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).
No formal antiepileptic drug (AED) treatment guidelines currently exist for individuals with HIV/AIDS. Seizure disorders are common in individuals infected with HIV, with a reported incidence as high as 11%; provoked seizures resulting from central nervous system (CNS) opportunistic infections may also require AED treatment (Wong et al., 1990; Holmberg et al., 1995; Kellinghaus et al., 2008) HIV/AIDS, especially prevalent in sub-Saharan Africa, is becoming a chronic condition as antiretroviral (ARV) therapies become increasingly available (Bradshaw et al., 2003). The indications for AEDs have expanded to include neurologic conditions other than epilepsy (e.g., painful peripheral neuropathy) and psychiatric conditions. Therefore, worldwide the concurrent use of AEDs and ARVs is substantial.
Potential interactions between ARVs and AEDs are complex and extensive. Potential interactions of greatest concern relate to the P450 system enzyme induction effects of several older-generation AEDs (e.g., phenobarbital, carbamazepine, phenytoin), which might be expected to lower the effective dose of nonnucleotide reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), which are also metabolized by the P450 system. But several additional potential mechanisms of interaction and the impact of ARVs on AEDs also warrant consideration. Effective HIV care requires lifelong treatment using regimens typically comprising at least three drugs (World Health Organization, 2006). Many patients with HIV also require treatment for tuberculosis, which also includes use of enzyme-inducing medications (Di Perri et al., 2005; Breen et al., 2006; Baciewicz et al., 2008). Specific guidelines for treating tuberculosis in the setting of HIV infection have been developed (World Health Organization, 2007), yet none currently exists for AED–ARV therapy.
AED–ARV interactions that raise blood levels of drugs in either class may increase toxicity risk. Use of ARVs that reduce AED levels could lead to loss of therapeutic AED effects, including seizure control. Use of AEDs that decrease ARV levels [e.g., the enzyme-inducing AEDs (EI-AEDs) phenytoin, phenobarbital, and carbamazepine] may lead to virologic failure, resulting in immunologic decline, clinical disease progression, and development of ARV resistance. Because first-line AED availability in most low- and middle-income countries is limited to phenobarbital, carbamazepine, and phenytoin, and ARV regimen options may also be limited, there is substantial risk for occurrence of clinically important drug interactions (Anon, 2007; Birbeck et al., 2007).
The panel asked the following questions: In people treated with ARVs for HIV/AIDS who also have conditions requiring AED use, does concurrent treatment with AEDs and ARVs lead to drug interactions? If so, are these interactions clinically meaningful? The panel also performed a systematic literature review to estimate the worldwide prevalence of potential co-usage of AEDs and ARVs.
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 Article first published online: 4 JAN 2012 Source Epilepsia
