17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

PHENOTYPIC AND GENOTYPIC DETERMINANTS OF RESISTANCE TO DARUNAVIR: ANALYSIS OF DATA FROM TREATMENT-EXPERIENCED PATIENTS IN POWER 1, 2, 3 AND DUET-1 AND 2

Antivir Ther. 2008; 13(Suppl. 3):A33 (abstract no. 31)

S De Meyer¹, I Dierynck¹, E Lathouwers¹, B Van Baelen¹, T Vangeneugden¹, S Spinosa-Guzman¹, M Peeters¹, G Picchio² and M-P de Béthune^1
1Tibotec BVBA, Mechelen, Belgium; ²Tibotec Inc, Yardley, PA, USA

BACKGROUND: Analyses from treatment-experienced patients receiving the protease inhibitor (PI) darunavir plus low-dose ritonavir (DRV/r) in POWER 1–3 (n=458) revealed clinical cut-offs of 10 and 40, and showed a diminished response when =3 of 11 DRV resistance-associated mutations (RAMs; V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89V [2006 list]) were present at baseline. New analyses were performed on data from DRV/r-treated patients in POWER 1–3 (n=467) and from DRV/r- and placebo-treated patients in DUET-1 and 2 (n=604).

METHODS: Clinical cut-offs were determined by analyzing viral load change versus baseline DRV fold change (FC) using an ANCOVA model and inverse prediction. DRV RAMs were defined as protease mutations fulfilling at least two of the following criteria: associated with an increased DRV FC; when present at baseline, associated with a diminished virological response at week 24 in patients who did not use/re-used enfuvirtide; developing in ≥10% of rebounders. Genotypes and phenotypes were determined by Virco. Virological response (HIV-1 RNA <50 copies/ml) was determined by time-to-loss of virological response analysis, censoring discontinuations for reasons other than virological failure.

RESULTS: The clinical cut-offs of 10 and 40 were confirmed. Ten of the 11 2006 DRV RAMs (all except G73S) were confirmed and a new mutation T74P was identified, resulting in the 2007 DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V and L89V. Each of these mutations was present with a median number of 13–15 PI RAMs (2006 IAS-USA list). In patients who did not use/re-used enfuvirtide, a diminished response was found when ≥3 2007 DRV RAMs were present at baseline. ANOVA models on response confirmed the predictive value of the number of 2006 DRV RAMs and showed that the number of 2007 DRV RAMs was slightly more predictive. The prevalence of 2007 DRV RAMs was low in PI-resistant routine clinical samples received at Virco.

CONCLUSIONS: Analyses of a larger clinical dataset confirmed the previously defined phenotypic and genotypic determinants of DRV resistance. An updated DRV RAMs list was defined, containing 10 of the 11 2006 DRV RAMs and one new mutation, T74P.

2008-06-10
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