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

A Borghetti, A Calcagno, F Lombardi, J Cusato, S Belmonti, A D'Avolio, N Ciccarelli, S La Monica, M Colafigli, V Delle Donne, R De Marco, E Tamburrini, E Visconti, G Di Perri, A De Luca, S Bonora, S Di Giambenedetto

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalThe Journal of antimicrobial chemotherapy
DOIs
Publication statusE-pub ahead of print - Dec 14 2018

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Psychiatry
HIV
Hostility
dolutegravir
Cations
Genes
Lamivudine
Checklist
Headache
Anxiety
Logistic Models
Genotype
Interviews

Cite this

Borghetti, A., Calcagno, A., Lombardi, F., Cusato, J., Belmonti, S., D'Avolio, A., ... Di Giambenedetto, S. (2018). SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV. The Journal of antimicrobial chemotherapy. https://doi.org/10.1093/jac/dky508

SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV. / Borghetti, A; Calcagno, A; Lombardi, F; Cusato, J; Belmonti, S; D'Avolio, A; Ciccarelli, N; La Monica, S; Colafigli, M; Delle Donne, V; De Marco, R; Tamburrini, E; Visconti, E; Di Perri, G; De Luca, A; Bonora, S; Di Giambenedetto, S.

In: The Journal of antimicrobial chemotherapy, 14.12.2018.

Research output: Contribution to journalArticle

Borghetti, A, Calcagno, A, Lombardi, F, Cusato, J, Belmonti, S, D'Avolio, A, Ciccarelli, N, La Monica, S, Colafigli, M, Delle Donne, V, De Marco, R, Tamburrini, E, Visconti, E, Di Perri, G, De Luca, A, Bonora, S & Di Giambenedetto, S 2018, 'SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV', The Journal of antimicrobial chemotherapy. https://doi.org/10.1093/jac/dky508
Borghetti, A ; Calcagno, A ; Lombardi, F ; Cusato, J ; Belmonti, S ; D'Avolio, A ; Ciccarelli, N ; La Monica, S ; Colafigli, M ; Delle Donne, V ; De Marco, R ; Tamburrini, E ; Visconti, E ; Di Perri, G ; De Luca, A ; Bonora, S ; Di Giambenedetto, S. / SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV. In: The Journal of antimicrobial chemotherapy. 2018.
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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.",
author = "A Borghetti and A Calcagno and F Lombardi and J Cusato and S Belmonti and A D'Avolio and N Ciccarelli and {La Monica}, S and M Colafigli and {Delle Donne}, V and {De Marco}, R and E Tamburrini and E Visconti and {Di Perri}, G and {De Luca}, A and S Bonora and {Di Giambenedetto}, S",
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TY - JOUR

T1 - SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV

AU - Borghetti, A

AU - Calcagno, A

AU - Lombardi, F

AU - Cusato, J

AU - Belmonti, S

AU - D'Avolio, A

AU - Ciccarelli, N

AU - La Monica, S

AU - Colafigli, M

AU - Delle Donne, V

AU - De Marco, R

AU - Tamburrini, E

AU - Visconti, E

AU - Di Perri, G

AU - De Luca, A

AU - Bonora, S

AU - Di Giambenedetto, S

PY - 2018/12/14

Y1 - 2018/12/14

N2 - 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.

AB - 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.

U2 - 10.1093/jac/dky508

DO - 10.1093/jac/dky508

M3 - Article

C2 - 30561642

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

ER -