薄层色谱法测定阿德福韦酯有关物质

目的：建立阿德福韦酯有关物质薄层色谱检查法。方法：反相薄层色谱法，甲醇-水(3：1)为展开剂，在紫外光254nm下检视。结果：经方法学验证本法能有效分离并检测阿德福韦酯中的有关物质。最小检测限为0．1μg。结论：反相薄层色谱法避免了阿德福韦酯在硅胶薄层色谱法中发生分解的现象，且分离效果好，检测灵敏度高。     

阿德福韦酯对慢性乙肝患者白细胞介素-8及其mRNA表达的影响

目的探讨阿德福韦酯对慢性乙肝患者白细胞介素-8（IL--8）及其mRNA表达的影响。方法随机选择（信封法）典型HBV感染患者，以ELISA法检测患者血清IL-8水平；Real-timePCR检测PBMC中IL．8mRNA含量，以lgcDNA／lgGAPDH代表其mRNA水平。结果慢性乙肝患者外周血IL-8水平为（3．536±O．383）×105pg／L，IL-8mRNA为（1．1045±0．2267），其中“大三阳”组为（4．702±0．572）×105pg／L，治疗24周为（4．503±0．473）×105pg／L、48周IL-8水平为（4．114±0．420）×105pg／L，其IL-8mRNA分别为（1．1645±0．1340）lgcDNA／lgGAPDH、（1．0267±0．1344）lgcDNA／lgGAPDH、（0．8223±0．1643）lgcDNA／lgGAP·DH，与“小三阳”组相比差异有统计学意义（P〈0．05）。结论阿德福韦酯除发挥抗病毒作用外，还能间接下调因IL-8过度表达所致的炎性反应。     

Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

BACKGROUND: The recurrence of chronic hepatitis B after liver transplantation results in increased risk for graft failure and death of patients. Lamivudine has been shown to be effective in the treatment of chronic hepatitis B, but resistance to this agent is common after prolonged administration. METHODS: One patient with chronic hepatitis B virus (HBV) infection developed resistance to lamivudine after 15 months of treatment. The resistance was confirmed by mutation in the HBV DNA polymerase gene. The patient was treated subsequently with adefovir dipivoxil for 7 months. RESULT: HBV DNA and HBsAg were tested negative, but HBeAb and HBsAb were positive. CONCLUSION: This study provides an evidence that adefovir dipivoxil can be effective in the treatment of lamivudine-resistant HBV mutants.     

阿德福韦酯致范可尼综合征1例及41例不良反应报道汇总分析

目的:探讨阿德福韦酯致范可尼综合征的临床特征、机制以及分布特点。方法:对1例应用阿德福韦酯治疗慢性乙型肝炎后发生低血磷性骨软化症的病例进行分析,并在全球范围内就其发生情况进行文献复习。结果:1例患者的临床症状出现时间是连续服用阿德福韦酯10 mg qd 5年之后,在停用阿德福韦酯24 d后,临床症状减轻,血磷恢复正常(症状较重时0.53 mmol·L-1,停用阿德福韦酯24 d时升至0.81 mmol·L-1),诊断为阿德福韦酯相关范可尼综合征、低血磷性骨软化症。复习文献发现阿德福韦酯导致的范可尼综合征均有血磷下降,尿酸水平下降,碱性磷酸酶上升,伴或不伴血钙下降及肌酐清除率下降。结论:服用阿德福韦酯治疗乙型肝炎的患者建议定期监测血磷、肌酐水平,如果出现低血磷提示发生肾小管损害,考虑更换抗病毒药物;长期服用阿德福韦酯的患者出现骨痛症状,考虑发生低血磷性骨软化症的可能性。     

初始拉米夫定联合阿德福韦酯治疗乙肝肝硬化的效果

目的：观察初始拉米夫定联合阿德福韦酯治疗乙肝肝硬化的效果。方法：病例来源于2012年5月～2014年5月在医院门诊接受治疗的乙肝肝硬化患者80例,利用随机数字表法分为观察组和对照组,每组40例。观察组在口服初始拉米夫定的基础上,服用阿德福韦酯进行治疗。对照组口服初始拉米夫定药物治疗,治疗结束后,对两组的治疗效果及不良反应进行观察和评价。结果：两组患者乙肝病毒的检测结果由阳转阴的时间和治疗时间的差异具有统计学意义（P<0.05）。观察组总有效率为87.5%（35/40）,对照组总有效率为55%（22/40）,差异具有统计学意义（X2=7.75,P<0.05）。观察组不良反应发生率为5%（2/40）,对照组不良反应发生率为27.5%（11/40）,差异具有统计学意义（X2=7.73,P<0.05）。结论：联合使用拉米夫定和阿德福韦酯的有效率高于仅口服拉米夫定,不良反应发生率低于后者,而且能够明显减少治疗需要的时间,减轻患者痛苦,具有更高的安全性,能得到更好的治疗效果,值得临床推广。     

Pegylated IFN-α2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B

AIM: To investigate the role of pegylated-interferon (IFN)α-2b in the management of patients with lamivudine-resistant chronic hepatitis B. METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFNα-2b (100μg sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. RESULTS: Nine patients (45%) had a partial viro-logical end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n = 5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms. CONCLUSION: Pegylated IFNα-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.     

阿德福韦耐药乙型肝炎病毒株的快速检测和动态观察

目的设计PCR联合限制性片段长度多态性（PCR—RFLP）快速检测HBV阿德福韦耐药变异（rtN236T）的方法以及观察阿德福韦耐药毒株的动态变化情况。方法7例乙型肝炎患者在阿德福韦单药治疗过程中出现病毒突破或应答不完全。对其系列血清标本的HBVDNA逆转录酶部分区域进行直接或克隆后测序，设计和应用PCR—RFLP方法对rt236位点的变异情况进行检测。采用Hamming距离法计算HBV部分逆转录酶区域的基因多样性。结果l例患者出现rtA18IV变异，3例为rtN236T变异。建立了基于限制性内切酶DraI或HpaI的PCR—RFLP方法检测rtN236T变异：可以检测至少10％的弱势毒株，特异性为100％。在病毒突破前8个月可以检测到耐药毒株；该耐药毒株后来成为优势毒株。1例患者停用阿德福韦3个月后野生毒株取代耐药毒株重新成为优势株。1例患者在病毒突破后继续服用阿德福韦，rtN236T突变被一个新的突变株（rtN236V）替代。拉米夫定耐药患者的HBV逆转录酶有更明显的基因多样性。结论建立了PCR—RFLP快速检测rtN236T变异的方法；阿德福韦耐药毒株可以表现为不同的转化过程。     

阿德福韦酯治疗乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎的近期疗效

目的 观察阿德福韦酯治疗乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎的近期疗效.方法 选择6例乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎患者,定量PCR测得血清HBVDNA＞105拷贝/ml,肾组织HBV DNA阳性,肝功能Child-Pugh分级均为A级,在常规治疗基础上加用阿德福韦酯10 mg/d 1年.于治疗后1、3、6个月复查血常规、尿蛋白定量、肝肾功能、血清HBV标志物变化情况.结果 治疗后3、6个月血清HBV DNA转阴的分别有2例和5例,HBeAg转阴的分别有1例和4例,抗HBe转阳的均只有1例;ALT复常的分别有5例和6例,总胆红素复常的分别有4例和5例.治疗6个月后尿蛋白量＜0.3 g/d的2例,尿蛋白量较治疗前下降＞50%的3例.巩固治疗1年时完全缓解3例,部分缓解2例. 结论 阿德福韦酯治疗乙型肝炎肝硬化合并乙型肝炎病毒相关性肾炎近期安全有效.     

Telbivudine protects renal function in patients with chronic hepatitis B infection in conjunction with adefovir‐based combination therapy

Previous studies have demonstrated that the treatment of chronic hepatitis B (CHB) infection with adefovir (ADV) can impair renal function. In contrast, treatment with telbivudine (LdT) improves renal function in CHB patients. The aim of this study was to evaluate the renoprotective effect of LdT in CHB patients receiving ADV‐based combination therapy. The effects of treatment with ADV + LdT on renal function were compared to those resulting from treatment with ADV + entecavir (ETV), ADV + lamivudine (LAM), ADV alone and ETV alone. The consecutive cohort analysis included 831 CHB patients who received ADV + LdT, ADV + LAM, ADV + ETV, ADV alone or ETV alone for 96 weeks. Alterations in estimated glomerular filtration rate (eGFR) were compared between the five groups using a linear mixed‐effects model. HBV DNA levels were also compared between the five groups during the 96‐week period. Among the five treatment groups, significant improvements in eGFR were observed in the ADV + LdT and ADV + LAM groups over time (P < 0.001 for each group compared with baseline eGFR). In patients with a baseline eGFR between 50 and 90 mL/min, the change in eGFR was the most significant in the ADV + LdT group (+0.641 mL/min; P < 0.001). Age, gender, baseline eGFR and treatment option were significant predictive factors for eGFR changes. In conclusion, our results suggest that the combination therapy of LdT and ADV is significantly associated with renoprotective effects in CHB patients when compared with other ADV‐based combination or single therapies.     

Combination therapy of interferon and nucleotide/nucleoside analogues for chronic hepatitis B

Chronic hepatitis B is one of the leading causes of cirrhosis and hepatocellular carcinoma globally. At present, seven drugs, including two interferons and five oral nucleos(t)ide analogues (NAs), have been approved for the treatment of chronic hepatitis B. Interferon works by immunomodulation, but is successful in less than a third of treated patients and is a relatively weak antiviral. NAs directly suppress the hepatitis B virus but have limited durability. Based on current data, combination of NA and interferon results in greater viral suppression but does not translate to off‐treatment sustained response. Concomitant or sequential treatment also does not make a difference. Combining telbivudine and interferon also runs the risk of severe peripheral neuropathy. On the other hand, interferon switch or additional therapy in patients well controlled with NAs appears to improve the durability of off‐treatment response. This article reviews current data on interferon and NA combination and discusses potential future developments.