603 Determination of an Indinavir Susceptibility Cutoff for Indinavir-ritonavir Containing Regimens J Szumiloski*1, H. Wilson1, R. Campo2, N. Miller2, H. Rice3, A. Zolopa3, D. Klein4, M. Horburg5, N. Hellmann6, M. Bates6, J. Condra1 1Merck Res Labs, West Point, PA; 2Univ of Miami, FL; 3Stanford Univ, Palo Alto, CA; 4Kaiser Permanente Med Ctr, Hayward, CA; 5Kaiser Permanente Med Ctr, Santa Clara, CA; and 6ViroLogic, San Francisco, CA
Background: Phenotypic resistance to many antiretroviral drugs, including indinavir (IDV), was traditionally assessed relative to "cutoffs" defined by assay sensitivity rather than by therapeutic responses. However, the virologic efficacy of IDV is thought to depend on both viral susceptibility and IDV exposure. In vivo IDV exposure, in turn, is substantially increased by the co-administration of ritonavir (RTV). IDV-RTV-based regimens are thus expected to be more efficacious against IDV-resistant viruses than IDV regimens without RTV co-dosing. We sought to identify a clinical cutoff for IDV resistance by assessing the impact of IDV phenotypic susceptibility on therapeutic responses to RTV-enhanced IDV regimens.
Methods: We identified 171 patients (pts) from 3 observational cohorts and 1 prospective clinical study. All pts received regimens of IDV/RTV 800/200 mg bid plus one or more reverse transcriptase inhibitors. Meta-analyses were performed, using generalized additive models, to assess the relationships between baseline IDV resistance (ViroLogic PhenoSense assay) and subsequent virologic responses to the IDV-RTV regimen. Many virologic response endpoints over 24 wks (e.g., AUC, log change, reduction to < 400/mL, reduction > 0.5, 1.0, 1.5, 2.0 log) were examined, with adjustment for other demographic and therapeutic factors (e.g., previous/concurrent therapies, baseline viral load). A cutoff for IDV resistance was defined by the highest IDV IC50-fold change that was associated with a statistically indistinguishable change in viral suppression from the maximum observed virologic response.
Results: Virologic responses to IDV-RTV treatment were observed across a wide range of IDV phenotypes. Responses were similar below approximately 10-fold, with reduced responses at greater phenotypic shifts (up to 178-fold). After correcting for other factors, maximum viral suppression was observed between 1.9- and 5.6-fold, depending on endpoint, with the point of first significant drop from maximum seen between 8.8- and 22-fold.
Conclusions: Baseline IDV resistance predicted viral suppression by IDV-RTV based regimens. In these studies, approximately equivalent virologic responses were observed up to approximately 10-fold decreases in IDV susceptibility, with diminishing viral suppression at higher degrees of resistance. These data are consistent with an IDV clinical cutoff for IDV/RTV 800/200 of approximately 10-fold.
