Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial.
Humans
Male
Female
Adult
Middle Aged
Anti-HIV Agents
/ therapeutic use
HIV Infections
/ drug therapy
Emtricitabine
/ therapeutic use
Single-Blind Method
HIV-1
AIDS Dementia Complex
/ drug therapy
Maraviroc
/ therapeutic use
Darunavir
/ therapeutic use
Cobicistat
/ therapeutic use
Neurocognitive Disorders
/ drug therapy
Electroencephalography
Cognition
/ drug effects
Journal
Journal of acquired immune deficiency syndromes (1999)
ISSN: 1944-7884
Titre abrégé: J Acquir Immune Defic Syndr
Pays: United States
ID NLM: 100892005
Informations de publication
Date de publication:
01 Oct 2024
01 Oct 2024
Historique:
received:
15
09
2023
accepted:
02
04
2024
medline:
9
9
2024
pubmed:
9
9
2024
entrez:
9
9
2024
Statut:
ppublish
Résumé
The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.
Sections du résumé
BACKGROUND
BACKGROUND
The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited.
METHODS
METHODS
Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models.
RESULTS
RESULTS
Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed.
CONCLUSIONS
CONCLUSIONS
In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.
Identifiants
pubmed: 39250652
doi: 10.1097/QAI.0000000000003480
pii: 00126334-202410010-00011
doi:
Substances chimiques
Anti-HIV Agents
0
Emtricitabine
G70B4ETF4S
Maraviroc
MD6P741W8A
Darunavir
YO603Y8113
Cobicistat
LW2E03M5PG
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
180-191Subventions
Organisme : ViiV Healthcare
Informations de copyright
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors have no funding or conflicts of interest to disclose.
Références
González-Scarano F, Martín-García J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005;5:69–81.
Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17:3–16.
Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69:1789–1799.
Grant I, Franklin DR Jr, Deutsch R, et al. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology. 2014;82:2055–2062.
Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV; 2021. Available at: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/hiv-and-older-person. Accessed May 31, 2022.
Kamal S, Locatelli I, Wandeler G, et al. The presence of human immunodeficiency virus-associated neurocognitive disorders is associated with a lower adherence to combined antiretroviral treatment. Open Forum Infect Dis. 2017;4:ofx070.
Nightingale S, Ances B, Cinque P, et al. Cognitive impairment in people living with HIV: consensus recommendations for a new approach. Nat Rev Neurol. 2023;19:424–433.
Muñoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Nadir CD4 cell count predicts neurocognitive impairment in HIV-infected patients. AIDS Res Hum Retroviruses. 2008;24:1301–1307.
Hammond ER, Crum RM, Treisman GJ, et al. The cerebrospinal fluid HIV risk score for assessing central nervous system activity in persons with HIV. Am J Epidemiol. 2014;180:297–307.
Pascual-Marqui RD. Standardized low-resolution brain electromagnetic tomography (sLORETA): technical details. Methods Find Exp Clin Pharmacol. 2002;24(suppl D):5–12.
Pascual-Marqui RD. Discrete, 3D distributed, linear imaging methods of electric neuronal activity. Part 1: Exact, Zero Error Localization. arXiv:0710.3341. [math-ph], October 17, 2007.
Babiloni C, Buffo P, Vecchio F, et al. Cortical sources of resting-state EEG rhythms in “experienced” HIV subjects under antiretroviral therapy. Clin Neurophysiol. 2014;125:1792–1802.
Babiloni C, Pennica A, Capotosto P, et al. Brain and cognitive functions in two groups of naïve HIV patients selected for a different plan of antiretroviral therapy: a qEEG study. Clin Neurophysiol. 2016;127:3455–3469.
European AIDS Clinical Society. Guidelines version 10.1; 2020. Available at: http://eacsociety.org. Accessed May 31, 2022.
Calcagno A, Di Perri G, Bonora S. Treating HIV infection in the central nervous system. Drugs. 2017;77:145–157.
Santos GMA, Locatelli I, Métral M, et al. Cross-sectional and cumulative longitudinal central nervous system penetration effectiveness scores are not associated with neurocognitive impairment in a well treated aging human immunodeficiency virus-positive population in Switzerland. Open Forum Infect Dis. 2019;6:ofz277.
Force G, Ghout I, Ropers J, et al. Improvement of HIV-associated neurocognitive disorders after antiretroviral therapy intensification: the Neuro+3 study. J Antimicrob Chemother. 2021;76:743–752.
De Benedetto I, Trunfio M, Guastamacchia G, et al. A review of the potential mechanisms of neuronal toxicity associated with antiretroviral drugs. J Neurovirol. 2020;26:642–651.
Underwood J, Robertson KR, Winston A. Could antiretroviral neurotoxicity play a role in the pathogenesis of cognitive impairment in treated HIV disease?. AIDS. 2015;29:253–261.
Robertson KR, Su Z, Margolis DM, et al. Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology. 2010;74:1260–1266.
Hellmuth J, Muccini C, Colby DJ, et al. Central nervous system safety during Brief Analytic treatment interruption of antiretroviral therapy within 4 human immunodeficiency virus Remission trials: an observational study in Acutely treated people living with human immunodeficiency virus. Clin Infect Dis. 2021;73:e1885–e1892.
Muñoz-Moreno JA, Fumaz CR, Prats A, et al. Interruptions of antiretroviral therapy in human immunodeficiency virus infection: are they detrimental to neurocognitive functioning? J Neurovirol. 2010;16:208–218.
Robertson K, Liner J, Meeker RB. Antiretroviral neurotoxicity. J Neurovirol. 2012;18:388–399.
Chong WK, Sweeney B, Wilkinson ID, et al. Proton spectroscopy of the brain in HIV infection: correlation with clinical, immunologic, and MR imaging findings. Radiology. 1993;188:119–124.
INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in Early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807.
Ndhlovu LC, Umaki T, Chew GM, et al. Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND). J Neurovirol. 2014;20:571–582.
Geno2pheno coreceptor 2.5. Max Planc Institute of Informatic. Available at: https://coreceptor.geno2pheno.org/ Accessed May 31, 2022.
Major HIV-1 Drug Resistance Mutations. 2020. Available at: hivdb.stanford.edu Accessed May 31, 2022.
Available at: https://www.hiv-druginteractions.org/prescribing_resources Accessed May 31, 2022.
Available at: www.randomization.com Accessed May 31, 2022.
Sacktor NC, Wong M, Nakasujja N, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS. 2005;19:1367–1374.
Trunfio M, De Francesco D, Vai D, et al. Screening accuracy of Mini addenbrooke's cognitive examination test for HIV-associated neurocognitive disorders in people ageing with HIV. AIDS Behav. 2022;26:2203–2211.
Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory Second Edition (BDI-II). San Antonio. Psychological Corporation; 1996.
Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–55.
Appollonio I, Leone M, Isella V, et al. The Frontal Assessment Battery (FAB): normative values in an Italian population sample. Neurol Sci. 2005;26:108–116.
Giovagnoli AR, Del Pesce M, Mascheroni S, et al. Trail making test: normative values from 287 normal adult controls. Ital J Neurol Sci. 1996;17:305–309.
Costa A, Bagoj E, Monaco M, et al. Standardization and normative data obtained in the Italian population for a new verbal fluency instrument, the phonemic/semantic alternate fluency test. Neurol Sci. 2014;35:365–372.
Caffarra P, et al. Una versione abbreviata del Test di Stroop:dati normativi nella popolazione italiana. Nuova rivirsta di neurologia. 2002;12:111.
Monaco M, Costa A, Caltagirone C, et al. Forward and backward span for verbal and visuo-spatial data: standardization and normative data from an Italian adult population. Neurol Sci. 2013;34:749–754.
Standardizzazione e taratura italiana di test neuropsicologici. Gruppo italiano per lo studio neuropsicologico dell'Invecchiamento [Italian standardization and classification of neuropsychological tests. The Italian group on the neuropsychological study of aging]. Ital J Neurol Sci. 1987(suppl 8):1–120. Italian.
Frasson P, Ghiretti R, Catricalà E, et al. Free and cued selective reminding test: an Italian normative study. Neurol Sci. 2011;32:1057–1062.
Lafayette Instrument Company. Grooved Pegboard Test User Instruction. Lafayette, IN: Lafayette Instrument Company; 2002.
Blackstone K, Moore DJ, Franklin DR, et al. Defining neurocognitive impairment in HIV: deficit scores versus clinical ratings. Clin Neuropsychol. 2012;26:894–908.
Available at: https://search.r-project.org/CRAN/refmans/rstatix/html/wilcox_effsize.html Accessed May 31, 2022.
Barco A, Orlando S, Stroffolini G, et al. Correlations between cerebrospinal fluid biomarkers, neurocognitive tests, and resting-state electroencephalography (rsEEG) in patients with HIV-associated neurocognitive disorders. J Neurovirol. 2022;28:226–235.
Ghose C, Ly M, Schwanemann LK, et al. The virome of cerebrospinal fluid: viruses where we once thought there were none. Front Microbiol. 2019;10:2061.
Lupia T, Milia MG, Atzori C, et al. Presence of Epstein-Barr virus DNA in cerebrospinal fluid is associated with greater HIV RNA and inflammation. AIDS. 2020;34:373–380.
Trunfio M, Sacchi A, Vai D, et al. Intrathecal production of anti-Epstein-Barr virus viral capsid antigen IgG is associated with neurocognition and tau proteins in people with HIV. AIDS. 2024;38:477–486.
Readhead B, Haure-Mirande JV, Funk CC, et al. Multiscale analysis of independent alzheimer's cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018;99:64–82.e7.
Trentalange A, Prochet A, Imperiale D, et al. Cerebral white matter Hyperintensities in HIV-positive patients. Brain Imaging Behav. 2020;14:10–18.
Ulfhammer G, Edén A, Mellgren Å, et al. Persistent central nervous system immune activation following more than 10 years of effective HIV antiretroviral treatment. AIDS. 2018;32:2171–2178.
Nightingale S, Winston A, Letendre S, et al. Controversies in HIV-associated neurocognitive disorders. Lancet Neurol. 2014;13:1139–1151.
Jadhav S, Nema V. HIV-associated neurotoxicity: the interplay of host and viral proteins. Mediators Inflamm. 2021;2021:1267041.
Mora-Peris B, Bouliotis G, Ranjababu K, et al. Changes in cerebral function parameters with maraviroc-intensified antiretroviral therapy in treatment naive HIV-positive individuals. AIDS. 2018;32:1007–1015.
Barber TJ, Imaz A, Boffito M, et al. CSF inflammatory markers and neurocognitive function after addition of maraviroc to monotherapy darunavir/ritonavir in stable HIV patients: the CINAMMON study. J Neurovirol. 2018;24:98–105.
Calcagno A, Simiele M, Alberione MC, et al. Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control. Clin Infect Dis. 2015;60:311–317.
Pérez Valero I, González-Baeza A, Montes Ramírez ML. Central nervous system penetration and effectiveness of darunavir/ritonavir monotherapy. AIDS Rev. 2014;16:101–108.
Cabello-Úbeda A, Baeza AG, García JT, et al. Changes in quality of sleep, mood, and other neuropsychiatric symptoms after switching dolutegravir/lamivudine/abacavir to darunavir/cobicistat/emtricitabine/tenofovir alafenamide in a randomized study of people with human immunodeficiency virus with poor sleep quality: GESIDA 10418. Open Forum Infect Dis. 2022;9:ofac345. 10.1093/ofid/ofac345
doi: 10.1093/ofid/ofac345
Gates TM, Cysique LA, Siefried KJ, et al. Maraviroc-intensified combined antiretroviral therapy improves cognition in virally suppressed HIV-associated neurocognitive disorder. AIDS. 2016;30:591–600.