598 GW433908 in ART-naive Subjects: Absence of Resistance at 48 Weeks with Boosted Regimen and APV-like Resistance Profile with Unboosted Regimen S. Macmanus1, P.Yates1, S. White2, N. Richards2, W. Snowden*1 1GlaxoSmithKline, Stevenage, UK and 2GlaxoSmithKline, Greenford, UK
Background: GW433908 (908) is an investigational protease inhibitor (PI) for which safety and efficacy results from 2 trials in ART-na´ve HIV-infected subjects (NEAT and SOLO) are presented elsewhere. NEAT and SOLO were randomized 48-wk Phase III studies comparing 908 unboosted (1,400 mg BID n = 166 randomized and exposed) and 908 boosted with ritonavir (908/RTV 1,400/200 mg QD n = 322), respectively, versus nelfinavir (NFV 1,250 mg BID NEAT n = 83: SOLO n = 327). All subjects (total n = 898) received abacavir (ABC) 300 mg BID + lamivudine (3TC) 150 mg BID as their NRTI backbone.
Methods: Emergence of resistance was examined by genotypic and phenotypic analyses (ViroLogic. Inc.) of virus in paired baseline and on-therapy plasma samples from all subjects with VL > 1000 c/ml at 2 consecutive visits between wk 12 and end of study.
Results: NEAT: Mutations characteristic of development of APV resistance were detected in virus from 5/29 (17%) 908 treated subjects analyzed (3% subjects exposed) and included I54L/M, V32I + I47V and M46I. Mutations observed with other PIs (D30N, I54V, V82A/T/S, L90M) were not observed with 908. NFV-selected mutations (D30N, N88D/S, or L90M) were detected in 6/26 (23%) NFV-treated subjects analyzed (7% subjects exposed). SOLO: No selection of resistance by 908/RTV was observed in virus from 31 (0/31 [0%]) subjects analyzed. Emergence of resistance with NFV was significantly greater (p < 0.001) with D30N and/or L90M detected in 20/55 (36%) NFV-treated subjects analyzed. The incidence of 3TC resistance (M184I/V) was significantly lower in 908/RTV-treated than NFV-treated subjects analyzed (4/32 [13%] vs (30/55 [55%] p < 0.001). ABC resistance (M184V + key RT mutations K65R or L74V) was rare (5/898 (< 1%) all ABC exposed) with all phenotypic shifts < 4-fold.
Conclusions: The absence of resistance selection at 48 wks by 908/RTV indicates a high genetic barrier to resistance. Greater selective pressure provided by the boosted regimen reduces the pool of replicating virus, restricting development of resistance to both PI and NRTI components of the regimen. The absence of resistance to 908/RTV and minimal cross-resistance to other PIs after unboosted 908, indicates that the failure of a regimen containing 908▒RTV should have limited impact on susceptibility to subsequent PI-containing therapy.