Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nat Med. 2012 Feb 19;18(3):446-51. doi: 10.1038/nm.2649.
Highly active antiretroviral therapy (HAART) has dramatically decreased mortality from HIV-1 infection and is a major achievement of modern medicine. However, there is no fundamental theory of HAART. Elegant models describe the dynamics of viral replication, but a metric for the antiviral activity of drug combinations relative to a target value needed for control of replication is lacking. Treatment guidelines are based on empirical results of clinical trials in which other factors such as regimen tolerability also affect outcome. Why only certain drug combinations control viral replication remains unclear. Here we quantify the intrinsic antiviral activity of antiretroviral drug combinations. We show that most single antiretroviral drugs show previously unappreciated complex nonlinear pharmacodynamics that determine their inhibitory potential at clinical concentrations. We demonstrate that neither of the major theories for drug combinations accurately predicts the combined effects of multiple antiretrovirals. However, the combined effects can be understood with a new approach that considers the degree of independence of drug effects. This analysis allows a direct comparison of the inhibitory potential of different drug combinations under clinical concentrations, reconciles the results of clinical trials, defines a target level of inhibition associated with treatment success and provides a rational basis for treatment simplification and optimization.
高效抗逆转录病毒疗法（HAART）显著降低了 HIV-1 感染的死亡率，是现代医学的重大成就。然而，HAART 并没有基本理论。优雅的模型描述了病毒复制的动态，但缺乏衡量药物组合相对于控制复制所需目标值的抗病毒活性的指标。治疗指南基于临床试验的经验结果，其中方案耐受性等其他因素也会影响结果。为什么只有某些药物组合能够控制病毒复制仍然不清楚。在这里，我们量化了抗逆转录病毒药物组合的内在抗病毒活性。我们表明，大多数单一抗逆转录病毒药物表现出以前未被认识的复杂非线性药代动力学，这决定了它们在临床浓度下的抑制潜力。我们证明，两种主要的药物组合理论都不能准确预测多种抗逆转录病毒药物的联合效应。然而，通过考虑药物作用的独立性程度，可以用一种新的方法来理解联合效应。这种分析允许在临床浓度下直接比较不同药物组合的抑制潜力，调和临床试验的结果，定义与治疗成功相关的抑制目标水平，并为治疗简化和优化提供合理的依据。
