GENOTYPIC AND PHENOTYPIC CHARACTERIZATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VARIANTS ISOLATED FROM AIDS PATIENTS AFTER PROLONGED ADEFOVIR DIPIVOXIL THERAPY

Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally b ioavailable prodrug of adefovir [9-(2-phosphonylmethoxyethyl)adenine], is currently in phase III clinical trials for the treatment of human immunodeficiency virus (HIV). In vitro experiments demonstrated that e ither a K65R or a K70E mutation in HIV reverse transcriptase (RT) was selected in the presence of adefovir, conferring a 16- or 9-fold decre ase in susceptibility to adefovir, respectively. Previous data demonst rated that patients receiving adefovir dipivoxil monotherapy (125 mg d aily) for 12 weeks experienced a median decrease in HIV RNA levels of 0.5 log(10) copies/ml and that resistance to adefovir dipivoxil did no t arise during that period. In the present investigation, a further st udy was undertaken to investigate whether RT mutations developed among viruses from patients who completed the 12-week study and who opted t o enroll in a maintenance phase of prolonged (6- to 12-month) adefovir dipivoxil therapy (120 mg daily), Concomitant treatment with antiretr oviral agents was permitted during the maintenance phase. The median d ecreases in HIV RNA levels for patients who completed 6 or 12 months o f maintenance-phase dosing were 0.6 and 1.14 log(10) copies/ml, respec tively. The reductions in the HIV RNA levels were similar among patien ts who received adefovir dipivoxil with or without concomitant treatme nt with antiretroviral agents. Viruses from 8 of 29 patients dosed for up to 12 months developed RT mutations that were not present at basel ine; these mutations may have been related to adefovir dipivoxil thera py. Viruses from two of the eight patients developed the K70E mutation while the patients were on therapy, but none of the viruses from pati ents developed the K65R RT substitution, Despite the development of RT mutations, sustained reductions (6 to 12 months) in viral load (great er than or equal to 0.7 log(10) copies/ml decrease from baseline) were observed in all eight patients.