Prevention of hepatitis B virus recurrence after liver transplantation

Abstract:  Liver transplantation for hepatitis B virus (HBV)-related liver disease has changed from a contraindication to outcomes comparable with non-HBV-related liver transplantations during the last two decades. Mainly the implementation of immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and the use of nucleoside analogs such as lamivudine and adefovir account for this dramatic change. The standard of care in most centers today consists of lamivudine treatment in replicating hepatitis B pre-orthotopic liver transplantation (OLT) and a combination regimen of lamivudine and HBIG post-OLT. With adefovir, a potent antiviral drug became available in recent years that allows for the treatment of patients with lamivudine-resistant tyrosine-methionine-aspartate-aspartate (YMDD)-mutant HBV. In the transplantation setting, first studies indicate that a triple prophylactic therapy consisting of lamivudine, adefovir, and HBIG will become the standard of care for YMDD-mutant-related hepatitis B. With new drugs emerging for the treatment of chronic HBV, there is optimism for new options also in the transplant setting.     

阿德福韦二吡呋酯在猕猴体内的药代动力学及在大鼠体内的组织分布

目的　研究了新型抗病毒药物阿德福韦二吡呋酯 (ADV)po给药后在动物体内的吸收、分布、代谢和消除过程。方法　采用液相色谱质谱联用方法测定样品中的药物浓度。结果　猕猴po或iv给药ADV后 ,血液中只检测到活性代谢物阿德福韦(ADF) ,因此用ADF的血药浓度 时间曲线来估算药代动力学参数。猕猴poADV后 ,tmax为 0 .99～ 1.70h ,t1/ 2 为 1.6 4～ 5 .4 3h ,Cl为 9.14～ 13.91L·h- 1·kg- 1,绝对生物利用度为 19.9%。连续 7dpo给药(每日 1次 )后未发现药物累积现象。肾脏和肝脏中ADF的含量仅次于胃肠内容物。ADF主要经肾脏排出体外。结论　在给药量范围内表现为线性动力学 ,在靶器官肝脏中分布较多 ,主要从尿液中排出。     

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。     

Nucleos(t)ide analogues for hepatitis B virus: Strategies for long-term success

Nucleoside and nucleotide analogues are potent HBV suppressors, but these agents rarely eradicate HBV. Therefore, the durability of viral response is a problem, and long-term therapy is usually required to ensure maintained HBV suppression. Studies have shown that long-term therapy starting with lamivudine may significantly improve survival, reduce the risk of liver-related major complications, and prevent the development of cirrhosis and HCC in chronic hepatitis B patients. However, drug resistance is a critical challenge during long-term nucleos(t)ide analogue maintenance therapy. The emergence of these mutants is characterized by an increasing level of serum HBV DNA, elevation of ALT level, and even hepatitis flare or decompensation. The prevention and proper management of drug resistance are crucial to ensure long-term success. To start treatment in the right patients at the right time with the right drug is essential in minimizing the problem of drug resistance. Each of these agents has a different profile of resistant mutations. In choosing a direct antiviral agent to initiate therapy, resistance profile is a crucial factor to consider, apart from potency and cost. In the case of drug resistance emerging, timely institution of a drug without cross-resistance may rescue the adverse effects of drug resistance and ensure the long-term success of nucleos(t)ide analogue therapy. To develop strategies for enhancing the therapeutic response and shortening the duration of therapy is an ultimate goal to avoid the problems of drug resistance.⁶⁸

• nucleos(t)ide analogues for hepatitis B virus (HBV) are highly effective in suppressing HBV replication but rarely eliminate the virus

• long-term therapy is usually required

• emergence of drug-resistant HBV mutations is a critical challenge

• to treat the right patient at the right time with the drug with highest genetic barrier to drug resistance is essential to minimize the problem with drug resistance

• the strategy of on-treatment adjustment based on level of suppression of HBV DNA needs to be clarified

• studies are needed to find the optimal combination therapy for both better therapeutic efficacy and less drug resistance

• oral antiviral agents able to attack cccDNA are urgently needed

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.     

RP-HPLC 法同时测定成人血清中苦参素和阿德福韦酯的浓度方法学研究

目的：建立一种简易的测定联合服用苦参素和阿德福韦酯成人血清中苦参素和阿德福韦酯含量方法。方法采用Shim-pack VP-ODS C18色谱柱（250 mm ×4．6 mm,5μm）,流动相为甲醇∶水（70∶30）,流速为1．1 mL·min －1,检测波长为229 nm。结果苦参素保留时间4．6 min 左右,标准曲线的线性范围为0．0125～2 mg·L －1,r ＝0．9992。阿德福韦酯保留时间7．3 min 左右,标准曲线的线性范围为0．0125～0．75 mg·L －1,r ＝0．9991,苦参素和阿德福韦酯的日间、日内变异系数均在7％以下,回收率＞92％。结论该法简便,灵敏,快速,可用于苦参素和阿德福韦酯临床联用治疗的成人血药浓度的监测。     

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。     

阿德福韦酯片治疗HBeAg阳性慢性乙型肝炎多中心临床研究

目的评价国产阿德福韦酯片治疗成人HBeAg阳性慢性乙型肝炎的有效性和安全性。方法采用多中心、开放试验方法,入选1930例患者服用阿德福韦酯片10mg／d。随访观察采用标准操作规程（SOP）,观察12周、24周、36周、52周的生化、病毒学指标及不良反应。结果1930例患者治疗12周、24周、36周、52周,HBVDNA阴转率分别为16．42％、28．55％、37．25％、43．32％,ALT复常率分别为29．69％、49．02％、56．42％、62．95％。治疗24周、52周HBeAg阴转率分别为12．59％、19．38％。随着疗程延长,HBVDNA阴转率、ALT复常率、HBeAg阴转率越高。治疗52周时耐药率为0．17％。不良反应率0．72％,极少数病例出现尿常规轻微异常,未发现肾功或生殖系统受损。结论国产阿德福韦酯片治疗HBeAg阳性慢性乙型肝炎具有良好的有效性及安全性。