SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV

J Antimicrob Chemother. 2019 Apr 1;74(4):1035-1043. doi: 10.1093/jac/dky508.

Abstract

Background: Neuropsychiatric symptoms (NPs) have been reported with dolutegravir use. We hypothesized that increasing dolutegravir trough concentrations (Ctrough) and/or polymorphism in the SLC22A2 gene, encoding the organic cation transporter-2 (OCT2), which is involved in monoamine clearance in the CNS and is inhibited by dolutegravir, might be associated with NPs.

Methods: A cross-sectional cohort of HIV-positive patients treated with a dolutegravir-containing regimen underwent determination of allelic discrimination for SLC22A2 808 C → A polymorphism and dolutegravir Ctrough. The Symptom Checklist-90-R [investigating 10 psychiatric dimensions and reporting a general severity index (GSI)], a self-reported questionnaire and the Mini-International Neuropsychiatric Interview were offered to investigate current NPs. The effects of dolutegravir Ctrough and the SLC22A2 gene variant on NPs were explored by multivariable logistic regression.

Results: A cohort of 203 patients was analysed: 71.4% were male, with median age 51 years and 11 years of ART exposure. Median time on dolutegravir was 18 months. Dolutegravir was associated with different antiretroviral combinations (mainly lamivudine, 38.9%, and abacavir/lamivudine, 35.5%). SLC22A2 CA genotype was independently associated with an abnormal GSI [adjusted OR (aOR) 2.43; P = 0.072], anxiety (aOR 2.61; P = 0.044), hostility (aOR 3.76; P = 0.012) and with moderate to severe headache (aOR 5.55; P = 0.037), and dolutegravir Ctrough was associated with hostility (fourth versus first quartile aOR 6.70; P = 0.007) and psychoticism (fourth versus first quartile aOR 19.01; P = 0.008). Other NPs were not associated with SLC22A2 polymorphism or dolutegravir Ctrough.

Conclusions: A variant of the OCT2-encoding gene, in addition to or in synergy with higher dolutegravir Ctrough, is associated with a set of NPs observed during dolutegravir therapy.

MeSH terms

  • Adult
  • Alleles
  • Antiretroviral Therapy, Highly Active
  • CD4 Lymphocyte Count
  • Cross-Sectional Studies
  • Female
  • Genetic Variation*
  • Genotype
  • HIV Infections / complications
  • HIV Infections / drug therapy
  • HIV Infections / epidemiology*
  • HIV Infections / genetics*
  • Heterocyclic Compounds, 3-Ring / adverse effects
  • Heterocyclic Compounds, 3-Ring / pharmacokinetics*
  • Humans
  • Male
  • Mental Disorders / diagnosis
  • Mental Disorders / etiology
  • Mental Disorders / psychology
  • Middle Aged
  • Organic Cation Transporter 2 / genetics*
  • Oxazines
  • Pharmacogenomic Variants*
  • Piperazines
  • Public Health Surveillance
  • Pyridones
  • Severity of Illness Index
  • Symptom Assessment
  • Viral Load

Substances

  • Heterocyclic Compounds, 3-Ring
  • Organic Cation Transporter 2
  • Oxazines
  • Piperazines
  • Pyridones
  • SLC22A2 protein, human
  • dolutegravir