title: Moderate to severe HIV-associated neurocognitive impairment: A randomized placebo-controlled trial of lithium.
abstract: BACKGROUND
  HIV-associated neurocognitive disorder (HAND) remains highly prevalent despite effective anti-retroviral therapy (ART). A number of adjunctive pharmacotherapies for HAND have been studied with disappointing results, but preliminary data suggest that lithium may provide clinical benefit. In addition, the low cost of lithium would facilitate access in low- and middle-income countries which carry the greatest burden of HIV.
  
  
  METHODS
  Our objective was to evaluate the 24-week efficacy and safety of lithium in patients with moderate to severe HAND. Our primary efficacy endpoint was the change in Global Deficit Score (GDS) from baseline to 24 weeks, whereas our secondary endpoint was the change in proton magnetic resonance spectroscopy (H-MRS) brain metabolite concentrations. We conducted a 24-week randomized placebo-controlled trial of lithium as adjunctive pharmacotherapy. We enrolled participants with moderate to severe HAND, on ART for at least 6 months, with suppressed viral loads and attending public sector primary care clinics in Cape Town, South Africa. We randomized 66 participants to lithium (n = 32) or placebo (n = 34). Lithium or placebo was dosed 12-hourly and titrated to achieve the maintenance target plasma concentration of 0.6 to 1.0 mmol/L. Sham lithium concentrations were generated for participants receiving placebo.
  
  
  RESULTS
  Totally 61 participants completed the study (lithium arm = 30; placebo arm = 31). Participants at enrolment had a mean age of 40 years and a median CD4+ T-cell count of 500 cells/μL. The median change in GDS between baseline and week 24 for the lithium and placebo arms were -0.57 (95% confidence interval [CI] -0.77, -0.32) and -0.56 (-0.69, -0.34) respectively, with a mean difference of -0.054 (95% CI -0.26, 0.15); P = 0.716. The improvement remained similar when analyzed according to age, severity of impairment, CD4+ count, time on ART, and ART regimen. Standard H-MRS metabolite concentrations were similar between the treatment arms. The study drug was well tolerated in both study arms. Six serious adverse events occurred, but none were considered related to the study drug.
  
  
  CONCLUSIONS
  Adjunctive lithium pharmacotherapy in patients on ART with HAND was well tolerated but had no additional benefit on neurocognitive impairment.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University Division of Neuropsychiatry, Department of Psychiatry and Mental Health, Faculty of Health Sciences Division of Epidemiology and Biostatistics, School of Public Health and Family Medicine Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa Department of Psychiatry, University of Oxford, United Kingdom Institute of Virology and Immunobiology, University of Würzburg, Germany Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Decloedt
authors.forename: Carla
authors.initials: C
authors.lastname: Freeman
authors.forename: Fleur
authors.initials: F
authors.lastname: Howells
authors.forename: Martine
authors.initials: M
authors.lastname: Casson-Crook
authors.forename: Maia
authors.initials: M
authors.lastname: Lesosky
authors.forename: Eleni
authors.initials: E
authors.lastname: Koutsilieri
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.forename: John A
authors.initials: JA
authors.lastname: Joska
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D018791:CD4 Lymphocyte Count / Q000379:methods; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000175:diagnosis / Q000523:psychology; D006801:Humans; D018020:Lithium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D019965:Neurocognitive Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D009483:Neuropsychological Tests; D066244:Proton Magnetic Resonance Spectroscopy / Q000379:methods; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000493:pharmacokinetics; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D018020:Lithium Compounds; D011619:Psychotropic Drugs