早在10年前,联合抗病毒治疗就受到重视,在一项国际多中心临床试验中,比较了聚乙二醇干扰素α-2a或拉米夫定与二者联合治疗HBeAg阳性慢性乙型肝炎的疗效,尽管研究结果未显示HBeAg血清学转换的差异,但联合治疗比单种药物治疗患者48周时的HBV DNA抑制率更明显[5]。另有一项研究比较了拉米夫定和拉米夫定联合阿德福韦酯治疗慢性乙型肝炎患者的疗效,结果显示联合治疗104周时,HBV DNA < 200 IU/ml的患者占26%,明显高于拉米夫定治疗患者的14%[6]。最近国内也有关于联合治疗的临床研究报告。其中一项研究结果显示,拉米夫定联合阿德福韦酯治疗患者48周时HBV DNA < 300拷贝/ml者占90.7%,高于恩替卡韦治疗患者的76.0%;联合治疗96周时的HBV DNA<300拷贝/ml者占96.1%、HBeAg血清学转换率为41.7%,明显高于恩替卡韦治疗患者的79.2%和16.7%[7]。另一项拉米夫定联合阿德福韦酯对比拉米夫定治疗失代偿性乙型肝炎肝硬化患者的研究结果也显示出联合治疗患者对抑制病毒复制和改善肝脏功能更明显[8]。这些研究中,联合治疗的方法主要是采用起始联合的方法,结果提示联合抗病毒治疗是提高抗病毒疗效,特别是抑制病毒复制的重要方法,值得进一步扩大样本深入研究。
二、联合治疗是预防和减少耐药的主要方法
在药物压力下发生基因突变和耐药是核苷(酸)类似物治疗慢性乙型肝炎的主要障碍之一。一般认为严格掌握治疗指征、规范选择适合的患者和药物、避免单药序贯治疗是防止和减少耐药的重要方法。其实增强抗病毒治疗的效果才是预防耐药的根本方法,只有彻底抑制了病毒复制,才能有效预防发生基因突变和耐药。即所谓“No Virus, No Variation;No Replication,No Resistance”。已经有研究结果提示,核苷(酸)类似物治疗患者的早期病毒学应答较好的患者或通过联合治疗增强了抗病毒疗效的患者发生病毒学突破和耐药的机会是减少的。在替比夫定治疗慢性乙型肝炎的全球多中心临床试验中,接受替比夫定和拉米夫定治疗24周时血清HBV DNA < 300拷贝/ml,HBeAg阳性患者分别占45%和32%,HBeAg阴性患者分别占80%和71%[9]。这些患者继续治疗到52周时,HBeAg阳性和阴性患者血清HBV DNA仍< 300拷贝/ml者分别占90%和83%、耐药发生率分别为2%和1%,明显低于早期病毒学应答不佳的患者。在拉米夫定联合阿德福韦酯对比拉米夫定的研究中,联合治疗患者治疗过程中发生病毒学突破率为19%(10/53),明显低于拉米夫定治疗患者的病毒学突破率(44%,24/55)。这正是由于联合治疗增强了病毒抑制作用的结果[6]。
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