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Will Etravirine Work Once Daily--With Once-Daily Darunavir?
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9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow
Mark Mascolini
Etravirine given once daily to treatment-naive people attained equivalent levels with or without once-daily darunavir [1]. The minimum concentration achieved with once-daily etravirine in this 42-day study was well above the level needed to handcuff nonmutant HIV.
Because etravirine has a 30- to 40-hour half-life, it seems a good candidate for once-daily dosing. Now etravirine must be taken twice daily with two 100-mg tablets at each dosing. This new nonnucleoside is licensed for treatment-experienced people with virus resistant to other nonnucleosides. The ritonavir-boosted protease inhibitor (PI) darunavir, originally licensed for twice-daily dosing in treatment-experienced patients, recently won approval as a once-daily drug for people starting their first regimen.
This study involved 20 men and 3 women with no antiretroviral experience and fewer than 3 etravirine-related mutations. The study group included 9 African Americans, 9 whites, and 5 Hispanics with an average pretreatment viral load around 15,000 copies and median CD4 count of 403 (range 144 to 895). Their age averaged 35.7 years. First they took 400 mg of etravirine once daily with tenofovir/emtricitabine (TDF/FTC) for 14 days. Then they added darunavir/ritonavir at 800/100 mg once daily for 14 days. After that they dropped the etravirine for 14 days. At the end of this three-phase trial, people could continue darunavir/ritonavir plus TDF/FTC.
Twenty people completed the first 42 days of the trial. Viral loads dropped by an average 1.7 log (about 50-fold) by day 14, by 1.8 log by day 28, and by 2.0 log (100-fold) by day 42. In that time the median CD4 gain measured 56 cells.
Concentrations of etravirine taken with darunavir virtually mirrored concentrations measured with etravirine alone. The least squared mean ratios (etravirine with darunavir/etravirine alone) were 0.96 for the minimum concentration, 1.03 for the maximum concentration, and 0.99 for the area under the curve.
At day 14, the end of the etravirine-without-darunavir phase, etravirine's maximum concentration was higher and its minimum concentration lower than in treatment-experienced people who took etravirine twice daily in the DUET trials. Even so, the average minimum concentration for once-daily etravirine--with or without darunavir--was more than 50 times higher than the 50% effective concentration against wild-type (nonmutant) virus. Etravirine's area under the curve was similar with once- and twice-daily dosing. Darunavir levels with etravirine were slightly higher than in people not taking etravirine in earlier studies.
There were no serious or grade 3 or 4 side effects in this study, and no one dropped out because of side effects. Neither were there any grade 3 or 4 liver enzyme or lipid elevations. One person had grade 3 neutropenia during the etravirine-without-darunavir phase. Rash, which may be seen with either etravirine or darunavir, affected 3 people in this study. None of these rashes were considered serious or grade 3 or 4.
Reference
1.Lalezari J, DeJesus E, Osiyemi O, et al. Pharmacokinetics of once-daily etravirine without and with once-daily darunavir/ritonavir in antiretroviral-naive HIV-1 infected adults. 9th International Congress on Drug Therapy in HIV Infection, November 9-13, 2008, Glasgow. Abstract O413.
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