A DYNAMIC BAYESIAN NONLINEAR MIXED-EFFECTS MODEL OF HIV RESPONSE INCORPORATING MEDICATION ADHERENCE, DRUG RESISTANCE AND COVARIATES().

HIV dynamic studies have contributed significantly to the understanding of HIV pathogenesis and antiviral treatment strategies for AIDS patients. Establishing the relationship of virologic responses with clinical factors and covariates during long-term antiretroviral (ARV) therapy is important to the development of effective treatments. Medication adherence is an important predictor of the effectiveness of ARV treatment, but an appropriate determinant of adherence rate based on medication event monitoring system (MEMS) data is critical to predict virologic outcomes. The primary objective of this paper is to investigate the effects of a number of summary determinants of MEMS adherence rates on virologic response measured repeatedly over time in HIV-infected patients. We developed a mechanism-based differential equation model with consideration of drug adherence, interacted by virus susceptibility to drug and baseline characteristics, to characterize the long-term virologic responses after initiation of therapy. This model fully integrates viral load, MEMS adherence, drug resistance and baseline covariates into the data analysis. In this study we employed the proposed model and associated Bayesian nonlinear mixed-effects modeling approach to assess how to efficiently use the MEMS adherence data for prediction of virologic response, and to evaluate the predicting power of each summary metric of the MEMS adherence rates. In particular, we intend to address the questions: (i) how to summarize the MEMS adherence data for efficient prediction of virologic response after accounting for potential confounding factors such as drug resistance and covariates, and (ii) how to evaluate treatment effect of baseline characteristics interacted with adherence and other clinical factors. The approach is applied to an AIDS clinical trial involving 31 patients who had available data as required for the proposed model. Results demonstrate that the appropriate determinants of MEMS adherence rates are important in order to more efficiently predict virologic response, and investigations of adherence to ARV treatment would benefit from measuring not only adherence rate but also its summary metric assessment. Our study also shows that the mechanism-based dynamic model is powerful and effective to establish a relationship of virologic responses with medication adherence, virus resistance to drug and baseline covariates.