Zalcitabine is a dideoxynucleoside antiretroviral agent that is phosphorylated to the active metabolite 2',3'-dideoxycytidine 5'-triphosphate (ddCTP) within both uninfected and HIV-infected cells. At therapeutic concentrations, ddCTP inhibits HIV replication by inhibiting the enzyme reverse transcriptase and terminating elongation of the proviral DNA chain. The results of 3 large pivotal trials comparing zidovudine monotherapy with combination therapy have now clearly established that zalcitabine plus zidovudine combination with an improvement in viral load and CD4+ cell count compared with zidovudine monotherapy. More recently, clinical end-point and surrogate marker data have established the efficacy of zalcitabine in combination with the protease inhibitor saquinavir in zidovudine-experienced patients. Other studies have demonstrated the utility of zalcitabine in combination with ritonavir and the nucleoside analogue lamivudine. Importantly, early use of zalcitabine in the treatment sequence does not appear to limit the therapeutic efficacy of subsequent therapy with other nucleoside analogues such as lamivudine. Peripheral neuropathy is the most frequent dose-limiting adverse effect associated with zalcitabine therapy and is generally reversible on discontinuation of treatment. Stomatitis and mouth ulcers may occur frequently with zalcitabine therapy but tend to resolve with continuing treatment. Haematological toxicity, which is a common adverse effect associated with zidovudine, is reported infrequently with zalcitabine. Overall, combination therapy with zalcitabine plus zidovudine or saquinavir has been shown to have a tolerability profile comparable to that of either agent alone, although treatment with zidovudine plus zalcitabine was associated with a significant increase in the incidence of haematological toxicity compared with zidovudine monotherapy in one study. Therefore, current data suggest that zalcitabine is a useful antiretroviral agent for inclusion as a component of initial double combination therapy with zidovudine or as part of triple combination therapy including zidovudine plus a protease inhibitor in the management of patients with HIV infection.

译文

扎西他滨是一种双脱氧核苷抗逆转录病毒药物,在未感染和HIV感染的细胞中被磷酸化为活性代谢物2 ',3'-二脱氧胞苷5 '-三磷酸 (ddCTP)。在治疗浓度下,ddCTP通过抑制反转录酶和终止前病毒DNA链的延伸来抑制HIV复制。比较齐多夫定单药治疗与联合治疗的3项大型关键试验的结果现已清楚地确定,与齐多夫定单药治疗相比,扎西他滨加齐多夫定联合治疗的病毒载量和CD4细胞计数有所改善。最近,临床终点和替代标记数据已经确定了扎西他滨与蛋白酶抑制剂沙奎那韦联合使用齐多夫定经验的患者的疗效。其他研究表明扎西他滨与利托那韦和核苷类似物拉米夫定联合使用。重要的是,在治疗序列中早期使用扎西他滨似乎不会限制随后使用其他核苷类似物 (例如拉米夫定) 进行治疗的疗效。周围神经病变是与扎西他滨治疗相关的最常见的剂量限制性不良反应,并且在停止治疗后通常是可逆的。扎西他滨治疗可能经常发生口腔炎和口腔溃疡,但随着继续治疗而趋于缓解。扎西他滨很少报道血液学毒性,这是与齐多夫定相关的常见不良反应。总体而言,扎西他滨联合齐多夫定或沙奎那韦的联合治疗已被证明具有与单独使用任何一种药物相当的耐受性特征,尽管在一项研究中,与齐多夫定单药治疗相比,齐多夫定联合扎西他滨治疗与血液学毒性发生率显着增加有关。因此,目前的数据表明,扎西他滨是一种有用的抗逆转录病毒药物,可作为齐多夫定的初始双重联合疗法的一部分或作为齐多夫定加蛋白酶抑制剂的三重联合疗法的一部分纳入HIV感染患者。

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