Production of resistant HIV mutants during antiretroviral therapy

HIV drug therapy often fails because of the appearance of multidrug-resista nt virus. There are two possible scenarios for the outgrowth of multidrug-r esistant virus in response to therapy, Resistant virus may preexist at low frequencies in drug-naive patients and is rapidly selected in the presence of drugs. Alternatively, resistant virus is absent at the start of therapy but is generated by residual viral replication during therapy. Currently av ailable experimental methods are generally too insensitive to distinguish b etween these two scenarios, Here we use deterministic and stochastic models to investigate the origin of multidrug resistance. We quantify the probabi lities that resistant mutants preexist, and that resistant mutants are gene rated during therapy. The models suggest that under a wide range of conditi ons, treatment failure is most likely caused by the preexistence of resista nt mutants.