Palabras clave
Inhibidores de la Integrasa
Trastornos Neuroconductuales
Insomnio
Depresión
Ansiedad
Farmacovigilancia
Cómo citar
Resumen
Antecedentes. Dolutegravir (DTG), un inhibidor de la integrasa empleado como terapia antirretroviral de primera línea, destaca por su alta eficacia y buena tolerabilidad. No obstante, desde su introducción se han reportado efectos adversos neuropsiquiátricos (EANP), como insomnio, ansiedad, depresión, mareos y quejas cognitivas, generando controversia por la discordancia entre ensayos clínicos y datos de vida real.
Objetivo. El objetivo de esta revisión es analizar críticamente la evidencia disponible sobre la posible asociación entre DTG y EANP, identificando discrepancias, factores explicativos y áreas de investigación pendiente.
Métodos. Se realizó una búsqueda narrativa en PubMed, Scopus y Web of Science utilizando términos DeCS y MeSH relacionados con dolutegravir, inhibidores de la integrasa y manifestaciones neuropsiquiátricas. Se incluyeron ensayos clínicos, estudios observacionales, reportes de farmacovigilancia y revisiones relevantes.
Resultados. Los ensayos clínicos muestran baja incidencia de EANP, comparable a otros antirretrovirales, mientras que varios estudios observacionales documentan tasas mayores, especialmente insomnio y ansiedad, con discontinuación del tratamiento en un subgrupo susceptible. Las discrepancias podrían explicarse por diferencias poblacionales, variabilidad en la definición de eventos, sesgos de reporte, y factores farmacogenéticos o farmacocinéticos individuales.
Limitaciones. Las principales limitaciones de la evidencia incluyen subrepresentación de mujeres y adultos mayores, ausencia de biomarcadores y heterogeneidad metodológica.
Conclusión. La evidencia es contradictoria: DTG es seguro para la mayoría, pero un subgrupo vulnerable puede presentar EANP clínicamente relevantes. Se requieren estudios con evaluación neuropsiquiátrica estandarizada y diseños robustos
Citas
Povar-Echeverría M, Comet-Bernad M, Gasso-Sánchez A, Ger-Buil A, Navarro-Aznarez H, Martínez-Álvarez R, et al. Efectos adversos neuropsiquiátricos de dolutegravir en la práctica clínica real. Enferm Infecc Microbiol Clin [Internet]. 2021 Feb 1 [cited 2025 Nov 13];39(2):78–82. Available from: https://www.elsevier.es/es-revista-enfermedades-infecciosas-microbiologia-clinica-28-articulo-efectos-adversos-neuropsiquiatricos-dolutegravir-practica-S0213005X20300525
Jakimiuk A, Piechal A, Wiercińska-Drapało A, Nowaczyk A, Mirowska-Guzel D. Central nervous system disorders after use of dolutegravir: evidence from preclinical and clinical studies. Pharmacological Reports 2023 75:5 [Internet]. 2023 Aug 21 [cited 2025 Nov 13];75(5):1138–51. Available from: https://link.springer.com/article/10.1007/s43440-023-00515-y
Taramasso L, Orofino G, Ricci E, Menzaghi B, De Socio GV, Squillace N, et al. Reversibility of Central Nervous System Adverse Events in Course of Art. Viruses [Internet]. 2022 May 1 [cited 2025 Nov 13];14(5):1028. Available from: https://www.mdpi.com/1999-4915/14/5/1028/htm
Hoffmann C, Llibre JM. Neuropsychiatric adverse events with dolutegravir and other integrase strand transfer inhibitors. AIDS Rev. 2019 Jan 1;21(1):4–10.
Hoffmann C, Welz T, Sabranski M, Kolb M, Wolf E, Stellbrink HJ, et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med [Internet]. 2017 Jan 1 [cited 2025 Nov 13];18(1):56–63. Available from: /doi/pdf/10.1111/hiv.12468
Cabello-Úbeda A, Baeza AG, García JT, de La Fuente Moral S, Mena MN, Martínez AP, 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 Poo…. Open Forum Infect Dis [Internet]. 2022 Sep 1 [cited 2025 Nov 13];9(9). Available from: https://pubmed.ncbi.nlm.nih.gov/36147597/
Fettiplace A, Stainsby C, Winston A, Givens N, Puccini S, Vannappagari V, et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr (1988) [Internet]. 2017 Apr 1 [cited 2025 Nov 13];74(4):423–31. Available from: https://journals.lww.com/jaids/fulltext/2017/04010/psychiatric_symptoms_in_patients_receiving.11.aspx
Capetti AF, Di Giambenedetto S, Latini A, Sterrantino G, De Benedetto I, Cossu M V., et al. Morning dosing for dolutegravir-related insomnia and sleep disorders. HIV Med [Internet]. 2018 May 1 [cited 2025 Nov 13];19(5):e62–3. Available from: https://pubmed.ncbi.nlm.nih.gov/28762661/
Dolutegravir and central nervous system side-effects: abacavir, older age increase the risk | aidsmap [Internet]. [cited 2025 Nov 13]. Available from: https://www.aidsmap.com/news/oct-2016/dolutegravir-and-central-nervous-system-side-effects-abacavir-older-age-increase-risk
Turkova A, White E, Gibb DM, Ford D, Kekitiinwa AR, Bbuye D, et al. Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial. Lancet Child Adolesc Health [Internet]. 2023 Oct 1 [cited 2025 Nov 13];7(10):718–27. Available from: https://www.thelancet.com/action/showFullText?pii=S2352464223001645
Li J, Chen D, Wen Z, Du Y, Huang Z, Zhong H, et al. Real-world efficacy and safety of dolutegravir plus lamivudine versus tenofovir plus lamivudine and efavirenz in ART-naïve HIV-1-infected adults. Medicine [Internet]. 2022 Oct 21 [cited 2025 Nov 13];101(42):E31100. Available from: https://pubmed.ncbi.nlm.nih.gov/36281149/
Brehm TT, Franz M, Hüfner A, Hertling S, Schmiedel S, Degen O, et al. Safety and efficacy of elvitegravir, dolutegravir, and raltegravir in a real-world cohort of treatment-naïve and -experienced patients. Medicine [Internet]. 2019 Aug 1 [cited 2025 Nov 13];98(32). Available from: https://pubmed.ncbi.nlm.nih.gov/31393378/
Kolakowska A, Maresca AF, Collins IJ, Cailhol J. Update on Adverse Effects of HIV Integrase Inhibitors. Curr Treat Options Infect Dis [Internet]. 2019 Dec [cited 2025 Nov 13];11(4):372–87. Available from: https://pubmed.ncbi.nlm.nih.gov/33380904/
Chan P, Yoon B, Colby D, Kroon E, Sacdalan C, Sriplienchan S, et al. Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection. Clin Infect Dis [Internet]. 2023 Feb 1 [cited 2025 Nov 13];76(3):E718–26. Available from: https://pubmed.ncbi.nlm.nih.gov/35687498/
Neuropsychiatric side-effects lead only 1 in 40 to drop dolutegravir, French study shows | aidsmap [Internet]. [cited 2025 Nov 13]. Available from: https://www.aidsmap.com/news/aug-2018/neuropsychiatric-side-effects-lead-only-1-40-drop-dolutegravir-french-study-shows
Elliot ER, Wang X, Singh S, Simmons B, Vera JH, Miller RF, et al. Increased Dolutegravir Peak Concentrations in People Living With Human Immunodeficiency Virus Aged 60 and Over, and Analysis of Sleep Quality and Cognition. Clinical Infectious Diseases [Internet]. 2019 Jan 1 [cited 2025 Nov 13];68(1):87–95. Available from: https://dx.doi.org/10.1093/cid/ciy426
Yombi JC. Dolutegravir Neuropsychiatric Adverse Events: Specific Drug Effect or Class Effect. AIDS Rev. 2018;20(1).
Cusato J, Borghetti A, Teti E, Milesi M, Tettoni MC, Bonora S, et al. Dolutegravir Discontinuation for Neuropsychiatric Symptoms in People Living with HIV and Their Outcomes after Treatment Change: A Pharmacogenetic Study. Metabolites [Internet]. 2022 Dec 1 [cited 2025 Nov 13];12(12):1202. Available from: https://www.mdpi.com/2218-1989/12/12/1202/htm
Lepik KJ, Yip B, Ulloa AC, Wang L, Toy J, Akagi L, et al. Adverse drug reactions to integrase strand transfer inhibitors. AIDS. 2018 Apr 24;32(7):903–12.
Ene L, Duiculescu D, Ruta SM. How much do antiretroviral drugs penetrate into the central nervous system? J Med Life [Internet]. 2011 [cited 2025 Nov 13];4(4):432. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC3227164/
Huang C, Hoque T, Bendayan R. Antiretroviral drugs efavirenz, dolutegravir and bictegravir dysregulate blood-brain barrier integrity and function. Front Pharmacol. 2023 Mar 8;14:1118580.
Animut MD, Sorrie MB, Birhanu YW, Teshale MY. High prevalence of neurocognitive disorders observed among adult people living with HIV/ AIDS in Southern Ethiopia: A cross-sectional study. PLoS One. 2019 Mar 1;14(3).
Abers MS, Shandera WX, Kass JS. Neurological and psychiatric adverse effects of antiretroviral drugs. CNS Drugs. 2014 Feb;28(2):131–45.
Ma Q, Schifitto G, Venuto C, Ocque A, Dewhurst S, Morse GD, et al. Effect of Dolutegravir and Sertraline on the Blood Brain Barrier (BBB). Journal of Neuroimmune Pharmacology 2020 15:1 [Internet]. 2020 Jan 15 [cited 2025 Nov 13];15(1):7–9. Available from: https://link.springer.com/article/10.1007/s11481-020-09904-z
Nickoloff-Bybel EA, Calderon TM, Gaskill PJ, Berman JW. HIV Neuropathogenesis in the Presence of a Disrupted Dopamine System. Journal of Neuroimmune Pharmacology 2020 15:4 [Internet]. 2020 Jun 6 [cited 2025 Nov 13];15(4):729–42. Available from: https://link.springer.com/article/10.1007/s11481-020-09927-6
Purohit V, Rapaka R, Shurtleff D. Drugs of Abuse, Dopamine, and HIV-Associated Neurocognitive Disorders/HIV-Associated Dementia. Molecular Neurobiology 2011 44:1 [Internet]. 2011 Jul 1 [cited 2025 Nov 13];44(1):102–10. Available from: https://link.springer.com/article/10.1007/s12035-011-8195-z
Nestler EJ, Carlezon WA. The Mesolimbic Dopamine Reward Circuit in Depression. Biol Psychiatry [Internet]. 2006 Jun 15 [cited 2025 Nov 13];59(12):1151–9. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0006322305012436
Dunlop BW, Nemeroff CB. The Role of Dopamine in the Pathophysiology of Depression. Arch Gen Psychiatry [Internet]. 2007 Mar 1 [cited 2025 Nov 13];64(3):327–37. Available from: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/482227
Channer B, Matt SM, Nickoloff-Bybel EA, Pappa V, Agarwal Y, Wickman J, et al. Dopamine, Immunity, and Disease. Pharmacol Rev [Internet]. 2023 Jan 1 [cited 2025 Nov 13];75(1):62–158. Available from: https://pubmed.ncbi.nlm.nih.gov/36757901/
Griesel R, Sinxadi P, Kawuma A, Joska J, Sokhela S, Akpomiemie G, et al. Pharmacokinetic and pharmacogenetic associations with dolutegravir neuropsychiatric adverse events in an African population. J Antimicrob Chemother [Internet]. 2022 Nov 1 [cited 2025 Nov 13];77(11):3110–7. Available from: https://pubmed.ncbi.nlm.nih.gov/36031789/
Anderson AM, Jang JH, Easley KA, Fuchs D, Gisslen M, Zetterberg H, et al. Cognitive and Neuronal Link with Inflammation: A Longitudinal Study in People with and Without HIV Infection. J Acquir Immune Defic Syndr (1988) [Internet]. 2020 Dec 15 [cited 2025 Nov 13];85(5):617–25. Available from: https://journals.lww.com/jaids/fulltext/2020/12150/cognitive_and_neuronal_link_with_inflammation__a.16.aspx
Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, et al. Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS [Internet]. 2011 Mar 13 [cited 2025 Nov 13];25(5):625–33. Available from: https://journals.lww.com/aidsonline/fulltext/2011/03130/persistence_of_hiv_associated_cognitive.11.aspx
Fettiplace A, Stainsby C, Winston A, Givens N, Puccini S, Vannappagari V, et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr (1988) [Internet]. 2017 Apr 1 [cited 2025 Nov 13];74(4):423–31. Available from: https://journals.lww.com/jaids/fulltext/2017/04010/psychiatric_symptoms_in_patients_receiving.11.aspx
Turkova A, White E, Gibb DM, Ford D, Kekitiinwa AR, Bbuye D, et al. Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial. Lancet Child Adolesc Health [Internet]. 2023 Oct 1 [cited 2025 Nov 13];7(10):718–27. Available from: https://www.thelancet.com/action/showFullText?pii=S2352464223001645
Heglar R, Mood R, Priest JL, Schulman KL, Fusco GP. Benchmarking HIV Quality Measures in the US OPERA HIV Cohort. Open Forum Infect Dis [Internet]. 2019 Oct 1 [cited 2025 Nov 13];6(10). Available from: https://pubmed.ncbi.nlm.nih.gov/31660374/
Squillace N, Ricci ED, Orofino G, Forcina G, Albini L, Menzaghi B, et al. Neuropsychiatric adverse events in people with HIV initiating a new integrase strand transfer inhibitor-based regimen in Italy: findings from the NEURO-INSTI study. BMC Infectious Diseases 2025 25:1 [Internet]. 2025 May 27 [cited 2025 Nov 13];25(1):763-. Available from: https://bmcinfectdis.biomedcentral.com/articles/10.1186/s12879-025-11090-3
Rossetti B, Ferrara M, Taramasso L, Bai F, Lombardi F, Ciccarelli N, et al. Evolution of Self-reported Neuropsychiatric Symptoms After Switching from Dolutegravir/Abacavir/Lamivudine to Bictegravir/Emtricitabine/Tenofovir Alafenamide: Results from the Randomized DOBINeuro Trial. Infectious Diseases and Therapy 2024 14:1 [Internet]. 2024 Nov 29 [cited 2025 Nov 13];14(1):293–304. Available from: https://link.springer.com/article/10.1007/s40121-024-01083-1
Dow DE, Bartlett JA, Dow DE, Bartlett JA. Dolutegravir, the Second-Generation of Integrase Strand Transfer Inhibitors (INSTIs) for the Treatment of HIV. Infectious Diseases and Therapy 2014 3:2 [Internet]. 2014 Jun 24 [cited 2025 Nov 13];3(2):83–102. Available from: https://link.springer.com/article/10.1007/s40121-014-0029-7
Gesesew HA, Ward P, Hajito KW, Feyissa GT, Mohammadi L, Mwanri L. Discontinuation from Antiretroviral Therapy: A Continuing Challenge among Adults in HIV Care in Ethiopia: A Systematic Review and Meta-Analysis. PLoS One [Internet]. 2017 Jan 1 [cited 2025 Nov 13];12(1):e0169651. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169651
Hughes AJ, Mattson CL, Scheer S, Beer L, Skarbinski J. Discontinuation of antiretroviral therapy among adults receiving HIV care in the United States. J Acquir Immune Defic Syndr (1988) [Internet]. 2014 May 1 [cited 2025 Nov 13];66(1):80–9. Available from: https://journals.lww.com/jaids/fulltext/2014/05010/discontinuation_of_antiretroviral_therapy_among.11.aspx
Youvan DC, Ai Y. A Critique of ViiV Healthcare’s Identity-Based HIV Advertising. 2025 [cited 2025 Nov 13]; Available from: https://www.researchgate.net/publication/392361715
Elliot ER, Neary M, Else L, Khoo S, Moyle G, Carr DF, et al. Genetic influence of ABCG2, UGT1A1 and NR1I2 on dolutegravir plasma pharmacokinetics. Journal of Antimicrobial Chemotherapy [Internet]. 2020 May 1 [cited 2025 Nov 13];75(5):1259–66. Available from: https://dx.doi.org/10.1093/jac/dkz558
Chen S, St Jean P, Borland J, Song I, Yeo AJ, Piscitelli S, et al. Evaluation of the effect of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics [Internet]. 2014 Jan [cited 2025 Nov 13];15(1):9–16. Available from: https://www.tandfonline.com/doi/abs/10.2217/pgs.13.190
Borghetti A, Calcagno A, Lombardi F, Cusato J, Belmonti S, D’Avolio A, et al. SLC22A2 variants and dolutegravir levels correlate with psychiatric symptoms in persons with HIV. Journal of Antimicrobial Chemotherapy [Internet]. 2019 Apr 1 [cited 2025 Nov 13];74(4):1035–43. Available from: https://dx.doi.org/10.1093/jac/dky508
Calcagno A, Moltó J, Borghetti A, Gervasoni C, Milesi M, Valle M, et al. Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV. Clinical Pharmacokinetics 2020 60:1 [Internet]. 2020 Aug 1 [cited 2025 Nov 13];60(1):103–9. Available from: https://link.springer.com/article/10.1007/s40262-020-00916-9
Elliot ER, Wang X, Singh S, Simmons B, Vera JH, Miller RF, et al. Increased Dolutegravir Peak Concentrations in People Living With Human Immunodeficiency Virus Aged 60 and Over, and Analysis of Sleep Quality and Cognition. Clinical Infectious Diseases [Internet]. 2019 Jan 1 [cited 2025 Nov 13];68(1):87–95. Available from: https://dx.doi.org/10.1093/cid/ciy426
Atkinson JH, Grant I. Natural history of neuropsychiatric manifestations of HIV disease. Psychiatric Clinics of North America [Internet]. 1994 Mar 1 [cited 2025 Nov 13];17(1):17–33. Available from: https://www.psych.theclinics.com/action/showFullText?pii=S0193953X1830128X
Blackstone K, Moore DJ, Heaton RK, Franklin DR, Woods SP, Clifford DB, et al. Diagnosing Symptomatic HIV-Associated Neurocognitive Disorders: Self-Report Versus Performance-Based Assessment of Everyday Functioning. Journal of the International Neuropsychological Society [Internet]. 2012 Jan [cited 2025 Nov 13];18(1):79–88. Available from: https://www.cambridge.org/core/journals/journal-of-the-international-neuropsychological-society/article/abs/diagnosing-symptomatic-hivassociated-neurocognitive-disorders-selfreport-versus-performancebased-assessment-of-everyday-functioning/DE88AD4D5384D9FE941A2644040A7CC9
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