Valproic Acid in HIV-Positive Patients: Increased Risk?
Valproic Acid in HIV-Positive Patients: Increased Risk?
Abstract & Commentary
Synopsis: The use of VPA in HIV-positive patients may have the potential for increased HIV replication. Since this finding has not been demonstrated in patients, the use of VPA should not be considered contraindicated in HIV-infected patients at this time.
Source: Jennings HR, Romanelli F. The use of valproic acid in HIV-positive patients. Ann Pharmacother 1999;33: 1113-1116.
The management of patients with hiv disease typically revolves around the suppression of HIV replication by antiviral agents such as protease inhibitors and reverse transcriptase inhibitors, as well as treatment and prophylaxis of common opportunistic infections. However, HIV-positive patients are also at risk for developing neurologic manifestations such as seizures (even without a history of a seizure disorder prior to HIV infection) and psychiatric illnesses such as major depression and bipolar disorder. As a result, valproic acid (VPA) preparations (Depakote), are commonly prescribed to HIV-positive patients. There is some interesting evidence that VPA may induce the viral replication of HIV. This evidence consists of several small in vitro studies that were reviewed by Jennings and associates. The proposed mechanism for the increased viral replication by VPA relates to changes in intracellular glutathione concentrations. VPA interferes with the glutathione metabolic pathway via the inhibition of glutathione reductase. This results in decreased reduced glutathione, which provides protection against cellular oxidative damage as well as the modulation of T-cell activation. At this time, there is no conclusive evidence that the use of VPA causes increases in HIV replication in infected patients.
Comment by Michael F. Barber, pharmD
Given the susceptibility of HIV-infected patients to seizures and psychiatric disorders as well as the large role of VPA in the treatment of these conditions, the possibility of increased HIV replication by VPA is important. However, no studies have shown that VPA does actually cause such increases in HIV replication in actual patients; quite often, in vitro studies do not directly translate into in vivo results. In addition, there are no studies that have looked at the ability of antiretrovirals to offset such increased viral replication as a result of lower intracellular reduced glutathione concentrations. It is clear that this area must be thoroughly evaluated before any steps toward the elimination of the use of VPA in HIV-infected individuals can be taken. These results should merely increase the awareness of clinicians and researchers to the possibility of complications in the treatment of HIV-infected patients by the use of VPA. It may be clinically warranted to pay particular attention to the viral load counts after the introduction of VPA to the profile of HIV-infected patients. If there are subsequent increases in viral load that are unaccounted for by other factors (i.e., nonadherence to the therapeutic regimen), it may be advisable to consider a change to another anticonvulsant (or mood stabilizer).
It is also important to consider other important factors that are present when adding VPA to therapeutic regimens of HIV-infected patients. First, patients with HIV disease often have hypoalbuminemia, which would result in increases in free fractions of VPA and increase the likelihood of toxicity. Second, there is an increased likelihood for pharmacokinetic and pharmacodynamic drug interactions. For instance, VPA has been shown to elicit a two- to three-fold increase in cerebrospinal fluid concentrations of zidovudine. While this drug interaction may in fact increase the therapeutic efficacy of vidovudine, there may be other drug interactions that may be harmful that are as yet unreported.
The use of VPA in HIV-positive patients may have the potential for increased HIV replication. Since this finding has not been demonstrated in patients, the use of VPA should not be considered contraindicated in HIV-infected patients at this time. However, it would be prudent to keep a watchful eye on viral load counts in patients who receive VPA. (Dr. Barber is Assistant Professor of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, TX.)
Valproic acid may have the potential for increased HIV replication, but this finding has not been demonstrated in patients. As such, the use of valproic acid is not contraindicated in HIV-infected patients, but it may be prudent to keep a watchful eye on viral load counts in such patients who receive VPA.
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