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Background:  To determine the effect of novel RT mutations and non-B subtypes on NNRTI response in subjects in North and South America over 48 weeks, we examined the virologic response of subjects on a regimen of 3TC (twice daily vs once daily) + ZDV + EFV in relation to baseline phylogenetic analysis of the HIV-1 RT coding region and HIV genotype and phenotype.

Methods:  Plasma samples from 184 ART-naïve subjects including subjects who experienced virologic failure (HIV-1 RNA ³400 copies) were evaluated by phylogenetic analysis of the HIV-1 RT coding region and by HIV genotype, phenotype, and plasma HIV-1 RNA at baseline and follow-up where available (n = 90).

Results:  Of 184 subjects, 46 (25%) had non-B subtypes at baseline. No NNRTI-associated mutations were detected at baseline in 45/46 (98%) non-B subtype and 130/138 (94%) subtype B viruses. A mutation at codon 135 was observed for 56% (24/43) of subjects with non-B subtype virus, compared with 39% (52/133) with B subtype (p = 0.054). Decreased susceptibility to EFV and/or NVP (³2.5-fold increase in IC₅₀) at baseline was seen in samples with mutations at codon 135 (18% with mutation, 10% without; p = 0.107). For the 90 subjects with matched baseline and follow-up data, 48 experienced virologic failure. 12 of these 48 subjects (23%) had non-B subtype virus. Baseline mutations at codon 135 (T/M/V/L/R/K) that persisted on treatment were observed in virus from 36 subjects; only one subject had a treatment-emergent mutation at codon 135. With a 135 mutation at baseline, 40% (17/43) of the subjects developed at least 1 NNRTI associated mutation; in the absence of a 135 mutation at baseline, only 17% (8/47) of subjects developed NNRTI mutations (p = 0.017). The NNRTI associated mutations detected at follow-up were 100I, 103N, 106M, 108I, 188H, 190S, 225H. No treatment associations were seen with respect to HIV-1 RNA, subtype, phenotype or novel mutations.

Conclusions:  Of these ART-naïve North and South American subjects, 25% have non-B subtypes; and 56% of non-B subtype viruses have a mutation at codon 135. Mutations at codon 135 at baseline are associated with the accumulation of NNRTI-resistance mutations. These data indicate the need for obtaining an HIV genotype to screen for the presence of mutations at codon 135 on subjects prior to the initiation of NNRTI-containing regimens.

Keywords: NNRTI; subtype; resistance