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  XVII International AIDS Conference
Mexico City
3-8 August 2008
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Responding to Darunavir/Etravirine For Patients With Resistance
  XVII International AIDS Conference
August 3-8, 2008
Mexico City>
Mark Mascolini
About two thirds of treatment-experienced patients with up to a total of 3 darunavir plus etravirine mutations will respond to those two drugs when given with a background of NRTIs in a salvage regimen, according to analysis of the DUET trials [1]. The same proportion responded if they had up to 40-fold resistance to darunavir but remained susceptible to etravirine. People with more darunavir plus etravirine resistance mutations or a higher fold-change in susceptibility to darunavir and etravirine probably need other active drugs in their salvage regimen to ensure a good response, a team of DUET researchers concluded.>
Richard Haubrich (University of California, San Diego) and DUET colleagues performed a retrospective analysis of 406 DUET enrollees not using enfuvirtide for the first time in their darunavir/etravirine salvage regimen. The researchers also excluded anyone who quit the study before week 24 for reasons other than virologic failure. All study participants took twice-daily doses of 600/100 mg of darunavir/ritonavir plus 200 mg of etravirine, a nonnucleoside and background NRTI. Importantly, in these univariate analyses, the contribution of NRTI was not assessed, but all patients did receive NRTI selected by the investigators for each patient based on resistance testing. The study also evaluated two mutational scoring systems for etravirine, the original with 13 etravirine mutations (Vingerhoets J, et al. IHDRW 2007. Abstract 32 ) and a revised with 17 etravirine mutations (Vingerhoets J, et al. IHDRW 2008. Abstract 24)>
The investigators classified sub-50-copy response rates according to whether patients had (1) 0, 1, 2, 3, or more than 3 darunavir-associated mutations before salvage and 0, 1, 2, 3, or more than 3 etravirine-associated mutations before salvage, or (2) less than 10-fold, 10- to 40-fold, or more than 40-fold decrease in susceptibility to darunavir before salvage and less than 3-fold, 3- to 13-fold, or more than 13-fold decrease in susceptibility to etravirine before salvage. Tibotec researchers identified darunavir-specific and etravirine-specific resistance mutations in three earlier studies.>
These analyses, which used an etravirine scoring system of 13 mutations, showed that at least 67% of people with no darunavir mutations and up to 3 etravirine mutations had a viral load under 50 copies at DUET week 24, and at least 73% with no etravirine mutations and up to 3 darunavir mutations had a sub-50 response at 24 weeks. Response rates reached at least 71% in patients who had any other combination of darunavir plus etravirine mutations that added up to 3 or less. Thirteen of 14 people (93%) with 2 etravirine mutations and 1 darunavir mutation had a 24-week viral load under 50 copies.>
Among DUET participants with less than a 3-fold drop in susceptibility to etravirine and less than a 10-fold decline in susceptibility to darunavir, 76% had fewer than 50 HIV RNA copies at week 24. Among those with less than a 3-fold change in susceptibility to etravirine and a 10- to 40-fold decrease in susceptibility to darunavir (intermediate resistance), 65% had an undetectable load at week 24.>
No one with more than 3 etravirine mutations plus more than 3 darunavir mutation responded by week 24 in this 406-person analysis. Nor did anyone with more than 40-fold resistance to darunavir plus more than 3-fold resistant to etravirine. Other subgroups with less than a 30% response rate were those with more than 3 darunavir mutations and 2 or more etravirine mutations, those with 2 darunavir mutations and 3 or more etravirine mutations, and those with more than 13-fold resistance to etravirine plus more than 10-fold resistance to darunavir.>
A few other subgroups had more than a 50% week-24 response rate, such as those with 3 etravirine mutations plus 1 darunavir mutation, 2 etravirine mutations plus 2 darunavir mutations, and 1 etravirine mutation plus 3 darunavir mutations.>
The shortcomings of this analysis are the small numbers of patients in some subgroups (11 or fewer people in all subgroups with 3 or more etravirine mutations) and the inability to account for other pretreatment and on-treatment variables, such as starting viral load and adherence to the salvage regimen. Also, the contribution of the NRTI to the activity of the regimen was not analyzed- all patient received NRTI in the background regimen. >
The subtitle of this report--when can we spare the other new classes?--and the 65% response cutoff suggest that assessing response to a salvage regimen may be improved by algorithms that can account for two of the agents in the regimen (i.e, darunavir and etravirine in this case). In some situations, clinicians may consider constructing a salvage regimen relying on darunavir and etravirine plus NRTI as the only active new drugs . But other physicians will surely add that integrase inhibitor or CCR5 antagonist to better the odds of shutting down HIV right away.>
1. Haubrich R, Schapiro J, Vingerhoets J, et al. Combined darunavir (DRV) and etravirine (TMC125; ETR) resistance analysis of the pooled DUET trials: when can we spare the other new classes? XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract TUPE0048.