Adefovir and tenofovir susceptibilities of HIV-1 after 24 to 48 weeks of adefovir dipivoxil therapy: Genotypic and phenotypic analyses of study GS-96-408

Objective: To determine whether genotypic changes in HIV-1 (HIV) reverse tr anscriptase (RT) occur during adefovir dipivoxil (ADV) therapy that may alt er the susceptibility of HIV to adefovir or the related nucleotide inhibito r, tenofovir. Design and Methods: GS-96-408 was a 1:1 randomized, double-blind, phase III clinical trial assessing the safety and efficacy of 120-mg daily ADV compa red with placebo for the treatment of HIV when added to stable background a ntiretroviral therapy (ART). Of 442 patients enrolled, 142 were prospective ly selected for a virology substudy. Baseline and posttreatment (weeks 24-4 8) plasma samples were genotypically analyzed in HIV RT. HIV from ADV-treat ed patients who developed PZT mutations at week 24 were also phenotypically analyzed. Results: Nucleoside-associated RT mutations arose with similar frequency am ong the ADV- and placebo-treated patients, 32% (n = 23) and 28%, (n = 20), respectively, during the 24-week blinded treatment phase. RT mutations prev iously selected by adefovir in vitro (K70E or K65R) did not develop in any patient. Most mutations were typical zidovudine (ZDV)-resistance mutations (e.g., M41L, D67N, K70R, T215Y) in patients taking ZDV or stavudine (d4T) c oncomitantly, demonstrating directly in the placebo arm that d4T is able to select for these mutations. There appeared to be more patients developing D67N and K70R mutations in the ADV arm versus more T215Y mutations in the p lacebo arm. Between weeks 24 and 48, 19 of 50 patients (38%) in the ADV arm developed similar RT mutations. The mean MV RNA responses at weeks 24 and 48 among the ADV-treated patients developing RT mutations were -0.68 log(10 ) copies/ml (n = 23) and -0.52 log(10) copies/ml (n = 19), respectively, si milar to the overall week-24 and week-48 responses (-0.53 and 0.48 log(10) copies/ml, week-24 and week respectively). Patient-derived I-HV expressing the observed RT mutations showed insignificant decreases in adefovir suscep tibility compared with wild-type in 12 of 16 cases (< threefold). HIV from I patient showed significantly reduced susceptibility to tenofovir. which w as in association with a double insertion mutation after codon 69 that was also present at baseline. Conclusions: HIV RT changes that arose during ADV therapy appear attributab le to the patient's background ART. ADV therapy may have influenced the pat tern of ZDV-associated resistance mutations that developed, but this did no t result in an observed loss of viral load suppression. There was a trend t oward decreased phenotypic susceptibility to adefovir in ADV-treated patien ts, with 4 of 16 analyzed patients showing mild, but significantly decrease d susceptibility associated with the additional ZDV-associated mutations. D ecreased susceptibility to the related nucleotide analog, tenofovir, was no t observed to develop in ADV-treated patients.