A combinatorial ledge: reverse transcriptase fidelity, total body viral burden, and the implications of multiple-drug HIV therapy for the evolution of antiviral resistance
A combinatorial ledge: reverse transcriptase fidelity, total body viral burden, and the implications of multiple-drug HIV therapy for the evolution of antiviral resistance
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DOI：
10.1016/s0166-3542(98)00062-x
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发表时间：
1999-02-01
影响因子：
7.6
通讯作者：
Japour, A
中科院分区：
文献类型：
--
作者：
Colgrove, R;Japour, A
艾滋病毒在“稳定”感染阶段的慢性化、高变异率和高循环滴度使耐药突变的快速演变成为抗逆转录病毒疗效的关键预测因素。在病毒RNA滴度、周转动力学和体内耐药突变谱的测量方面的最新进展使得能够在体内真实地估计患者内部病毒耐药性演变的重要动力学参数。对许多抗逆转录病毒联合疗法耐药所需的病毒基因型频率的一级估计表明，许多这种基因型在开始治疗之前就已经存在于患者身上。然而，观察到的多重耐药基因的组合性质，以及目前对全身病毒载量和病毒周转动态的估计，意味着从两种药物到三种药物抗逆转录病毒方案的变化有一个惊人的急剧转变：先前存在的耐药性在第一种情况下几乎是确定的，但在第二种情况下极不可能。这一突如其来的变化是一种“组合悬崖”，它对理解和控制艾滋病毒感染以及抗病毒治疗的其他潜在目标具有许多重要意义。(C)1999 Elsevier Science B.V.保留所有权利。
The chronicity, high mutation rates, and high circulating titers of HIV during the 'stable' phase of infection make rapid evolution of resistance mutations a key predictor of antiretroviral efficacy. Recent advances in measurement of viral RNA titers, turnover dynamics and the in vivo spectrum of resistance mutations allow realistic in vivo estimates of important kinetic parameters of within-patient evolution of viral resistance. First-order estimates of the frequency of viral genotypes necessary for resistance to many antiretroviral combination regimens indicate that many such genotypes pre-exist in patients prior to initiation of therapy. The combinatorial nature of observed multiply-resistant genotypes, however, along with current estimates of total-body viral load and viral turnover dynamics, imply a strikingly sharp transition associated with the change from two-drug to three-drug antiretroviral regimens: pre-existing resistance being near-certain in the first instance but highly unlikely in the second. This abrupt change, a 'combinatorial ledge', carries with it a number of important implications for the understanding and control of HIV infection and other potential targets of antiviral therapy. (C) 1999 Elsevier Science B.V. All rights reserved.