Psychosomatics 41:452-453, October 2000
© 2000 The Academy of Psychosomatic Medicine
Hepatotoxicity With Combination of Valproic Acid, Ritonavir, and Nevirapine: A Case Report
Kelly L. Cozza, M.D.,
Edward J. Swanton, M.D., and
Christopher W. Humphreys, M.D. , Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, DC
Key Words: Hepatotoxicity • Valproic Acid • Antiretrovirals
TO THE EDITOR: Hepatotoxicity due to valproic acid (VPA) is a known event, but the etiology and risk factors are poorly understood. VPA's use in psychiatry for mood stabilization has enlarged the at-risk population. In pediatric epilepsy, risk factors include neurological disease, male gender, and concomitant use of hepatic cytochrome P450 inducing drugs.1,2 The authors present a case of a human immunodeficiency virus (HIV) infected man who developed acute hepatitis due to VPA with cytochrome P450 active drugs. Further study of this hepatic effect is explored.
Case Report
Mr. C. is a 51-year-old White male with bipolar disorder and a 5-year history of multidrug-resistant HIV. He was started on VPA for mood stabilization while on an antiretroviral drug holiday. Five weeks later a new antiretroviral regimen was initiated with BID dosing of ritonavir (400 mg), saquinavir (400 mg), stavudine (40 mg) and nevirapine (200 mg). Initial laboratory values were CD4: 628 cells/cu mm, viral load 78,512 copies/ml, with normal liver associated enzymes (LAEs). Serum VPA was therapeutic. Three weeks into therapy Mr. C. developed headache, nausea, vomiting, anorexia, fevers, photophobia, and neck stiffness. Emergency Department evaluation diagnosed a urinary tract infection (UTI) and added trimethoprim-sulfamethoxazole.
Mr. C. presented 2 days later for routine psychiatric appointment complaining of a blanching, pruritic rash, neck stiffness, continued nausea, vomiting, diarrhea, malaise, dizziness, and photophobia. Physical exam revealed a temperature of 101.3, diaphoresis, orthostasis, and poor concentration. Lumbar puncture was negative. Screening laboratories revealed hepatitis and no UTI; trimethoprim-sulfamethoxazole was discontiued. Serology testing for hepatitis A, B, and C, cytomegalovirus, and Epstein-Barr virus; and cultures of urine, blood, and cerebrospinal fluid (CSF) were negative. Ascites and pleural effusions developed on Day 5. With a negative infectious workup, all drugs were discontinued on Day 5. Etiology for Mr. C.'s hepatic dysfunction and clinical presentation was assumed to be the VPA, enhanced by either the P450 enzyme inhibitor ritonavir or by the enzyme inducer nevirapine or both; VPA serum level remained therapeutic. Rash was deemed secondary to the sulfa drug. Serum carnitine from Day 1 was low, and levocarnitine (1 gm tid) was started on Day 6 after a review of the pediatric neurology literature. On Day 7 LAEs trended downward. Mr. C. felt better on Day 8 and was discharged on Day 11, only on levocarnitine. One month later, levocarnitine was discontinued, and antiretrovirals were reinitiated. Efavirenz (600 mgs qhs) replaced the nevirapine. LAEs remained normal, CD4 count was 652, and viral load was undetectable. He has completed a course of electroconvulsive therapy (ECT) with good outcome and remains in maintenance ECT.
DISCUSSION
Hepatotoxicity as a result of valproic acid therapy is well documented, although the mechanism for this toxicity remains unknown. In children, it is hypothesized that the causes of VPA-induced hepatotoxicity include VPA induced hypocarnitinemia and/or the formation of toxic metabolites, 2-N- propyl-4-pantanoic acid, or 4-ene-VPA through a hepatic P450 function.1,3L- carnitine supplementation seems to have a protective effect against VPA's effects in children1,4 and replacement of carnitine in VPA overdose may be protective.5 There are no studies to determine if carnitine replacement is of benefit in established hepatotoxicity. A review of pediatric hepatotoxicity due to VPA2 found the patients at greatest risk for fatalities were males with neurological illnesses and seizures; on polytherapy with cytochrome P450-inducing agents like phenobarbital or carbamazepine. Our patient, although an adult, had a neurological disease (HIV) and was on polytherapy, including a P450 3A3/4-inducer (nevirapine). The potent inhibitor ritonavir may have played a role. We had difficulty finding a laboratory to evaluate toxic metabolites of VPA, nor could we find clear recommendations in the adult literature for management of VPA-induced hepatotoxicity. In vivo studies of VPA's P450 metabolism do not exist. Most adult psychiatrists and psychopharmacologists knew of VPA's hepatotoxicity but were not aware of VPA-induced hypocartinemia. Most physicians felt that the therapeutic VPA level indicated that there was no drug interaction, not knowing that toxic metabolites are not routinely tested. Interestingly, adefovir, another antiretroviral, is associated with hypocartinemia and hepatotoxicity, so the patient's primary physician was quite receptive to carnitine replacement. Current studies are needed of the metabolic pathways and interactions of this potetially fatal medication. Physicians who treat patients with HIV, or any neurological disorder, who also prescribe VPA need to be aware of the potential for carnitine depletion, the potential accumulation of toxic VPA metabolites, and the possibility of hepatotoxicity, even with therapeutic serum VPA levels. We feel that the replacement of carnitine and discontinuation of VPA will lead to recovery in this patient.
ACKNOWLEDGMENTS
The opinion or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Department of the Army or the U.S. Department of Defense.
REFERENCES
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DeVivo DC, Bohan TP, Coulter DL, et al: L- carnitine supplementation in childhood epilepsy: current perspectives. Epilepsia 1998; 39:1216–1225
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Dreifuss FE, Langer DH, Moline KA, et al: Valproic acid hepatic fatalities II. United States experience since 1984. Neurology 1989; 39:201–207[Abstract/Free Full Text]
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Rettie AE, Rettenmeier AW, Howald WN, et al: Cytochrome P450-catalyzed formation of delta-4-VPA, a toxic metabolite of valproic acid. Science 1987; 235:890–893[Abstract/Free Full Text]
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Sugimoto T, Nishida N, Murakami K, et al: Valproate-induced hepatotoxicity: protective effect of L-carnitine supplementation. Japanese J of Psychiatry Neurol 1990; 44:387– 388
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Ishikura H, Matsuo N, Matsubara M, et al: Valproic acid overdose and L-carnitine therapy. J Analytical Toxic 1996; 20:55–58
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