Virologic outcomes of HAART with concurrent use of cytochrome P450 enzyme-inducing antiepileptics: a retrospective case control study

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>Participants 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.</p> <p>Results</p> <p>EI-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).</p> <p>Conclusions</p> <p>Consistent 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.</p

PRN OPINION PAPER: Application of precision medicine across pharmacy specialty areas

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/1/jac51107_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149551/2/jac51107.pd

Antiepileptic drug selection for people with HIV/AIDS: Evidence-based guidelines from the ILAE and AAN

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C)

The impact of enzyme-inducing antiepileptic drugs on antiretroviral drug levels: A case-control study

Purpose: To evaluate the impact of enzyme-inducing antiepileptic drugs (EI-AEDs) on serum antiretroviral (ARV) levels in patients with HIV. Methods: Data from the U.S. Military HIV Natural History Study were screened to identify participants taking ARVs with EI-AEDs and controls taking ARVs with non enzyme-inducing AEDs (NEI-AEDs). The proportion of serum ARV levels below the recommended minimum concentrations (C-min) was compared between these groups. Results: ARV levels were available for 10 individuals exposed to 16 intervals on combined ARVs/EI-AEDs (phenytoin and carbamazepine) and for 25 controls exposed to 30 overlap intervals on combined ARVs/NEI-AEDs. The percentage of overlap intervals with >= 1 ARV levels below Cmin was higher in the EI-AED group than in controls (37.5% vs. 23.3%; p = 0.124). After excluding intervals associated with serum levels of EI-AEDs below the reference range (n = 6), the proportion of intervals with >= 1 ARV level below C-min was significantly greater among EI-AED recipients (60%) compared to controls (23.3%; p = 0.008). Conclusions: ARV levels below C-min were more common in participants receiving EI-AEDs, the difference being statistically significant for intervals associated with EI-AED levels within the reference range. These data suggest that, in agreement with current guidelines, EI-AEDs should be avoided in patients receiving ARV therapy. (c) 2012 Elsevier B.V. All rights reserved

Aqueous and Vitreous Penetration of Linezolid and Levofloxacin After Oral Administration

Purpose: To evaluate the time course of drug concentrations achieved in aqueous (AQ), vitreous (V), and serum (S) compartments after oral administration of linezolid and levofloxacin. Design: Randomized, clinical trial. Methods: Settings: Clinical practice. Patient population: Sixteen patients (16 eyes) undergoing vitrectomy who had not had a prior pars plana vitrectomy in the study eye were randomly assigned to one of 4 groups. Intervention: AQ, V, and S samples were obtained from all subjects after single concomitant doses of linezolid 600mg and levofloxacin 750mg between 1 and 12 h before the procedure: group A - 1-3 h; group B - 3-6 h; group C - 6-9 h; group D - 9-12 h. Main outcome measures: AQ, V, and S concentrations of linezolid and levofloxacin. Results: Overall mean concentrations +/- standard deviation (mu g/mL) achieved by linezolid in AQ, V, and S compartments were 3.32 +/- 2.06, 2.98 +/- 1.87, and 7.91 +/- 3.94, respectively. Overall mean concentrations +/- standard deviation (mu g/mL) achieved by levofloxacin in AQ, V, and S compartments were 2.19 +/- 1.92, 1.95 +/- 1.27, and 7.38 +/- 3.47, respectively. Conclusions: Single concomitant doses of linezolid and levofloxacin achieved AQ and V concentrations above the minimum inhibitory concentration for 90% of common ocular gram-positive and gram-negative pathogens up to 12 h after administration. The combination of linezolid and levofloxacin represents a viable option for the prophylaxis and management of endophthalmitis

Aqueous and Vitreous Penetration of Linezolid and Levofloxacin After Oral Administration

Purpose: To evaluate the time course of drug concentrations achieved in aqueous (AQ), vitreous (V), and serum (S) compartments after oral administration of linezolid and levofloxacin. Design: Randomized, clinical trial. Methods: Settings: Clinical practice. Patient population: Sixteen patients (16 eyes) undergoing vitrectomy who had not had a prior pars plana vitrectomy in the study eye were randomly assigned to one of 4 groups. Intervention: AQ, V, and S samples were obtained from all subjects after single concomitant doses of linezolid 600mg and levofloxacin 750mg between 1 and 12 h before the procedure: group A - 1-3 h; group B - 3-6 h; group C - 6-9 h; group D - 9-12 h. Main outcome measures: AQ, V, and S concentrations of linezolid and levofloxacin. Results: Overall mean concentrations +/- standard deviation (mu g/mL) achieved by linezolid in AQ, V, and S compartments were 3.32 +/- 2.06, 2.98 +/- 1.87, and 7.91 +/- 3.94, respectively. Overall mean concentrations +/- standard deviation (mu g/mL) achieved by levofloxacin in AQ, V, and S compartments were 2.19 +/- 1.92, 1.95 +/- 1.27, and 7.38 +/- 3.47, respectively. Conclusions: Single concomitant doses of linezolid and levofloxacin achieved AQ and V concentrations above the minimum inhibitory concentration for 90% of common ocular gram-positive and gram-negative pathogens up to 12 h after administration. The combination of linezolid and levofloxacin represents a viable option for the prophylaxis and management of endophthalmitis