[27] RESISTANCE-ASSOCIATED AMINO ACID SUBSTITUTIONS AND DRUG SUSCEPTIBILITY ANALYSIS OF VIRUS FROM SUBJECTS ENTERING THE PHASE II DOSE-RANGING STUDY OF A NEW PROTEASE INHIBITOR (PI), BRECANAVIR, HPR20001 (STRIVE)

15th International HIV Drug Resistance Workshop

13-17 June 2006, Sitges, Spain

RESISTANCE-ASSOCIATED AMINO ACID SUBSTITUTIONS AND DRUG SUSCEPTIBILITY ANALYSIS OF VIRUS FROM SUBJECTS ENTERING THE PHASE II DOSE-RANGING STUDY OF A NEW PROTEASE INHIBITOR (PI), BRECANAVIR, HPR20001 (STRIVE)

Antivir Ther. 2006, 11:S32 (abstract no. 27)

C Craig¹, P Yates¹, J Flemming², J Horton³, H Zhao³ on behalf of the STRIVE Study Team
¹GlaxoSmithKline, Stevenage, UK; ²GlaxoSmithKline, Greenford, UK; ³GlaxoSmithKline RTP, NC, USA

OBJECTIVE: To analyse baseline genotype/phenotype of brecanavir, a high-affinity binding PI with picomolar potency, in HPR20001 (STRIVE), a Phase II dose-ranging study.

METHODS: Baseline genotypes and drug susceptibilities (PhenoSense™) from 119/147 subjects were analysed. Correlations between PI mutations, (current IAS.USA defined), and PI susceptibilities were examined. Indinavir was omitted for assay formatting reasons. Recursive partitioning analysis was performed using major PI mutations to predict effects on fold change (FC).

RESULTS: The most prevalent PI mutations were at codons 46 (n=87/119), 90 (n=78/119), 82 (n=74/119), 84 (n=47/119) and 33 (n=47/119). Major PI mutations at positions 30, 48, 50 (V and L) and 88 were underrepresented (n=5, 6, 5, 2 and 0 respectively). The mean number of major PI mutations/isolate was 3.2 (range: 0-7) with mean total PI mutations 11 (range 5-17). Median IC₅₀s for other PIs were significantly above that for brecanavir (median IC₅₀ nM: brecanavir:0.5; amprenavir:230, lopinavir:270, saquinavir:117, ritonavir:1700, nelfinavir:340, atazanavir:74, tipranavir:250). Median FC for brecanavir was lower than other PIs apart from TPV (median FC: brecanavir:5.9, amprenavir:21, saquinavir:29, nelfinavir:59, ritonavir:162, lopinavir:82, atazanavir:69, tipranavir:3.4). At clinically derived cut-offs for lopinavir/ritonavir (10-FC), atazanavir/ritonavir (5.2FC) and tipranavir/ritonavir (4-FC or 2-FC), 83%, 87%, 40% and 65% of isolates were resistant to these PI respectively. For brecanavir, proportions above 10-, 5.2-, 4- and 2-FC were 35%, 55%, 61% and 79% respectively. The mean number of major PI mutations for isolates with FCs ≥ and < cut off were: 3.4/2.2, 3.4/1.9, 3.8/2.8 and 3.5/2.7 for lopinavir, atazanavir and tipranavir (4- and 2-fold) respectively; and 4.0/2.7, 3.8/2.5 and 3.6/2.5 and 3.4/2.3 for brecanavir at the same FCs (10, 5.2, 4 and 2 respectively).

DISCUSSION: Brecanavir shows greater intrinsic antiviral activity than the other PIs tested, and lower FC than all PIs tested except tipranavir/ritonavir, which displays relatively low intrinsic potency and low clinical cut-off. The number of major PI mutations appears to differentiate viruses above and below thresholds. Preliminary analysis of this relatively small dataset suggests that specific mutations associated with increased FC might reflect in part association with higher numbers of mutations. These hypotheses are undergoing clinical evaluation in ongoing trials.

2006-06-13
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