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Combined protease inhibitor (PI) and NNRTI resistance analysis of the pooled DUET trial: towards a regimen-based resistance interpretation
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From Jules: this analysis is a unique attempt to evaluate response to HAART based on a "combined regimen-based" or "combined genetic barrier" look at multiple drugs in a regimen. Perhaps to potentially identify if one can predict response to HAART based on 'combined genetic barrier' to a combination of drugs in HAART.
Reported by Jules Levin
Presented at the 6th European HIV Drug Resistance Workshop, Budapest, Hungary, 26-28 March 2008.
Jonathan M Schapiro,1 Johan Vingerhoets,2 Steven Nijs,2 Monika Peeters,2 Goedele De Smedt,2 Brian Woodfall,2 Marie-Pierre de Bethune,2
Gaston Picchio3
1National Hemophilia Center, Sheba Medical Center, Tel Hashomer, Israel; 2Tibotec BVBA, Mechelen, Belgium; 3Tibotec Inc., Yardley, PA, USA
INTRODUCTION
Resistance determinations are currently performed for each drug componnt in isolation.
Resistance interpretation of drug combinations could lead to improved predictions of virological response
The DUET trials included the combination of a potent protease inhibitor (PI) and NNRTI (darunavir [DRV] and etravirine [ETR])
This afforded an opportunity to perform analyses on the combined impact of resistance mutations for these 2 antiretroviral classes on virological response
AUTHOR CONCLUSIONS
In this highly treatment experienced population, patients with 1 or less mutations to each drug had virological responses similar to those seen in trials of drug naive patients
Responses below 50% required at least 3 mutations to either drug
DRV continued to contribute to responses >/=50% even in the presence of 3 mutations
Resistance to a drug regimen appears to be a function of the combined genetic barrier to resistance (GBR) of the different drug components
Efficacy analyses based on resistance interpretations considering drug combinations may be more clinically relevant than those addressing only each drug individually
AUTHOR RESULTS: SUMMARY
Virological response rates declined with increasing numbers of combined baseline DRV and ETR RAMs (resistance associated mutation):
0 total RAMs: 77.8%
>7 total RAMs: 14.3%
For patients with 0 or 1 RAM to each of the drugs (4 subgroups):
Median DRV FC: 0.7 - 2.4
Median ETR FC: 0.5 - 3.2
Response rates: 66.7% to 81.8%
For patients with 2 or less RAMs to each drug (9 subgroups):
Median DRV FC: 0.7 - 6.4
Median ETR FC: 0.5 - 3.2
Response rates: 56.3% to 100.0%
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