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Etravirine With Darunavir Stays Strong Through 48 Weeks in DUET Trials
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15th Conference on Retroviruses and Opportunistic Infections
February 3-6, 2008
Boston
Mark Mascolini
DUET-1 and DUET-2--the trials that compared the nonnucleoside etravirine (TMC125) with placebo in people starting a darunavir-containing salvage regimen--held no surprises at the 48-week mark [1,2]. These key findings emerged:
· A 61% sub-50-copy response rate at week 24 held steady through week 48.
· People who added first-time enfuvirtide to etravirine/darunavir had a better chance of suppressing HIV than those who did not.
· People whose virus was susceptible to darunavir and added more other active drugs at study entry did better than those who added fewer other active drugs.
· The side effect profile reported was similar between patients receiving etravirine and those that did not receive etravirine in DUET, except that more patients receiving etravirine experienced rash. 19% of study patients developed rash, but most cases cleared on their own and 2% to 2.4% taking etravirine in either trial dropped out because of rash.
This ongoing 96-week trial randomized people with documented resistance to nonnucleosides and at least three primary protease inhibitor (PI) mutations to etravirine (200 mg twice daily) or placebo, each with the PIs darunavir/ritonavir, nucleosides, and, if appropriate, the fusion inhibitor enfuvirtide. The study population was 90% male and 70% white. Starting viral load stood at 4.8 log in the combined etravirine arms and the placebo arms, while starting CD4 counts measured 99 with etravirine and 109 with placebo.
Almost 60% of study participants had AIDS, and two thirds had tried 10 to 15 other antiretrovirals. Nearly one third of enrollees had two or more etravirine-related mutations when the study began. A quarter of patients taking either etravirine or placebo started enfuvirtide for the first time. Unless otherwise stated, all results below compare the combined etravirine arms from the two trials with the combined placebo arms.
After 48 weeks a time-to-loss-of-virologic-response analysis registered a 61% sub-50-copy response rate with etravirine versus 40% with placebo, a highly significant difference (P < 0.0001). In DUET-1, 94% with a sub-50 response at week 24 repeated that feat at week 48. In DUET-2, 90% under 50 copies at week 24 had fewer than 50 at week 48. Proportions in the placebo arms maintaining a sub-50 response from week 24 to week 48 were 89% in DUET-1 and 88% in DUET-2. People taking etravirine in either study gained significantly more CD4 cells through 48 weeks than people taking placebo (98 versus 73, P = 0.0006).
Among people taking enfuvirtide for the first time in the DUET studies, 71% also taking etravirine had a week 48 sub-50 response versus 59% taking placebo (P = 0.0116). Respective sub-50 rates in people not taking efavirenz were 57% with etravirine and 33% with placebo (P < 0.0001). Among people with virus susceptible to darunavir (fold-change in susceptibility below 10), 46% of those taking no other active drugs, 63% taking one other active drug, and 78% taking two or more other active drugs with etravirine had fewer than 50 copies at week 48. Respective proportions in the placebo arms were 6%, 32%, and 67%.
Rates of grade 3 or 4 adverse events stood at 33% in the combined etravirine arms and 35% in the combined placebo arms. Discontinuation rates for adverse events were 7% with etravirine and 6% with placebo. A slightly higher proportion in the placebo groups had diarrhea (24% versus 18% with etravirine).
The etravirine and placebo groups did not differ in rates of other side effects or lab abnormalities--except for rash, which flared in 19% taking etravirine and 11% taking placebo. In DUET-1 overall new-rash rates were 22% with etravirine versus 11% with placebo (P = 0.0003). Most rashes cropped up in the second study week, lasted a median of 14 days, and were mild to moderate. Because most rashes resolved on their own, only 2% taking etravirine dropped out of DUET-1 because of rash. In DUET-2 new-rash rates were 17% with etravirine and 11% with placebo (P = 0.0577). Median onset came at day 17, median duration stretched to 18 days, and 2.4% of people taking etravirine dropped out because of rash.
References
1. Haubrich R, Cahn P, Grinsztejn B, et al. DUET-1: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 612 treatment-experienced HIV-1-infected patients. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 790.
2. Johnson M, Campbell T, Clotet B, et al. DUET-2: week-48 results of a phase III randomized double-blind trial to evaluate the efficacy and safety of TMC125 vs placebo in 591 treatment-experienced HIV-1-infected patients. 15th Conference on Retroviruses and Opportunistic Infections. February 3-6, 2008. Boston. Abstract 791.
pdf for DUET-1: http://www.retroconference.org/2008/PDFs/790.pdf
pdf for DUET-2: http://www.retroconference.org/2008/PDFs/791.pdf
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