Dam Elisabeth, Lebel-Binay Sophie, Rochas Séverine, Thibaut Laurent, Faudon Jean-Louis, Thomas Claire-Marie, Essioux Laurent, Hill Andrew, Schutz Malte, Clavel François
Viralliance, Paris, France.
Antivir Ther. 2007;12(3):371-80.
Double-boosted protease inhibitors (PIs) are under investigation for the treatment of patients who are unable to take nucleoside reverse transcriptase inhibitors because of cross-resistance and/or intolerance. Evidence of synergistic inhibition of wild-type HIV has been reported for saquinavir with atazanavir or lopinavir.
We investigated the activity of these two combinations against a panel of six site-directed mutant HIV-1 strains and 14 clinically derived recombinant HIV-1 strains presenting a range of PI-resistance profiles.
No evidence of synergy was observed against wild-type virus for either combination. The combination of saquinavir and lopinavir showed evidence of synergy against four viruses displaying high-level resistance to lopinavir and low-level resistance to saquinavir. Similarly, evidence of synergy between saquinavir and atazanavir was only observed in two viruses which were more susceptible to saquinavir than to atazanavir.
We hypothesize that differences between the PIs in intracellular protein-binding behaviour or inhibition of drug transporters (P glycoprotein, MDR1 and MDR2) could result in intracellular levels of saquinavir being increased by co-administration with lopinavir or atazanavir. The effect of this increase would be masked in cases involving viruses that were susceptible to atazanavir or lopinavir. In virus resistant to lopinavir or atazanavir but susceptible to saquinavir, the majority of the antiviral effect is due to saquinavir; thus even small increases in intracellular concentration could significantly increase virus inhibition. These results confirm that in vitro synergy can be observed between PIs and suggest that the degree of synergy observed might depend on the resistance profile of the virus.
因交叉耐药和/或不耐受而无法服用核苷类逆转录酶抑制剂的患者，正在接受双重强化蛋白酶抑制剂（PIs）治疗。已报道沙奎那韦与阿扎那韦或洛匹那韦联合使用对野生型HIV具有协同抑制作用。
我们研究了这两种联合用药对一组6种位点定向突变的HIV-1毒株和14种临床分离的重组HIV-1毒株的活性，这些毒株呈现出一系列PI耐药谱。
两种联合用药对野生型病毒均未观察到协同作用的证据。沙奎那韦与洛匹那韦联合使用对4种对洛匹那韦呈现高水平耐药和对沙奎那韦呈现低水平耐药的病毒显示出协同作用的证据。同样，沙奎那韦与阿扎那韦之间的协同作用仅在2种对沙奎那韦比对阿扎那韦更敏感的病毒中观察到。
我们推测，PIs在细胞内蛋白结合行为或对药物转运体（P糖蛋白、MDR1和MDR2）的抑制作用方面的差异，可能导致沙奎那韦与洛匹那韦或阿扎那韦联合使用时细胞内沙奎那韦水平升高。在涉及对阿扎那韦或洛匹那韦敏感的病毒的情况下，这种升高的影响会被掩盖。在对洛匹那韦或阿扎那韦耐药但对沙奎那韦敏感的病毒中，大部分抗病毒作用归因于沙奎那韦；因此，即使细胞内浓度的小幅升高也可能显著增强病毒抑制作用。这些结果证实了PIs之间在体外可观察到协同作用，并表明观察到的协同程度可能取决于病毒的耐药谱。
