Barry M, Mulcahy F, Merry C, Gibbons S, Back D
Trinity Centre for Health Sciences, Department of Pharmacology and Therapeutics, St James's Hospital, Dublin, Ireland.
Clin Pharmacokinet. 1999 Apr;36(4):289-304. doi: 10.2165/00003088-199936040-00004.
There are 3 groups of drugs available for the treatment of patients with HIV disease. These are the nucleoside reverse transcriptase inhibitors ('nucleoside analogues') [zidovudine, didanosine, zalcitabine, lamivudine and abacavir]; the non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz); and the protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir and amprenavir). The preferred initial regimen should reduce and maintain plasma HIV RNA below the level of detection. Presently, the regimen of choice consists of 2 nucleoside analogues plus a protease inhibitor with high in vivo efficacy. An alternative combination consists of 2 nucleoside analogues plus a non-nucleoside reverse transcriptase inhibitor. Drug interactions are one of the major problems associated with these multidrug regimens. Changes in plasma concentrations of the nucleoside analogues are unlikely to be of clinical relevance as drug effect is mainly dependent on the rate and extent of intracellular phosphorylation. Combinations of zidovudine plus stavudine, and probably zalcitabine plus lamivudine, should be avoided as competition for phosphorylating enzymes may occur. The antiviral efficacy of some nucleoside analogues, e.g. stavudine, may be compromised by prior treatment with other nucleosides (e.g. zidovudine). However, these data need to be clarified in further studies. It is unlikely that administration of other antiretrovirals will influence the activity of nucleoside analogues. Protease inhibitors are metabolised by hepatic cytochrome P450 (CYP) 3A4. Combination protease inhibitor therapy can result in drug interactions mediated by enzyme inhibition. Ritonavir is the most potent inhibitor, saquinavir the least. The protease inhibitors also interact with the non-nucleoside reverse transcriptase inhibitors. Nevirapine and efavirenz induce drug metabolising enzymes and may reduce plasma concentrations of protease inhibitors. A study in healthy volunteers showed that nelfinavir concentrations are increased by combination with efavirenz. Delavirdine inhibits drug metabolising enzymes and increases the plasma concentration of coadministered protease inhibitors. The nucleoside analogues would not be expected to interact with the protease inhibitors. Apart from the ability of didanosine to reduce the area under the concentration-time curve of delavirdine, there are no reports of clinically significant interactions of other antiretrovirals with the non-nucleoside reverse transcriptase inhibitors. Triple therapy is the current standard of care for patients with HIV disease. However, studies of quadruple therapy are already under way. Drug interactions are likely to remain one of the major considerations when selecting a therapeutic regimen for patients with HIV.
有三类药物可用于治疗艾滋病患者。它们是核苷类逆转录酶抑制剂（“核苷类似物”）[齐多夫定、去羟肌苷、扎西他滨、拉米夫定和阿巴卡韦]；非核苷类逆转录酶抑制剂（奈韦拉平、地拉韦定和依非韦伦）；以及蛋白酶抑制剂（沙奎那韦、利托那韦、茚地那韦、奈非那韦和安普那韦）。首选的初始治疗方案应将血浆中的艾滋病毒RNA降低并维持在检测水平以下。目前，选择的治疗方案包括两种核苷类似物加一种体内疗效高的蛋白酶抑制剂。另一种组合是两种核苷类似物加一种非核苷类逆转录酶抑制剂。药物相互作用是这些多药治疗方案相关的主要问题之一。核苷类似物血浆浓度的变化不太可能具有临床相关性，因为药物作用主要取决于细胞内磷酸化的速率和程度。应避免齐多夫定加司他夫定的组合，可能还有扎西他滨加拉米夫定的组合，因为可能会发生对磷酸化酶的竞争。一些核苷类似物（如司他夫定）的抗病毒疗效可能会因先前使用其他核苷（如齐多夫定）而受到影响。然而，这些数据需要进一步研究加以阐明。使用其他抗逆转录病毒药物不太可能影响核苷类似物的活性。蛋白酶抑制剂由肝细胞色素P450（CYP）3A4代谢。联合蛋白酶抑制剂治疗可导致由酶抑制介导的药物相互作用。利托那韦是最强的抑制剂，沙奎那韦最弱。蛋白酶抑制剂也与非核苷类逆转录酶抑制剂相互作用。奈韦拉平和依非韦伦可诱导药物代谢酶，可能会降低蛋白酶抑制剂的血浆浓度。一项针对健康志愿者的研究表明，奈非那韦与依非韦伦联合使用时浓度会升高。地拉韦定可抑制药物代谢酶，增加同时使用的蛋白酶抑制剂的血浆浓度。预计核苷类似物不会与蛋白酶抑制剂相互作用。除了去羟肌苷能够降低地拉韦定浓度 - 时间曲线下的面积外，没有其他抗逆转录病毒药物与非核苷类逆转录酶抑制剂发生具有临床意义的相互作用的报道。三联疗法是目前艾滋病患者的标准治疗方法。然而，四联疗法的研究已经在进行中。在为艾滋病患者选择治疗方案时，药物相互作用可能仍然是主要考虑因素之一。
