title: Rate of virologic failure and selection of drug resistance mutations using different triple nucleos(t)ide analogue combinations in HIV-infected patients.
abstract: Virologic failure seems to occur more frequently in HIV-infected patients treated with triple nucleoside analogue (NA) combinations than with regimens including nonnucleoside reverse transcriptase inhibitors or protease inhibitors. However, the rate of failure and resistance profiles may differ with distinct triple NA combinations. A retrospective review of all HIV-infected individuals who received triple NA combinations at our institution was conducted. Virologic failure was defined as lack of achievement of plasma HIV-RNA<50 copies/ml at week 16 following initiation of antiretroviral therapy or as viral rebound in subjects with prior undetectable viremia. Genotypic analyses were performed at the time of first virological failure. Of the 261 patients identified, 13 were drug naive, 126 had underwent simplification, and 122 were antiretroviral-experienced patients with detectable viral load. Virologic failure was recorded in 95 (36.4%) after an average follow-up of 19 months. Rates were 0.67 in drug-naive, 0.55 in simplification, and 2.38 in rescue interventions for 100 persons-month follow-up. Factors associated with virologic failure in the multivariate Cox regression analysis were rescue vs naive or simplification strategies (OR 2.6; 95% CI 1.6-4.2) and using tenofovir as part of the combination (OR 2.04; 95% CI 1.3-3.2). In contrast, the use of AZT prevented virologic failure (OR 0.52; 95% CI 0.3-0.8). M184V was the most frequent resistance mutation (75.4%), followed by T215Y (52.5%) and K65R (14.8%). Of note, K65R did not develop in patients taking AZT nor in those with prior thymidine-associated mutations (TAMs). Conversely, subjects who developed K65R did not accumulate TAMs. Virologic failure is relatively frequent in patients treated only with triple NA regimens, particularly in the setting of rescue therapy. The use of TDF might be associated with a higher risk of virologic failure and, conversely, AZT might be protective. The presence of TAMs precluded the selection of K65R in patients treated with TDF. Resistance pathways for TDF and thymidine analogues seem to be divergent and could be the basis to explore a synergism between these drugs.
authors.affiliation: Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain. luz-martin@inicia.es
authors.forename: Luz
authors.initials: L
authors.lastname: Martín-Carbonero
authors.forename: Paldma
authors.initials: P
authors.lastname: Gil
authors.forename: Teresa
authors.initials: T
authors.lastname: García-Benayas
authors.forename: Pablo
authors.initials: P
authors.lastname: Barreiro
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco
authors.forename: Carmen
authors.initials: C
authors.lastname: de Mendoza
authors.forename: Ivana
authors.initials: I
authors.lastname: Maida
authors.forename: Juan
authors.initials: J
authors.lastname: González-Lahoz
authors.forename: Vincent
authors.initials: V
authors.lastname: Soriano
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000494:pharmacology; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000068698:Tenofovir; D017211:Treatment Failure; D019562:Viral Load; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D044966:Anti-Retroviral Agents; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D000068698:Tenofovir; D000225:Adenine