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Low-End Clinical Cutoff Proposed for Etravirine
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XVII International HIV Drug Resistance Workshop
June 10-14, 2008, Sitges, Spain
Mark Mascolini
"As in the Tibotec study [1], the Monogram analysis accounted for activity of the background regimen."
Two groups independently proposed a low-end clinical cutoff to guide clinicians in prescribing the new nonnucleoside etravirine (TMC125) for treatment-experienced people [1,2]. Neither research team had enough data to figure an upper clinical cutoff, and an intermediate resistance threshold advanced by one group touched off a debate.
Monika Peeters and coworkers at Tibotec, etravirine's maker, merged 24-week response data from the DUET-1 and -2 trials [3,4] to correlate virologic response with pretreatment change in 50% effective concentration (EC50) in analyses that factored in activity of the background regimen. They figured clinical cutoffs by starting with week-24 responses in DUET participants randomized to placebo who did not take enfuvirtide for the first time. Virologic response in that group averaged a 1.4-log drop in viral load. Then they probed for etravirine cutoffs by calculating fold-change in EC50 for people taking etravirine without new enfuvirtide who had a 1-log (10-fold) better response than the placebo group, that is, a 2.4-log viral load swoon at week 24.
Among etravirine takers at the 2.4-log mark, the fold-change in EC50 stood at 13. When Tibotec divided etravirine-treated people into groups above and below the 13-fold cutoff, they still found substantial response rates in the group above 13-fold. For example, 6 of 19 people (31.6%) with a fold change between 13 and 20 had a viral load below 50 copies at week 24, as did 8 of 19 (42.1%) with a fold change between 20 and 45. So they proposed 13-fold as an intermediate cutoff.
In further analysis of 24-week responses according to fold-change in susceptibility, 3-fold emerged as a candidate lower clinical cutoff:
· Less than 3-fold: 190 of 269 patients (71%) with a 24-week load below 50 copies, average 2.67-log viral load drop
· 3 to 13-fold: 37 of 74 people (50%) with a 24-week load below 50 copies, average 2.39-log viral load drop
· Above 13-fold: 22 of 60 people (37%) with a 24-week load below 50 copies, average 1.79-log viral load drop
· Overall placebo group response: 149 of 414 people (36%) with a 24-week load below 50 copies, average 1.51-log viral load drop
Because of the relatively small number of DUET participants with a fold-change above 13, Tibotec could not reckon an upper clinical cutoff in this patient population.
With Tibotec collaborators, Eoin Coakley and Monogram colleagues calculated biologic and clinical cutoffs in 199 samples from DUET participants not taking enfuvirtide [2]. As in the Tibotec study [1], the Monogram analysis accounted for activity of the background regimen. Coakley defined the biologic cutoff as the 99th percentile of etravirine fold-change values in routinely submitted viral samples with no detectable mutations conferring resistance to nucleosides, nonnucleosides, or protease inhibitors. That value came to 2.9-fold.
Only 23 of the 199 DUET samples (11.5%) had reduced susceptibility to both darunavir (a fold change in susceptibility above 10) and etravirine (fold change above 2.9). Statistical models accounting for activity of antiretrovirals in the DUET trial background regimens determined that virologic response to etravirine regimens began to fall off at the 2.9-fold mark, indicating that this biologic cutoff could also serve as a lower clinical cutoff. Because only 5 DUET participants in this study group had an etravirine fold-change above 10, Monogram could not set an upper clinical cutoff for the nonnucleoside.
Together these studies appear to establish a 3-fold change in susceptibility as a reliable lower clinical cutoff for etravirine, meaning a large majority of people below that threshold should respond to this nonnucleoside plus a reasonable background regimen.
Debate swirled around what the proposed 13-fold intermediate cutoff may mean. Jonathan Schapiro (National Hemophilia Center, Israel) argued that proposing such a benchmark will only confuse clinicians trying to figure whether an already treated patient should start etravirine. He suggested physicians may misinterpret 13-fold as a hard-and-fast value without understanding that responses to a drug wane over a continuum of fold-change values. Schapiro maintained it would be better for Tibotec to say "it's not clear" what a 13-fold (or 12-fold or 14-fold) change in susceptibility means.
Richard Haubrich (University of California, San Diego) disagreed, reasoning that any data correlating susceptibility with response to a new drug is valuable. The concepts of lower, intermediate, and upper cutoffs should be familiar to clinicians by now, Haubrich suggested. Typically, the lower cutoff marks the point below which clinicians can expect a person to respond to a drug in a regimen with other active agents, the intermediate cutoff signals when clinicians can expect response rates to start falling off rapidly, and the upper cutoff delineates the threshold at which clinicians should no longer expect any response. Tibotec's Monika Peeters noted that the proposed 13-fold intermediate cutoff would not be listed in phenotypic reports sent to clinicians.
References
1. Peeters M, Nijs S, Vingerhoets J, et al. Determination of phenotypic clinical cut-offs for etravirine: pooled week 24 results of the DUET-1 and DUET-2 trials. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 121.
2. Coakley E, Chappey C, Benhamida J, et al. Biological and clinical cut-off analysis or etravirine in the PhenoSense HIV assay. XVII International HIV Drug Resistance Workshop. June 10-14, 2008, Sitges, Spain. Abstract 122.
3. Madruga JV, Cahn P, Grinsztejn B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:29-38.
4. Lazzarin A, Campbell T, Clotet B, et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1-infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. Lancet. 2007;370:39-48.
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