Effect of Divalproex Sodium on Viral Load A Retrospective

The Effect of Divalproex Sodium on Viral Load: A Retrospective Review of HIV-Positive Patients With Manic Syndromes Julie D Maggi, MD1, Mark H Halman, MD, FRCPC2 Objective: In vitro studies report that valproic acid causes an increase in HIV-1 replication. This retrospective study examines a sample of patients with HIV disease and behavioural disturbances, for which the treatment of choice is divalproex sodium (DVP), to determine whetherDVP causes an increase in HIV-1 replication. Method: A chart and database review identified 15 patients with HIV disease presenting with either 1) mania or hypomania or 2) dementia with mania or with hypomania or behavioural disturbances. HIV-1 viral load was compared before and after mood stabilizer initiation. Results: Eleven patients started therapy with DVP, and 4 patients declined treatment with a mood stabilizer. Nine of the 11 patients taking DVP were also receiving antiretroviral therapy. HIV-1 viral load did not increase in 6 of the 9 patients who had measurements between 1 week and 3.5 months after DVP initiation. No follow-up was available for the other 3 patients. Of the 2 patients receiving DVP but not antiretroviral medication, 1 had an increase of 0.17 log in HIV-1 viral load at 4 months. No follow-up record was available for the second patient. The 4 patients not taking DVP were all on antiretroviral therapy; viral loads in 2 of them remained nondetectable over 3 to 4 months, and 1 had an increase of 0.32 log in HIV-1 viral load at 3 months. No follow-up record was available for the fourth patient. Conclusions: These preliminary data suggest that, in the presence of effective antiretroviral therapy, HIV-1 viral load appears not to be adversely affected by the administration of DVP. The results for the patients receiving DVP in the absence of antiretroviral medication remain indeterminate. Further prospective study is required. (Can J Psychiatry 2001;46:359–362) Key Words: mania, HIV, AIDS, valproic acid, divalproex sodium, HIV-1 viral load D ivalproex sodium (DVP) and its metabolite valproic acid (VPA) are anticonvulsant drugs indicated in the treatment of bipolar mood disorder (1,2) and may have a particular advantage over the traditional agents of lithium and antipsychotics in organic manic syndromes, including HIVassociated mania (3). Prevalence rates for manic syndromes in patients with HIV disease have been reported to be between 1.4% and 4% in ambulatory HIV–AIDS specialty clinics (3–5). These rates are comparable with the rate of manic syndromes in the general population, which is 1% (95%CI, 0.4% to 1.6%) (6). Manic syndromes in patients with HIV disease may be caused by a primary bipolar mood disorder, or they may be secondary to medications used to treat HIV infection or its complications, or they may be secondary to a general medical condition, such as HIV brain infection or HIV-related central nervous system opportunistic conditions. Secondary mania is considered to be a late-stage consequence of HIV disease. It is accompanied by significant immunosuppression (3,4) and abnormal magnetic resonance (MR) imaging (3,4), and it may occur in patients with no personal or family history of mood disorders (5). The optimal treatment of manic syndromes in patients with HIV disease remains unclear. One retrospective case series (3) and 1 case report (7) support the use of anticonvulsants over the traditional agents of lithium in combination with neuroleptics. In many HIV psychiatry clinics, VPA has emerged as the treatment of choice, not only for acute manic syndromes and bipolar disorder in HIV-infected patients, but also in managing the behavioural disturbances that may complicate HIV-associated dementia (3,7,8). Recently, in vitro studies in both acutely and chronically infected cell lines have demonstrated that VPA activates HIV-1 359 Manuscript received May 2000, revised, and accepted September 2000. This paper was presented as a Poster Presentation at the American Psychiatric Association Meeting, Washington, DC, 1999. 1Resident, Department of Psychiatry, University of Toronto, and St Michael’s Hospital Mental Health Service, Toronto, Ontario. 2Assistant Professor, Department of Psychiatry, University of Toronto; Director, HIV Psychiatry Program, St Michael’s Hospital Mental Health Service, St Michael’s Hospital, Toronto, Ontario. Address for correspondence: Dr MH Halman, HIV Psychiatry Program, St Michael’s Hospital, Wellesley Site, 160 Wellesley Street East, Suite 334, Jones Building, Toronto, ON M4Y 1J3 e-mail: mark.halman@utoronto.ca Can J Psychiatry, Vol 46, May 2001 360 The Canadian Journal of Psychiatry Table 1. Summary of patient profiles Divalproex sodium Antiretroviral therapy Viral load 1 (+/–)a (+/–)a (copies/ml) + + + + + + + + + + + – – – – + + + + + + + + + – – + + + + < 50 Not completed Not completed 37 170 < 500 7 033 264 000 4 000 225 900 Not completed < 500 < 500 < 500 16 000 b Vol 46, No 4 Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 a Viral load 2 (copies/ml) < 500 < 50 < 500 < 500 15 150 < 500 c Time between starting divalproex sodium treatment and viral load 2 (months) 3.5 1 2 1 2 0.25 Not applicable Not applicable Not applicable 4 10 Not applicable Not applicable Not applicable Not applicable Not completed Not completed Not completed Not completed 331 900 17 474 < 500 < 500 1 056 Not completed + receiving treatment, – not receiving treatment; b before starting divalproex sodium treatment; cafter starting divalproex sodium treatment. Data analysis was retrospective and descriptive. For the purpose of comparison, patients who began DVP treatment were considered as a separate group from those who declined treatment with a mood-stabilizing agent. Because of ARV’s ef fect on decreas ing HIV-1 vi ral load (13), patients were fur ther di choto mized based on whether they were re ceiv ing ARV therapy. replication at concentrations frequently reached in the plasma of VPA-treated patients (9–11). The implication of these in vitro findings for the patient with HIV disease is not known, and the need for further study addressing this issue has recently been raised (12). The objective of this case-series report is to retrospectively examine a clinical sample of patients treated with DVP to understand the in vivo implications of the in vitro data. That is, the study will examine whether DVP, when administered to HIV-infected patients presenting with behavioural disturbances for which it is the treatment of choice, results in an increase in HIV-1 replication as measured by HIV-1 viral load. As antiretroviral (ARV) drug therapy is known to decrease HIV-1 viral load (13), we predicted that the impact of DVP on viral load would be less in patients receiving ARV medications than in those not receiving them. Method We conducted a retrospective chart and database review of 250 patients presenting to our ambulatory HIV Psychiatry Clinic between 1994 and 1998. Patients diagnosed with mania, hypomania, behavioural disturbances complicating HIV dementia, and bipolar disorder were identified. Clinical and demographic information was extracted from the database and charts (stage of HIV disease in accordance with the 1993 classification of the Center for Disease Control [CDC], age, medication history, HIV-1 viral load). HIV-1 viral load was compared before and after mood stabilizer initiation, to determine whether change in HIV-1 viral load had resulted. HIV-1 viral load tests were carried out using either the Quantiplex HIV RNA 2.0 Assay or the Quantiplex HIV RNA 3.0 Assay (Chiron Corporation). Two testing methods were used because information on patients was collected at a time when Ontario provincial testing laboratories were switching from using the 2.0 Assay to the 3.0 Assay (personal communication, Carol Major, 1999). The lowest detectable HIV-1 viral loads are 500 copies/ml and 50 cop ies/ml for the 2.0 Assay and 3.0 Assay, respectively; lower values are considered nondetectable. An increase in viral load was considered significant if the increase was greater than 0.5 log, based on conventional clinical practice. Patients were considered to have no increase in HIV-1 viral load if the HIV-1 viral load documented after DVP administration was equal to or lower than the HIV-1 viral load prior to initiation of DVP. As well, in the absence of a documented HIV-1 viral load prior to initiation of DVP, HIV-1 viral load was considered to be not increased if the value after initiation of DVP was nondetectable by either the 2.0 or the 3.0 Assay. The maintenance of the HIV Psychiatry Program clinical database and analyses from that database, including this study, are approved by the Research Ethics Board of the Wellesley Central Hospital. Results Fifteen patients who met the diagnostic criteria were identified out of a sample of 250 patients. Psychiatric diagnoses included mania or hypomania (n = 7) and dementia with mania or with hypomania or behavioural disturbances (n = 8). CDC staging of patients was: CDC A = asymptomatic (n = 4), CDC May 2001 A Retrospective Review of HIV-Positive Patients With Manic Syndromes 361 B = symptomatic (n = 1), and CDC C = AIDS (n = 10). All patients were men. The mean age was 41.5 years. Eleven patients began treatment with DVP, and 4 patients declined treatment with a mood stabilizer. Nine of the 11 patients taking DVP were also receiving ARV therapy. In 3 of those patients, no follow-up viral loads were available. Of the remaining 6 patients, none had an increase in viral load when measured between 1 week and 3.5 months (median 1.5 months) after DVP initiation. Of the 2 patients receiving DVP but not ARV medication, 1 had an increase of 0.17 log HIV-1 viral load at 4 months after DVP initiation. No follow-up record was available for the second patient. All 4 patients not taking DVP were on ARV therapy. Of these, 2 had nondetectable viral loads at 3 to 4 months follow-up, and 1 had an increase of 0.32 log at 3 months. No follow-up record was available for the fourth patient. Patient profiles are summarized in Table 1. Discussion This retrospective case series report of 15 patients with HIV disease is the first to report on the clinical impact of the addition of DVP on HIV-1 viral load. These preliminary clinical data assist in translating the basic science implicating VPA as an inducer of HIV-1 replication into information necessary to make clinical decisions. Further, this study highlights the importance of better understanding drug interactions when treating psychiatric conditions in medically ill patients. The known benefits of Highly Active Antiretroviral Therapy (HAART) in maintaining viral suppression (13) make it important to consider a patient’s use of ARV medication when analyzing factors that impact on HIV-1 viral load. In this study, all patients with full follow-up data who were receiving ARV medications showed no increase in HIV-1 viral load when measured 1 week to 3.5 months after initiation of DVP. These preliminary data suggest that, in the presence of ARV medications, the addition of DVP may not lead to an adverse increase in HIV-1 viral load in the clinical setting. In the absence of ARV medications, we were unable to determine the impact of DVP on HIV-1 viral load because there was only 1 patient who fit this profile. Additional cases must be examined to answer this question. The retrospective nature of the study limits our ability to control for clinical factors that can impact on HIV-1 viral load, including intercurrent infections (14), stage of HIV disease (15), and adherence to ARV medications (16,17). It also precludes uniformity in diagnostic evaluation and limits our ability to obtain complete follow-up data sets. As the sample size Clinical Implications • This study highlights the importance of drug interactions in patients with HIV disease. • When considering the use of divalproex sodium in patients with HIV disease, viral load should be monitored. • The clinical significance of basic science studies examining the interaction of valproic acid and HIV needs to be validated with in vivo samples. Limitations • Because this is a retrospective observational report, the ability to control for clinical factors that can impact on HIV-1 viral load, including intercurrent infections, stage of HIV disease, and adherence to antiretroviral medications, is limited. • Complete follow-up data are not available. • Given that the rate of mania in HIV disease is between 1.4% to 4% in HIV–AIDS specialty clinics, the sample size is small, and statistical analysis was not possible. is small and not powered to reach statistical significance, the data are presented as an observational case-series report. As preliminary clinical data, the observations suggest that, in the presence of ARV therapy, HIV-1 viral load remains nondetectable or not significantly increased after administration of DVP. The results for the patients receiving DVP in the absence of ARV medication remain indeterminate. Further prospective study is currently underway at our site to examine the clinical impact of DVP on HIV-1 replication. The main objective of that study is to determine whether DVP causes an increase in HIV-1 replication, as measured by HIV-1 viral load, when administered to patients with HIV disease presenting with mania, hypomania, or HIV dementia with behavioural disturbances. The prospective study will control for many of the confounding variables raised in this retrospective review, including ARV adherence, uniformity in diagnostic evaluation, timing of serial HIV-1 viral load testing, sample size, and completeness of follow-up data points. Acknowledgements The authors thank Dr Sean Rourke, Dr Ken Balderson, and Dr Gary Rodin for reviewing the manuscript. References 1. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, and others. Efficacy of divalproex vs lithium and placebo in the treatment of mania [published erratum appears in JAMA 1994; 271;1830]. JAMA 1994;271:918–24. 2. Keck PE Jr, McElroy SL, Nemeroff CB. Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci 1992;4:395– 405. 3. Halman MH, Worth JL, Sanders KM, Renshaw PF, Murray GB. Anticonvulsant use in the treatment of manic syndromes of patients with HIV-1 infection. J Neuropsychiatry Clin Neurosci 1993;5:430 – 4. 4. Kieburtz K, Zettelmaier AE, Ketonen L, Tuite M, Caine ED. Manic syndromes in AIDS. Am J Psychiatry 1991;148:1068–70. 362 The Canadian Journal of Psychiatry Vol 46, No 4 5. Lyketsos CG, Hanson AL, Fishman M, Rosenblatt A, McHugh PR, Treisman GJ. Manic syn drome early and late in the course of HIV. Am J Psychia try 1993;150:326–7. 6. Robins LN, Helzer JE, Weissman MM, Orvaschel H, Gruenberg E, Burke JD Jr, and others. Lifetime prevalence of specific psychiatric disorders in three sites. Arch Gen Psychiatry 1984;41:949–58. 7. RachBeisel JA, Weintraub E. Valproic acid treatment of AIDS-related mania [letter]. J Clin Psychiatry 1997;58:406–7. 8. Worth JL, Halman MH. HIV Disease/AIDS. In: Rundell JR, Wise MG, editors. American Psychiatric Press Textbook of Consultation-Liaison Psychiatry. Washington (DC): American Psychiatric Press; 1996. p 832–77. 9. Moog C, Kuntz-Simon G, Caussin-Schwemling C, Obert G. Sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels. J Gen Virol 1996;77:1993–9. 10. Simon G, Moog C, Obert G. Valproic acid reduces the intracellular level of glutathione and stimulates human immunodeficiency virus. Chem Biol Interact 1994;91:111–21. 11. Witvrouw M, Schmit JC, Van Remoortel B, Daelemans D, Este JA, Vandamme AM, and others. Cell type-dependent effect of sodium valproate on human immu- nodeficiency virus type 1 replication in vitro. AIDS Res Hum Retroviruses 1997;13:187–92. 12. Jefferson JW. Possible risks associated with valproate treatment of AIDS-related mania [letter]. J Clin Psychiatry 1998;59:317. 13. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, and others. Antiretroviral therapy for HIV infection in 1998: updated recommen da tions of the In ter na tional AIDS So ci ety—USA panel. JAMA 1998;280:78–86. 14. Zang Y, Nakata K, Weiden M, Rom WN. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication by transcriptional activation at the long terminal repeat. J Clin Invest 1995;95:2324–31. 15. Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma [published erratum appears in Science 1997;275:14]. Science 1996;272:1167–70. 16. Haubrich RH, Little SJ, Currier JS, Forthal DN, Kemper CA, Beall GN, and others. The value of patient-reported adherence to antiretroviral therapy in predicting virologic and immunologic response. AIDS 1999;13:1099–1107. 17. Paterson D, Swindells S, Mohr J, Brester M, Vergis C, Squier C, and others. How much adherence is enough? A prospective study of adherence to protease inhibitor therapy using MEMSCaps [abstract no. 92]. Proceedings of the 6th Conference on Retroviruses and Opportunistic Infections; 1999; Chicago, IL. Résumé — L’effet du divalproex de sodium sur la charge virale : une étude rétrospective des patients séropositifs souffrant de syndromes maniaques Objectif : Les études in vitro indiquent que l’acide valproïque cause une augmentation de la réplication du VIH-1. Cette étude rétrospective examine un échantillon de patients séropositifs souffrant de troubles du comportement pour lesquels le traitement de choix est le divalproex de sodium (DVP), afin de déterminer si le DVP cause une augmentation de la réplication du VIH-1. Méthode : Une revue des dossiers et des bases de données a permis de repérer 15 patients séropositifs qui présentaient soit 1) une manie ou hypomanie, soit 2) une démence avec manie ou hypomanie ou des troubles du comportement. La charge virale du VIH-1 a été comparée avant et après le début du traitement au régulateur de l’humeur. Résultats : Onze patients ont commencé un traitement au DVP et 4 patients ont refusé le traitement du régulateur de l’humeur. Neuf des 11 patients prenant du DVP recevaient également un traitement antirétroviral. La charge virale du VIH-1 ne s’est pas accrue chez 6 des 9 patients qui ont été évalués entre 1 semaine et 3,5 mois après le début du traitement au DVP. Il n’y avait pas de suivi disponible pour les 3 autres patients. Des 2 patients qui recevaient du DVP mais pas de médicaments antirétroviraux, 1 affichait une augmentation de 0,17 log de la charge virale du VIH-1 à 4 mois. Le dossier de suivi du deuxième patient n’était pas disponible. Les 4 patients ne prenant pas de DVP recevaient tous un traitement antirétroviral; 2 d’entre eux demeuraient indétectables après 3 à 4 mois et 1 avait une augmentation de 0,32 log de la charge virale du VIH-1 à 3 mois. Le dossier de suivi du quatrième patient n’était pas disponible. Conclusions : Ces données préliminaires indiquent qu’en présence d’un traitement antirétroviral efficace, l’administration du DVP ne semble pas nuire à la charge virale du VIH-1. Les résultats des patients recevant du DVP mais pas de médicaments antirétroviraux sont encore indéterminés. D’autres études rétrospectives sont requises.