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.     

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。     

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.     

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。     

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.     

宫内膜干细胞治疗失代偿期乙型肝炎肝硬化疗效的初步探讨

目的探讨宫内膜干细胞移植治疗失代偿期乙肝肝硬化患者的临床疗效。方法选择乙肝肝硬化失代偿期患者43例,随机分成两组,其中对照组30例,采用拉米夫定、阿德福韦酯抗病毒治疗;实验组13例,在对照组治疗基础上加用宫内膜干细胞治疗。分别在治疗后1、6、12个月检查各组患者肝脏功能、甲胎蛋白、胆碱酯酶、肝纤维化、凝血酶原时间,观察病毒学应答、临床症状及不良反应情况。结果治疗后1、6、12个月,实验组患者ALT、AST、TBIL、ALB、肝纤维化系列（LN、HA、PC-Ⅲ、Ⅳ）、CHE、PT等指标较对照组明显改善（ALT：F实验组=11.432,F对照组=8.231;AST：F实验组=13.197,F对照组=9.732;TBIL：F实验组=10.964,F对照组=8.692;Alb：F实验组=2.846,F对照组=3.691;CHE：F实验组=67.428,F对照组=70.285;LN：F实验组=20.462,F对照组=16.390;HA：F实验组=30.421,F对照组=23.521;PCⅢ：F实验组=23.532,F对照组=17.397;IV：F实验组=20.386,F对照组=15.496;PT：F实验组=1.752,F对照组=0.950。P均〈0.05）;治疗后12个月实验组和对照组HBVDNA阴转率和HBeAg血清转换率均较治疗后6月显著增加,且实验组显著优于对照组（P〈0.05）;两组患者治疗前后临床症状和体征均有所改善,治疗期间均未发现严重不良反应。结论采用宫内膜干细胞治疗乙肝肝硬化失代偿期患者,肝脏功能及临床症状明显改善,病毒应答率高,短期观察安全可靠,不良反应小,提高了患者的生活质量,值得临床进一步研究。