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Upper and Lower Clinical Cutoffs Proposed for Darunavir from Monogram
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5th European HIV Drug Resistance Workshop
Cascais, Portugal
March 30, 2007
Mark Mascolini
Analyzing virologic responses of 176 people enrolled in the POWER 1, 2, and 3 trials of darunavir, Monogram Biosciences researchers set the lower and upper clinical cutoffs for this protease inhibitor (PI) at 10 and 90 respectively [1]. According to these cutoffs, more baseline POWER viral isolates were susceptible to darunavir than to other PIs tested.
Monogram defined the lower clinical cutoff as the fold change in susceptibility at which the virologic response to darunavir first declined relative to wild-type (nonmutant) virus. The upper clinical cutoff is the fold-change in susceptibility above which the viral load change from baseline measured less than 0.3 log copies/mL.
Using these definitions, Monogram analyzed samples from 176 people who took 600/100 mg of darunavir/ritonavir twice daily in the POWER trials who did not take the fusion inhibitor enfuvirtide. Of those samples, 76 were from who people had no other active drugs in their background regimen and so, in effect, took darunavir monotherapy. In this subset of "monotherapy" isolates, baseline darunavir fold change in susceptibility correlated with week 4 change in viral load at an R value of 0.42 (P< 0.0001). Taking 0.42 as the lowest darunavir fold change, the Monogram scientists saw that week 4 drops in viral load were uniform (at a median -1.99 log) up to a fold change of 10, so they set 10 as the lower clinical cutoff.
For viral isolates from the "darunavir monotherapy" subset with a fold change in susceptibility greater than 10, virologic responses tapered as the fold change rose (R = 0.37, P = 0.015, median week 4 viral load change from baseline -1.11 log). In this range of fold changes, Monogram set the upper clinical cutoff at 90.
Viral load changes from baseline at weeks 2, 4, and 8 supported the accuracy of the cutoffs (Table).
Viral load changes in POWER trials according to Monogram clinical cutoffs
The Monogram group applied these upper and lower clinical cutoffs to all 176 baseline samples and compared proportions of samples susceptible to darunavir versus other PIs, for which susceptibility rates were determined with Monogram clinical cutoffs for those agents. While 53.8% of samples were judged fully susceptible to darunavir/ritonavir, 33.7% were fully susceptible to tipranavir/ritonavir, 18.5% to amprenavir/ritonavir, 14.6% to atazanavir/ritonavir, 11.4% to lopinavir/ritonavir, and 9.8% to saquinavir/ritonavir. Proportions of isolates fully resistant to these PIs, that is, above their upper clinical cutoffs, were 3% for darunavir/ritonavir, 31% for tipranavir/ritonavir, 66.3% for amprenavir/ritonavir, 70% for lopinavir/ritonavir, and 71.7% for saquinavir/ritonavir.
Reference
1. Petropoulos C, Coakley E, Chappey C, et al. Defining the upper and lower phenotypic clinical cut-offs: defining darunavir/r activity within the POWER 1,
2, and 3 trials as exemplary datasets by the PhenoSense assay. 5th European HIV Drug Resistance Workshop. March 28-30, 2007. Cascais, Portugal. Abstract 61.
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