15th International HIV Drug Resistance Workshop 13-17 June 2006, Sitges, Spain

PHENOTYPIC AND GENOTYPIC DETERMINANTS OF RESISTANCE TO TMC-114: POOLED ANALYSIS OF POWER 1, 2 AND 3

Antivir Ther. 2006, 11:S83 (abstract no. 73)

S De Meyer¹, T Vangeneugden¹, E Lefebvre², H Azijn¹, I De Baere¹, B Van Baelen¹ and M-P de Béthune^1
1Tibotec BVBA, Mechelen, Belgium; ²Tibotec Inc., Yardley, PA, USA

BACKGROUND: TMC-114 (darunavir) with low-dose ritonavir (TMC-114/ritonavir) showed significant antiviral efficacy in treatment-experienced patients in POWER 1, 2 and 3: 42% of patients reached HIV RNA <50 copies/ml at Week 24. This analysis provides further insight into the phenotypic and genotypic determinants of resistance to TMC-114.

METHODS: In POWER 1, 2 and 3, 458/924 patients initiated treatment with TMC-114/ritonavir 600/100mg twice-daily, the recommended dose for treatment-experienced patients. Non-completer = failure analysis was used for change in viral load [VL] and time-to-loss-of virological response analysis was used for the proportion reaching HIV RNA <50 copies/ml at Week 24. Phenotyping was performed by Antivirogram®. Site-directed mutants (SDMs) were constructed using Medigenomix™ proprietary technology.

RESULTS: Baseline TMC-114 EC₅₀ fold change (FC) was the strongest predictor of Week 24 virological response. Clinical cut-offs of 10 and 40 were determined by analysis of VL change versus baseline TMC-114 FC, using an ANCOVA model and inverse prediction. At baseline, 70% and 13% of viruses had TMC-114 FC ≤10 and >40, respectively. At Week 24, 50%, 25% and 13% of patients with FC ≤10, 10<FC≤40 and FC >40, respectively, reached HIV RNA <50 copies/ml. TMC-114 FC increased with the number of PI resistance-associated mutations. Analysis of baseline isolates of all patients showed median TMC-114 FC <10, close to or >10, and >40, for subgroups with <10, 10 or 11, and ≥12 PI resistance-associated mutations, respectively. Diminished responses observed in the last two subgroups reinforced the correlation between FC, number of mutations and virological outcome. SDMs were constructed with up to three protease mutations either associated with a lower response to TMC-114/ritonavir when present at baseline, or related to resistance to amprenavir, a structural analogue of TMC-114. Whereas amprenavir FC >10 was observed in 8/30 strains with 2–3 mutations, and 4<FC≤10 for 6/30, only one strain had 4<FC≤10 for TMC-114; none had FC >10.

CONCLUSIONS: Baseline TMC-114 FC was the strongest predictor of virological response. Reduced response at TMC-114 FC >10 correlated with ≥10 PI resistance-associated mutations. No mutation associated with a diminished response, alone or in combination with 1–2 others, resulted in TMC-114 FC >10.

2006-06-13
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