Ribera Esteban, Curran Adrian
Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
Drugs. 2008;68(16):2257-67. doi: 10.2165/0003495-200868160-00001.
Despite the clinical benefit observed with early highly active antiretroviral therapy, its toxicity and inconvenience, and the strategy of sequentially adding newly available drugs to failing regimens meant that for many patients, it was difficult to build an effective regimen soon after starting therapy. In this setting, the idea of using double-boosted protease inhibitors (PIs) to build a potent regimen emerged. The rationale for the simultaneous use of two PIs is (i) to provide synergistic or additive activity against HIV; (ii) to achieve higher plasma concentrations of both PIs with only one booster; (iii) to increase the genetic barrier to resistance; and/or (iv) to avoid toxicity with nucleoside reverse transcriptase inhibitor-sparing regimens.Double-boosted PI strategies are not recommended in treatment-naive patients because of their low success rate and the availability of more convenient and effective regimens.There are no adequate trials in treatment-experienced patients to establish the clinical efficacy of double-boosted PI regimens; however, the published non-comparative studies suggest considerable efficacy with certain combinations (e.g. lopinavir/ritonavir plus atazanavir, lopinavir/ritonavir plus saquinavir and others) in patients in whom a conventional regimen with one boosted PI could have little chance of success.New drugs of old and new classes that are better tolerated and have different resistance profiles have become available in recent years. These drugs have demonstrated their efficacy in randomized clinical trials, even in patients with extensive treatment experience and high drug resistance. Nowadays, in almost all patients, it is possible to elaborate a regimen with three active drugs, achieving success rates similar to those obtained in treatment-naive patients with recommended regimens. In this context, it is unthinkable that double-boosted PIs could play any role.Double-boosted PIs may be an alternative for those patients with limited therapeutic options in resource-poor settings, where new expensive drugs are not currently available. The fixed combination of lopinavir/ritonavir tablets makes it easier to boost with another PI at the same time, without requiring ritonavir refrigeration, and this may be particularly useful in this setting.
尽管早期高效抗逆转录病毒疗法显示出临床益处，但其毒性和不便之处，以及在治疗方案失败时依次添加新可用药物的策略意味着，对许多患者来说，在开始治疗后不久很难构建有效的治疗方案。在这种情况下，使用双倍增效蛋白酶抑制剂（PIs）构建强效治疗方案的想法应运而生。同时使用两种PIs的理论依据是：（i）对HIV提供协同或相加活性；（ii）仅用一种增效剂就能使两种PIs达到更高的血浆浓度；（iii）增加耐药的遗传屏障；和/或（iv）避免核苷类逆转录酶抑制剂节省方案带来的毒性。由于双倍增效PI策略成功率低且有更方便有效的治疗方案可供选择，因此不建议初治患者使用。在经治患者中，尚无足够的试验来确立双倍增效PI治疗方案的临床疗效；然而，已发表的非对照研究表明，某些组合（如洛匹那韦/利托那韦加阿扎那韦、洛匹那韦/利托那韦加沙奎那韦等）在使用一种增效PI的传统治疗方案成功可能性很小的患者中具有相当的疗效。近年来，出现了耐受性更好且耐药谱不同的新旧类别新药。这些药物在随机临床试验中已证明了其疗效，即使是在有广泛治疗经验和高耐药性的患者中。如今，几乎在所有患者中，都有可能制定出包含三种活性药物的治疗方案，成功率与推荐方案治疗的初治患者相似。在这种情况下，双倍增效PIs发挥任何作用都是不可想象的。对于资源匮乏地区治疗选择有限且目前尚无新的昂贵药物的患者，双倍增效PIs可能是一种选择。洛匹那韦/利托那韦片的固定组合使得同时用另一种PI进行增效更容易，且无需冷藏利托那韦，这在这种情况下可能特别有用。
