Response to Birbeck et al.

Abstract

To the Editors: With their letter, Birbeck and colleagues call the attention of the epileptologic community to the problems that derive from the pharmacokinetic interaction between antiretroviral agents (ARTs) and antiepileptic drugs (AEDs). This issue is particularly important in sub-Saharan African countries where AIDS prevalence is dramatically high and epilepsy comorbidity is rather frequent due to opportunistic central nervous system infections. As stressed by the authors, no systematic studies of ART–AED interactions have been carried out to date, the available evidence being exclusively based on case reports. Liedtke et al. (2004) reported that carbamazepine levels are increased by approximately two- to threefold with concurrent ART ritonavir, resulting in carbamazepine-related toxicity. The same authors found the effect of ritonavir on phenytoin to be variable; a 30% reduction in phenytoin serum concentration occurred in one patient, while no apparent change was observed in another patient. Another ART, nelfinavir, decreased the plasma levels of phenytoin in a patient who subsequently developed recurrent seizures. Of even more severe concern is the reciprocal effect of enzyme inducer AEDs, which significantly shorten the half-life of the ART, navirapine. The resulting suboptimal levels of navirapine can lead to drug resistance and ART failure. Thus, the enzyme inducers carbamazepine and phenobarbital, two of the most widely-used traditional AEDs, may have a contra-productive effect on antiviral therapy, leading to loss of viral suppression and the emergence of resistance. Conversely, the other widely used traditional AED, sodium valproate, is an enzyme inhibitor and may therefore lead to an unwanted increase in ARTs levels. Moreover, in vitro studies suggest that sodium valproate may increase viral replication (Jennings and Romanelli, 1999). The above problems can be significantly reduced with the use of newer AEDs whose metabolism is independent from, or only partially dependent on the cytochrome P450 system—and thus are less likely to interact with coadministered ARTs. Since some newer AEDs have no enzyme inducing properties, they have little potential for reducing ART effect. The obvious recommendation of using newer AEDs when dealing with AIDS-epilepsy comorbidity clashes with the issue of economic sustainability, which is particularly dramatic in some sub-Saharan countries where the per capita health expenditure is only $5/year. The International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE) have among its priorities the epilepsy care across the world. Through the Global Campaign Against Epilepsy (GCAE), a joint ILAE-IBE-World Health Organization (WHO) program, ILAE and IBE are strongly engaged in reducing the treatment gap in developing countries. The problem raised in the letter from Birbeck et al., will be brought to the attention of the GCAE with the following recommendations: A group of experts should review the available evidence about AED–ART interactions. Prospective studies, which focus on systematic monitoring of plasma levels of both AEDs and ARTs, should be carried out in more developed countries. Using these findings, the GCAE should develop a plan that WHO can implement in Africa to face this emergency. To find the necessary resources for implementation, GCAE should seek the collaboration of the pharmaceutical industry.