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