QUASI-SPECIES DYNAMICS AND THE EMERGENCE OF DRUG-RESISTANCE DURING ZIDOVUDINE THERAPY OF HIV-INFECTION

Objective: To investigate the roles of mutation, competition and popul ation dynamics in the emergence of drug resistant mutants during zidov udine therapy. Design: A mathematical model of the population dynamics of the viral quasispecies during zidovudine therapy was investigated. Methods: The model was used to simulate changes in the numbers of uni nfected and infected cells and the composition of the viral quasispeci es in the years following initiation of therapy. Resulting scenarios i n asymptomatic and AIDS patients were compared. The model was also use d to investigate the efficacy of a treatment regimen involving alterna ting zidovudine and dideoxyinosine therapy. Results: The behaviour of the model can be divided into three stages. Before therapy, mutation m aintains a small pool of resistant mutants, outcompeted to very low le vels by sensitive strains. When therapy begins there is a dramatic fal l in the total viral load and resistant strains suddenly have the comp etitive advantage. Thus, it is resistant strains that infect the risin g number of uninfected CD4+ cells. During this second stage the rapid effects of population dynamics swamp any effects of mutation between s trains. When the populations of infected and uninfected cells approach their treatment equilibrium levels, mutation again becomes important in the slow generation of highly resistant strains. Conclusions: The s hort-term reduction in viral replication at the initiation of therapy generates a pool of uninfected cells which cause the eventual increase in viral burden. This increase is associated with (but not caused by) a rise in frequency of resistant strains which are at a competitive a dvantage in the presence of the drug. When therapy is ceased, reversio n of resistance is slow as resistant strains are nearly as fit as sens itive strains in the absence of drug.