Sodium Valproate and Highly Active Antiretroviral Therapy in HIV Positive Patients Who Develop New Onset Seizures

Seizure 20 (2011) 80–82

Contents lists available at ScienceDirect

Seizure

journal homepage: www.elsevier.com/locate/yseiz

Short communication Sodium valproate and highly active antiretroviral therapy in HIV positive patients who develop new onset seizures

Yaseen Yacoob a,*, Ahmed Iqbal Bhigjee a, Pravikrishnen Moodley b, Raveen Parboosing b a Department of Neurology, Nelson R. Mandela School of Medicine, University of Kwa-Zulu Natal, Durban, South Africa b Department of Virology, National Health Laboratory Service, University of Kwa-Zulu Natal, Durban, South Africa

ARTICLE INFO ABSTRACT

Article history: Recurrent seizures may occur in up to 11% of HIV positive patients. The aetiology of the seizures includes Received 11 May 2010 opportunistic infections, neoplasia, HIV itself, metabolic derangements and drugs. Apart from treating Received in revised form 8 September 2010 the cause of the seizures, the challenge is to use the appropriate anticonvulsant drug (AED) to avoid Accepted 10 September 2010 potentially adverse drug–drug interactions in patients who are on concurrent highly active antiretroviral therapy (HAART). Initial recommendations were that the newer AEDs should preferably be used because Keywords: of their simpler pharmacokinetics. Seizures We report on our experience with the use sodium valproate (SV) in eight patients who were on HIV concurrent HAART. There were two males and six females with a mean age of 34.1 years. The mean dose Anticonvulsants Antiretroviral agents of SV was 1075 mg per day. Seizure control was excellent, the CD4 count improved and there was successful viral suppression in all patients. This small study showed that SV was safe and effective. It is also relatively inexpensive compared to the newer AEDs – an important consideration in resource poor settings. ß 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction We report on the clinical and laboratory ﬁndings of eight patients who were on concurrent sodium valproate (SV) and Recurrent seizures represent an important clinical manifesta- HAART. tion of neurological disease in HIV infection. Frequency rates of 3– 11% have been reported in hospital based studies of HIV infected 2. Methods and case studies individuals.1–6 The aetiology of seizures in HIV-infected individuals include opportunistic infections, neoplasia, HIV itself, HIV positive patients on HAART who developed new onset 1–6 metabolic derangements and drugs. seizures were recruited for the study. Patients or their guardians Apart from identifying and treating the underlying cause of the who gave consent were included in the study. Exclusion criteria seizures, the challenge is to use the appropriate anticonvulsant included known allergy to SV, hepatic enzymes greater than 10 (AED) in patients who are on highly active anti-retroviral therapy times the upper limit of normal, a prothrombin time that was 5 or (HAART). Protein binding and metabolism via cytochrome P450 more seconds than the control value, and pregnancy. The study system could lead to adverse drug–drug interaction and loss of was approved by the Bioethics Committee of the University of viral suppression. Initial recommendations were that the newer KwaZulu-Natal. AEDs such as gabapentin, levetiracetam and tiagabine should All patients underwent a complete clinical examination. At preferably be used as they have simpler pharmacokinetics than the baseline the following routine blood investigations were done: full 7,8 older AEDs such as phenytoin and carbamazepine. The same blood count (FBC), urea and electrolytes (U&E), liver function tests authors advised caution with the use of valproate/valproic acid (LFTs), glucose, calcium, magnesium, phosphate, international (SV/VA) as, in vitro studies suggested that this drug promoted viral normalised ratio (INR), rapid plasma reagin (RPR) and antinuclear 9,10 replication. factor (ANF). CD4 counts and viral loads were measured at baseline and at approximately 2–6 month intervals. All patients had a chest radiograph and either a CT or MRI scan of the brain. If indicated, cerebrospinal ﬂuid was subjected to routine chemistry, microsco- py, bacterial and fungal culture, viral polymerase chain reaction * Corresponding author at: Department of Neurology, Inkosi Albert Luthuli Central Hospital, Private Bag X03, Mayville 4058, South Africa. studies, cryptococcal antigen and cytological examination. Tel.: +27 31 2402359x63; fax: +27 31 2402358. According to the South African national guidelines for HAART, E-mail address: [email protected] (Y. Yacoob). all except one patient were on either regimen 1a (Stavudine,

Table 1 Clinical and radiological data. Patient 4 was followed up as part of another trial using a different regimen – tenofovir, emtricitabine and efavirenz. 1a = stavudine, lamivudine and efavirenz. 1b = stavudine, lamivudine and nevirapine.

Patient Age and HAART Duration of Aetiology of Radiological Daily dose of sodium Seizure gender regimen HAART (months) seizures ﬁndings valproate (mg) control

1 45 (M) 1a 12 Uncertain MRI normal 600 Excellent 2 42 (F) 1b Started at Tuberculomata MRI – multiple enhancing 1200 Occasional seizure seizure onset surface lesions 3 36 (F) 1b 8 Uncertain CT normal 900 Improved 4 39 (F) TRU/EFV 13 Old TB CT calciﬁed granuloma 900 Excellent 5 12 (F) 1a 1 Drug related CT normal 900 Improved 6 27 (F) 1b 2 Uncertain CT normal 1200 Improved 7 39 (M) 1a 1 Old TB CT calciﬁed granuloma 900 Excellent 8 33 (F) 1a 1 TBM MRI enhancing lesions 2000 Excellent

Lamivudine and Efavirenz) or 1b (Stavudine, Lamivudine and studies. As many as 14% of HIV seropositive patients on phenytoin Nevirapine). had hypersensitivity reactions.1 Drugs such as phenytoin, carbamazepine and phenobarbitone may increase the metabolism of the 3. Results protease inhibitors (PI) and result in loss of viral suppression.11 Conversely, inhibition of the CYP 450 enzyme system by the PIs The clinical and radiological data are summarized in Table 1. may lead to toxic levels of phenytoin and carbamazepine.12 Factors The duration of follow up after institution of AEDs, the CD4 counts such as these, as well as the concern that SV/VA may increase viral and viral loads are summarized in Table 2. There were two males replication9,10 led to the earlier recommendation that the older and six females with a mean age of 34.1 years (range 12–45). The AEDs should be avoided in HIV seropositive patients who were on duration of HAART therapy ranged from 0 to 13 months prior to HAART. commencements of SV. The mean daily dose of SV was 1075 mg Although there are no large prospective studies examining (range 600–2000 mg). The duration of follow up after initiation of drug–drug interactions, the earlier concern about SV/VA has not SV ranged from two to thirty nine (mean of 15) months. The been confirmed by more recent studies. Maggi and Helman13 did aetiology of seizures was tuberculosis in two patients. Patient 2 not find increased viral loads in six patients taking valproate. In with brain tuberculomata presented with seizures and was fact a proof of concept study suggested that the addition of valproic commenced on ARVs at seizure onset. Patient 8 was diagnosed acid to HAART may be beneficial in depleting latent HIV with TB meningitis a month after ARV initiation. An IRIS infection.14 Although, this concept was not confirmed,15,16 these phenomenon was considered. Both patients were given standard studies did show that SV/VA was safe. 4 drug antituberculous therapy together with a month of Our small study confirms the efficacy and safety of SV/VA in HIV prednisone at 40 mg daily. Patient 1 had lamotrigine (25 mg bd) seropositive patients on HAART. In all patients there was a rise in and patient 8 had gabapentin (300 mg tds) added to their CD4 counts and adequate viral suppression. None of our patients treatment. Four became seizure free, one had the occasional was on zidovudine whose bioavailability (and hence side effects) is seizure, two had a single seizure each in 6 months and 1 had a increased in the presence of SV/VA.14 Nor was any patients on PIs. seizure in 2 months of follow up. The mean CD4 count at baseline The data on PIs and SV/VA is scanty but close monitoring is was 187 with a range from 2 to 550. The CD4 count improved in all advised.17 patients. The viral load was suppressed in all patients. 5. Conclusion 4. Discussion There is little information about the combination of HAART and Potential adverse drug-disease and drug–drug interactions in newer AEDs. Locatelli et al.18 studied seven patients on HAART and HIV infected individuals have been reported in isolated case Leviteracetam. The combination was safe and effective. Despite the initial call for use of the newer AEDs for patients on HAART because of their (AEDs) simpler pharmacokinetics, the data on the newer AEDs is limited. There is the additional aspect of the cost of the Table 2 newer AEDs – an important consideration in resource poor The duration of follow up on AEDs and HAART, the CD4 counts and viral loads. Patient 4 was part of another trial where the viral load cut off value was settings. Currently, there is increasing evidence that SV/VA can <400 copies/ml. ND = not done due to technical difficulties. Patient 5 had a baseline be used safely and effectively in patients who are on HAART. CD4 value >200 as the CD4 percentage rather than absolute CD4 value is used in paediatric ARV clinics as a criteria for initiation of ARVs. Patient 7 was re-instated on Acknowledgement ARVs following a 6 month default and the baseline CD4 represents the point of re- initiation. Secretarial assistance was provided by Ms M. Hlongwane. Patient Duration of CD4 counts VL (copies/ml) follow up Baseline Latest Baseline Latest References (months)

1 36 2 270 ND <25 1. Holtzman DM, Kaku DA, So YT. New-onset seizures associated with human 2 32 20 523 9300 <25 immunodeficiency virus infection: causation & clinical features in 100 cases. 3 9 130 418 <25 <25 Am J Med 1989;87:173–7. 4 18 183 247 12,900 <400 2. Wong MC, Suite ND, Laban DR. Seizures in human immunodeficiency virus 5 6 550 875 ND <25 infection. Arch Neurol 1990;47:640–2. 6 2 44 328 7900 <25 3. Pascual-Sedano B, Iranzo A, Martifabregas. Domingo P, Escartin A, Fuster M, 7 6 480 688 230 <25 et al. Prospective study of new-onset seizures in patients with human immu- 8 6 88 292 ND <25 nodeficiency virus infection. Etiologic and clinical aspects. Arch Neurol 1999;56: 609–12. 82 Y. Yacoob et al. / Seizure 20 (2011) 80–82

4. Chadha DS, Handa A, Sharma SK, Varadarajulu P, Singh AP. Seizures in patients 12. Garcia AB, Latorse IA, Porta EJ, Martinez SA, Perez MD, Siaz DR, et al. Protease with human immunodeficiency virus infection. J Assoc Physicians India inhibitors-induced carbamazepine toxicity. Clin Neuropharmacol 2000;23: 2000;48:573–6. 216–8. 5. Mullin P, Green G, Bakshi R. Special populations: the management of seizures in 13. Maggi JD, Helman MH. The effect of divalproex sodium on viral load: a HIV positive patients. Curr Neurol Neurosci Rep 2004;4:308–14. retrospective review of HIV positive patients with manic syndromes. Can J 6. Kellinghaus C, Engbring C, Kovac S, Moddel G, Boesebeck F, Fischera M, et al. Psychiatry 2001;46:359–62. Frequency of seizures and epilepsy in neurological HIV infected patients. Seizure 14. Lehrman G, Hogue B, Palmar S, Jennings C, Spina CA, Wiegand A, et al. Depletion 2008;17(1):27–33. of latent HIV-1 infection in vivo: a proof of concept study. Lancet 2005;366: 7. Romanelli F, Jennings HR, Nath A, Ryan M, Berger J. Therapeutic dilemma. The 549–55. use of anticonvulsants in HIV-positive individuals. Neurology 2000;54:1404–7. 15. Sagot-Lexolle N, Lamine A, Chaix M-L, Boufassa F, Aboulker JP, Costagliola. et al. 8. Romanelli F, Pomeroy C. Concurrent use of antiretrovirals and anticonvulsants Prolonged valproic acid treatment does not reduce the size of latent HIV in human immunodeficiency virus (HIV) seropositive patients. Curr Pharm Des reservoir. AIDS 2008;22:1125–9. 2003;9:1433–9. 16. Archin NM, Eron JJ, Palmar S, Hartmann-Duff A, Martinson JA, Wiegand A, et al. 9. Simon G, Moog C, Obert G. Valproic acid reduces the intracellular level of Valproic acid without intensified antiviral therapy has limited impact glutathione and stimulates human immunodeficiency virus. Chem Biol Interact on persistent HIV infection of resting CD4 and Tcells. AIDS 2008;22: 1994;91:111–21. 1131–5. 10. Moog C, Kantz-Simon G, Caussin-Shwemling C, Obert G. Sodium valproate, an 17. www.hiv-druginteractions.org. Abstracted 17 June 2009. anticonvulsant drug, stimulates human immunodeficiency virus type 1 repli- 18. Locatelli P, Lapadula G, Costarelli S, Pezolli MC, Casari S. Long term follow up on cation independently of glutathione levels. J Gen Virol 1996;77:1993–9. levetiracetam in patients with HIV infection & HAART therapy.26th IEC 11. Jennings HR, Romanelli F. The use of valproic acid in HIV-positive patients. Ann Proceedings. Epilepsia 2005;46(Suppl. 6):106. Pharmacother 1999;33:1113–6.