HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE GENOTYPES AND IN-VITRO PROTEASE INHIBITOR SUSCEPTIBILITIES OF ISOLATES FROM INDIVIDUALS WHO WERE SWITCHED TO OTHER PROTEASE INHIBITORS AFTER LONG-TERM SAQUINAVIR TREATMENT

An understanding of the mechanisms of virologic cross-resistance betwe en human immunodeficiency virus type 1 protease inhibitors is importan t for the establishment of effective treatment strategies for patients who no longer respond to their initial protease inhibitor. Protease g ene sequencing results from patients treated with saquinavir showed si gnificant increases in the frequency of the G48V protease mutation in patients receiving higher doses of the drug. In addition, all six pati ents who developed the G48V mutation during saquinavir therapy develop ed the V82A mutation either on continued saquinavir or after a switch to nelfinavir or indinavir. In vitro susceptibility assays showed that all 13 isolates with reduced susceptibilities to two or more protease inhibitors had either the G48V or L90M mutation, along with an averag e of six other protease mutations. Reduced susceptibility to nelfinavi r was found in 14 isolates, but only 1 possessed the D30N mutation. Th ese results suggest that mutations selected in vivo by initial saquina vir therapy may provide more cross-resistance to the other protease in hibitors than has been previously reported.