Katsounas A, Jochum C, Canbay A, Schlaak J, Gerlich W H, Gerken G
Medical Department gastroenterology and hepatology, University of Duisburg-Essen, Germany.
Eur J Med Res. 2008 Oct 27;13(10):472-5.
In chronic hepatitis B patients undergoing therapy with LAM or ADV, viral breakthrough is possible due to the emergence of drug resistance. LAM resistant HBV strains are susceptible to ADV, while ADV resistant mutants remain sensitive to LAM.
A male patient with HBV-related cirrhosis developed viral breakthrough (HBV DNA>1.8 x 106 IU/ml) after 4 1/2 years of treatment with LAM, and therapy was switched to ADV (10 mg/d). After three months, HBV remained highly replicative without any changes of ALT values, and ADV dose was increased (20 mg/d). Because of unchanged VL sequence analysis was performed three months later, which showed the mutation (rtS219A) and the concomitant mutation (sS210R) and 2 mutations in core promoter region (A1762T), (G1764A). During the sixth month of ADV monotherapy the patient developed liver failure. After administration of TDF plus LAM, HBV DNA became undetectable within 39 days. At day 41, the patient underwent OLT. TDF plus LAM were well tolerated, and the patient maintained undetectable HBV DNA levels, and in addition to HBIG a sustained HBsAg negative status over twenty-eight months post OLT.
TDF plus LAM is a safe drug combination in case of viral breakthrough during LAM treatment and subsequent primary non-response to ADV. High VL persisting for >or= 6 months of continuous antiviral treatment may indicate drug resistance. Especially in cirrhotic patients with LAM resistance, "add on" of a nucleotide analogue is the right therapeutic strategy even before viral breakthrough gets apparent.
在接受拉米夫定（LAM）或阿德福韦酯（ADV）治疗的慢性乙型肝炎患者中，由于耐药性的出现，病毒突破是可能的。对LAM耐药的HBV毒株对ADV敏感，而对ADV耐药的突变体对LAM仍敏感。
一名患有HBV相关肝硬化的男性患者在接受LAM治疗4年半后出现病毒突破（HBV DNA>1.8×106 IU/ml），治疗改为ADV（10mg/d）。三个月后，HBV仍高度复制，ALT值无任何变化，ADV剂量增加（20mg/d）。由于病毒载量（VL）未改变，三个月后进行了序列分析，结果显示存在突变（rtS219A）和伴随突变（sS210R）以及核心启动子区域的两个突变（A1762T）、（G1764A）。在ADV单药治疗的第六个月，患者发生肝衰竭。给予替诺福韦酯（TDF）加LAM后，39天内HBV DNA变得无法检测。在第41天，患者接受了肝移植（OLT）。TDF加LAM耐受性良好，患者维持HBV DNA不可检测水平，并且除了乙肝免疫球蛋白（HBIG）外，OLT后28个月内持续保持HBsAg阴性状态。
在LAM治疗期间出现病毒突破以及随后对ADV原发性无反应的情况下，TDF加LAM是一种安全的药物组合。持续抗病毒治疗≥6个月的高病毒载量可能表明耐药。特别是在对LAM耐药的肝硬化患者中，即使在病毒突破明显之前，添加一种核苷酸类似物也是正确的治疗策略。
