Characterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies.
The randomized, placebo-controlled Phase III DUET studies enrolled treatment-experienced, HIV-1-infected patients. We examined the genotypic and phenotypic changes at endpoint relative to baseline, including the emergence of individual reverse transcriptase (RT) mutations, in patients who received the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine and experienced virologic failure by rebound by the time of the Week 96 analysis. Patients received etravirine 200 mg twice-daily in combination with a background regimen containing darunavir/ritonavir, investigator-selected nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. Virologic failure by rebound occurred in 93 (15.5%) etravirine-treated patients (compared with 170 [28.1%] placebo-treated patients). Patients experiencing virologic failure had more baseline antiretroviral resistance and lower activity of the background regimen relative to those not experiencing failure. Emergence of NNRTI resistance-associated mutations was observed in 55 of 93 patients. The most frequently emerging RT mutations were V179F, V179I, and Y181C, with positions K101 and E138 also showing frequent changes. Mutations usually emerged in a background of multiple other NNRTI mutations and were, in most cases, associated with a decrease in phenotypic sensitivity to etravirine at endpoint. Further analysis is needed to clarify the role of mutations at position 138 as determinants of etravirine resistance.
Tambuyzer
Lotke
L
Tibotec BVBA , Mechelen, Belgium. ltambuyz@its.jnj.com
Vingerhoets
Johan
J
Azijn
Hilde
H
Daems
Bjorn
B
Nijs
Steven
S
de Béthune
Marie-Pierre
MP
Picchio
Gastón
G
D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic; D000069454:Darunavir; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000008:administration & dosage; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D009570:Nitriles; D010446:Peptide Fragments / Q000008:administration & dosage; D011724:Pyridazines / Q000008:administration & dosage*; D011743:Pyrimidines; D016032:Randomized Controlled Trials as Topic; D019438:Ritonavir / Q000008:administration & dosage; D017422:Sequence Analysis, DNA; D013449:Sulfonamides / Q000008:administration & dosage; D017211:Treatment Failure; D019562:Viral Load
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D009570:Nitriles; D010446:Peptide Fragments; D011724:Pyridazines; D011743:Pyrimidines; D013449:Sulfonamides; C451734:etravirine; D000077560:Enfuvirtide; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D019438:Ritonavir; D000069454:Darunavir