Mo Hongmei, Lu Liangjun, Dekhtyar Tatyana, Stewart Kent D, Sun Eugene, Kempf Dale J, Molla Akhteruzzaman
Global Pharmaceutical Research Development, Department R47D, Abbott Laboratories, Building AP52N, 200 Abbott Park Road, Abbott Park, IL 60064-6217, USA.
Antiviral Res. 2003 Aug;59(3):173-80. doi: 10.1016/s0166-3542(03)00107-4.
Lopinavir (LPV, formerly ABT-378) is an HIV protease inhibitor (PI) that is co-administered with a small amount of ritonavir (RTV), which greatly increases and sustains the plasma levels of LPV. Lopinavir/ritonavir (LPV/r) has shown potent antiviral activity in both therapy-nai;ve and PI-experienced patients. To assess the effect of pharmacologically relevant ratios of LPV/RTV (LPV/r) on the emergence of resistant HIV in vitro, HIV-1 pNL4-3 was passaged in the presence of increasing concentrations of LPV alone and LPV/r. Passages with fixed 5/1 and 15/1 concentration ratios of LPV/r initially selected I84V and I50V/M46I mutants, respectively. Selection with LPV alone also generated the same initial mutants (I50V/M46I) as the 15/1 LPV/r passage. Further passage produced other mutations previously found to be associated with PI-resistance. Phenotypic susceptibility to both LPV and RTV decreased with successive passages, irrespective of whether RTV was present in the selection experiment. Furthermore, in the two selection experiments that included RTV (at either 5/1 or 15/1 LPV/r ratio), the IC(50) of RTV at each passage evaluated was at least five-fold higher than the concentration of RTV employed at that passage, while the IC(50) of LPV toward the passaged virus was similar to the concentration of LPV used at that passage, indicating that the selective pressure was attributable to LPV and not RTV.
洛匹那韦（LPV，原名ABT - 378）是一种HIV蛋白酶抑制剂（PI），与少量利托那韦（RTV）联合使用，这可极大提高并维持LPV的血浆水平。洛匹那韦/利托那韦（LPV/r）在初治患者和有PI治疗史的患者中均显示出强大的抗病毒活性。为了评估药理学相关比例的LPV/RTV（LPV/r）对体外HIV耐药性出现的影响，HIV - 1 pNL4 - 3在单独增加浓度的LPV和LPV/r存在的情况下传代。以固定的5/1和15/1浓度比例的LPV/r传代最初分别选择了I84V和I50V/M46I突变体。单独用LPV传代也产生了与15/1 LPV/r传代相同的初始突变体（I50V/M46I）。进一步传代产生了先前发现与PI耐药相关的其他突变。无论选择实验中是否存在RTV，对LPV和RTV的表型敏感性都随着连续传代而降低。此外，在包括RTV的两个选择实验（LPV/r比例为5/1或15/1）中，每次传代评估的RTV的IC50比该传代所用的RTV浓度至少高五倍，而LPV对传代病毒的IC50与该传代所用的LPV浓度相似，表明选择压力归因于LPV而非RTV。
