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  10th International Workshop on Clinical Pharmacology of HIV Therapy
April 15-17, 2009
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Enfuvirtide-to-Raltegravir Switch Lowers Levels of Darunavir and Tipranavir
  10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam
Mark Mascolini
Replacing enfuvirtide with raltegravir in a salvage regimen lowered concentrations of the protease inhibitors (PIs) darunavir and tipranavir in the French EASIER trial [1]. However, minimum and maximum concentrations (Cmin and Cmax) of the PIs stayed in the range of previously reported levels, reported Anne-Marie Taburet, and the falling PI concentrations in EASIER had no apparent impact on virologic outcome.
EASIER randomized people taking an enfuvirtide-containing salvage regimen for at least 3 months to continue enfuvirtide or to switch to raltegravir for 24 weeks. All of these highly experienced patients had a viral load below 400 copies when they entered the trial, and everyone maintained the same background regimen after randomization. To assess changes in PI concentrations before and after the change to raltegravir, Taburet focused on 11 people taking 600/100 mg of darunavir/ritonavir twice daily and 7 taking 500/200 mg of tipranavir/ritonavir twice daily.
Of the 11 people taking darunavir, 9 were men. This group had a median age of 49.3 years, a median CD4 count of 252 (interquartile range [IQR] 177 to 289), and a median weight of 79 kg (IQR 63 to 85). After the switch to raltegravir, darunavir Cmin was 67% of the Cmin with enfuvirtide (90% confidence interval [CI] 46% to 95%), Cmax was 68% (90% CI 59% to 79%), and area under the curve (AUC) was 63% (90% CI 53% to 76%):
⋅ Cmin (ng/mL) 5454 +/- 2679 with enfuvirtide and 3746 +/- 2053 with raltegravir
⋅ Cmax (ng/mL) 11,417 +/- 2785 with enfuvirtide and 8113 +/- 3127 with raltegravir
⋅ AUC (ng/h/mL) 76,608 +/- 24,417 with enfuvirtide and 50,677 +/- 20,678 with raltegravir
Among the 7 people taking tipranavir, 5 were men. Median age stood at 45.6 years, median weight at 60 kg (IQR 53 to 64), and median CD4 count at 475 (IQR 330 to 624). After these people traded enfuvirtide for raltegravir, tipranavir Cmin fell to 43% of its level with enfuvirtide (90% CI 30% to 62%), Cmax dropped to 69% (90% CI 56% to 84%), and AUC to 57% (90% CI 44% to 77%).
⋅ Cmin (mg/L) 35.0 +/- 13.3 with enfuvirtide and 16.5 +/- 8.8 with raltegravir
⋅ Cmax (mg/L) 67.1 +/- 16.6 with enfuvirtide and 46.9 +/- 13.5 with raltegravir
⋅ AUC (mg/h/L) 478.9 +/- 117.9 with enfuvirtide and 289.1 +/- 103.2 with raltegravir
Taburet recommended continued study of people trading enfuvirtide for raltegravir to assess the potential impact on PI levels. In the EASIER trial, the lower PI concentrations with raltegravir apparently did not affect 24-week virologic outcome, since the study found switching to raltegravir noninferior to staying with enfuvirtide. Earlier research determined that enfuvirtide raises PI concentrations, Taburet added. As a result, dropping PI concentrations with raltegravir could represent a return to normal values.
1. Goldwirt L, Braun J, de Castro N, et al. Tipranavir and darunavir pharmacokinetics in patients switching from enfuvirtide to raltegravir: a sub-study of the ANRS 138 EASIER trial. 10th International Workshop on Clinical Pharmacology of HIV Therapy, April 15-17, 2009, Amsterdam. Abstract O_12.