Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor

Archana Asundi; Yvonne Robles; Tyler Starr; Alan Landay; Jennifer Kinslow; Joshua Ladner; Laura White; Rebeca M. Plank; Kathleen Melbourne; Daniel Weisholtz; Monica Bennett; Hong Pan; Emily Stern; Alexander Lin; Daniel R. Kuritzkes; Nina H. Lin

doi:10.1097/QAI.0000000000002079

Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor

Archana Asundi, Yvonne Robles, Tyler Starr, Alan Landay, Jennifer Kinslow, Joshua Ladner, Laura White, Rebeca M. Plank, Kathleen Melbourne, Daniel Weisholtz, Monica Bennett, Hong Pan, Emily Stern, Alexander Lin, Daniel R. Kuritzkes, Nina H. Lin

Research output: Contribution to journal › Article › peer-review

Abstract

Background: The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV. Setting: Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017. Methods: Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses. Results: NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4⁺ and CD8⁺ HLA-DR-/CD38⁺ subsets both increased (P = 0.05, 0.02). Conclusions: Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.

Original language	English (US)
Pages (from-to)	585-593
Number of pages	9
Journal	Journal of Acquired Immune Deficiency Syndromes
Volume	81
Issue number	5
DOIs	https://doi.org/10.1097/QAI.0000000000002079
State	Published - Aug 15 2019
Externally published	Yes

Keywords

efavirenz
HIV
inflammation
integrase inhibitors
neurocognition

ASJC Scopus subject areas

Infectious Diseases
Pharmacology (medical)

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10.1097/QAI.0000000000002079

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Asundi, A., Robles, Y., Starr, T., Landay, A., Kinslow, J., Ladner, J., White, L., Plank, R. M., Melbourne, K., Weisholtz, D., Bennett, M., Pan, H., Stern, E., Lin, A., Kuritzkes, D. R., & Lin, N. H. (2019). Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor. Journal of Acquired Immune Deficiency Syndromes, 81(5), 585-593. https://doi.org/10.1097/QAI.0000000000002079

Asundi, A, Robles, Y, Starr, T, Landay, A, Kinslow, J, Ladner, J, White, L, Plank, RM, Melbourne, K, Weisholtz, D, Bennett, M, Pan, H, Stern, E, Lin, A, Kuritzkes, DR & Lin, NH 2019, 'Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor', Journal of Acquired Immune Deficiency Syndromes, vol. 81, no. 5, pp. 585-593. https://doi.org/10.1097/QAI.0000000000002079

@article{d22d1f47667c42e4bd40391d271ec078,

title = "Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor",

abstract = "Background: The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV. Setting: Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017. Methods: Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses. Results: NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4+ and CD8+ HLA-DR-/CD38+ subsets both increased (P = 0.05, 0.02). Conclusions: Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.",

keywords = "efavirenz, HIV, inflammation, integrase inhibitors, neurocognition",

author = "Archana Asundi and Yvonne Robles and Tyler Starr and Alan Landay and Jennifer Kinslow and Joshua Ladner and Laura White and Plank, {Rebeca M.} and Kathleen Melbourne and Daniel Weisholtz and Monica Bennett and Hong Pan and Emily Stern and Alexander Lin and Kuritzkes, {Daniel R.} and Lin, {Nina H.}",

year = "2019",

month = aug,

day = "15",

doi = "10.1097/QAI.0000000000002079",

language = "English (US)",

volume = "81",

pages = "585--593",

journal = "Journal of Acquired Immune Deficiency Syndromes",

issn = "1525-4135",

publisher = "Wolters Kluwer Health",

number = "5",

}

TY - JOUR

T1 - Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor

AU - Asundi, Archana

AU - Robles, Yvonne

AU - Starr, Tyler

AU - Landay, Alan

AU - Kinslow, Jennifer

AU - Ladner, Joshua

AU - White, Laura

AU - Plank, Rebeca M.

AU - Melbourne, Kathleen

AU - Weisholtz, Daniel

AU - Bennett, Monica

AU - Pan, Hong

AU - Stern, Emily

AU - Lin, Alexander

AU - Kuritzkes, Daniel R.

AU - Lin, Nina H.

PY - 2019/8/15

Y1 - 2019/8/15

N2 - Background: The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV. Setting: Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017. Methods: Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses. Results: NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4+ and CD8+ HLA-DR-/CD38+ subsets both increased (P = 0.05, 0.02). Conclusions: Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.

AB - Background: The biological mechanisms by which efavirenz (EFV) causes central nervous system (CNS) effects are unclear. The objective of this pilot study was to elucidate the mechanisms underlying these CNS effects by correlating well-described neuropsychological (NP) changes with neurometabolites and immunologic markers following switch off EFV. Setting: Two single-arm parallel switch studies among HIV-infected adults in Boston, USA, from 2015 to 2017. Methods: Twenty asymptomatic HIV-infected adults on EFV-containing regimens were switched to an integrase strand transfer inhibitor-based regimen for 8 weeks. NP assessments were conducted before and after switch and correlated with neurometabolite changes measured using magnetic resonance spectroscopy and immunological markers. All pre-EFV and post-EFV measures were evaluated using matched-paired analyses. Results: NP testing demonstrated improvement in the domains of mood, cognition, and sleep off EFV. Magnetic resonance spectroscopy revealed decreases in the neurometabolite glutathione level (P = 0.03), a marker of oxidative stress after switch. Inhibitory neuronal activity as reflected by gamma-amino butyric acid levels increased (P = 0.03), whereas excitatory neurotransmitters glutamine + glutamate (Glx) and aspartate decreased (P = 0.04, 0.001). Switching off EFV was also associated with changes in inflammatory markers; plasma markers sCD14 (P = 0.008) decreased, whereas I-FABP and TNFRI levels increased (P = 0.05, 0.03). Cellular markers CD4+ and CD8+ HLA-DR-/CD38+ subsets both increased (P = 0.05, 0.02). Conclusions: Even asymptomatic participants showed improvements in NP parameters when switched off EFV. These improvements were associated with decreased CNS oxidative stress and excitatory neuronal activity. Changes in immune activation biomarkers suggested overall decreased inflammation. EFV may exert CNS effects through oxidative and inflammatory pathways, providing insight into possible mechanisms of EFV neurotoxicity.

KW - efavirenz

KW - HIV

KW - inflammation

KW - integrase inhibitors

KW - neurocognition

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JF - Journal of Acquired Immune Deficiency Syndromes

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ER -

Immunological and Neurometabolite Changes Associated With Switch From Efavirenz to an Integrase Inhibitor

Abstract

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