型肝炎患者病情进展及减少了肝癌的发生。本院在应用替比夫定治疗慢性乙型肝炎方面疗效满意。

重组干扰素治疗慢性乙型肝炎38例

乙型肝炎病程迁延；易转为慢性，常发展为肝硬化，肝衰竭，甚至肝癌。目前认为乙肝病毒不断复制和机体抗病毒的免疫应答为引起肝损害的原因。采用有效的抗病毒治疗，清除病毒感染，终止免疫应答，对患者病情的稳定具有很大作用。干扰素是具有抗病毒和免疫调节作用的生物活性物质，在治疗慢性乙型肝炎方面取得了较好的疗效。现将我科采用重组干扰素A—1b（赛诺金）治疗慢性乙肝的疗效观察报告如下。

Role of Antivirus Therapy in Treatment of Hepatocellular Carcinoma with Chronic Hepatitis B Infection

Objective： To observe the recurrence and prognosis of hepatocellular carcinoma （HCC） patients coexisting with chronic hepatitis B infection with active virus replication after receiving antivirus therapy using lamivudine and thymosin α1 （Tα1） postoperatively. Methods： From Jan. 2000 to Dec. 2003, 70 patients with HCC coexisting chronic hepatitis B infection with active virus replication were prospectively divided into two groups： control group （n=35） received hepatectomy only; treatment group （n=35） received hepatectomy and lamivudine plus Tα1 therapy postoperatively. The suppression of HBV-DNA, HBeAg seroconverted rate, tumor recurrent rate and the median survival for the two groups were observed and calculated. Results： In treatment group and control group, the 2-year HBV-DNA suppression rate was 100% vs. 4% （P=0.0000）; HBeAg seroconverted rate was 73.0% vs. 7.5% （P〈0.05）; the recurrent rate was 10.0 vs 6.5 months （P=0.0032）; the median survival time was 12.5 vs. 6.0 months （P=0.0023）, respectively. Conclusion： Antivirus therapy using lamivudine and Tα1 postoperatively may suppress the HBV reaction, delay the recurrent time and prolong the survival for HCC patients coexisting chronic HBV infection with active virus replication.

Interferon-α response in chronic hepatitis B-transfected HepG2.2.15 cells is partially restored by lamivudine treatment

AIM：To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBV- transfected HepG2.2.15 cells. METHODS： HepG2.2.15 and HepG2 cells were stimulated with various concentrations of IFN-α 2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes （ISGs）. In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. RESULTS： Two genes （MxA, CigS） with completely abolished and 4 genes （IFITM1, -2, -3, and 6-16） with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes （IFITM1, 6-16）, the response to IFN-α could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Statl activation and ISGF3 formation after stimulation with IFN-α in HepG2.2.15 compared to HepG2 cells. CONCLUSION： These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expressionby reducing HBV gene expression and replication.

Therapeutic effect of autologous dendritic cell vaccine on patients with chronic hepatitis B: A clinical study

AIM: To investigate the therapeutic effect of autologous HBsAg-loaded dendritic cells (DCs) on patients with chronic hepatitis B. METHODS: Monocytes were isolated from fresh peripheral blood of 19 chronic HBV-infected patients by Ficoil-Hypaque density gradient centrifugation and cultured by plastic-adherence methods. DCs were induced and proliferated in the culture medium with recombinant human granulocyte-macrophage-colony- stimulating factor (rhGM-CSF) and human interleukin-4 (rhIL-4). DCs pulsed with HBsAg for twelve hours were injected into patients subcutaneously twice at intervals of two weeks. Two patients received 100 mg oral lamivudine daily for 12 mo at the same time. HBV-DNA and viral markers in sera of patients were tested every two months. RESULTS: By the end of 2003, 11 of 19 (57.9%) patients had a clinical response to DC-treatment. HBeAg of 10 (52.6%) patients became negative, and the copies of HBV-DNA decreased 101.77±2.39 averagely (t = 3.13, P<0.01). Two cases co-treated with DCs and lamivudine had a complete clinical response. There were no significant differences in the efficient rate between the cases with ALT level lower than 2xULN and those with ALT level higher than 2xULN before treatment (X2 = 0.0026). CONCLUSION: Autologous DC-vaccine induced in vitro can effectively suppress HBV replication, reduce the virus load in sera, eliminate HBeAg and promote HBeAg/anti-HBe transformation. Not only the patients with high serum ALT levels but also those with normal ALT levels can respond to DC vaccine treatment, and the treatment combining DCs with lamivudine can eliminate viruses more effectively.

He Jie Tang in the treatment of chronic hepatitis B patients

AIM： To explore the effect of He .lie Tang （decoction for medication） on serum levels of T lymphocyte subsets, NK cell activity and cytokines in chronic hepatitis B patients. METHODS： Eighty-five patients with chronic hepatitis B were divided randomly into two groups. Fifty patients in group I were treated with He .lie Tang （HIT） and 35 patients in group II were treated with combined medication. The levels of T-lymphocyte subsets （CD^3＋, CD^4＋, CD^8＋）, NK cell activity, cytokines （TNF-α, IL-8, sIL-2R） were observed before and after the treatment. Another 20 normal persons served as group 3. RESULTS： The level of CD^4＋ cells and NK cell activity were lower, whereas the level of CD^8＋ cells in patients was higher than that in normal persons （t = 2.685, 3.172, and 2.754 respectively; P〈0.01）. The levels of TNF-α, IL-8, and sIL-2R in chronic hepatitis B patients were higher than those in normal persons （t = 3.526, 3.170, and 2.876 respectively; P〈0.01）. After 6 months of treatment, ALT, AST, and TB levels in the two groups were obviously decreased （t = 3.421, 3.106, and 2.857 respectively; P〈0.01）. The level of CD^4＋ cells and NK cell activity were increased whereas the level of CD^8＋ cells decreased （t = 2.179, 2.423, and 2.677 respectively; P〈0.05） in group I. The levels of TNF-α, IL-8, and sIL- 2R in group I were decreased significantly after the treatment （t = 2.611, 2.275, and 2.480 respectively; P〈0.05） but had no significant difference in groupII after the treatment （t = 1.906, 1.833, and 2.029 respectively; P〉0.05）. The total effective rate had no significant difference between the two groups （X^2 = 2.882, P〉0.05） but the markedly effective rate was significantly different between the two groups （X^2 = 5.340, P〈0.05）. CONCLUSION： HIT is effective in treating chronic hepatitis B. HIT seems to exert its effect by improving the cellular immune function and decreasing inflammatory cytokines in chronic hepatitis B patients. The function of HIT in protecting liver function in the process of eliminating virus needs to be further studied.

Antiviral efficacy of adefovir dipivoxil versus lamivudine in patients with chronic hepatitis B sequentially treated with lamivudine and adefovir due to lamivudine resistance

AIM： To compare the antiviral efficacy of adefovir （ADV） in lamivudine （LMV）-resistant patients with LMV treatment in nucleoside-naive patients, using serum samples collected sequentially during the course of treatment progressing from LMV to ADV.METHODS： Forty-four patients with chronic hepatitis B （CHB） were included. The patients were initially treated with LMV and then switched to ADV when LMV resistance developed. Antiviral efficacy was assessed by measuring the following： reduction in serum HBV DNA from baseline, HBV DNA negative conversion （defined as HBV DNA being undectable by the hybridization assay）, and HBV DNA response （either HBV DNA level ≤ 10^s copies/mL or a ≥ 2 log10 reduction from baseline HBV DNA level）.RESULTS： After two and six months of treatment, HBV DNA reduction was greater with LMV compared to ADV treatment （P = 0.021）. HBV DNA negative conversion rates were 64% and 27% after one month of LMV and ADV treatment respectively （P = 0.001）. Similarly, HBV DNA response rates were 74% and 51% after two months of LMV and ADV treatment respectively （P = 0.026）. The time taken to HBV DNA negative conversion and to HBV DNA response were both delayed in ADV treatment compared with LMV.CONCLUSION： The antiviral efficacy of ADV in LMV-resistant patients is slower and less potent than that with LMV in nucleoside-naive patients during the early course of treatment.

Construction and characterization of a cDNA library from human liver tissue with chronic hepatitis B

Objective: To construct a cDNA library from human liver tissue with chronic hepatitis B and check its quality for investigating the expression level of liver tissue infected by hepatitis B virus. This will then be used to find the relevant genes and interesting proteins associated with the development of hepatitis B. Methods: The total RNA from liver tissue with chronic hepa- titis B was extracted and the mRNA was purified using TRIZOL method. Switching mechanism at 5′ end of the RNA transcript (SMART) technique and CDS III/3′ primer were used for first-strand cDNA synthesis. Long distance polymerase chain reaction (LD PCR) was then used to synthesize the double-strand cDNA that was then digested by Sfi I and fractionated by CHROMA SPIN-400 column. The longer than 0.4 kb cDNAs were collected and ligated to λTriplEx2 vector. Then λ phage packaging reaction and library amplification were performed. The qualities of both unamplified and amplified cDNA libraries were strictly checked by conventional titer determination. Fourteen plaques were randomly picked and tested using PCR with universal primers derived from the sequence flanking the vector. Results: The titers of unamplifed and amplified libraries were 1.94×106 pfu/ml and 1.49×109 pfu/ml respectively. The percentages of recombinants from both libraries were 98.15% in unamplified library and 98.76% in amplified library. The lengths of the inserts were 1.23 kb in average, 1?2 kb in 64.29%, and 0.5?1.0 kb in 35.71%. Conclusion: A high quality cDNA library from human liver tissue with chronic hepatitis B was successfully constructed.

What MELD score mandates use of entecavir for ACLF-HBV HBeAg-negative patients?

AIM: To investigate optimal timing for therapeutic efficacy of entecavir for acute-on-chronic hepatitis B liver failure (ACLF-HBV) in hepatitis B e antigen (HBeAg)negative patients. METHODS: A total of 109 inpatients with ACLF-HBV were recruited from the Department of Infectious Diseases of the Third Affiliated Hospital, Sun Yat-sen University from October 2007 to October 2010. Entecavir 0.5 mg/d was added to each patient's comprehensive therapeutic regimen. Patients were divided into threegroups according to model for end-stage liver disease (MELD) score: high (≥ 30, 20 males and 4 females, mean age 47.8 ± 13.5 years); intermediate (22-30, 49 males and 5 females, 45.9 ± 12.4 years); and low (≤ 22, 28 males and 3 females, 43.4 ± 9.4 years). Statistical analysis were performed using SPSS 11.0 software. Data with normal distribution were expressed as mean ± SD and comparisons were made with Student's t tests. A value of P < 0.05 was considered statistically significant. Viral loads were related exponentially and logarithmic data were used for analysis. RESULTS: For 24 patients with MELD score ≥ 30, treatment lasted 17.2 ± 16.5 d. Scores before and after treatment were significantly different (35.97 ± 4.87 and 40.48 ± 8.17, respectively, t = -2.762, P = 0.011); HBV DNA load was reduced (4.882 ± 1.847 copies log10/mL to 3.685 ± 1.436 copies log10/mL); and mortality rate was 95.83% (23/24). Of 54 patients with scores of 22-30, treatment lasted for 54.0 ± 43.2 d; scores before and after treatment were 25.87 ± 2.33 and 25.82 ± 13.92, respectively (t = -0.030, P = 0.976); HBV DNA load decreased from 6.308 ± 1.607 to 3.473 ± 2.097 copies log10/mL; and mortality was 51.85% (28/54). Of 31 patients with scores ≤ 22, treatment lasted for 66.1 ± 41.9 d; scores before and after treatment were 18.88 ± 2.44 and 12.39 ± 7.80, respectively, (t = 4.860, P = 0.000); HBV DNA load decreased from 5.841 ± 1.734 to 2.657 ± 1.154 copies log10/mL; and mortality was 3.23% (1/31). CONCLUSION: For HBeAg-negative patients with ACLF-HBV, when entecavir was added to comprehensive therapy, a MELD score ≥ 30 predicted very poor prognosis due to fatal liver failure.

Influence of HLA-DRB1 alleles and HBV genotypes on interferon-α therapy for chronic hepatitis B

AIM. To investigate the influence of HLA-DRB1 alleles and HBV genotypes on inberferon-α therapy for chronic hepatitis B. METHODS： HLA-DRBI＊03, ＊07, ＊09,＊12, ＊15 alleles were determined using polymerase chain reaction/sequence specific primer （PCR/SSP） technique in 126 patients with chronic hepatitis B and 76 normal control subjects in Shandong Province, and HBV genotypes were determined by nested-PCR analysis using type-specific primers in 126 patients. RESULTS： The positivity of HLA-DRB1＊07 allele in chronic hepatitis B group was significantly higher than that in normal control group （X^2 = 6.33, P〈0.025, RR = 2.37）. Among the 126 patients, genotype B was found in 38 （30.2%）, genotype C in 69 （54.8%）, and mixed genotype （B＋C） in 19 （15.0%）, genotypes D-F were not found. Among the 46 DRB1＊07（＋） patients, 7 were responders and 39 were non-responders among them （X^2 = 6.71, P〈0.05）. The positivity of HLADRB1＊07 and prevalence of HBV genotype C were significantly higher in non-responders than in responders. CONCLUSION： High positivities of HLA-DRB1 ＊07 allele and HBV genotype C are closely associated with the lower response to interferon-α therapy for chronic hepatitis B.

Hepatitis B and pregnancy: An update review article

Chronic hepatitis B, as a global health problem, is a disease that begins in the prenatal period and its complications gradually become clear later in life. About 5% of women worldwide are carriers of chronic hepatitis B virus(HBV). The most common method of transmission of HBV around the world is from mother to infant. This article aims to review the unique challenges of hepatitis B in pregnancy. Data for this review were collected from our previous studiesand experiences plus various data banks, such as Pub Med, EMBASE, ISI Web of science, Scopus, Google Scholar and Iranian databases. A comprehensive search was performed using the combinations of the keywords to review relevant literature and higher education journals. All published data up to February 2014 have been included in this review. This article addresses several interesting aspects. First, hepatitis B in pregnancy can vary regarding prevalence, virus behavior, prenatal transmission and outcome of the pregnancy. Second, the women of reproductive age with chronic HBV remain a major source for continued spread of the virus. Finally, pregnant women need screening in prenatal care to enable early intervention when necessary.

Inter-observer variability in histopathological assessment of liver biopsies taken in a pediatric open label therapeutic program for chronic HBV infection treatment

AIM： To our knowledge, the inter-observer variability of the liver biopsy findings in HBV-infected children have not been studied as yet. Hence, we aimed to compare different pathologist＇s assessment of grading and staging in liver biopsies obtained from children prior to interferon treatment. METHODS： We collected 920 biopsies from 11 medical centers. The biopsies were independently reviewed by 6 pathologists from academic centers who assessed Batts-Ludwig score for grading and staging. Satisfactory agreement among observers was defined as at least 60% of observers having the same opinion. Satisfactory dispersion between maximal and minimal score for the same biopsy specimen was defined as a maximum 1 point. RESULTS： Satisfactory inter-observer agreement for grading was obtained in 51.6% and for staging in 75.7% of biopsies. Satisfactory dispersion for grading scores was observed in 44.5% and for staging in 72.7% of cases. CONCLUSION： Our study demonstrates that： （1） pathologists differ in their assessment of grading and staging of liver biopsies; （2） inter-observer variability for staging is lower than that for grading; and （3） regardless of the inter-observer variability of assessments, the majority of children with chronic HBV infection have mild to moderate inflammation and mild to moderate fibrosis.

慢性乙肝的中医辨证治疗

我国是乙型肝炎高发地区，据统计有7．5亿人曾感染过HBV（占全国人口57．6％），其中慢性：HBV感染者约7．2亿，慢性感染者中75％-25％最终也将死于与HBV相关的肝病，如肝硬化和肝癌，我国每年约30万例因乙型肝炎相关死亡，占传染病死亡第一位。自古以来，中国传统医学在治疗慢性乙型肝炎方面积累了丰富的经验，直到目前为止，中医药独特的辨证方法在慢性乙肝的治疗方面仍处於主导地位。