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

IMPACT OF GAG CLEAVAGE SITE MUTATIONS ON THE VIROLOGICAL RESPONSE TO DARUNAVIR/RITONAVIR IN TREATMENT-EXPERIENCED PATIENTS IN POWER 1, 2 AND 3

Antivir Ther. 2007; 12:S23 (abstract no. 21)

I Dierynck, S De Meyer, K Cao-Van, H Van Marck, E Lathouwers, K Thys, B Maes and M-P de Béthune
Tibotec BVBA, Mechelen, Belgium

BACKGROUND: Virological outcome of treatmentexperienced HIV-1 patients on the protease inhibitor (PI) darunavir (TMC114) with low-dose ritonavir (darunavir/r) is genotypically determined by a series of 11 protease mutations. Mutations of protease cleavage sites (CS) in the Gag region have been associated with enhanced phenotypic resistance to PIs. A preliminary analysis of the association of Gag CS mutations with the virological response to darunavir/r was performed on the pooled POWER trials.

METHODS: Pooled data of all treatment-experienced subjects from the POWER 1, 2 and 3 trials who initiated darunavir/r treatment at the recommended dose of 600/100 mg twice-daily (n=467) with an optimized background regimen were analysed in a univariate analysis. Virological response was defined as viral load ≤50 copies/ml at week 24. Mutations in the five Gag CS were determined at baseline and confirmed point of rebound and/or a later time point within the treatment phase.

RESULTS: In this population of highly-experienced patients (326 subjects with a Gag genotype available at baseline), the median number of Gag CS and IAS-USA PI resistance-associated mutations at baseline was 5 and 12, respectively. Among the CS mutations present in ≥10 patients at baseline, only E428G, S451T and R452S were linked with a reduced virological response to darunavir/r at week 24 (<75% of overall response). Analysis of the rebounder population (73 subjects) identified V128I as the only CS mutation emerging in more than 10% of the rebounders and appearing in most cases (80%) only after a long period of treatment (≥48 weeks). There was a strong correlation between the emergence of V128I and the presence or emergence of the protease V32I mutation.

CONCLUSIONS: Preliminary analyses on the pooled data of the POWER trials indicate that in treatment-experienced patients some baseline CS mutations in the Gag region have an impact on the virological response to darunavir/r at week 24. V128I was the only emerging CS mutation in the rebounder population, and seemed to be strongly correlated with the protease V32I mutation. The impact of the Gag CS mutations V128I, E428G, S451T and R452S on darunavir susceptibility will be further explored through site-directed mutagenesis.

2007-06-12
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