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Up to Four 'Combined' Darunavir/Etravirine Mutations Needed for Sub-50-Copy Response. New Concept in Resistance: Combined Resistance to Multiple Drugs in Regimen
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6th European HIV Drug Resistance Workshop
March 26-28, 2008
Budapest, Hungary
Mark Mascolini
Under-50-copy response rates stayed above 50% after 24 weeks of the DUET trials of etravirine (TMC125) and darunavir in people with up to four combined mutations conferring resistance to one or the other drug [1]. Response rates fell below 50% in people with more than three mutations to either drug, and rates fell to 40% or lower only in people with (1) more than three etravirine mutations or (2) more than three darunavir mutations plus one or more etravirine mutations.
The placebo-controlled DUET trials enrolled people with genotypic evidence of resistance to nonnucleosides, three or more primary protease inhibitor (PI) mutations, and a viral load above 5000 copies [2,3]. Everyone enrolled took darunavir/ritonavir plus other antiretrovirals. A 48-week time-to-loss-of-virologic-response analysis found a significantly better sub-50-copy response rate in the etravirine group (61% versus 40%, P < 0.001).
The new analysis aimed to gauge the impact of combined baseline etravirine- and darunavir-related mutations on virologic response, defined as a confirmed viral load under 50 copies after 24 weeks. The investigators used Virco systems to determine viral genotype and phenotype (fold change in susceptibility to darunavir or etravirine). The analysis included 406 people, all of them taking etravirine, none of them starting enfuvirtide for the first time, and none who dropped out of the studies for reasons other than virologic failure. Etravirine-related mutations are V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V, and G190A/S. Darunavir-related mutations are V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, and L89V.
Jonathan Schapiro (Sheba Medical Center, Tel Hashomer, Israel) and coworkers hypothesized that figuring combined resistance to both the nonnucleoside etravirine and the PI darunavir--instead of resistance to one drug at a time--would yield better estimates of response to the double drugs by treatment-experienced people. When the DUET trials began, study participants had a range of 0 to 7 darunavir-associated mutations correlating with 0.7- to 909-fold reductions in susceptibility to the PI. Enrollees had 0 to 5 etravirine-linked mutations correlating with 0.2- to 42.4-fold falls in susceptibility to this new nonnucleoside.
Sub-50-copy response rates fell as the number of combined pretreatment darunavir and etravirine mutations rose: Among people with no baseline mutations, 77.8% had a week-24 viral load below 50 copies, while only 14.3% of people with more than 7 combined mutations had fewer than 50 copies at week 24. Among people with 0 or 1 mutation conferring resistance to either drug (four subgroups), 66.7% to 81.8% had a sub-50 response at week 24. Among those with 0, 1, or 2 mutations to each drug (nine subgroups), response rates ranged from 56.3% to 100%. Response rates at 24 weeks stayed above 50% in people with up to 4 combined darunavir/etravirine mutations.
The investigators also uncovered a possible pattern in the relation between accumulated darunavir and etravirine mutations. People with 1 etravirine mutation and 1, 2, or 3 darunavir mutations had respective 24-week response rates of 71.1%, 75.0%, and 50.0%. People with 3 darunavir mutations and 0, 1, or 2 etravirine mutations had respective response rates of 77.5%, 50.0%, and 45.0%. While 31 of 60 people (51%) with 3 or more etravirine mutations also had 3 or more darunavir mutation, only 31 of 176 people (18%) with 3 or more darunavir mutations also had 3 or more etravirine mutations. The researchers speculated these findings may mean detecting 3 or more etravirine mutations signals a bigger chance of multiple mutations to both drugs and a higher risk of virologic failure.
The DUET team concluded that "antiviral activity to a drug regimen appears to be a function of the combined genetic barrier to resistance of the different drug components." They suggested that interpreting resistance to combined drugs, rather than to one at a time, may be a better way to predict response.
References
1. Schapiro JM, Vingerhoets J, Nijs S, et al. Combined PI and NNRTI resistance analysis of the pooled DUET trial: towards a regimen-based resistance interpretation. 6th European HIV Drug Resistance Workshop. March 26-28, 2008. Budapest. Abstract 46.
2. 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.
3. 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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