Department of Microbiology and Immunology, Centre Hospitalier de l'Université de Montréal, Montréal, Canada.
Ther Clin Risk Manag. 2008 Aug;4(4):759-66. doi: 10.2147/tcrm.s1709.
Darunavir is a second-generation protease inhibitor designed to have antiviral efficacy against HIV-1 isolates harboring multiple resistance mutations to protease inhibitors. Pivotal trials conducted in treatment-experienced HIV-infected individuals have demonstrated significantly greater virological suppression when darunavir was added to an optimized background treatment compared with a control protease inhibitor. This virological suppression was associated with an increase in CD4 counts and was sustained over time. Darunavir resistance-associated mutations have been defined as V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V. In clinical trials, baseline darunavir susceptibility was a strong predictor of virological response. Prior use of fosamprenavir was associated with darunavir resistance mutations. Darunavir has a high genetic barrier and has a distinct resistance profile. Although some cross-resistance exists with other second-generation protease inhibitors such as tipranavir, different resistance mutation patterns have been observed upon failure to these regimens. It was found that mutations at 47V, 54M, 85V, and 73T were most prevalent in isolates resistant to both PIs. Mutations 48V, 50V, and 54L were associated with resistance to darunavir but not to tipranavir. 82S and 82T were associated with resistance to tipranavir but not to darunavir. Therefore, darunavir provides potent virological efficacy as well as high genetic barrier that can be useful to preserve treatment options in HIV-infected, treatment-experienced individuals.
达芦那韦是一种第二代蛋白酶抑制剂，旨在对携带多种蛋白酶抑制剂耐药突变的 HIV-1 分离株具有抗病毒疗效。在有治疗经验的 HIV 感染者中进行的关键性试验表明，与对照蛋白酶抑制剂相比，当达芦那韦加入优化的背景治疗时，病毒学抑制效果显著提高。这种病毒学抑制与 CD4 计数的增加有关，并随着时间的推移而持续。已经定义了达芦那韦耐药相关突变，包括 V11I、V32I、L33F、I47V、I50V、I54L/M、G73S、L76V、I84V 和 L89V。在临床试验中，基线达芦那韦敏感性是病毒学反应的一个强有力预测因素。先前使用福沙那韦与达芦那韦耐药突变有关。达芦那韦具有较高的遗传屏障和独特的耐药谱。虽然与其他第二代蛋白酶抑制剂（如替拉那韦）存在一定的交叉耐药性，但在这些方案失败时观察到了不同的耐药突变模式。发现 47V、54M、85V 和 73T 突变在对两种 PI 均耐药的分离株中最为常见。48V、50V 和 54L 突变与达芦那韦耐药有关，但与替拉那韦耐药无关。82S 和 82T 与替拉那韦耐药有关，但与达芦那韦耐药无关。因此，达芦那韦提供了强大的病毒学疗效和较高的遗传屏障，这在有治疗经验的 HIV 感染者中可用于保留治疗选择。
