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 transcriptase (RT) occur during adefovir dipivoxil (ADV) therapy that may alter the susceptibility of HIV to adefovir or the related nucleotide inhibitor, tenofovir.


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 compared with placebo for the treatment of HIV when added to stable background antiretroviral therapy (ART). Of 442 patients enrolled, 142 were prospectively selected for a virology substudy. Baseline and posttreatment (weeks 24-48) plasma samples were genotypically analyzed in HIV RT. HIV from ADV-treated patients who developed RT mutations at week 24 were also phenotypically analyzed.


RESULTS
Nucleoside-associated RT mutations arose with similar frequency among the ADV-and placebo-treated patients, 32% (n = 23) and 28% (n = 20), respectively, during the 24-week blinded treatment phase. RT mutations previously 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) concomitantly, 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 placebo arm. Between weeks 24 and 48, 19 of 50 patients (38%) in the ADV arm developed similar RT mutations. The mean HIV 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, similar to the overall week-24 and week-48 responses (-0.53 and 0.48 log(10) copies/ml, respectively). Patient-derived HIV expressing the observed RT mutations showed insignificant decreases in adefovir susceptibility compared with wild-type in 12 of 16 cases (< threefold). HIV from 1 patient showed significantly reduced susceptibility to tenofovir, which was 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 attributable to the patient's background ART. ADV therapy may have influenced the pattern of ZDV-associated resistance mutations that developed, but this did not result in an observed loss of viral load suppression. There was a trend toward decreased phenotypic susceptibility to adefovir in ADV-treated patients, with 4 of 16 analyzed patients showing mild, but significantly decreased susceptibility associated with the additional ZDV-associated mutations. Decreased susceptibility to the related nucleotide analog, tenofovir, was not observed to develop in ADV-treated patients.
Miller
M D
MD
Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA 94404, U.S.A. Michael_Miller@gilead.com
Margot
N A
NA
Lamy
P D
PD
Fuller
M D
MD
Anton
K E
KE
Mulato
A S
AS
Cherrington
J M
JM
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D004311:Double-Blind Method; D005814:Genes, Viral; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000068698:Tenofovir
D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; C053001:adefovir; D000068698:Tenofovir; D054303:HIV Reverse Transcriptase; D000225:Adenine