Effects of Valproic Acid Coadministration on Plasma Efavirenz and Lopinavir Concentrations in Human Immunodeficiency Virus-Infected Adults

University of Rochester Medical Center, Clinical Pharmacology Unit, 601 Elmwood Ave., Box 315, Room 1.6124, Rochester, NY 14642, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 12/2004; 48(11):4328-31. DOI: 10.1128/AAC.48.11.4328-4331.2004
Source: PubMed


Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive
impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir.
HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to
24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples
drawn before (C0) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking
either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic
parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals
(CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from
0 to 24 h (AUC0-24s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC0-8s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C0 and 8-h VPA concentrations versus the control (n = 11) were −1.0 (−9.4, 7.4) μg/ml and −2.1 (−11.1, 6.9) μg/ml for EFV (n = 10) and −5.0 (−13.2, 3.3) μg/ml and −6.7 (−17.6, 4.2) μg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended
to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with
EFV or LPV/r will significantly influence trough concentrations of VPA.

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    • "Moreover, several studies have utilized this characteristic of VPA in patients receiving this drug in combination with high doses of cART in an effort to deplete latent viral reservoirs, with some success [99,100]. Although there is evidence that VPA may affect the metabolism of some concomitant medications, it is noteworthy that co-administration of VPA with efavirenz or lopinavir does not alter the plasma concentrations of these drugs [101], thus substantiating the potential efficacy of VPA as an adjunctive therapy for HIV infection. "
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    ABSTRACT: Human immunodeficiency virus type 1 (HIV) continues to be one of the most prevalent global health afflictions to date. The advent and introduction of combined antiretroviral therapy (cART) has made a significant impact on the course of infection. However, as patients are living longer, many HIV-associated illnesses are becoming prevalent among the infected population, especially those associated with chronic inflammation. Consistently, HIV-associated neuroinflammation is believed to be a major catalyst in the development of HIV-associated neurocognitive disorders (HAND), which are estimated to persist in approximately 50% of infected individuals regardless of cART. This dramatically underscores the need to develop effective adjunctive therapies capable of controlling this aspect of the disease, which are currently lacking. We previously demonstrated that the inflammatory mediator soluble CD40 ligand (sCD40L) is elevated in both the plasma and cerebrospinal fluid of cognitively impaired infected individuals compared to their non-impaired infected counterparts. Our group, and others have recently demonstrated that there is an increasing role for this inflammatory mediator in the pathogenesis of HIV-associated neuroinflammation, thereby identifying this molecule as a potential therapeutic target for the management of HAND. Platelets are the major source of circulating sCD40L, and these small cells are increasingly implicated in a multitude of inflammatory disorders, including those common during HIV infection. Thus, antiplatelet therapies that minimize the release of platelet-derived inflammatory mediators such as sCD40L are an innovative, non-traditional approach for the treatment of HIV-associated neuroinflammation, with the potential to benefit other HIV-associated illnesses.
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    • "cells/µL. All patients were on a stable antiretroviral regimen containing efavirenz (EFV) or nevirapine (NEVP) and/or nucleoside reverse transcriptase inhibitors for at least 4 weeks before and during the entire period (7 days) of these studies, as described [24]. All patients gave written consent for all procedures, which were approved by the University of Rochester Research Subjects Review Board. "
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    ABSTRACT: Despite the use of highly active antiretroviral therapies (HAART), a majority of Human Immunodeficiency Virus Type 1 (HIV) infected individuals continually develop HIV - Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistent with this notion, we have previously shown that levels of the inflammatory mediator soluble CD40 ligand (sCD40L) are elevated in the plasma and cerebrospinal fluid (CSF) of HIV infected, cognitively impaired individuals, and that excess sCD40L can contribute to blood brain barrier (BBB) permeability in vivo, thereby signifying the importance of this inflammatory mediator in the pathogenesis of HAND. Here we demonstrate that the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) induces the release of circulating sCD40L in both HIV infected individuals and in an in vitro suspension of washed human platelets, which are the main source of circulating sCD40L. Additionally, EFV was found to activate glycogen synthase kinase 3 beta (GSK3β) in platelets, and we now show that valproic acid (VPA), a known GSK3β inhibitor, was able to attenuate the release of sCD40L in HIV infected individuals receiving EFV, and in isolated human platelets. Collectively these results have important implications in determining the pro-inflammatory role that some antiretroviral regimens may have. The use of antiretrovirals remains the best strategy to prevent HIV-associated illnesses, including HAND, however these drugs have clear limitations to this end, and thus, these results underscore the need to develop adjunctive therapies for HAND that can also minimize the undesired negative effects of the antiretrovirals.
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    • "For the treatment of epilepsy in the setting of HIV infection, alternative agents to EI-AEDs should be administered if available. Valproic acid is available in many regions, however this drug is a weak inhibitor of CYP450 and may lead to increased HAART levels and toxicity, especially when used with lopinavir/ritonavir[4,22]. Due to its additional property as a non-selective histone deacyltase (HDAC) inhibitor, in vitro studies indicate valproic acid may increase HIV outgrowth from resting CD4+ T cells[23]. "
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