Fillekes, Q; Muro, EP; Chunda, C; Aitken, S; Kisanga, ER; Kankasa, C; Thomason, MJ; ... Burger, DM; + view all Fillekes, Q; Muro, EP; Chunda, C; Aitken, S; Kisanga, ER; Kankasa, C; Thomason, MJ; Gibb, DM; Walker, AS; Burger, DM; - view fewer (2013) Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose nevirapine for perinatal HIV prevention: a randomized pilot trial. Journal of Antimicrobial Chemotherapy , 68 (11) pp. 2609-2615. 10.1093/jac/dkt246.

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Abstract

Objectives To confirm whether 7-days phenytoin, an enzyme inducer, decreases the elimination half-life of single-dose nevirapine and to investigate its effect on nevirapine resistance development in pregnant, HIV-infected women. Methods In a pharmacokinetic pilot trial(NCT01187719), Zambian/Tanzanian HIV-infected, antiretroviral (ARV)-naive pregnant women ≥18 years with CD4 >350 cells/mm3 were randomized 1:1 to control (zidovudine pre-delivery, single-dose nevirapine/zidovudine/lamivudine at delivery, zidovudine/lamivudine for 7 days post-delivery) or intervention (control plus 184mg phenytoin once-daily for 7 days post-delivery) groups. Primary endpoints were nevirapine pharmacokinetics and resistance. Results 35/37 women were allocated to control/intervention groups with median (IQR) age of 27 (23-31) and 27 (23-33) years, respectively. 23/23 had detectable nevirapine levels at delivery and subsequent samples in control/intervention groups, respectively. Geometric mean (95%CI) nevirapine plasma levels at delivery were 1.02 (0.58-1.78) mg/L and 1.14 (0.70-1.86) mg/L in control/intervention groups (p=0.76). One week after delivery, 0/23 (0%) and 15/22 (68%) control/intervention mothers had undetectable levels (<0.05 mg/L; p<0.001). One week later, this was 10/21 (48%) and 18/19 (95%), respectively (p=0.002). GM(95%CI) nevirapine half-lives were 63.2 (52.8-75.7) versus 25.5 (21.6-30.1) hours in control versus intervention groups (p<0.001). New nevirapine mutations were found in 0/20 (0%) intervention vs. 1/21 (5%) control mothers. There was no difference in adverse events (p>0.28). Conclusions Adding 7-days of an enzyme inducer to single-dose nevirapine to prevent mother-to-child transmission significantly reduced subtherapeutic nevirapine levels by shortening nevirapine half-life. As prolonged subtherapeutic nevirapine leads to resistance emergence, a single-dose nevirapine could be used with phenytoin as an alternative if other ARVs are unavailable.

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