Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from AIDS patients after prolonged adefovir dipivoxil therapy.

Abstract

Adefovir dipivoxil [bis(pivaloyloxymethyl)-ester prodrug], an orally bioavailable 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 either a K65R or a K70E mutation in HIV reverse transcriptase (RT) was selected in the presence of adefovir, conferring a 16- or 9-fold decrease in susceptibility to adefovir, respectively. Previous data demonstrated that patients receiving adefovir dipivoxil monotherapy (125 mg daily) for 12 weeks experienced a median decrease in HIV RNA levels of 0.5 log10 copies/ml and that resistance to adefovir dipivoxil did not arise during that period. In the present investigation, a further study was undertaken to investigate whether RT mutations developed among viruses from patients who completed the 12-week study and who opted to enroll in a maintenance phase of prolonged (6- to 12-month) adefovir dipivoxil therapy (120 mg daily). Concomitant treatment with antiretroviral agents was permitted during the maintenance phase. The median decreases in HIV RNA levels for patients who completed 6 or 12 months of maintenance-phase dosing were 0.6 and 1.14 log10 copies/ml, respectively. The reductions in the HIV RNA levels were similar among patients who received adefovir dipivoxil with or without concomitant treatment with antiretroviral agents. Viruses from 8 of 29 patients dosed for up to 12 months developed RT mutations that were not present at baseline; these mutations may have been related to adefovir dipivoxil therapy. Viruses from two of the eight patients developed the K70E mutation while the patients were on therapy, but none of the viruses from patients developed the K65R RT substitution. Despite the development of RT mutations, sustained reductions (6 to 12 months) in viral load (> or = 0.7 log10 copies/ml decrease from baseline) were observed in all eight patients.