Early Virologic Failure and Rescue Therapy of Tenofovir, Abacavir, and Lamivudine for Initial Treatment of HIV-1 Infection: TONUS Study

Abstract

Convergent genetic pathway to resistance, in conjunction with lower antiretroviral potency, may explain the high rate of selection K65R and M184V mutations. These mutations did not appear to have a negative effect on rescue therapy with a variety of regimens.

Effectiveness of antiretroviral regimens containing abacavir with tenofovir in treatment-experienced patients: Predictors of virological response and drug resistance evolution in a multi-cohort study

“…This incidence is higher than that in the group of patients receiving a potent/high genetic barrier regimen (21.6 per 100 patient-year, log rank p = 0.033) and similar, although a little low, to the results of the TO-NUS and ESS3009 trial. Among the reasons investigated to explain their data, the investigators of the Tonus trial emphasized the fact that just two point mutations (M184V and K65R), each selected by at least two of the NRTIs used, were required to produce resistance to the whole regimen [13][14][15]. Another reason for the high rate of virological failure may have been the physiological compartmentalization of nucleoside and nucleotide analogues and the subsequent diversity of distribution and activation among the CD4 cells [13].…”

“…Among the reasons investigated to explain their data, the investigators of the Tonus trial emphasized the fact that just two point mutations (M184V and K65R), each selected by at least two of the NRTIs used, were required to produce resistance to the whole regimen [13][14][15]. Another reason for the high rate of virological failure may have been the physiological compartmentalization of nucleoside and nucleotide analogues and the subsequent diversity of distribution and activation among the CD4 cells [13]. If this were the case, the use of another drug class or of a thymidine analogue with a different activation pathway could have prevented this phenomenon and, ultimately, the viroimmunological failure in our patients.…”

“…Despite this, the Tonus trial, which studied the ABC + 3TC + TDF combination in 38 patients in a oncedaily regimen, had to be stopped prematurely because of poor results: 12 (33%) of 36 enrolled patients experienced virologic failure by week 24 [13]. A number of reasons have been suggested to explain this poor outcome, with the strongest evidence pointing to the low genetic barrier to resistance of this association [14,15].…”

Thérapeutiques antirétrovirales : principes du traitement de l’infection par le VIH

“…Ainsi, la trithérapie associant zidovudine, lamivudine et abacavir s'est avérée moins puissante qu'une trithérapie associant zidovudine, lamivudine et éfavirenz en particulier chez les patients ayant une charge virale élevée (> 100 000 copies/ mL) [63]. Plus récemment, d'autres trithérapies d'inhibiteurs nucléosidiques/nucléotidique ont été évaluées mais leur utilisation s'accompagne d'un nombre d'échecs primaires plus élevé que les trithérapies classiques avec sélection de virus résistants [64], à l'exception de l'association zidovudine, lamivudine et ténofovir évaluée avec succès dans une étude pilote [65]. Des combinaisons sans inhibiteur nucléosidique/nucléotidique ont été proposées pour limiter la toxicité mitochondriale des molécules de cette classe [66].…”

Sensitivity of Phenotypic Susceptibility Analyses for Nonthymidine Nucleoside Analogues Conferred by K65R or M184V in Mixtures with Wild-Type HIV-1

“…The regimens included the combination of tenofovir (TDF for studies in vivo, and TFV for in vitro assays), lamivudine (3TC), and didanosine (ddI) or abacavir (ABC) [1][2][3][4][5]. In these studies, high rates of selection for the reverse-transcriptase (RT) mutations K65R and M184I/V were observed by population sequencing.…”