Abstract
BackgroundTo evaluate the efficacy of highly-active antiretroviral therapy (HAART) in individuals taking cytochrome P450 enzyme-inducing antiepileptics (EI-EADs), we evaluated the virologic response to HAART with or without concurrent antiepileptic use.MethodsParticipants in the US Military HIV Natural History Study were included if taking HAART for ≥6 months with concurrent use of EI-AEDs phenytoin, carbamazepine, or phenobarbital for ≥28 days. Virologic outcomes were compared to HAART-treated participants taking AEDs that are not CYP450 enzyme-inducing (NEI-AED group) as well as to a matched group of individuals not taking AEDs (non-AED group). For participants with multiple HAART regimens with AED overlap, the first 3 overlaps were studied.ResultsEI-AED participants (n = 19) had greater virologic failure (62.5%) compared to NEI-AED participants (n = 85; 26.7%) for the first HAART/AED overlap period (OR 4.58 [1.47-14.25]; P = 0.009). Analysis of multiple overlap periods yielded consistent results (OR 4.29 [1.51-12.21]; P = 0.006). Virologic failure was also greater in the EI-AED versus NEI-AED group with multiple HAART/AED overlaps when adjusted for both year of and viral load at HAART initiation (OR 4.19 [1.54-11.44]; P = 0.005). Compared to the non-AED group (n = 190), EI-AED participants had greater virologic failure (62.5% vs. 42.5%; P = 0.134), however this result was only significant when adjusted for viral load at HAART initiation (OR 4.30 [1.02-18.07]; P = 0.046).ConclusionsConsistent with data from pharmacokinetic studies demonstrating that EI-AED use may result in subtherapeutic levels of HAART, EI-AED use is associated with greater risk of virologic failure compared to NEI-AEDs when co-administered with HAART. Concurrent use of EI-AEDs and HAART should be avoided when possible.
Highlights
To evaluate the efficacy of highly-active antiretroviral therapy (HAART) in individuals taking cytochrome P450 enzyme-inducing antiepileptics (EI-EADs), we evaluated the virologic response to HAART with or without concurrent antiepileptic use
Two participants were prescribed rifampin and 1 participant had a history of itraconazole use, none of these medications were prescribed during the HAART periods investigated in this study
Virologic failure was more common in HAART episodes for EI-Antiepileptic drugs (AEDs) (63.3%) compared to NEI-AED individuals (27.9%; P = 0.006) and the average log10 viral loads (VLs) during the overlap period was significantly higher in the EI-AED group (3.3 ± 1.3 vs. 2.5 ± 1.3; P = 0.005)
Summary
To evaluate the efficacy of highly-active antiretroviral therapy (HAART) in individuals taking cytochrome P450 enzyme-inducing antiepileptics (EI-EADs), we evaluated the virologic response to HAART with or without concurrent antiepileptic use. Concurrent use of Several first-generation AEDs, including phenytoin, carbamazepine, and phenobarbital are metabolized by the cytochrome P450 (CYP450) enzyme system. This pathway of drug metabolism is utilized by protease inhibitors (PIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and the CCR5 inhibitor maraviroc [4,5]. In addition to competing for enzyme binding sites, some antiretrovirals and AEDs intrinsically induce CYP450 metabolism with the potential to decrease blood levels of both agents. As a consequence, this drug interaction may limit the effectiveness of HAART and predispose patients to adverse HIV treatment outcomes, including virologic failure, accumulation of antiretroviral drug resistance mutations, and HIV disease progression. Lower AED blood levels may have deleterious effects due to lack of efficacy, including loss of seizure control or inadequate control of neuropathic pain
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