恩替卡韦与阿德福韦酯对拉米夫定耐药慢性乙肝患者疗效比较

目的:比较恩替卡韦与阿德福韦酯对挽救拉米夫定耐药慢性乙型肝炎患者的临床疗效及安全性。方法:43例慢性乙型肝炎患者随机分为A、B组。比较治疗后丙氨酸氨基转移酶复常率、乙型肝炎病毒阴转率及拷贝数下降情况、HBe Ag阴转率及不良反应。结果:A组患者ALT复常率、HBV DNA拷贝数较低(P<0.05)。结论:恩替卡韦与拉米夫定联合挽救治疗拉米夫定耐药慢性乙型肝炎。

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.

Immunostaining of PD-1/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma

AIM: To investigate the expression of programmed death (PD)-1,PD ligand 1 (PD-L1) and PD-L2 in liver tissues in the context of chronic hepatitis and hepatocellular carcinoma (HCC).METHODS: Liver biopsies and HCC specimens from patients were collected and histologically examined.The expression of PD-1,PD-L1,and PD-L2 in biopsy specimens of chronic hepatitis and HCC specimens was evaluated by immunohistochemical staining.The association between the expression level of PD-1,PD-L1,and PD-L2 and clinical and pathological variables was analyzed statistically.RESULTS: Expression of PD-1 was found in liverinfiltrating lymphocytes.In contrast,PD-L1 and PD-L2 were expressed in non-parenchyma liver cells and tumor cells.The expression of PD-L1 was significantly correlated with hepatitis B virus infection (1.42 ± 1.165 vs 0.50 ± 0.756,P = 0.047) and with the stage of HCC (7.50 ± 2.121 vs 1.75 ± 1.500 vs 3.00 ± 0.001,P = 0.018).PD-1 and PD-Ls were significantly up-regulated in HCC specimens (1.40 ± 1.536 vs 5.71 ± 4.051,P = 0.000;1.05 ± 1.099 vs 4.29 ± 3.885,P = 0.004;1.80 ± 1.473 vs 3.81 ± 3.400,P = 0.020).CONCLUSION: PD-L1 may contribute to negative regulation of the immune response in chronic hepatitis B.PD-1 and PD-Ls may play a role in immune evasion of tumors.

Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B

AIM： To study the relationship between hepatitis B virus （HBV） DNA levels and liver histology in patients with chronic hepatitis B （CHB） and to determine the prevalence and characteristics of hepatitis B e antigen （HBeAg） negative patients.METHODS： A total of 213 patients with CHB were studied, and serum HBV DNA levels were measured by the COBAS Amplicor HBV Monitor test. All patients were divided into two groups according to the HBeAg status.The correlation between serum HBV DNA levels and liver damage （liver histology and biochemistry） was explored.RESULTS： Of the 213 patients with serum HBV DNA levels higher than 10^5 copies/mL, 178 （83.6%） were HBeAg positive, 35 （16.4%） were HBeAg negative. The serum HBV DNA levels were not correlated to the age,history of CHB, histological grade and stage of liver disease in either HBeAg negative or HBeAg positive patients. There was no correlation between serum levels of HBV DNA and alanine aminotransferanse （ALT）,aspartate aminotrans-ferase （AST） in HBeAg positive patients. In HBeAg negative patients, there was no correlation between serum levels of HBV DNA and AST,while serum DNA levels correlated with ALT （r = 0.351, P = 0.042）. The grade （G） of liver disease correlated with ALT and AST （P 〈 0.05, r = 0.205, 0.327 respectively）in HBeAg positive patients. In HBeAg negative patients,correlations were shown between ALT, AST and the G （P 〈 0.01, and r = 0.862, 0.802 respectively）. HBeAg negative patients were older （35 ± 9 years vs 30 ±9 years, P 〈 0.05 ） and had a longer history of HBV infection （8 ± 4 years vs 6 ± 4 years, P 〈 0.05） and a lower HBV DNA level than HBeAg positive patients （8.4± 1.7 Log HBV DNA vs 9.8 ± 1.3 Log HBV DNA, P 〈0.001）. There were no significant differences in sex ratio,ALT and AST levels and liver histology between the two groups.CONCLUSION： Serum HBV DNA level is not correlated to histological grade or stage of liver disease in CHB patients with HBV DNA more than 10^5 copies/mL.Compared to HBeAg positive patients, HBeAg negative patients are older and have a lower HBV DNA level and a longer HBV infection history. There is no significant difference in sex ratio, ALT and AST levels and liver histology between the two groups.

Future prospectives for the management of chronic hepatitis B

Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately a million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. The amount of viral replication reflected in the viral load （HBV-DNA） plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory （interferons） and antiviral suppressants （nucleoside and nucleotide analogues） all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the cross-resistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion： chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.

A combination treatment of entecavir and early-phase corticosteroid in severe exacerbation of chronic hepatitis B

Of patients with severe exacerbation of chronic hepatitis B accompanied by jaundice and coagulopathy,20%-30%have a fatal outcome.In this report,we describe 2 cases of severe exacerbation of chronic hepatitis B with jaundice and coagulopathy who were successfully treated with a combination of entecavir and corticosteroid.In both cases,rapid reductions in serum hepatitis B virus(HBV)-DNA levels were observed,and corticosteroid was stopped after serum HBV-DNA levels became undetectable.Entecavir treatment was continued.Generally,entecavir treatment reduced serum HBV-DNA levels rapidly,although the improvement in liver function was delayed by a few weeks.During this time lag,liver cell injury continued and the disease progressed.Corticosteroid suppressed the excessive host immune response and was useful for stopping progressive deterioration.A combination of entecavir and early-phase corticosteroid may be a useful treatment in severe exacerbation of chronic hepatitis B.

Long-term alpha interferon and lamivudine combination therapy in non-responder patients with anti-HBe-positive chronic hepatitis B:Results of an open,controlled trial

AIM: To investigate the safety and efficacy of long-term combination therapy with alpha interferon and lamivudine in non-responsive patients with anti-HBe-positive chronic hepatitis B.METHODS: 34 patients received combination treatment (1 month lamivudine, 12 month lamivudine+interferon, 6month lamivudine), 24 received lamivudine (12 months),24 received interferon (12 months). Interferon was administered at 6 MU tiw and lamivudine at 100 mg orally once daily. Patients were followed up for 6 months after treatment.RESULTS: At the end of treatment, HBV DNA negativity rates were 88 % with lamivudine+interferon, 99 % with lamivudine and 55 % with interferon, (P=0.004, combination therapy vs. interferon, and P=0.001 lamivudine vs.interferon), and serum transaminase normalization rates were 84 %, 91% and 53 % (P=0.01 combination therapy vs. interferon, and P=0.012 lamivudine vs. interferon). Six months later, HBV DNA negativity rates were 44 % with lamivudine+interferon, 33 % with lamivudine and 25 % with interferon, and serum transaminase normalization rates were 61%, 42 % and 45 %, respectively, without statistical significance. No YMDD variants were observed with lamivudine+interferon (vs. 12 % with lamivudine). The combination therapy appeared to be safe. CONCLUSION: Although viral clearance and transaminase normalization are slower with long-term lamivudine+interferon than that with lamivudine alone, the combination regimen seems to provide more lasting benefits and to protect against the appearance of YMDD variants. Studies with other regimens regarding sequence and duration are needed.

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.

Mechanism of T cell hyporesponsiveness to HBcAg is associated with regulatory T cells in chronic hepatitis B

AIM： To study the mechanisms of hyporesponsiveness of HBV-specific CD4^＋ T cells by testing TH1 and TH2 commitment and regulatory T cells. METHODS： Nine patients with chronic hepatitis B were enrolled. Peripheral blood mononuclear cells were stimulated with HBcAg or HBsAg to evaluate their potential to commit to TH1 and TH2 differentiation. HBcAg-specific activity of regulatory T cells was evaluated by staining with antibodies to CD4, CD25, CTLA-4 and interleukin-10. The role of regulatory T cells was further assessed by treatment with anti-interleukin-10 antibody and depletion of CD4^＋CD25^＋ cells. RESULTS： Level of mRNAs for T-bet, IL-12R β2 and IL-4 was significantly lower in the patients than in healthy subjects with HBcAg stimulation. Although populations of CD4^＋CD25^highCTLA-4^＋ T cells were not different between the patients and healthy subjects, IL-10 secreting cells were found in CD4^＋ cells and CD4^＋CD25^＋ cells in the patients in response to HBcAg, and they were not found in cells which were stimulated with HBsAg. Addition of anti-IL-10 antibody recovered the amount of HBcAgspecific TH1 antibody compared with control antibody （P 〈 0.01, 0.34% ± 0.12% vs 0.15% ± 0.04%）. Deletion of CD4^＋CD25^＋ T cells increased the amount of HBcAgspecific TH1 antibody when compared with lymphoo/tes reconstituted using regulatory T cells （P 〈 0.01, 0.03% ± 0.02% vs 0.18% ± 0.05%）.CONCLUSION： The results indicate that the mechanism of T cell hyporesponsiveness to HBcAg includes activation of HBcAg-induced regulatory T cells in contrast to an increase in TH2-committed cells in response to HBsAg.

Safety of lamivudine treatment for chronic hepatitis B in early pregnancy

AIM:To evaluate the safety of lamivudine(LAM) treatment for chronic hepatitis B in early pregnancy.METHODS:A total of 92 pregnant women who received LAM treatment either before pregnancy or in early pregnancy were enrolled in this study.All of the pregnant women volunteered to take lamivudine during pregnancy and were not co-infected with hepatitis C virus,human immunodeficiency virus,cytomegalovirus,or other viruses.All infants received passiveactive immunoprophylaxis with 200 IU hepatitis B immunoglobulin and three doses of 10 μg hepatitis B vaccines(0-1-6 mo) according to the guidelines for the prevention and treatment of chronic hepatitis B.Adverse events were observed throughout the entire pregnancy and perinatal period,and the effectiveness of lamivudine treatment for blocking mother-to-infant transmission of hepatitis B virus(HBV) was evaluated.All adverse events in mothers and infants during pregnancy and the perinatal period and the HBV motherto-infant transmission blocking rate were compared with the literature.RESULTS:Among the 92 pregnant women,spontaneous abortions occurred in 11 cases,while 3 mothers had a second pregnancy after the initial abortion;72 mothers delivered 73 live infants,of whom 68 infants were followed up for no less than 6 mo,and 12 mothers were still pregnant.During pregnancy,the main maternal adverse events were vaginitis(12/72,16.7%),spontaneous abortion(11/95,11.6%),and gestational diabetes(6/72,8.3%);only one case had 1-2 degree elevation of the creatine kinase level(195 U/L).During the perinatal period,the main maternal adverse events were premature rupture of the membranes(8/72,11.1%),preterm delivery(5/72,6.9%),and meconium staining of the amniotic fluid(4/72,5.6%).In addition,2 infants were found to have congenital abnormalities;1 had a scalp hemangioma that did not change in size until 7 mo,and the other had early cerebral palsy,but with rehabilitation training,the infant's motor functions became totally normal at 2 years of age.The incidence of adverse events among the mothers or abnormalities in the infants was not higher than that of normal mothers or HBV-infected mothers who did not receive lamivudine treatment.In only 2 cases,mother-to-infant transmission blocking failed;the blocking rate was 97.1%(66/68),which was higher than has been previously reported.CONCLUSION:Lamivudine treatment is safe for chronic HBV-infected pregnant mothers and their fetuses with a gestational age of less than 12 wk or throughout the entire pregnancy.

Reduced bone mineral density and altered bone turnover markers in patients with non-cirrhotic chronic hepatitis B or C infection

AIM: Previous studies suggest that loss of bone mineral density (BMD) frequently occurs in patients with chronic viral liver disease, presenting with histologically proven liver cirrhosis. However, little is known about the occurrence of bone disease in non-cirrhotic patients with chronic hepatitis B or C. Therefore, it was the aim of this study to evaluate this particular population for BMD and bone turnover markers. METHODS: Biochemical markers of bone turnover and BMD were measured in 43 consecutive patients with HCV (n = 30) or HBV (n = 13) infection without histological evidence for liver cirrhosis. Mean age was 49 years (range 26-77 years). BMD was measured by dual X-ray absorptiometry in the femoral neck (FN) and the lumbar spine (LS) region. In addition, bone metabolism markers were measured. RESULTS: BMD was lowered in 25 (58%) of the patients with chronic hepatitis B or C (FN; 0.76 (0.53-0.99); LS: 0.96 (0.62-1.23) g/cm2). Eight (32%) osteopenic patients were diagnosed with osteoporosis. Bone-specific alkaline phosphatase (P= 0.005) and intact parathyroid hormone (iPTH) (P = 0.001) were significantly elevated in the more advanced stages of fibrosis. Mean T-score value was lower in patients with chronic hepatitis C as compared to patients suffering from chronic hepatitis B; however, the difference was not statistically significant (P= 0.09). CONCLUSION: There was a significantly reduced BMD in non-cirrhotic patients with chronic hepatitis B or C infection. Alterations of bone metabolism already occurred in advanced liver fibrosis without cirrhosis. According to our results, these secondary effects of chronic viral hepatitis should be further investigated.

T cell immunopathogenesis and immunotherapeutic strategies for chronic hepatitis B virus infection

Hepatitis B is caused by the host immune response and T cells play a major role in the immunopathogenesis. More importantly,T cells not only destroy hepatocytes infected by hepatitis B virus(HBV),but also control HBV replication or eradicate HBV in a noncytolytic manner.Therefore,analysis of T cell immune response during acute and chronic HBV infection is important to develop a strategy for successful viral control,which could lead to immunotherapy for terminating persistent HBV infection.There have been many attempts at immunotherapy for chronic HBV infection,and some have shown promising results.High viral load has been shown to suppress antiviral immune responses and immunoinhibitory signals have been recently elucidated, therefore,viral suppression by nucleos(t)ide analogs, stimulation of antiviral immune response,and suppression of the immunoinhibitory signals must be combined to achieve desirable antiviral effects.

Association of polymorphisms of interleukin-18 gene promoter region with chronic hepatitis B in Chinese Han population

AIM: To investigate the polymorphisms of interleukin-18 (IL-18) gene promoters, and to disclose whether such polymorphisms are associated with susceptibility to chronic hepatitis B in Chinese Han population. METHODS: Using polymerase chain reaction with sequence specific primers (PCR-SSP) method, the single nucleotide polymorphisms (SNPs) of the promoter region of IL-18 gene at position -607 and -137 were detected in 231 patients with chronic hepatitis B and 300 normal controls. RESULTS: Allele C at position -607 in the promoter of IL-18 gene was detected in 48.7% of normal controls and 51.9% of patients, while allele A at position -607 was detected in 51.3% of normal controls and 48.1% of patients. The frequencies of -607CC, -607 CA and -607AA genotypes in normal controls were 22.0%, 53.3% and 24.7% respectively and in chronic hepatitis B patients were 26.8%, 50.2% and 23.0% respectively. Allele G at position -137 in the promoter of IL-18 gene was detected in 82.3% of normal controls and 88.5% of chronic hepatitis B patients, while allele C at position -137 was detected in 17.7% of normal controls and 11.5% of patients. The frequencies of -137GG, GC and CC genotype were 67.3%, 30.0% and 2.7% in normal controls respectively, while in chronic hepatitis B patients were 78.8%, 19.5% and 1.7% respectively. The frequency of-137GG genotype in chronic hepatitis B groups was significantly higher than that in normal controls (x2=8.55, P=0.003 <0.05), whereas the frequencies of -607C/-137C and -607A/-137C haplotypes in chronic hepatitis B groups were significantly lower than that in normal controls. The association between genotypes of IL-18 promoter region polymorphisms and HBV copies showed that the frequency of -607AA genotype in high HBV-DNA copies groups was lower than that in low HBV-DNA copies groups (x2=6.03, P=0.014 <0.05). CONCLUSION: The polymorphisms of the promoter region of IL-18 gene at position -607 and -137 are closely associated with susceptibility to chronic hepatitis B. The people with allele C at position -137 in the promoter of IL-18 gene may be protected against HBV infection; moreover AA genotype at position -607 may be closely linked to inhibit HBV-DNA replication. These findings give some new clues to the study of pathogenesis of chronic hepatitis B.

Treatment strategies using adefovir dipivoxil for individuals with lamivudine-resistant chronic hepatitis B

AIM:To investigate retrospectively the long-term efficacy of various treatment strategies using adefovir dipivoxil(adefovir) in patients with lamivudine-resistant chronic hepatitis B.METHODS:We included 154 consecutive patients in two treatment groups:the "add-on" group(n = 79),in which adefovir was added to ongoing lamivudine treatment due to lamivudine resistance,and the "switch/combination" group(n = 75),in which lamivudine was first switched to adefovir and then re-added later as needed.The "switch/combination" group was then divided into two subgroups depending on whether participants followed(group A,n = 30) or violated(group B,n = 45) a proposed treatment strategy that determined whether to add lamivudine based on the serum hepatitis B virus(HBV) DNA levels(< 60 IU/mL or not) after 6 mo of treatment(roadmap concept).RESULTS:The cumulative probability of virologic response(HBV DNA < 60 IU/mL) was higher in group A than in the "add-on" group and in group B(P < 0.001).In contrast,the cumulative probability of virologic breakthrough was lower in the "add-on" group than in group B(P = 0.002).Furthermore,the risk of virologic breakthrough in the multivariate analysis was significantly lower in the "add-on" group than in group A(hazard ratio = 0.096;95%CI,0.015-0.629;P = 0.015).CONCLUSION:The selective combination of adefovir with lamivudine based upon early treatment responses increased the odds of virologic breakthrough relative to the use of uniform combination therapy from the beginning of treatment.

Predictors of the outcomes of acute-on-chronic hepatitis B liver failure

AIM： To identify the risk factors in predicting the out- come of acute-on-chronic hepatitis B liver failure pa- tients. METHODS： We retrospectively divided 113 patients with acute-on-chronic liver failure-hepatitis B virus （ACLF-HBV） and without concurrent hepatitis C or D virus infection and hepatocellular carcinoma into two groups according to their outcomes after anti-HBV therapy. Their demographic, clinical, and biochemical data on the day of diagnosis and after the first week of treatment were analyzed using the Mann-Whitney U test, Fisher＇s exact test, and a multiple logistic regres- sion analysis. RESULTS： The study included 113 patients （87 men and 26 women） with a mean age of 49.84 years. Fifty- two patients survived, and 61 patients died. Liver failure （85.2%）, sepsis （34.4%）, and multiple organ failure （39.3%） were the main causes of death. Mul- tivariate analyses showed that Acute Physiology and Chronic Health Evaluation （APACHE） Ⅱ scores ≥ 12 [odds ratio （OR） = 7.160, 95% CI： 2.834-18.092, P 〈 0.001] and positive blood culture （OR = 13.520, 95% CI： 2.740-66.721, P = 0.001） on the day of diagnosis and model for end-stage liver disease （MELD） scores 28 （OR = 8.182, 95% CI： 1.884-35.527, P = 0.005） after the first week of treatment were independent predictors of mortality. CONCLUSION： APACHE II scores on the day of diag- nosis and MELD scores after the first week of anti-HBV therapy are feasible predictors of outcome in ACLF- HBV patients.

Viral and host causes of fatty liver in chronic hepatitis B

AIM: To investigate the viral and host causes of fatty liver in chronic hepatitis B patients and the role of fat deposits in liver damage.METHODS: A total of 164 patients (113 males and 51 females, average age 35±11.3 years, and range 10-62 years) with previously untreated chronic hepatitis B were included in the study. The patients were divided into two groups depending on the result of liver biopsy: group without steatosis (100 patients with ＜5% hepatosteatosis) and group with steatosis (64 patients with ＞5% hepatosteatosis). The groups were compared in terms of gender, body mass index (BMI), liver enzymes (ALT, AST, ALP, GGT), cholesterol, triglyceride, HBeAg, viral load, and histological findings. In the group with steatosis, the patients were subdivided depending on the degree of steatosis into mild group (45 patients with 5-24% steatosis), and severe group (19 patients with ＞25% steatosis). RESULTS: In the group of chronic hepatitis B with steatosis, the mean age, BMI, cholesterol, and triglyceride levels were significantly higher than those in the group without steatosis (P＜0.05). Steatosis was found in 53 (46.9%) of male patients and 11 (22%) of female patients (P＜0.05). No significant difference was found in the positivity of ALT, AST, ALP, GGT, HBeAg, viral load, histological activity index (HAI) and stage between the two groups (P＞0.05). In the group with severe steatosis, the BMI was significantly higher than that in the group with mild steatosis (P＜0.05). No significant difference was found in the other parameters between the groups (P＞0.05). CONCLUSION: Steatosis in chronic hepatitis B appears to be a result of metabolic factors of the host rather than the effect of viruses. Steatosis is unrelated to the HAI and degree of fibrosis, which are considered as the histological indicators of liver damage.

Serum soluble interleukin-2 receptor levels in patients with chronic hepatitis B virus infection and its relation with antiHBc

AIM： To investigate the relationship between serum soluble interleukin-2 receptor （sIL-2R） level and anti-HBc in patients with chronic hepatitis B virus （HBV） infection. METHODS： Sera from 100 patients with chronic HBV infection and 30 healthy controls were included in this study. The patients were divided into group A [HBsAg （＋）, HBeAg （＋） and anti-HBc （＋）, n = 50] and group B [HBsAg （＋）, HBeAg （＋） and anti-HBc （-）, n = 50]. sIL-2R levels were determined using ELISA. HBV DNA and alanine aminotransferase （ALT） were also detected. RESULTS： Serum sIL-2R levels were significantly higher in patients with chronic HBV infection than in healthy controls. Moreover, serum sIL-2R levels were significantly higher in patients with HBsAg （＋）, HBeAg （＋） and antiHBc （＋） （976.56±213.51×10^3 U/L） than in patients with HBsAg （＋）, HBeAg （＋） and anti-HBc （-） （393.41±189.54 ×10^3 U/L, P〈 0.01）. A significant relationship was found between serum sIL-2R and ALT levels （P〈 0.01） in patients with chronic HBV infection, but there was no correlation between sIL-2R and HBV DNA levels. The anti-HBc status was significantly related to the age of patients （P〈 0.01）. CONCLUSION： The high sIL-2R level is related to positive anti-HBc in chronic hepatitis B patients. Positive anti-HBc may be related to T-lymphocyte activation and negative anti-HBc may imply immune tolerance in these patients.

Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy

AIM:To evaluate the health-related quality of life (HRQOL) based on the Chinese version of SF-36 and Chronic Liver Disease Questionnaire (CLDQ) in subjects with chronic hepatitis B,liver cirrhosis,including patients with minimal hepatic encephalopathy (MHE). METHODS:The SF-36 and CLDQ were administered to 160 healthy volunteers,20 subjects with chronic hepatitis B and 106 patients with cirrhosis (33 cases exhibited MHE). HRQOL scores were compared among the different study groups. The SF-36 includes eight health concepts:physical functioning,role-physical,body pain,general health,vitality,social functioning,role-emotion,and mental health. Six domains of CLDQ were assessed:abdominal symptoms,fatigue,systemic symptoms,activity,emotional function and worry. RESULTS:Compared with healthy controls (96.9 ± 4.5,86.6 ± 18.4,90.1 ± 12.5,89.0 ± 5.7,87.5 ± 4.3,95.8 ± 7.1,88.5 ± 15.9,88.7 ± 5.2 in SF-36 and 6.7 ± 0.5,6.1 ± 0.6,6.3 ± 0.6,6.5 ± 0.5,6.3 ± 0.5,6.8 ± 0.4 in CLDQ),patients with chronic hepatitis B (86.3 ± 11.0,68.8 ± 21.3,78.9 ± 14.4,60.8 ± 10.5,70.8 ± 8.6,76.1 ± 12.6,50.0 ± 22.9,72.2 ± 10.6 and 5.5 ± 1.0,4.5 ± 1.0,5.2 ± 1.1,5.3 ± 0.9,4.8 ± 0.9,4.9 ± 1.0) and cirrhosis (52.8 ± 17.4,32.8 ± 27.9,61.6 ± 18.9,30.2 ± 18.3,47.9 ± 20.1,54.0 ± 19.2,28.9 ± 26.1,51.1 ± 17.8 and 4.7 ± 1.2,3.9 ± 1.2,4.7 ± 1.2,4.7 ± 1.3,4.7 ± 1.0,4.4 ± 1.1) had lower HRQOL on all scales of the SF-36 and CLDQ (P < 0.01 for all). Increasing severity of liver cirrhosis (based on the Child-Pugh score/presence or absence of MHE) was associated with a decrease in most components of SF-36 and CLDQ,especially SF-36.CONCLUSION:The Chinese version of SF-36 along with CLDQ is a valid and reliable method for testing MHE in patients with liver cirrhosis. Cirrhosis and MHE are associated with decreased HRQOL.

Clinical features of chronic hepatitis B patients with YMDD mutation after lamivudine therapy

Objective: To study the clinical features of chronic hepatitis B (CHB) patients with tyrosine-methionine-aspartateaspartate (YMDD) mutation after lamivudine therapy. Methods: This investigation was a retrospective study of 63 CHB patients with YMDD mutation during lamivudine therapy. Clinical data, including period and types of YMDD mutation; hepatitis B virus (HBV) DNA levels and alanine aminotransferase (ALT) levels before and after YMDD mutation were measured. YMDD mutation in the HBV DNA polymerase gene was determined using polymerase chain reaction (PCR) and direct sequencing. HBV DNA quantification was determined using real-time PCR. Relevant serum markers of HBV were measured. The follow-up period was 12 months after YMDD mutation. Results: YMDD mutation occurred 7～44 months (median, 21.5 months) after the start of lamivudine therapy. The majority of the cases (42/63, 66.6%) had YMDD mutants detected between 12 and 24 months. Four types of YMDD mutation were observed in this study, rtL180M/M204V mutation was the predominant type (26/63, 41.3%). A proportion of patients (16/63, 25.4%; 12/63, 19.1%) had higher HBV DNA levels and ALT levels (after mutation vs before mutation),respectively. Conclusion: The majority of patients with YMDD mutants had similar or lower HBV DNA levels and ALT levels compared with baseline values. This subset of patients might have benefited from the continued lamivudine therapy. The patients with increased ALT and HBV DNA levels (breakthrough hepatitis) should benefit from the addition of a newer nucleotide analogue (e.g. adefovir).

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.