Identifying significant covariates for anti-HIV treatment response: mechanism-based differential equation models and empirical semiparametric regression models.

In this paper, the mechanism-based ordinary differential equation (ODE) model and the flexible semiparametric regression model are employed to identify the significant covariates for antiretroviral response in AIDS clinical trials. We consider the treatment effect as a function of three factors (or covariates) including pharmacokinetics, drug adherence and susceptibility. Both clinical and simulated data examples are given to illustrate these two different kinds of modeling approaches. We found that the ODE model is more powerful to model the mechanism-based nonlinear relationship between treatment effects and virological response biomarkers. The ODE model is also better in identifying the significant factors for virological response, although it is slightly liberal and there is a trend to include more factors (or covariates) in the model. The semiparametric mixed-effects regression model is very flexible to fit the virological response data, but it is too liberal to identify correct factors for the virological response; sometimes it may miss the correct factors. The ODE model is also biologically justifiable and good for predictions and simulations for various biological scenarios. The limitations of the ODE models include the high cost of computation and the requirement of biological assumptions that sometimes may not be easy to validate. The methodologies reviewed in this paper are also generally applicable to studies of other viruses such as hepatitis B virus or hepatitis C virus.