Ding A A, Wu H
Department of Mathematics, Northeastern University, Boston, MA 02115, USA.
Biostatistics. 2001 Mar;2(1):13-29. doi: 10.1093/biostatistics/2.1.13.
A virologic marker, the number of HIV RNA copies or viral load, is currently used to evaluate anti-HIV therapies in AIDS clinical trials. This marker can be used to assess the antiviral potency of therapies, but is easily affected by noncompliance, drug resistance, toxicities, and other factors during the long-term treatment evaluation process. Recently it has been suggested to use viral dynamics to assess the potency of antiviral drugs and therapies, since viral decay rates in viral dynamic models have been shown to be related to the antiviral drug potency directly, and they need a shorter evaluation time. In this paper we first review the two statistical approaches for characterizing HIV dynamics and estimating viral decay rates: the individual nonlinear least squares regression (INLS) method and the population nonlinear mixed-effect model (PMEM) approach. To compare the viral decay rates between two treatment arms, parametric and nonparametric tests, based on the estimates of viral decay rates (the derived variables) from both the INLS and PMEM methods, are proposed and studied. We show, using the concept of exchangeability, that the test based on the empirical Bayes' estimates from the PMEM is valid, powerful and robust. This proposed method is very useful in most practical cases where the INLS-based tests and the general likelihood ratio test may not apply. We validate and compare various tests for finite samples using Monte Carlo simulations. Finally, we apply the proposed tests to an AIDS clinical trial to compare the antiviral potency between a 3-drug combination regimen and a 4-drug combination regimen. The proposed tests provide some significant evidence that the 4-drug regimen is more potent than the 3-drug regimen, while the naive methods fail to give a significant result.*To whom correspondence should be addressed.
病毒学标志物，即HIV RNA拷贝数或病毒载量，目前用于评估艾滋病临床试验中的抗HIV治疗。该标志物可用于评估治疗的抗病毒效力，但在长期治疗评估过程中容易受到不依从、耐药性、毒性及其他因素的影响。最近有人建议使用病毒动力学来评估抗病毒药物和治疗的效力，因为病毒动力学模型中的病毒衰减率已被证明与抗病毒药物效力直接相关，而且评估时间较短。在本文中，我们首先回顾两种用于表征HIV动力学和估计病毒衰减率的统计方法：个体非线性最小二乘回归（INLS）方法和群体非线性混合效应模型（PMEM）方法。为了比较两个治疗组之间的病毒衰减率，我们提出并研究了基于INLS和PMEM方法估计的病毒衰减率（导出变量）的参数检验和非参数检验。我们使用可交换性的概念表明，基于PMEM的经验贝叶斯估计的检验是有效、有力且稳健的。在大多数基于INLS的检验和一般似然比检验可能不适用的实际情况下，这种提出的方法非常有用。我们使用蒙特卡罗模拟对有限样本的各种检验进行验证和比较。最后，我们将提出的检验应用于一项艾滋病临床试验，以比较三联药物联合治疗方案和四联药物联合治疗方案的抗病毒效力。提出的检验提供了一些重要证据，表明四联药物治疗方案比三联药物治疗方案更有效，而传统方法未能得出显著结果。*通信作者联系方式如下。
