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- Title
SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV.
- Authors
Borghetti, A; Calcagno, A; Lombardi, F; Cusato, J; Belmonti, S; D'Avolio, A; Ciccarelli, N; Monica, S La; Colafigli, M; Donne, V Delle; Marco, R De; Tamburrini, E; Visconti, E; Perri, G Di; Luca, A De; Bonora, S; Giambenedetto, S Di; La Monica, S; Delle Donne, V; De Marco, R
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
LAMIVUDINE; GENETIC polymorphisms; ALLELES; ANTIRETROVIRAL agents; HIV-positive persons
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2019, Vol 74, Issue 4, p1035
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dky508