国产基因工程α1干扰素治疗慢性乙型肝炎疗效观察

国产基因工程α＿１干扰素治疗慢性乙型肝炎疗效观察南京市传染病医院（２１０００８）范积华，施继元，刘宣俊，石世善，王永清，谢美容，陈仁慈，林丽我院１９９１年８月至１１月应用上海生物制品研究所提供的国产基因工程α１干扰素（商品名干扰灵，批号９１０３）治疗...

贾建伟教授从正气理论调节慢性乙型肝炎患者免疫状态验案

据世界卫生组织报道,全世界约20亿人感染乙型肝炎病毒(HBV),其中2.4亿人为慢性HBV感染者[1]。HBV和宿主免疫系统是驱动疾病进展的两大因素,其中机体免疫功能紊乱是导致HBV感染慢性化的一个重要原因[2]。抗病毒是治疗慢性乙型肝炎(CHB)的关键,免疫调节有望成为未来更重要的治疗手段[3]。

茵陈蒿汤治疗乙型病毒性肝炎高胆红素血症疗效观察

目的:观察茵陈蒿汤治疗乙型病毒性肝炎高胆红素血症的疗效。方法:将128例患者随机平均分为两组,对照组64例,采用甘草酸二铵注射液和葡醛内酯注射液静滴,同时口服联苯双酯滴丸保肝降酶。治疗组64例,在用同等剂量上述药物保肝治疗的基础上服用茵陈蒿汤,疗程21 d,对比两组患者的症状、体征和肝功能变化情况。结果:治疗组总有效率95.31%,对照组总有效率85.94%。治疗组疗效优于对照组,(P(0.01,)。治疗组治疗后肝功能较治疗前明显改善(P(0.01)且谷丙转氨酶(ALT)、总胆红素(TBIL)的下降优于对照组(P<0.05).结论:茵陈蒿汤能有效改善乙型病毒性肝炎高胆红素血症。

核苷（酸）类似药物抗乙型肝炎病毒治疗的不良反应及处理

慢性乙型肝类患者口服核苷（酸）类抗病毒药只能抑制乙型肝类病毒复制来实现阻止和延缓疾病的进展，减少肝硬化、肝癌及其并发症的发生，从而改善生活质理和延长存活时间。需长期用药，对于乙型肝类肝硬化患者则需终生抗病毒冶疗。随着病例数量不断增多和用药时间的延长，常见的和少见的不良反应时有报道，在个体上表现不一，有的不良事件比较严重。现就批准上市的拉米夫定、阿德福韦酯、恩替卡韦、替诺福韦酯5种核苷（酸）类抗乙型肝类病毒药物的不良反应作一综述。

探讨HER-2/neu基因与乙肝病毒及预后的关系

目的:探讨45例肝细胞癌(HCC)患者的癌及癌旁组织中,HER-2/neu基因、HBsAg、HBcAg的表达情况。方法:分别用SP法进行免疫组织化学染色,将结果进行统计学处理。结果:HER-2/neu、HBsAg在肝癌中的表达低于癌旁组织(χ2分别为22.77和15.65,P<0.01),HBcAg在肝癌及癌旁中的表达差异无统计学意义(χ2=2.70,P>0.05)。HER-2/neu基因癌组织阳性率与HBsAg、HBcAg均存在关联性(χ2分别为17.78和8.46,r分别为0.532和0.398)。而癌旁组织阳性率与HBsAg有关联性(χ2=15.33,r=0.254),与HBcAg不存在关联性(χ2=0.1267,P>0.05)。HER-2/neu基因癌组织阳性组(7例)中HBsAg阳性率高于阴性组(χ2=12.69,P<0.01),HBcAg阳性率也高于阴性组(χ2=5.08,P<0.05)。HER-2/neu基因癌旁组织阳性组(39例),HBsAg阳性率明显高于阴性组(χ2=11.84,P<0.05)。在临床分期(1989年日本分期)中,各组间差别均无统计学意义。结论:HER-2/neu基因阳性时,HBsAg、HBcAg的阳性率均明显升高。在临床分期中,随着癌组织的进展,癌旁HER-2/neu基因的表达有降低的趋势。

慢性乙型肝炎合并2型糖尿病的危险因素分析

目的分析慢性乙型肝炎患者易患糖尿病的危险因素。方法选择49例肝炎合并2型糖尿病的患者及随机选取的51例普通慢性乙型肝炎患者作为对照,进行非条件逻辑逐步回归分析。结果经单因素非条件逻辑回归分析显示,年龄、糖尿病家族史、合并脂肪肝、病毒定量、AST ALT比值、γ-GT、白蛋白与球蛋白比值是慢性乙型肝炎合并糖尿病的危险因素.AST/ALT比值为保护因素。多因素非条件逻辑回归分析显示,年龄、合并脂肪肝、病毒定量和γ-GT为慢性乙型肝炎合并2型糖尿病的危险冈素。结论对慢性乙型肝炎患者,尤其是年龄较大者,应注意监测γ-GT、病毒定量,预防脂肪肝,以减少发生2型糖尿病的可能性。

Classifying genotype F of hepatitis B virus into F1 and F2 subtypes

AIM： To explore the propriety of providing hepatitis B virus （HBV） genotypes F and H with two distinct genotypes. METHODS： Eleven HBV isolates of genotype F （HBV/F） were recovered from patients living in San Francisco, Japan, Panama, and Venezuela, and their full-length sequences were determined. Phylogenetic analysis was carded out among them along with HBV isolates previously reported. RESULTS： Seven of them clustered with reported HBV/F Isolates in the phylogenetic tree constructed on the entire genomic sequence. The remaining four flocked on another branch along with three HBV isolates formerly reported as genotype H. These seven HBV isolates, including the four in this study and the three reported, had a sequence divergence of 7.3-9.5% from the other HBV/F isolates, and differed by 〉13.7% from HBV isolates of the other six genotypes （A-E and G）. Based on a marked genomic divergence, falling just short of 〉8% separating the seven genotypes, these seven HBV/F isolates were classified into F2 subtype and the former seven into F1 subtype provisionally. In a pairwise comparison of the S-gene sequences among the 7 HBV/F2 isolates and against 47 HBV/F1 isolates as well as 136 representing the other six genotypes （A-E and G）, two clusters separated by distinct genetic distances emerged.CONCLUSION： Based on these analyses, dassifying HBV/ F isolates into two subtypes （F1 and F2） would be more appropriate than providing them with two distinct genotypes （F and H）.

Relationship between HLA-DR gene polymorphisms and outcomes of hepatitis B viral infections:A meta-analysis

AIM:To assess the rigorous relationship between human leukocyte antigens(HLA)-DR alleles and outcomes of hepatitis B virus(HBV) infections by means of metaanalysis.METHODS:Medline/PubMed,EMBASE,CNKI and VIP were searched to identify relevant studies.Study quality was evaluated using the Newcastle-Ottawa Scale.Odds ratios(OR) and 95% confidence interval(95% CI) were pooled using Stata 11.0.Subgroup analyses were performed by ethnicity.Heterogeneity and publication bias analyses were performed to validate the credibility.RESULTS:A total of 2609 patients with chronic hepatitis B and 2606 controls spontaneously recovering from prior HBV infection were included.Meta-analysis showed that HLA-DR*04(OR = 0.72,95% CI:0.60-0.85) and DR*13(OR = 0.27,95% CI:0.19-0.37) alleles were significantly associated with HBV clearance while patients carrying HLA-DR*03(OR = 1.47,95% CI:1.16-1.87) or DR*07(OR = 1.59,95% CI:1.24-2.03) alleles had a significantly increased risk of chronic HBV persistence.For the HLA-DR*01 polymorphism,a significantly association with HBV clearance was found in Chinese Han group(OR = 0.48,95% CI:0.26-0.86),but not found in other ethnic groups(P = 0.191).For other polymorphisms,no association with the HBV infection outcome was found.CONCLUSION:HLA-DR*04 and DR*13 alleles may be the protective factors for HBV clearance and HLADR*03,and DR*07 alleles may be the risk factors for HBV persistence.

Epigenetic changes in virus-associated human cancers

Epigenetics of human cancer becomes an area of emerging research direction due to a growing understanding ofspecific epigenetic pathways and rapid development of detection technologies. Aberrant promoter hypermethylation is aprevalent phenonmena in human cancers. Tumor suppressor genes are often hypermethylated due to the increasedactivity or deregulation of DNMTs. Increasing evidence also reveals that viral genes are one of the key players inregulating DNA methylation. In this review, we will focus on hypermethylation and tumor suppressor gene silencing andthe signal pathways that are involved, particularly in cancers closely associated with the hepatitis B virus, simian virus40 (SV40), and Epstein-Barr virus. In addition, we will discuss current technologies for genome-wide detection ofepigenetically regulated targets, which allow for systematic DNA hypermethylation analysis. The study of epigeneticchanges should provide a global view of gene profile in cancer, and epigenetic markers could be used for early detection,prognosis, and therapy of cancer.

Lamivudine treatment enabling right hepatectomy for hepatocellular carcinoma in decompensated cirrhosis

A 69-year-old man was admitted to our hospital in October 2003,for further examination of two liver tumors.He was diagnosed with hepatocellular carcinoma(HCC) arising from decompensated hepatitis B virus(HBV)-related cirrhosis.Long-term lamivudine administration improved liver function dramatically despite repeated treatment for HCC.His Child-Pugh score was 9 points at start of lamivudine treatment,improving to 5 points after 1 year.His indocyanine green at 15 min after injection test score was 48%before lamivudine treat-ment,improving to 22%after 2 years and to 5%after 4 years.Radiofrequency ablation controlled the HCC foci and maintained his liver function.In April 2009,abdominal computed tomography revealed a tumor thrombus in the right portal vein.Since his indocyanine green test results had improved to less than 10%,we performed a right hepatectomy,which was successful.To our knowledge,there have been no documented reports of patients undergoing successful right hepatectomy for HCC arising from decompensated cirrhosis.The findings observed in our patient indicate the importance of nucleoside analogs for treating HBV-related HCC.

Distribution of HBV genotypes among HBV carriers in Benin:phylogenetic analysis and virological characteristics of HBV genotype E

AIM: To determine the distribution of Hepatitis B virus (HBV) genotypes in Benin, and to clarify the virological characteristics of the dominant genotype.METHODS: Among 500 blood donors in Benin, 21 HBsAg-positive donors were enrolled in the study. HBV genotypes were determined by enzyme immunoassay and restriction fragment length polymorphism. Complete genome sequences were determined by PCR and direct sequencing.RESULTS: HBV genotype E (HBV/E) was detected in 20/21 (95.2%), and HBV/A in 1/21 (4.8%). From the age-specific prevalence of HBeAg to anti-HBe seroconversion (SC) in 19 HBV/E subjects, SC was estimated to occur frequently in late teens in HBV/E.The comparison of four complete HBV/E genomes from HBeAg-positive subjects in this study and five HBV/E sequences recruited from the database revealed that HBV/E was distributed throughout West Africa with very low genetic divers ity (nucleotide homology 96.7-99.2%).Based on the sequences in the basic core promoter (BCP)to precore region of the nine HBV/E isolates compared to those of the other genotypes, a nucleotide substitution in the BCP, G1757A, was observed in HBV/E.CONCLUSION: HBV/E is predominant in the Republic of Benin, and SC is estimated to occur in late teens in HBV/E. The specific nucleotide substitution G1757A in BCP, which might influence the virological characteristics,is observed in HBV/E.

Tenofovir rescue therapy for chronic hepatitis B patients after multiple treatment failures

AIM:To evaluate the efficacy and safety of tenofovir disoproxil fumarate(TDF) for chronic hepatitis B(CHB) patients after multiple failures.METHODS:A total of 29 CHB patients who had a suboptimal response or developed resistance to two or more previous nucleoside/nucleotide analogue(NA) treatments were included.Study subjects were treated with TDF alone(n = 13) or in combination with lamivudine(LAM,n = 12) or entecavir(ETV,n = 4) for ≥ 6 mo.Complete virologic response(CVR) was defined as an achievement of serum hepatitis B virus(HBV) DNA level ≤ 60 IU/mL by real-time polymerase chain reaction method during treatment.Safety assessment was based on serum creatinine and phosphorus level.Eleven patients had histories of LAM and adefovir dipivoxil(ADV) treatment and 18 patients were exposed to LAM,ADV,and ETV.Twenty-seven patients(93.1%) were hepatitis B e antigen(HBeAg) positive and the mean value of the baseline serum HBV DNA level was 5.5 log IU/mL ± 1.7 log IU/mL.The median treatment duration was 16 mo(range 7 to 29 mo).RESULTS:All the patients had been treated with LAM and developed genotypic and phenotypic resistance to it.Resistance to ADV was present in 7 patients and 10 subjects had a resistance to ETV.One patient had a resistance to both ADV and ETV.The cumulative probabilities of CVR at 12 and 24 mo of TDF containing treatment regimen calculated by the Kaplan Meier method were 86.2% and 96.6%,respectively.Although one patient failed to achieve CVR,serum HBV DNA level decreased by 3.9 log IU/mL from the baseline and the last serum HBV DNA level during treatment was 85 IU/mL,achieving near CVR.No patients in this study showed viral breakthrough or primary non-response during the follow-up period.The cumulative probability of HBeAg clearance in the 27 HBeAg positive patients was 7.4%,12%,and 27% at 6,12,and 18 mo of treatment,respectively.Treatment efficacy of TDF containing regimen was not statistically different according to the presence of specific HBV mutations.History of prior exposure to specific antiviral agents did not make a difference to treatment outcome.Treatment efficacy of TDF was not affected by combination therapy with LAM or ETV.No patient developed renal toxicity and no cases of hypophosphatemia associated with TDF therapy were observed.There were no other adverse events related to TDF therapy observed in the study subjects.CONCLUSION:TDF can be an effective and safe rescue therapy in CHB patients after multiple NA therapy failures.

Animal models for the study of hepatitis C virus infection and replication

Hepatitis C virus (HCV) hepatitis, initially termed non-A, non-B hepatitis, has become one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide. With the help of animal models, our understanding of the virus has grown substantially from the time of initial discovery. There is a paucity of available animal models for the study of HCV, mainly because of the selective susceptibility limited to humans and primates. Recent work has focused modification of animals to permit HCV entry, replication and transmission. In this review, we highlight the currently available models for the study of HCV including chimpanzees, tupaia, mouse and rat models. Discussion will include methods of model design as well as the advantages and disadvantages of each model. Particular focus is dedicated to knowledge of pathophysiologic mechanisms of HCV infection that have been elucidated through animal studies. Research within animal models is critically important to establish a complete understanding of HCV infection, which will ultimately form the basis for future treatments and prevention of disease.

A comparative review of HLA associations with hepatitis Band C viral infections across global populations

Hepatitis B （HBV） and hepatitis C （HCV） viral infection or co-infection leads to risk of development of chronic infection, cirrhosis and hepatocellular carcinoma （HCC）. Immigration and globalization have added to the challenges of public health concerns regarding chronic HBV and HCV infections worldwide. The aim of this study is to review existing global literature across ethnic populations on HBV and HCV related human leukocyte antigen （HLA） associations in relation to susceptibility, viral persistence and treatment. Extensive literature search was conducted to explore the HLA associations in HBV and HCV infections reported across global populations over the past decade to understand the knowledge status, weaknesses and strengths of this information in different ethnic populations. HLA DR13 is consistently associated with HBV clearance globally. HLADRB1＊11/＊12 alleles and DQB1＊0301 are associated with HBV persistence but with HCV clearance worldwide. Consistent association of DRB1＊03 and ＊07 is observed with HCV susceptibility and non-responsiveness to HBV vaccination across the population. HLA DR13 is protective for vertical HBV and HCV transmission in Chinese and Italian neonates, but different alleles are associated with their susceptibility in these populations. HLA class I molecule interactions with Killer cell immunoglobulin like receptors （KIR） of natural killer （NK） cells modulate HCV infection outcome via regulating immune regulatory cells and molecules. HLA associations with HBV vaccination, interferon therapy in HBV and HCV, and with extra hepatic manifestations of viral hepatitis are also discussed. Systematic studies in compliance with global regulatory standards are required to identify the HLA specific viral epitope, stage specific T cell populations interacting with different HLA alleles during disease progression and viral clearance of chronic HBV or HCV infections among different ethnic populations. These studies would facilitate stage specific therapeutic strategies for clearance of HBV and HCV infections or co-infections across global populations and aid in identification of HBV-HCV combined vaccine. HLA associations of chronic HBV or HCV development with confounding host factors including alcohol, drug abuse, insulin resistance, age and gender are lacking and warrant detailed investigation across global populations.

Intramuscular vs intradermal route for hepatitis B booster vaccine in celiac children

AIM： To compare intradermal （ID） and intramuscular （IM） booster doses, which have been used in healthy and high risk subjects, such as healthcare workers, haemodialysis patients, human immunodeficiency virus patients, and renal transplant recipients unresponsive to initial hepatitis B vaccination, in celiac individuals. METHODS： We conducted our study on 58 celiac pa- tients, vaccinated in the first year of life, whose blood analysis had showed the absence of protective hepati- tis B virus （HBV） antibodies. All patients had received the last vaccine injection at least one year before study enrolment and they had been on a gluten free diet for at least 1 year. In all patients we randomly performed an HBV vaccine booster dose by ID or IM route. Thirty celiac patients were revaccinated with recombinant hepatitis B vaccine （Engerix B） 2 μg by the ID route, while 28 celiac patients were revaccinated with Engerix B 10 μg by the IM route. Four weeks after every boost- er dose, the anti-hepatitis B surface （HBs） antibody titer was measured by an enzyme-linked immune- adsorbent assay. We performed a maximum of three booster doses in patients with no anti-HBs antibodies after the first or the second vaccine dose. The cut off value for a negative anti-HBs antibody titer was 10 IU/L.Patients with values between 10 and 100 IU/L were considered ＂low responders＂ while patients with an antibody titer higher than 1000 IU/L were considered ＂high responders＂. RESULTS： No significant difference in age, gender, du- ration of illness, and years of gluten intake was found between the two groups. We found a high percent- age of ＂responders＂ after the first booster dose （ID = 76.7%, IM = 78.6%） and a greater increase after the third dose （ID = 90%, IM = 96.4%） of vaccine in both groups. Mloreover we found a significantly higher num- ber of high responders （with an anti-HBs antibody titer 〉 1000 IU/L） in the ID （40%） than in the IM （7.1%） group, and this difference was evident after the first booster dose of vaccination （P 〈 0.01）. No side effects were recorded in performing delivery of the vaccine by either the ID or IM route. CONCLUSION： Our study suggests that both ID and IM routes are effective and safe options to administer a booster dose of HBV vaccine in celiac patients. Howev- er the ID route seems to achieve a greater number of high responders and to have a better cost/benefit ratio.

DNA-guided hepatitis B treatment:Viral load is insufficient with few exceptions

In DNA-guided hepatitis B treatment, viral load is insufficient, and requires other viral markers for treatment of hepatitis B patients as in patients with acute exacerbation of chronic hepatitis B, end-stage renal disease on dialysis, human immunodeficiency virus co-infected patients. There are exceptions to this rule： a residual level hepatitis B virus （HBV） DNA at 24 wk predicts beneficial outcome and reduced resistance at i year. The genotypic viral resistance to antiviral agents and occult HBV infection can be determined by HBV-DNA levels.