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Response to Nonnucleoside TMC278 Sustained Through 48 Weeks
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11th European AIDS Conference
October 24-27, 2007
Madrid
Mark Mascolini
TMC278, a nonnucleoside from Tibotec, looked potent in antiretroviral-naive people after 48 weeks, with little or no slippage in efficacy since week 24 [1]. Finding no dose-response relationship when testing 25, 75, and 150 mg of TMC278 once daily through 48 weeks, Tibotec chose a 75-mg once-daily pill for further development in previously untreated people.
This ongoing 96-week trial randomized 368 people to one of these TMC278 doses or to standard-dose efavirenz plus an investigator-selected nucleoside duo, AZT/3TC in 76% and tenofovir/FTC in 24%. About one third of study participants were women and just under half were white. Median viral load measured 69,300 copies in the combined TMC278 arms and 75,100 copies in the efavirenz group. Median CD4 counts stood around 100, and study participants had been infected for a median of only 1 year.
In the FDA-preferred time-to-loss-of-virologic response analysis, equivalent proportions in the four dosing groups (77% to 81%) had a viral load under 50 copies. Response curves describing the viral load drop through 48 weeks virtually overlapped in the four study arms at about -2.64 log copies/mL. Patrick Yeni and colleagues reckoned a 9% virologic failure rate in the 25-mg TMC278 group, a 5% failure rate in the 75-mg group, a 7% rate in the 150-mg group, and a 6% rate in the efavirenz group. CD4 counts rose substantially in all study arms, averaging gains from 125 to 145 cells.
A slightly higher proportion of enrollees had to stop TMC278 because of side effects than had to stop efavirenz (8.6% versus 5.6%), but that difference lacked statistical significance. Researchers plotted a bigger gap between proportions with grade 3 or 4 lab abnormalities when comparing TMC278 to efavirenz (24.7% versus 15.7%), but that difference also stopped short of statistical significance (P = 0.08). Rates of serious adverse events were equivalent with TMC278 (10.4%) and efavirenz (9%).
Rash bothered significantly more people taking efavirenz than TMC278 (19.1% versus 7.9%, P < 0.01), and the efavirenz group reported significantly more dizziness (30.3% versus 8.6%, P < 0.001), vertigo (11.2% versus 1.1%, P < 0.001), somnolence (11.2% versus 3.6%, P < 0.05), and abnormal dreams or nightmares (10.1% versus 2.5%, P < 0.01).
Total and low-density lipoprotein cholesterol rose significantly more with efavirenz than TMC278, but so did high-density lipoprotein cholesterol. So the total-to-high-density ratio varied little between the efavirenz and TMC278 groups. However, triglycerides climbed an average 18 mg/dL with efavirenz while falling an average 10 mg/dL with TMC278.
Reference
1. Yeni P, Goebel F, Thompson M, et al. TMC278, a next-generation NNRTI, demonstrates potent and sustained efficacy in ARV-naive patients: week 48 primary analysis of study TMC278-C204. 11th European AIDS Conference. October 24-27, 2007. Madrid. Abstract P7.2/08.
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