Murray John M, Emery Sean, Kelleher Anthony D, Law Matthew, Chen Joshua, Hazuda Daria J, Nguyen Bach-Yen T, Teppler Hedy, Cooper David A
National Centre in HIV Epidemiology and Clinical Research, Sydney, NSW 2052, Australia.
AIDS. 2007 Nov 12;21(17):2315-21. doi: 10.1097/QAD.0b013e3282f12377.
Raltegravir (MK-0518) belongs to the new class of HIV integrase inhibitors. To date, there have been no reports investigating the potential for differential effects on viral dynamics with integrase inhibitors relative to current antiretroviral drugs.
Patients in this phase II study (P004) were antiretroviral treatment naive. Part 1 of this study compared monotherapy with raltegravir (100 mg, 200 mg, 400 mg, or 600 mg twice daily) with placebo over 10 days. In part 2, patients were enrolled for 48 weeks of combination therapy, with randomization to one of the four dosages of raltegravir or to efavirenz, in addition to tenofovir and lamivudine. Mathematical models were used to investigate processes underlying viral dynamics.
From day 15 through to day 57, individuals in the raltegravir arm were significantly more likely to have HIV RNA < 50 copies/ml (P < or = 0.047). Plasma viral loads were 70% lower at initiation of second-phase decay for individuals taking raltegravir than for those taking efavirenz (P < 0.0001). This challenges the current hypothesis that second-phase virus originates from infected long-lived cells, as an integrase inhibitor should not impact on viral production from this cell population. Mathematical modeling supported two hypotheses as consistent with these observations: (i) that second-phase virus arises from cells newly infected by long-lived infected cells and (2) that it arises from activation of latently infected cells with full-length unintegrated HIV DNA.
These observations challenge the current understanding of HIV-1 turnover and compartmentalization. They also indicate the promise of this new integrase inhibitor raltegravir.
雷特格韦（MK - 0518）属于新型HIV整合酶抑制剂。迄今为止，尚无关于整合酶抑制剂与现有抗逆转录病毒药物相比对病毒动力学潜在差异影响的研究报道。
该II期研究（P004）中的患者既往未接受过抗逆转录病毒治疗。本研究的第1部分比较了雷特格韦单药治疗（100毫克、200毫克、400毫克或600毫克，每日两次）与安慰剂在10天内的疗效。在第2部分中，患者接受48周的联合治疗，随机分配至四种剂量的雷特格韦之一或依非韦伦，同时联合替诺福韦和拉米夫定。采用数学模型研究病毒动力学的潜在过程。
从第15天到第57天，接受雷特格韦治疗的患者HIV RNA < 50拷贝/毫升的可能性显著更高（P≤0.047）。与接受依非韦伦治疗的患者相比，接受雷特格韦治疗的患者在第二阶段病毒衰减开始时血浆病毒载量低70%（P < 0.0001）。这对当前关于第二阶段病毒源自受感染长寿细胞的假设提出了挑战，因为整合酶抑制剂不应影响该细胞群体的病毒产生。数学模型支持与这些观察结果一致的两种假设：（i）第二阶段病毒源自长寿感染细胞新感染的细胞；（ii）它源自具有全长未整合HIV DNA的潜伏感染细胞的激活。
这些观察结果挑战了目前对HIV - 1周转和区室化的理解。它们还表明了这种新型整合酶抑制剂雷特格韦的前景。
