Plosker Greg L, Scott Lesley J
Adis International Limited, Auckland, New Zealand.
Drugs. 2003;63(12):1299-324. doi: 10.2165/00003495-200363120-00007.
Protease inhibitor boosting involves concurrent administration of a protease inhibitor, such as saquinavir, plus a potent inhibitor of cytochrome P450 (CYP) 3A4, usually ritonavir in subtherapeutic doses. Since protease inhibitors are extensively metabolised by CYP3A4, this results in a marked increase in systemic exposure of saquinavir or other protease inhibitors boosted by ritonavir. As with traditional protease inhibitor regimens, boosted regimens are typically used in combination with nucleoside reverse transcriptase inhibitors (NRTIs). In protease inhibitor-experienced and -naive patients with HIV infection, twice-daily and once-daily boosted saquinavir regimens achieved good rates of viral suppression, improved CD4+ cell counts and were generally well tolerated in clinical trials. Encouraging results have also been reported in a number of small studies in heavily pretreated HIV-infected patients who received salvage therapy comprising double-boosted regimens of saquinavir plus lopinavir with subtherapeutic doses of ritonavir, along with other agents. The largest clinical trials have been multicentre, randomised comparisons of twice-daily boosted saquinavir versus twice-daily boosted indinavir (MaxCmin1) or lopinavir (MaxCmin2) regimens. In the MaxCmin1 study, >90% of patients in both groups had an undetectable viral load (<400 copies/mL) after 48 weeks of therapy in the on-treatment analysis. However, viral suppression was achieved in significantly more saquinavir than indinavir recipients in the intention-to-treat analysis, which appeared to be due to the significantly greater percentage of patients in the indinavir group who switched from randomised therapy because of adverse events. Interim 24-week results of the MaxCmin2 trial indicate that 90% of patients in both groups combined had plasma HIV RNA levels <400 copies/mL; final results at 48 weeks will report data separately for the boosted regimens of saquinavir and lopinavir.
Boosted protease inhibitor regimens (including two NRTIs) are recommended as a first-line option in current HIV treatment guidelines and are used extensively in clinical practice. The convenient administration schedule and good pharmacokinetic profile associated with boosted saquinavir regimens have the potential to increase adherence to therapy and improve antiretroviral effects through increased drug exposure. Twice-daily boosted saquinavir is one of the most extensively evaluated boosted protease inhibitor regimens and has been shown to have good efficacy on surrogate markers of HIV disease as well as significant tolerability advantages over boosted indinavir. Once-daily boosted saquinavir regimens may be most suitable for HIV-infected patients with busy lifestyles and those who would benefit from directly observed therapy.
蛋白酶抑制剂增效疗法涉及同时使用一种蛋白酶抑制剂，如沙奎那韦，再加上一种细胞色素P450（CYP）3A4的强效抑制剂，通常是小剂量的利托那韦。由于蛋白酶抑制剂主要通过CYP3A4进行广泛代谢，这会导致沙奎那韦或其他由利托那韦增效的蛋白酶抑制剂的全身暴露量显著增加。与传统的蛋白酶抑制剂治疗方案一样，增效方案通常与核苷类逆转录酶抑制剂（NRTIs）联合使用。在有蛋白酶抑制剂治疗经验和无治疗经验的HIV感染患者中，每日两次和每日一次的沙奎那韦增效方案在临床试验中实现了良好的病毒抑制率，提高了CD4 +细胞计数，并且总体耐受性良好。在一些针对接受挽救治疗的重度预处理HIV感染患者的小型研究中也报告了令人鼓舞的结果，这些患者接受了沙奎那韦加洛匹那韦与小剂量利托那韦的双重增效方案以及其他药物。最大规模的临床试验是多中心、随机比较每日两次的沙奎那韦增效方案与每日两次的茚地那韦（MaxCmin1）或洛匹那韦（MaxCmin2）增效方案。在MaxCmin1研究中，治疗期分析显示，两组中超过90%的患者在治疗48周后病毒载量检测不到（<400拷贝/毫升）。然而，在意向性分析中，沙奎那韦组实现病毒抑制的患者明显多于茚地那韦组，这似乎是因为茚地那韦组中因不良事件而退出随机治疗的患者比例显著更高。MaxCmin2试验的24周中期结果表明，两组合并后90%的患者血浆HIV RNA水平<400拷贝/毫升；48周的最终结果将分别报告沙奎那韦和洛匹那韦增效方案的数据。
在当前的HIV治疗指南中，增效蛋白酶抑制剂方案（包括两种NRTIs）被推荐作为一线选择，并在临床实践中广泛使用。与沙奎那韦增效方案相关的便捷给药方案和良好的药代动力学特征有可能提高治疗依从性，并通过增加药物暴露来改善抗逆转录病毒效果。每日两次的沙奎那韦增效方案是评估最广泛的增效蛋白酶抑制剂方案之一，已显示出对HIV疾病替代指标具有良好疗效，并且与茚地那韦增效方案相比具有显著的耐受性优势。每日一次的沙奎那韦增效方案可能最适合生活忙碌的HIV感染患者以及那些将从直接观察治疗中受益的患者。
