In vitro and animal model data demonstrate that valproic acid (VPA) can ameliorate HIV-associated neurotoxicity. The authors conducted a pilot 10-week placebo-controlled study of VPA 250 mg twice daily in 22 HIV-infected individuals with (n = 16) and without (n = 6) cognitive impairment. VPA was safe and well tolerated, with trends toward improved neuropsychological performance and brain metabolism in the impaired subjects.

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 lopinavirritonavir (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 (C 0 ) 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 (AUC 0-24 s) of EFV (n ‫؍‬ 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC 0-8 s of LPV (n ‫؍‬ 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C 0 and 8-h VPA concentrations versus the control (n ‫؍‬ 11) were ؊1.0 (؊9.4, 7.4) g/ml and ؊2.1 (؊11.1, 6.9) g/ml for EFV (n ‫؍‬ 10) and ؊5.0 (؊13.2, 3.3) g/ml and ؊6.7 (؊17.6, 4.2) g/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.

Objective-To assess lithium safety and tolerability and to explore its impact on cognition, function and neuroimaging biomarkers in HIV infected subjects with cognitive impairment.Methods-Fifteen cognitively impaired HIV infected subjects were enrolled in this 10-week openlabel study of lithium 300 mg twice daily. Neuroimaging was performed at baseline, and following 10 weeks of treatment and included magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and functional MRI (fMRI).Results-Thirteen of the 14 subjects (93%) that complied with the study visits were able to complete the study on lithium and 11 out of 13 (79%) completed the study at the originally assigned dose of 300 mg twice daily. There were no significant changes in CD4+ lymphocyte cell count and plasma HIV RNA. Cognitive performance and depressive mood did not improve significantly after the 10-week lithium treatment; however, neuroimaging revealed a decrease in the glutamate+glutamine (Glx) peak in the frontal gray matter, increased fractional anisotropy and decreased mean diffusivity in several brain areas, and changes in brain activation patterns, suggestive of improvement.Interpretation-Our results suggest that lithium can be used safely in HIV infected individuals with cognitive impairment. Furthermore, the neuroimaging results suggest that lithium may improve HIV-associated CNS injury; thus, further investigations of lithium as an adjunctive treatment for HIV-associated cognitive impairment are warranted.

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Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a