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SPECIAL ARTICLE
Evidence-based guideline: Antiepileptic drugselection for people with HIV/AIDSReport of the Quality Standards Subcommittee of the American Academy ofNeurology and the Ad Hoc Task Force of the Commission on TherapeuticStrategies of the International League Against Epilepsy ABSTRACT
Objective: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with
Methods: The literature was systematically reviewed to assess the global burden of relevant co-
morbid entities, to determine the number of patients who potentially utilize AEDs and antiretrovi- ral agents (ARVs), and to address AED-ARV interactions.
Results and Recommendations: 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 ϳ50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentra- tions (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosageincrease of ϳ50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadmin-istration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage ad- justment (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 nonnucleo-
side reverse transcriptase inhibitors, as pharmacokinetic interactions may result in virologic fail-
ure, 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 pharmacoki-
netic assessments to ensure efficacy of the ARV regimen (Level C). Neurology® 2012;78:139–145
GLOSSARY
AED
ϭ antiepileptic drug; ARV ϭ antiretroviral agent; AUC ϭ area under the serum concentration-time curve; CI ϭ confi-
dence interval; EI ϭ enzyme-inducing; NNRTI ϭ nonnucleotide reverse transcriptase inhibitor; PI ϭ protease inhibitor; VL ϭ
viral load.
No formal antiepileptic drug (AED) treatment ment.1–3 HIV/AIDS, especially prevalent in sub- guidelines currently exist for individuals with HIV/ Saharan Africa, is becoming a chronic condition as AIDS. Seizure disorders are common in individuals antiretroviral (ARV) therapies become increasingly infected with HIV, with a reported incidence as high available.4 The indications for AEDs have expanded as 11%; provoked seizures resulting from CNS op- to include neurologic conditions other than epilepsy portunistic infections may also require AED treat- (e.g., painful peripheral neuropathy) and psychiatric Supplemental data at
www.neurology.org

From the International Neurologic & Psychiatric Epidemiology Program (G.L.B.), Michigan State University, East Lansing; Epilepsy Care Team,Chikankata Hospital (G.L.B.), Mazabuka, Zambia; NYU Comprehensive Epilepsy Center (J.A.F.), New York, NY; Clinical Pharmacology Unit(E.P.), University of Pavia and Institute of Neurology IRCCS C Mondino Foundation, Pavia, Italy; Department of Neurology (D.M.S.), Mount SinaiSchool of Medicine, New York, NY; Division of Infectious Diseases (H.F.), Cooper University Hospital, UMDNJ-Robert Wood Johnson MedicalSchool, Camden, NJ; Department of Pharmacy Practice and Administration (J.M.G.), Philadelphia College of Pharmacy, Philadelphia, PA; InfectiousDisease Service (J.F.O.), San Antonio Military Medical Center, Fort Sam Houston, TX; Department of Neurology (D.B.C.), Washington Universityin St. Louis, St. Louis, MO; and Department of Pharmaceutics (H.H., R.H.L.), School of Pharmacy, University of Washington, Seattle.
Appendices e-1– e-6, tables e-1– e-4, and References e1– e18 are available on the Neurology® Web site at www.neurology.org.
Approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 6, 2011; and by the AAN Board ofDirectors on September 2, 2011.
Study funding: This guideline was developed with financial support from the American Academy of Neurology and the International League AgainstEpilepsy. None of the authors received reimbursement, honoraria, or stipends for their participation in development of this guideline.
Disclosure: Author disclosures are provided at the end of the article.
Copyright 2012 by AAN Enterprises, Inc.
conditions. Thus, worldwide the concurrent use of without language restrictions was conducted using MEDLINE, Cochrane Database, Web of Science, Potential interactions between ARVs and AEDs and EMBASE and the following strategy: [preva- are complex and extensive. Potential interactions of lence or incidence or epidemiology or comorbid] and greatest concern relate to the P450 system enzyme [HIV or AIDS] and [neuropathy or seizure or epi- induction effects of several older-generation AEDs lepsy]. Given the prevalence of HIV-associated neu- (e.g., phenobarbital, carbamazepine, phenytoin) ropathies in low-income countries and use of AEDs which might be expected to lower the effective dose to treat neuropathic pain, we included neuropathy in of nonnucleotide reverse transcriptase inhibitors the search. Because of the dearth of data and the (NNRTIs) and protease inhibitors (PIs), which are potential clinical value of this information regarding also metabolized by the P450 system. But several ad- specific AED-ARV combinations, details from case ditional potential mechanisms of interaction and the reports and uncontrolled series are provided in the impact of ARVs on AEDs also warrant consider- ation. Effective HIV care requires lifelong treatment To determine potential drug– drug interactions using regimens typically comprising at least 3 drugs.5 between AEDs and ARVs, a comprehensive list of Many patients with HIV also require treatment for AEDs and ARVs was developed (see table e-1 on the tuberculosis, which also includes use of enzyme- Neurology® Web site at www.neurology.org; note inducing medications.6–8 Specific guidelines for that investigational drugs as of April 2008 were not treating tuberculosis in the setting of HIV infection included). Using this list, the panel performed the have been developed,9 yet none currently exists for following search (1950 –2010): drug interaction and [antiepileptic or anticonvulsant or AED or {AED from AED-ARV interactions that raise blood levels of table e-1}] and [antiretroviral or ARV or ART or {ARV drugs in either class may increase toxicity risk. Use from table e-1}]. The authors’ literature files were also of ARVs that reduce AED levels could lead to loss of hand-searched for potentially relevant articles.
therapeutic AED effects, including seizure control.
Use of AEDs that decrease ARV levels (e.g., the Literature review. The broad search yielded 4,480 ar-
enzyme-inducing AEDs [EI-AEDs] phenytoin, phe- ticles with potential data (1,146 on co-usage of nobarbital, and carbamazepine) may lead to virologic AEDs and ARVs; 3,334 on AED-ARV drug– drug failure, resulting in immunologic decline, clinical interactions). At least 2 panelists reviewed the result- disease progression, and development of ARV resis- ing articles’ titles and abstracts. Additional publica- tance. Because first-line AED availability in most tions identified during review of selected articles were low- and middle-income countries is limited to phe- also obtained. The full article of any abstract deemed nobarbital, carbamazepine, and phenytoin, and ARV relevant was reviewed. At least 2 panelists indepen- regimen options may also be limited, there is sub- dently reviewed 68 full articles. Of these, 42 articles stantial risk for occurrence of clinically important were used for data abstraction using the elements listed below for each question. Where data abstraction find- The panel asked the following questions: In peo- ings from the 2 panel reviewers differed, a third panelist ple treated with ARVs for HIV/AIDS who also have reviewed the primary source. Data are presented in ta- conditions requiring AED use, does concurrent bles e-2 and e-3. The original and updated search strat- treatment with AEDs and ARVs lead to drug interac- egies are provided in appendices e-1 and e-2.
tions? If so, are these interactions clinically meaning- Findings in the systematic review of co-usage of AEDs
ful? The panel also performed a systematic literature and ARVs. Three Class III studies (n ϭ 434, 100,
review to estimate the worldwide prevalence of po- 550) suggest that 2.6%– 6.1% of people with HIV will experience a new-onset seizure, with most ofthese receiving AED treatment, at least ini- DESCRIPTION OF THE ANALYTIC PROCESS
tially.1,2,13,14 Three Class III studies (n ϭ 255, 101, Panel selection. Given the topic’s global relevance, the
272) indicate that peripheral neuropathy symptoms AAN Quality Standards Subcommittee formed a joint occur in 6.7%–52.5% of individuals infected with panel with the International League Against Epilepsy HIV who have not yet initiated ARV therapy, with via the World Health Organization (WHO). The AAN the highest rates in advanced HIV and in low- and guideline development processes are consistent with middle-income countries where dietary deficiencies may contribute to peripheral neuropathy develop- Literature search. To estimate the worldwide preva-
ment.15–18 Two Class III studies (n ϭ 173, 272) indi- lence of potential co-usage of AEDs and ARVs, a cate that 17%–55% of people without peripheral literature search (1950 to April 2008, updated 2010) neuropathy symptoms at ARV initiation will subse- quently develop such symptoms.15–17 In an analysis (AUC) of lopinavir and ritonavir by 33% (90% con- of a US-based cohort with HIV infection (Class II fidence interval [CI] 15% to 47%) and 28% (90% study, n ϭ 1,539), 57% had at least one sign of pe- CI 3% to 46%), respectively, as compared with the ripheral neuropathy (abnormal vibratory sensation in the feet or reduced ankle tendon reflexes) on neuro- Stiripentol: impact on saquinavir. A randomized,
logic examination.19 Among those with peripheral placebo-controlled, crossover study in healthy sub- neuropathy, 61% had symptoms, including pares- jects assessed effects of stiripentol 2,000 mg/day for 8 days on the pharmacokinetics of a single 400-mg doseof saquinavir.2 Mean saquinavir AUC and maximum ANALYSIS OF THE EVIDENCE Does concurrent
treatment with AEDs and ARVs lead to drug interac-
stiripentol and the placebo periods, but variability was tions? If so, are these interactions clinically meaning-
large, and appropriate sample size to determine equiva- ful? To be included in the analysis, articles had to
lence was not calculated in advance (Class III).
report human in vivo data and at least one outcome Valproic acid: impact on lopinavir, atazanavir, and
measure, either pharmacokinetic or pharmacody- ritonavir. A Class III study in 11 HIV-positive sub-
namic, during coadministration of AEDs and ARVs jects (8 evaluable) taking lopinavir/ritonavir 400/100 in comparison with measures during intake of either found that lopinavir AUC increased on average by AEDs or ARVs. For the purpose of characterizing a 38% (90% CI Ϫ2% to 94%) after administration of pharmacokinetic drug interaction, patients with the valproic acid 500 mg/day for 7 days.29 A Class III disease of interest and healthy volunteers were con- study of HIV-positive subjects showed no effect of sidered to be potentially representative populations.
valproic acid on atazanavir (12 subjects) or ritonavir We considered pharmacokinetic crossover studies as equivalent to a prospective matched cohort with an Atazanavir and atazanavir/ritonavir: impact on lam-
objective outcome (serum concentration), thus meet- otrigine. A Class II study of 21 healthy volunteers (17
evaluable) assessed the pharmacokinetics of single Thirty-one articles were identified. Five were 100-mg doses of lamotrigine without comedication rated Class II,20–24 and 8 were rated Class III.20,25–38 (day 1) and during coadministration of atazanavir Two additional articles described data in multiple co- (400 mg/day from day 8 to day 17, with lamotrigine horts, of which one cohort in each article produced given on day 13) and atazanavir/ritonavir (300/100 Class II evidence and the others Class III.29,39 Class mg/day from day 18 to day 32, with lamotrigine IV studies are not discussed further (table e-3 pres- given on day 27).20 Lamotrigine treatment alone was bioequivalent to lamotrigine plus atazanavir, whereas Clinical significance of serum HIV viral load. We se-
atazanavir/ritonavir reduced lamotrigine AUC by lected the impact of EI-AEDs on serum HIV viral 32% (90% CI 30% to 35%) and lamotrigine half- load (VL) in patients treated with ARVs as a clini- cally important parameter of HIV treatment out- Lopinavir/ritonavir: impact on lamotrigine. A Class III
come, because of the abundance of supporting data.
study assessed the effect of lopinavir/ritonavir (400/ The inability to maintain virologic suppression dur- 100 mg BID) on serum lamotrigine levels at steady ing ARV therapy results in immunologic failure as state in 24 healthy volunteers,38 18 of whom com- measured by CD4ϩ T-cell decline and in clinical pleted 20 days of treatment. Lamotrigine exposure HIV disease progression, manifesting as susceptibil- (AUC) on day 20, after 10 days’ cotreatment with ity to opportunistic infections.40,e1–e3 Patients with lopinavir/ritonavir, was 50% (90% CI 47% to 54%) subtherapeutic ARV levels have decreased virologic of the value on day 10 during lamotrigine mono- suppression rates as compared with those with levels therapy. A doubling of the lamotrigine dose was re- in the therapeutic range.e4 Lack of virologic suppres- quired to achieve serum lamotrigine levels comparable sion also leads to development of ARV resistance, with those prior to lopinavir/ritonavir treatment. Phar- limiting the number of potentially efficacious ARVs macokinetic parameters for lopinavir/ritonavir were available for treatment.e5,e6 Additionally, potential similar to those for historical controls.
person-to-person transmission of drug-resistant virus Lopinavir/ritonavir: impact on phenytoin. In 8 healthy
has significant public health implications.
volunteers, lopinavir/ritonavir (400/100 mg BID for What is the evidence for an interaction between AEDs
10 days) reduced mean steady-state exposure (AUC) and PI ARVs? Phenytoin: impact on lopinavir/ritonavir. A
to phenytoin by 31% (90% CI 16% to 43%) (down- study of 12 healthy volunteers found that phenytoin graded to Class III because of dropouts).39 (300 mg/day for 10 days) reduced mean steady-state Lopinavir/ritonavir: impact on valproic acid. Serum
area under the serum concentration-time curve valproic acid levels in a cohort of subjects infected with HIV and not receiving lopinavir/ritonavir (from 46 to 27 hours, p ϭ 0.021) or 7 days (from 55 to did not differ significantly from those in subjects 34 hours, p ϭ 0.021).e10 The median (range) decreases comedicated with lopinavir/ritonavir 400/100 mg in nevirapine half-life were 19 hours (11.4 –25.4) and twice daily; equivalence criteria were not defined 16.9 hours (10.9 –37.4), respectively. There was no sig- nificant change in mean nevirapine half-life after a sin-gle 184-mg phenytoin dose. Interpretation of these data What is the evidence for interaction between AEDs
and integrase inhibitors? Raltegravir: Impact on lam-

is limited by the small sample size, short treatment du- otrigine. One Class II study of 24 healthy volunteers
ration, and low phenytoin dose used.
assessed the pharmacokinetics of a single lamotrigine Valproic acid: impact on efavirenz. A Class II study in
dose (100 mg) with or without raltegravir coadmin- 11 HIV-positive subjects taking efavirenz 600 mg/day istration (400 mg BID for 5 days).21 The 90% confi- found that efavirenz AUC was not significantly affected dence limits for the geometric ratio of lamotrigine (mean change 0%, CI Ϫ15% to 17%) after administra- tion of valproic acid 500 mg/day for 7 days.29 occasions were within bioequivalence range (0.80 – Valproic acid: impact on zidovudine. In a Class II
1.25), indicating lack of interaction as assessed by open-label study, 6 patients with HIV received zid- ovudine 100 mg every 8 hours23; valproic acid 250 Raltegravir: impact on midazolam. A 2-period study
mg every 8 hours was added on days 6 –9. Zidovu- assessed the influence of raltegravir (800 mg/day) on dine levels were measured on days 5 and 10. Coad- the pharmacokinetics of midazolam (single 2-mg oral ministration with valproic acid resulted in mean dose), a marker of CYP3A4 activity (Class II).22 zidovudine AUC increase from 0.65 to 1.17 mg/h/L sence of raltegravir remained within bioequivalence Efavirenz: impact on carbamazepine. In a random-
limits, suggesting that raltegravir does not affect ized, open-label, crossover study (Class III due to dropouts), 18 healthy subjectse9 received carbamaz-epine titrated to 400 mg daily on days 1–21; on What is the evidence for an interaction between AEDs
days 22–35 carbamazepine 400 mg/day was coad- and nucleoside reverse transcriptase inhibitor and
ministered with efavirenz 600 mg/day. In the 12 NNRTI ARVs? Benzodiazepines: impact on zidovudine. A
evaluable subjects, efavirenz decreased carbamaz- Class III study found no significant differences in zidovudine levels between patients on benzodiaz-epines and those off benzodiazepines; statistical did not affect levels of the active metabolite Efavirenz: impact on valproic acid. Valproic acid lev-
Carbamazepine: Impact on efavirenz. In a random-
ized, open-label, crossover study (Class III due to els in a cohort of subjects with HIV not receiving dropouts), 18 healthy subjectse9 received efavirenz efavirenz did not differ significantly from those 600 mg/day on days 1–14; on days 15–35 efavirenz measured in subjects comedicated with efavirenz 600 mg/day was coadministered with carbamazepine 600 mg/day; equivalence criteria were not defined titrated up to 400 mg/day. In the 14 evaluable subjects, carbamazepine reduced efavirenz AUC by 36% (90% Zidovudine: impact on phenytoin. Another Class III
CI 32% to 40%) as compared with efavirenz alone.
study compared patients with AIDS on zidovudine(prospective study arm) plus phenytoin (n ϭ 109 Carbamazepine: impact on nevirapine. In a Class III
pilot study in 4 healthy women,e10 the mean half-life serum samples from 21 patients) with patients with- of nevirapine (single 200-mg dose) was reduced after out AIDS (historical controls) on phenytoin (n ϭ a single 400-mg dose of carbamazepine (from 52 to 1,231 serum samples from 557 patients).e11 The 33 hours, p ϭ 0.021), which corresponds to a me- most commonly prescribed phenytoin dose was 300 dian decrease of 18.8 hours (range 15.6 –38). These mg/day. Addition of zidovudine did not significantly data are difficult to interpret because of the study’s affect phenytoin concentrations in the study patients small sample size and single-dose design.
when compared with levels in the historical controls(8.8 Ϯ 0.88 mg/L and 8.9 Ϯ 1.2 mg/L, respectively; Phenobarbital: impact on nevirapine. This same Class
III studye10 in 4 women also found no significant change in mean nevirapine half-life after a single What is the evidence that AED-ARV interactions are
clinically meaningful? One Class II retrospective co-
Phenytoin: impact on nevirapine. In the same Class
hort study24 (derived from a database with prospec- III study conducted in healthy women (discussed tive outcome assessment) used data from the US above),e10 the mean nevirapine half-life was reduced Military HIV Natural History Study. This study after phenytoin treatment 184 mg/day for either 3 days matched patients having episodes of overlap of EI-AED therapy and PI/NNRTI ARV combination maintain unchanged lamotrigine serum concentra- therapy (n ϭ 19 patients, 34 episodes of overlap) with patients having episodes of overlap of newer, Coadministration of raltegravir or atazanavir and non–EI-AEDs and PI/NNRTI ARV combinations lamotrigine may not require lamotrigine dosage ad- (n ϭ 85 patients, 142 episodes of overlap). Evidence of virologic failure, as determined by Ն2 consecutive Coadministration of raltegravir and midazolam may VL of Ͼ400 copies/mL, was assessed. All patients not require midazolam dosage adjustment (Level C).
were taking ARVs for Ͼ6 months, with episodes of Patients may be counseled that it is unclear AED and ARV overlap of Ն28 days. The EI-AED whether dosage adjustment is necessary when other and non–EI-AED cohorts did not differ in CD4 count AEDs and ARVs are combined (Level U).
at ARV initiation, in prior AIDS-defining events, or It may be important to avoid EI-AEDs in people in ARV therapy type and duration. Patients on on ARV regimens that include PIs or NNRTIs, as EI-AEDϩARV therapy had significantly higher rates of pharmacokinetic interactions may result in virologic virologic failure (10/16, 63%) as compared with pa- failure, which has clinical implications for disease pro- tients on non–EI-AEDϩARV therapy (20/75, 27%) gression and development of ARV resistance. If such for the first ARVϩAED period, with an odds ratio of regimens are required for seizure control, patients may 4.58 (90% CI 1.47 to 14.25, p ϭ 0.009).24 be monitored through pharmacokinetic assessments to Additionally, 14 case studies (Class IV) described ensure efficacy of the ARV regimen (Level C).
patients whose AED concentrations changed after CLINICAL CONTEXT
ARV therapy was initiated.25–27,30–33,35,e12–e14 In some and numerous pharmacokinetic studies indicate that cases, this provides some confirmatory patient data sup- EI-AEDs interact with ARVs. The optimal choice of porting the significance of the human volunteer data. In epilepsy treatment in patients with HIV should re- other cases, it provides the only available interaction flect an accounting for the metabolic and inhibitory/ data. Table e-3 presents details regarding these data.
inducing profiles of coadministered drugs. Clinicianswho prescribe ARVs and AEDs are encouraged to CONCLUSIONS Phenytoin possibly reduces lopina-
vir and ritonavir levels by about 30% (1 Class II study).
refer to the Department of Health and Human Ser- Valproic acid possibly increases zidovudine expo- vices treatment guidelines for HIV/AIDS, whichprovide specific recommendations for the management of possible drug– drug interactions with AED-ARV Valproic acid possibly has no effect on efavirenz combinations (available at http://aidsinfo.nih.gov/ contentfiles/AdultandAdolescentGL.pdf). For newer Ritonavir/atazanavir possibly reduces lamotrigine ARV agents, minimal data exist on drug interactions exposure by about 30% (1 Class II study).
Raltegravir and atazanavir possibly have no effect on lamotrigine exposure (1 Class II study).
RECOMMENDATIONS FOR FUTURE RESEARCH
Raltegravir possibly has no effect on midazolam Future research regarding AED-ARV interactions is needed. Special priority should be given to the study The evidence is insufficient to support or refute of first-line AED-ARV combinations used in low- other pharmacokinetic AED-ARV interactions (sin- and middle-income countries where second-line gle Class III/multiple Class IV studies).
Coadministration of highly active antiretroviral ther- apy containing a PI or NNRTI and an EI-AED possibly AUTHOR CONTRIBUTIONS
results in higher virologic failure rates (1 Class II study).
Dr. Birbeck: drafting/revising the manuscript, study concept or design,analysis or interpretation of data, acquisition of data, study supervision, RECOMMENDATIONS Patients receiving pheny-
obtaining funding. Dr. French: drafting/revising the manuscript, study toin may require a lopinavir/ritonavir dosage increase concept or design, analysis or interpretation of data. Dr. Perucca: draft-ing/revising the manuscript, study concept or design, analysis or interpre- of about 50% to maintain unchanged serum concen- tation of data, acquisition of data. Dr. Simpson: drafting/revising the manuscript, study concept or design, analysis or interpretation of data.
Patients receiving valproic acid may require a zid- Dr. Fraimow: drafting/revising the manuscript, study concept or design, ovudine dosage reduction to maintain unchanged se- analysis or interpretation of data, acquisition of data. Dr. George: draft-ing/revising the manuscript, analysis or interpretation of data. Dr. Oku- rum zidovudine concentrations (Level C).
licz: drafting/revising the manuscript, study concept or design, analysis or Coadministration of valproic acid and efavirenz may interpretation of data, acquisition of data. Dr. Clifford: drafting/revising not require efavirenz dosage adjustment (Level C).
the manuscript, study concept or design, analysis or interpretation of data,acquisition of data. Dr. Hachad: drafting/revising the manuscript, analysis Patients receiving ritonavir/atazanavir may re- or interpretation of data. Dr. Levy: analysis or interpretation of data, quire a lamotrigine dosage increase of about 50% to DISCLOSURE
ceived speaker honoraria and funding for travel from GlaxoSmithKline, Dr. Birbeck serves on the editorial boards of Epilepsia and Epilepsy & Millennium Pharmaceuticals, Inc., and Genentech Inc.; has received re- Behavior; and receives/has received research support from the NIH, the search support from Pfizer Inc, Schering-Plough Corp., Bavarian Nordic, Doris Duke Charitable Foundation, the Dana Foundation, and the Rock- NeurogesX, GlaxoSmithKline, Tibotec Therapeutics, Boehringer Ingel- efeller Brothers Fund. Dr. French has served on scientific advisory boards heim, and Gilead Sciences, Inc.; and receives research support from the for UCB, Johnson & Johnson, Eisai Inc., Novartis, Valeant Pharmaceuti- NIH (NIMH, NINDS, NIAID, and Fogarty Institutes). Dr. Hachad cals International, Icagen, Inc., Intranasal Therapeutics Inc., Sepracor reports no disclosures. Dr. Levy serves on the editorial advisory board for Inc., and Marinus Pharmaceuticals, Inc.; has received funding for travel Drug Metabolism Letters; has served as a consultant for Johnson & John- from UCB, Kyowa Hakko Kirin Pharma, Inc., Eisai Inc., Johnson & son, Neurocrine Biosciences, Inc., Xenon, Biocodex, NeuroAdjuvants Johnson, Valeant Pharmaceuticals International, and GlaxoSmithKline; Inc., Allergan, Inc., Jazz Pharmaceuticals, and NeuroVista Corporation; serves as an Associate Editor for Epilepsy Currents and the supplements has received publishing royalties for Antiepileptic Drugs, 5th ed. (Lippin- editor for Epileptic Disorders; is president of the Epilepsy Study Consor- cott Williams & Wilkins, 2002); and has served as an expert witness in tium, which receives money from multiple pharmaceutical companies; 25% of her salary is paid to NYU by the consortium; and she has receivedresearch support from SK Pharma Co., Ltd., Valeant Pharmaceuticals DISCLAIMER
International, Pfizer Inc, UCB, Eisai, Johnson & Johnson, the NIH, and This statement is provided as an educational service of the American the Epilepsy Research Foundation. Dr. Perucca serves on scientific advi- Academy of Neurology and the International League Against Epilepsy sory boards for and has received funding for travel or speaker honoraria (ILAE). It is based on an assessment of current scientific and clinical from Bial, Eisai Inc., GlaxoSmithKline, Johnson & Johnson, Novartis, information. It is not intended to include all possible proper methods of Pfizer Inc, Vertex Pharmaceuticals, UCB, and Upsher-Smith Laborato- care for a particular neurologic problem or all legitimate criteria for choos- ries, Inc.; serves on editorial advisory boards for Epilepsia, Acta Neurologica ing to use a specific procedure. Neither is it intended to exclude any Scandinavica, CNS Drugs, Epileptic Disorders, Epilepsy Research, Seizure, reasonable alternative methodologies. The AAN and ILAE recognize that Lancet Neurology, Expert Reviews in Neurotherapeutics, Clinical Pharmaco- specific patient care decisions are the prerogative of the patient and the kinetics, Therapeutic Advances in Drug Safety and Clinical Drug Investiga- physician caring for the patient, based on all of the circumstances in- tion, European Neurological Journal, Neurosciences, and World Journal of volved. The clinical context section is made available in order to place the Pharmacology and Clinical Investigation; receives publishing royalties for evidence-based guideline(s) into perspective with current practice habits Antiepileptic Drugs (Raven Press/Lippincott, 2002), Epilepsy: A Compre- and challenges. No formal practice recommendations should be inferred.
hensive Textbook (Lippincott, 2008), and The Treatment of Epilepsy (WileyBlackwell, 2009); serves as a consultant for Bial, Eisai Inc., GlaxoSmith- CONFLICT OF INTEREST
Kline, Ibsa, Johnson & Johnson, Pfizer Inc, sanofi-aventis, SK HoldingsCo Ltd, UCB, Supernus Pharmaceuticals, Inc., Vertex Pharmaceuticals, The American Academy of Neurology is committed to producing inde- Medtronic, Inc., World Health Organization, and Upsher-Smith Labora- pendent, critical and truthful clinical practice guidelines (CPGs). Signifi- tories, Inc.; receives research support from UCB, European Commission, cant efforts are made to minimize the potential for conflicts of interest to Italian Medicines Agency, Italian Ministry of Health, Italian Ministry for influence the recommendations of this CPG. To the extent possible, the Education, and Institute of Neurology IRCCS C. Mondino Foundation, AAN keeps separate those who have a financial stake in the success orfailure of the products appraised in the CPGs and the developers of the Pavia, Italy; and prepared an affidavit in a medical-legal case. Dr. Simpson guidelines. Conflict of interest forms were obtained from all authors and serves/has served on scientific advisory boards for Cephalon, Inc., MEDA reviewed by an oversight committee prior to project initiation. AAN lim- Pharmaceuticals Inc., Endo Pharmaceuticals, NeurogesX, Eli Lilly and its the participation of authors with substantial conflicts of interest. The Company, Pfizer Inc, GlaxoSmithKline, Allergan, Inc., Merz Pharmaceu- AAN forbids commercial participation in, or funding of, guideline proj- ticals, LLC, Merck Serono, Covidien, Astellas Pharma Inc., Alpharma, ects. Drafts of the guideline have been reviewed by at least three AAN Biogen Idec, Ipsen, Gilead Sciences, Inc., Forest Laboratories, Inc., and committees, a network of neurologists, Neurology peer reviewers and rep- Acorda Therapeutics Inc.; serves on the editorial boards of Clinical Journal resentatives from related fields. The AAN Guideline Author Conflict of of Pain and AIDS Patient Care; has served on the speakers’ bureau for Eli Interest Policy can be viewed at www.aan.com.
Lilly and Company and GlaxoSmithKline; serves as a consultant for Neu-rogesX, Eli Lilly and Company, GlaxoSmithKline, Allergan, Inc., MerzPharmaceuticals, LLC, Astellas Pharma Inc., Ipsen, and US WorldMeds, Received June 6, 2011. Accepted in final form September 7, 2011. LLC.; has received speaker honoraria from Eli Lilly and Company, Glaxo-SmithKline, Allergan, Inc., and Astellas Pharma Inc.; receives research REFERENCES
support from NeurogesX, Pfizer Inc, Allergan, Inc., Eli Lilly and Com- Holmberg SD, Buchbinder SP, Conley LJ, et al. The spec- pany, the NIH (NINDS, NIMH), and the Peripheral Neuropathy Foun- trum of medical conditions and symptoms before acquired dation; and has given expert testimony regarding a case involving the immunodeficiency syndrome in homosexual and bisexual myotoxicity of statins. Dr. Fraimow has received research support from men infected with the human immunodeficiency virus.
JMI Laboratories and the NIH. Dr. Fraimow’s spouse has served on sci- Am J Epidemiol 1995;141:395– 404; discussion 405–396.
entific advisory boards for UCB, Johnson & Johnson, Eisai Inc., Novartis,Valeant Pharmaceuticals International, Icagen, Inc., Intranasal Therapeu- Kellinghaus C, Engbring C, Kovac S, et al. Frequency of tics Inc., Sepracor Inc., and Marinus Pharmaceuticals, Inc.; has received seizures and epilepsy in neurological HIV-infected pa- funding for travel from UCB, Kyowa Hakko Kirin Pharma, Inc., Eisai Inc., Johnson & Johnson, Valeant Pharmaceuticals International, and Wong MC, Suite ND, Labar DR. Seizures in human im- GlaxoSmithKline; serves as an Associate Editor for Epilepsy Currents and munodeficiency virus infection. Arch Neurol 1990;47: the supplements editor for Epileptic Disorders; is president of the Epilepsy Study Consortium, which receives money from multiple pharmaceutical Bradshaw D, Groenewald P, Laubscher R, et al. Initial companies; 25% of her salary is paid to NYU by the consortium; and she burden of disease estimates for South Africa, 2000. S Afr has received research support from SK Pharma Co., Ltd., Valeant Phar- maceuticals International, Pfizer Inc, UCB, Eisai, Johnson & Johnson, World Health Organization. Patient Monitoring Guide- the NIH, and the Epilepsy Research Foundation. Dr. George served on a lines for HIV Care and Antiretroviral Therapy. Geneva: scientific advisory board for Pfizer Inc. Dr. Okulicz reports no disclosures.
Dr. Clifford serves/has served on scientific advisory boards for Biogen Idec, Elan Corporation, Roche, Forest Laboratories, Inc., Genentech, Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update Inc., GlaxoSmithKline, Millennium Pharmaceuticals, Inc., Schering- on rifampin and rifabutin drug interactions. Am J Med Sci Plough Corp., Bristol-Meyers Squibb, and Genzyme Corporation; re- Breen RA, Swaden L, Ballinger J, Lipman MC. Tubercu- P450 enzyme-inducing antiepileptics: a retrospective case losis and HIV co-infection: a practical therapeutic ap- control study. AIDS Res Ther 2011;8:18.
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efavirenz. AIDS 2000;14:2793–2794.
Lack of appropriate treatment for people with comorbid Cazali N, Tran A, Treluyer JM, et al. Inhibitory effect of HIV/AIDS and epilepsy in sub-Saharan Africa. Epilepsia stiripentol on carbamazepine and saquinavir metabolism in human. Br J Clin Pharmacol 2003;56:526 –536.
American Academy of Neurology. Clinical Practice Guide- DiCenzo R, Peterson D, Cruttenden K, et al. Effects of line Process Manual: 2004 Edition. St. Paul, MN: Ameri- valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency Holtzman DM, Kaku DA, So YT. New-onset seizures as- virus-infected adults. Antimicrob Agents Chemother sociated with human immunodeficiency virus infection: causation and clinical features in 100 cases. Am J Med Garcia A, Ibarra A, Etessam J, et al. Protease inhibitor- induced carbamazepine toxicity. Clin Neuropharmacol Pascual-Sedano B, Iranzo A, Marti-Fabregas J, et al. Pro- spective study of new-onset seizures in patients with hu- Honda M, Yasuoka A, Aoki M, Oka S. A generalized sei- man immunodeficiency virus infection: etiologic and zure following initiation of nelfinavir in a patient with hu- clinical aspects. Arch Neurol 1999;56:609 – 612.
man immunodeficiency virus type 1 infection, suspected Birbeck GL, Chomba E, Kvalsund M, et al. Antiretroviral due to interaction between nelfinavir and phenytoin. In- adherence in rural Zambia: the first year of treatment avail- ability. Am J Trop Med Hyg 2009;80:669 – 674.
Hugen PW, Burger DM, Brinkman K, et al. Carbamazepi- Breen RA, Lipman MC, Johnson MA. Increased incidence ne–indinavir interaction causes antiretroviral therapy fail- of peripheral neuropathy with co-administration of stavu- ure. Ann Pharmacother 2000;34:465– 470.
dine and isoniazid in HIV-infected individuals. AIDS Kato Y, Fujii T, Mizoguchi N, et al. Potential interaction between ritonavir and carbamazepine. Pharmacotherapy Schifitto G, McDermott MP, McArthur JC, et al. Inci- dence of and risk factors for HIV-associated distal sensory Lim ML, Min SS, Eron JJ, et al. A two-way drug interac- polyneuropathy. Neurology 2002;58:1764 –1768.
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Ellis RJ, Rosario D, Clifford DB, et al. Continued high Mateu-de Antonio J, Grau S, Gimeno-Bayon JL, Carmona prevalence and adverse clinical impact of human immuno- A. Ritonavir-induced carbamazepine toxicity. Ann Phar- deficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study.
Olmedilla ML, Fernandez AH, Merino GC. Interaccion Indinavir-Fenitoina en un paciente VIHϩ: a proposito de Burger DM, Huisman A, Van Ewijk N, et al. The effect un caso. Farm Hosp 2000;24:406 – 407.
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