16th International HIV Drug Resistance Workshop 12-16 June 2007, Barbados

IMPACT OF BASELINE NNRTI MUTATIONS ON THE VIROLOGICAL RESPONSE TO TMC125 IN THE PHASE III CLINICAL TRIALS DUET-1 AND DUET-2

Antivir Ther. 2007; 12:S34 (abstract no. 32)

J Vingerhoets¹, A Buelens¹, M Peeters¹, G Picchio², L Tambuyzer¹, H Van Marck¹, G De Smedt¹, B Woodfall¹ and MP de Béthune^1
1Tibotec BVBA, Mechelen, Belgium ²Tibotec Inc., Yardley, PA, USA

BACKGROUND: TMC125 (etravirine) is a next generation NNRTI, with activity against NNRTI-resistant HIV-1 and a high genetic barrier to the development of resistance. This analysis was aimed at identifying baseline genotypic determinants of decreased virological response to TMC125 (200 mg twice daily) in the Phase III double-blind placebo-controlled trials DUET-1 and DUET-2.

METHODS: Effect of baseline phenotype (Antivirogram®) and genotype (virco®TYPE HIV-1) on the virological response to TMC125 at week 24 was studied in the subgroup of patients not using enfuvirtide as a new drug in analyses and excluded patients who discontinued for other reasons than virological failure (n=406). Decreased virological response was defined as a lower response than in the subgroup of patients with 0 detectable NNRTI resistanceassociated mutations (RAMs) at baseline (primary efficacy endpoint: <50 HIV-1 RNA copies/ml). Forty-four reverse transcriptase mutations were studied, but only those present in ≥5 patients at baseline were included in the final analyses.

RESULTS: Of the 44 mutations studied, 26 were present in ≥5 patients at baseline. Univariate analyses identified the following mutations to be associated with decreased virological response to TMC125: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A and G190S (TMC125-RAMs). Isolates with A98G, K101E, Y181C, V179F or G190A harboured more NNRTI mutations than isolates without these mutations. V179F was never present without Y181C. Y181V, G190S and V179F, which had the most pronounced effect on response, were present in <5% of patients. TMC125 fold change in EC₅₀ increased with increasing numbers of NNRTI-RAMs or TMC125-RAMs and was a strong predictor of virological response. Accordingly, virological response decreased progressively among subgroups with increasing numbers of TMC125-RAMs. The largest impact was observed in the subgroup of patients with greater then three TMC125-RAMs at baseline.

CONCLUSIONS: Thirteen mutations, mainly occurring in the presence of other NNRTI-RAMs were associated with a decreased response to TMC125. The decrease was function of the number of baseline TMC125-RAMs with the largest impact in the subgroup of patients with greater than three of those. Additional analyses will provide more insight into the role of these mutations, individually and combined, in resistance to TMC125.

2007-06-12
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