The application of multistate Markov models to HIV disease progression.

Abstract

Survival analysis is a well developed area which explores time to single event analysis. In some cases, however, such methods may not adequately capture the disease process as the disease progression may involve intermediate events of interest. Multistate models incorporate multiple events or states. This thesis proposes to demystify the theory of multistate models through an application based approach. We present the key components of multistate models, relevant derivations, model diagnostics and techniques for modeling the effect of covariates on transition intensities. The methods that are developed in the thesis are applied to HIV and TB data partly sourced from CAPRISA and the HPP programmes in the University of KwaZulu-Natal. HIV progression is investigated through the application of a five state Markov model with reversible transitions such that state 1: CD4 count 500, state 2: 350 CD4 count < 500, state 3: 200 CD4 count < 350, state 4: CD4 count < 200 and state 5: ARV initiation. The mean sojourn time in each state and transition probabilities are presented as well as the effect of covariates namely age, gender and baseline CD4 count on transition rates. A key finding, consistent with previous research, is that the rate of decline in CD4 count tends to decrease at lower levels of the marker. Further, patients enrolling with a CD4 count less than 350 had a far lower chance of immune recovery and a substantially higher chance of immune deterioration compared to patients with a higher CD4 count. We noted that older patients tend to progress more rapidly through the disease than younger patients.