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

doi:10.1016/j.eplepsyres.2012.07.009

Epilepsy Research

Volume 103, Issues 2–3, February 2013, Pages 245-253

https://doi.org/10.1016/j.eplepsyres.2012.07.009 Get rights and content

Summary

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 C_min 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.

Introduction

Antiepileptic drugs (AEDs) are commonly used in patients with HIV for associated seizure disorders and painful peripheral neuropathies. The occurrence of seizure disorders is increased among HIV-infected patients, with an incidence of up to 11% (Kellinghaus et al., 2008, Holtzman et al., 1989, Wong et al., 1990). A distal sensory polyneuropathy can also occur in up to 57% of patients with HIV (Cornblath and Mcarthur, 1988, Ellis et al., 2010, McArthur et al., 2005). AEDs are also used to treat other conditions, including migraine and mood disorders (Liedtke et al., 2004).

Evidence-based guidelines for AED selection for people with HIV/AIDS (Birbeck et al., 2012b, Birbeck et al., 2012c) indicate that clinically significant drug interactions can occur when antiretroviral (ARV) agents are combined with enzyme-inducing AEDs (EI-AEDs), including carbamazepine, phenytoin, and phenobarbital. These interactions can have bi-directional effects, resulting in altered serum levels of both EI-AEDs and ARVs. Lower EI-AED levels may lead to reduced efficacy including breakthrough seizures and neuropathic pain. Conversely, a reduction in ARV levels can lead to loss of virologic control, CD4 decline, acquired immune deficiency syndrome (AIDS), and ultimately death. Additionally, reduced efficacy of ARVs can facilitate the development of resistance mutations and increase the risk of transmitting drug-resistant virus.

We previously reported that combined use of ARVs and EI-AEDs led to higher rates of HIV treatment failure compared to use of ARVs in combination with AEDs that are not enzyme-inducing (NEI-AEDs) (Okulicz et al., 2011). To further evaluate and quantify this interaction, we used stored samples from the U.S. Military HIV Natural History Study (NHS) to measure serum levels of ARVs in patients on concurrent therapy with EI-AEDs and in a control group with co-administered NEI-AEDs.

Section snippets

Methods

Participants were identified from a database of over 5300 military members, retirees, and beneficiaries 18 years or older with HIV infection enrolled in the NHS since 1986 (Weintrob et al., 2008, Marconi et al., 2010). In this IRB-approved study, consented individuals are evaluated at participating United States military treatment facilities approximately every 6 months. Data including demographic characteristics, laboratory data, medication use, and clinical events with medical record

Results

Serum ARV levels were detectable in 31 of 32 (96.9%) samples in the EI-AED group and in 65 of 72 (90.3%) samples in the NEI-AED group, suggesting that adherence with ARV treatment was high in both groups. After exclusion of overlap intervals with ≥1 AED or ARV level below the limit of detection, 16 EI-AED/ARV overlap intervals in 10 EI-AED-treated subjects and 30 NEI-AED/ARV overlap intervals in 25 controls were included in the analysis. Details of participants in the two groups are provided in

Discussion

Because ARVs are metabolized by inducible cytochrome P450 (CYP) and UDP-glucuronsyltransferase (UGT) enzymes, the possibility of these agents being subject to clinically important interactions with EI-AEDs needs to be taken into consideration(Patsalos et al., 2008). In a previous study, we demonstrated that viral load suppression during ARV treatment was inferior in patients who were co-administered EI-AEDs compared to patients who were co-administered NEI-AEDs, a finding which was assumed to

Funding

Support for this work (IDCRP-000-03) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072.

Disclosures

Jason Okulicz – nothing to disclose

Greg Grandits Mr. Grandits receives support through a University of Minnesota contract with the Henry Jackson Foundation, which funds analysis of projects of the HIV Natural History Study.

Jacqueline French Jacqueline French serves as the president of The Epilepsy Study Consortium, a non-profit organization. NYU, where Dr. French is employed, receives a fixed amount from the Epilepsy Study Consortium towards Dr French1s salary. The money is for work performed

Authors’ Contributions

Jason Okulicz participated in study design, data analysis, and development of the manuscript.

Greg Grandits participated in study design and performed the statistical analysis.

Jacqueline French participated in study design and manuscript development including providing substantive feedback on early versions of this manuscript.

Emilio Perucca participated in study design and manuscript development including providing substantive feedback on early versions of this manuscript.

Jomy George

Acknowledgements

The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the NIH or the Department of Health and Human Services, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

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^☆: Statistical analysis completed by Greg Grandits.

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

Summary

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Funding

Disclosures

Authors’ Contributions

Acknowledgements

Am. J. Med.

Seizure

Lancet Neurol.

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines for the Quality Standards Subcommittee of the American Academy of Neurology and the ad hoc task force of the Commission on Therapeutic Strategies of the International League Against Epilepsy

Epilepsia

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

Epilepsia

Evidence-based guideline: Antiepileptic drug selection for people with HIV/AIDS: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Ad Hoc Task Force of the Commission on Therapeutic Strategies of the International League Against Epilepsy

Neurology

Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex

Neurology

Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the charter study

Arch. Neurol.

Pharmacokinetic interaction between efavirenz and carbamazepine after multiple-dose administration in healthy subjects

J. Clin. Pharmacol.