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Background:  CNA30024 was a 48-week randomized, double-blind, multicenter trial comparing the efficacy and safety of ZDV+3TC+EFZ and ABC+3TC+EFV (ABC, 3TC, and ZDV were administered twice daily and EFZ once daily) in ART-naïve adults. We report final results on treatment emergent mutations and other factors associated with virologic failure.

Methods:  Virologic failure (failure to achieve plasma HIV-1 RNA <50 copies/mL by week 48 or confirmed value >50 copies/mL after suppression) occurred for 33/649 subjects (20/324 for ABC group; 13/325 for ZDV group). HIV-1 RT genotype (TruGene) and phenotype (PhenoSense) were determined at baseline and following virologic failure.

Results:  Virologic failure was associated with higher baseline plasma HIV-1 RNA (+0.58 log₁₀ copies/mL, p <0.0001) and lower CD4/CD8 cell ratios (-0.08, p = 0.0104). More than half the subjects with virologic failure had plasma HIV-1 RNA <400 at week 48 (11/20 in ABC group and 7/13 in ZDV group).  Few subjects (2/33 or 6%) in the virologic failure population had mutations associated with study drugs at baseline. Post-failure genotypes were obtained for 18/33 subjects (11/20 in ABC group and 7/13 in ZDV group).  All samples which could not be genotyped had HIV-1 RNA levels <500 copies/mL. Ten subjects had wild type virus at failure (7 in ABC group and 3 in ZDV group).  Four subjects in the ABC group harbored virus with on-therapy mutations (K103N alone, n = 2; M184I+G190S, n = 1; K103N+M184V+P225H, n = 1).  Four patients in the ZDV group harbored virus with on-therapy mutations (K103N+M184V, n = 1; K103N+M184V+G190A, n = 1; K103N+M184V+P225H, n = 1; K103N+V108I+M184V, n = 1). Primary mutations associated with resistance to EFV were detected in all subjects with treatment emergent mutations. With the exception of M184V/I, no other treatment emergent ABC or ZDV associated mutations were detected.

Conclusions:  Virologic failure was rare in this study and was associated with higher baseline plasma HIV-1 RNA and lower CD4/CD8 ratios. Over half of all subjects with virologic failure had plasma HIV-1 RNA <400 at week 48, suggesting non-response or rebound above 50 copies/mL may often fail to predict failure above 400 copies/mL during this period. Primary NNRTI mutations were detected in all subjects with treatment emergent mutations. The only NRTI-associated mutation detected at the time of virologic failure was M184V/I, suggesting these regimens do not rapidly select for mutants with broad cross-resistance to the NRTI class.

Keywords: HIV; Clinical; Resistance