Updated Reviewed

Management of Medication Toxicity or Intolerance

Central Nervous System Toxicity

Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity
Table 17a. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity
  
  
  
  

References

  1. Allen Reeves A, Fuentes AV, Caballero J, Thomas JE, Mosley Ii JF, Harrington C. Neurotoxicities in the treatment of HIV between dolutegravir, rilpivirine and dolutegravir/rilpivirine: a meta-analysis. Sex Transm Infect. 2021;97(4):261-267. Available at: https://pubmed.ncbi.nlm.nih.gov/33782144.
  2. Arenas-Pinto A, Grund B, Sharma S, et al. Risk of suicidal behavior with use of efavirenz: results from the strategic timing of antiretroviral treatment trial. Clin Infect Dis. 2018;67(3):420-429. Available at: https://pubmed.ncbi.nlm.nih.gov/29538636.
  3. Apretude (cabotegravir extended-release injectable suspension), for intramuscular use [package insert]. Food and Drug Administration. 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215499s000lbl.pdf.
  4. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s002lbl.pdf.
  5. Capetti AF, Di Giambenedetto S, Latini A, et al. Morning dosing for dolutegravir-related insomnia and sleep disorders. HIV Med. 2018;19(5):e62-e63. Available at: https://pubmed.ncbi.nlm.nih.gov/28762661.
  6. Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS. 2013;27(6):939-950. Available at: https://pubmed.ncbi.nlm.nih.gov/23211772.
  7. Cuzin L, Pugliese P, Katlama C, et al. Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort. J Antimicrob Chemother. 2019;74(3):754-760. Available at: https://pubmed.ncbi.nlm.nih.gov/30534993.
  8. de Boer MG, van den Berk GE, van Holten N, et al. Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in real-life clinical practice. AIDS. 2016;30(18):2831-2834. Available at: https://pubmed.ncbi.nlm.nih.gov/27824625.
  9. Fernandez C, Michie K, et al. Adverse events and discontinuation of dolutegravir-based therapy in naive and experienced HIV patients: tertiary HIV centre experience. Abstract #P212. Presented at: HIV Drug Therapy. 2016. Glasgow, Scotland. Available at: https://hivglasgow.org/2016-abstracts.
  10. Fettiplace A, Stainsby C, Winston A, et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr. 2017;74(4):423-431. Available at: https://pubmed.ncbi.nlm.nih.gov/27984559.
  11. Food and Drug Administration. FDA drug safety communication: serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution. 2011. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm246002.htm.
  12. FDA application review files, Vocabria and Cabenuva, integrated review. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/212887Orig1s000,212888Orig1s000IntegratedR.pdf.
  13. FDA application review files, Apretude, integrated review. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215499Orig1s000IntegratedR.pdf.
  14. Ford N, Shubber Z, Pozniak A, et al. Comparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line antiretroviral therapy: a systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2015;69(4):422-429. Available at: https://pubmed.ncbi.nlm.nih.gov/25850607.-
  15. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm, open-label, multicentre, Phase 2/3 trial. Lancet Child Adolesc Health. 2021;5(9):642-651. Available at: https://pubmed.ncbi.nlm.nih.gov/34302760.
  16. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an adult AIDS Clinical Trials Group study. AIDS. 2004;18(18):2391-2400. Available at: https://pubmed.ncbi.nlm.nih.gov/15622315.
  17. Hammond CK, Eley B, Ing N, Wilmshurst JM. Neuropsychiatric and neurocognitive manifestations in HIV-infected children treated with efavirenz in South Africa–a retrospective case series. Front Neurol. 2019;10:742. Available at: https://pubmed.ncbi.nlm.nih.gov/31338063.
  18. Hauptfleisch MP, Moore DP, Rodda JL. Efavirenz as a cause of ataxia in children. S Afr Med J. 2015;105(11):897-898. Available at: https://pubmed.ncbi.nlm.nih.gov/26632310.
  19. Hoffmann C, Llibre JM. Neuropsychiatric adverse events with dolutegravir and other integrase strand transfer inhibitors. AIDS Rev. 2019;21(1):4-10. Available at: https://pubmed.ncbi.nlm.nih.gov/30899113.
  20. Hoffmann C, Schewe K, Fenske S, et al. Short-term neuropsychiatric tolerability of bictegravir combined with emtricitabine/tenofovir alafenamide in clinical practice. Antivir Ther. 2020;25(2):83-90. Available at: https://pubmed.ncbi.nlm.nih.gov/32235038.
  21. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med. 2017;18(1):56-63. Available at: https://pubmed.ncbi.nlm.nih.gov/27860104.
  22. Kheloufi F, Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. AIDS. 2015;29(13):1723-1725. Available at: https://pubmed.ncbi.nlm.nih.gov/26372287.
  23. Leutscher PD, Stecher C, Storgaard M, Larsen CS. Discontinuation of efavirenz therapy in HIV patients due to neuropsychiatric adverse effects. Scand J Infect Dis. 2013;45(8):645-651. Available at: https://pubmed.ncbi.nlm.nih.gov/23427878.
  24. Lombaard J, Bunupuradah T, et al. Rilpivirine as a treatment for HIV-infected antiretroviral-naïve adolescents: Week 48 safety, efficacy, virology and pharmacokinetics. Pediatr Infect Dis J. 2016;35(11)1215-221.https://pubmed.ncbi.nlm.nih.gov/27294305/
  25. Madeddu G, Menzaghi B, Ricci E, et al. Raltegravir central nervous system tolerability in clinical practice: results from a multicenter observational study. AIDS. 2012;26(18):2412-2415. Available at: https://pubmed.ncbi.nlm.nih.gov/23032413.
  26. Mills A, Garner W, Pozniak A, et al. Patient-reported symptoms over 48 weeks in a randomized, open-label, Phase IIIb non-inferiority trial of adults with HIV switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir DF versus continuation of non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir DF. Patient. 2015;8(4):359-371. Available at: https://pubmed.ncbi.nlm.nih.gov/26045359.
  27. Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014;161(1):1-10. Available at: https://pubmed.ncbi.nlm.nih.gov/24979445.
  28. Mollan KR, Tierney C, Hellwege JN, et al. Race/ethnicity and the pharmacogenetics of reported suicidality with efavirenz among clinical trials participants. J Infect Dis. 2017;216(5):554-564. Available at: https://pubmed.ncbi.nlm.nih.gov/28931220.
  29. Munsami L, Schutte CM, de Villiers M, Hiesgen J. Late-onset efavirenz toxicity: a descriptive study from Pretoria, South Africa. South Afr J HIV Med. 2023;24(1):1439. Available at: https://pubmed.ncbi.nlm.nih.gov/36751478.
  30. Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a Phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at: https://pubmed.ncbi.nlm.nih.gov/30527329.
  31. Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident association between efavirenz use and suicidality was identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214. Available at: https://pubmed.ncbi.nlm.nih.gov/25192857.
  32. Nkhoma ET, Coumbis J, Farr AM, et al. No evidence of an association between efavirenz exposure and suicidality among HIV patients initiating antiretroviral therapy in a retrospective cohort study of real world data. Medicine (Baltimore). 2016;95(3):e2480. Available at: https://pubmed.ncbi.nlm.nih.gov/26817882.
  33. Perez Valero I, Cabello A, Ryan P, et al. Randomized trial evaluating the neurotoxicity of dolutegravir/abacavir/lamivudine and its reversibility after switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide: GESIDA 9016. Open Forum Infect Dis. 2020;7(12):ofaa482. Available at: https://pubmed.ncbi.nlm.nih.gov/33335931.
  34. Pinillos F, Dandara C, Swart M, et al. Case report: severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation. BMC Infect Dis. 2016;16:56. Available at: https://pubmed.ncbi.nlm.nih.gov/26831894.
  35. Preta LH, Chroboczek T, Treluyer JM, Chouchana L. Association of depression and suicidal behaviour reporting with HIV integrase inhibitors: a global pharmacovigilance study. J Antimicrob Chemother. 2023;78(8):1944-1947. Available at: https://pubmed.ncbi.nlm.nih.gov/37311223.
  36. Puthanakit T, Tanpaiboon P, Aurpibul L, Cressey TR, Sirisanthana V. Plasma efavirenz concentrations and the association with CYP2B6-516G >T polymorphism in HIV-infected Thai children. Antivir Ther. 2009;14(3):315-320. Available at: https://pubmed.ncbi.nlm.nih.gov/19474465.
  37. Reiss KA, Bailey JR, Pham PA, Gallant JE. Raltegravir-induced cerebellar ataxia. AIDS. 2010;24(17):2757. Available at: https://pubmed.ncbi.nlm.nih.gov/20980871.
  38. Rizzardini G, Overton ET, Okrin C, et al. Long-acting cabotegravir+rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85:498-506. Available at: https://pubmed.ncbi.nlm.nih.gov/33136751.
  39. Rubin, LH, O’Halloran, JA, Williams, DW, et al. Integrase inhibitors are associated with neuropsychiatric symptoms in women with HIV. J Neuroimmune Pharmacol. 2022 Feb 17:10.1007/s11481-021-10042-3. Available at: https://pubmed.ncbi.nlm.nih.gov/35178611.
  40. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403-1412. Available at: https://pubmed.ncbi.nlm.nih.gov/23343913.
  41. Smith C, Ryom L, Monforte A, et al. Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study. J Int AIDS Soc. 2014;17(4 Suppl 3):19512. Available at: https://pubmed.ncbi.nlm.nih.gov/25394021.
  42. Strehlau R, Martens L, Coovadia A, et al. Absence seizures associated with efavirenz initiation. Pediatr Infect Dis J. 2011;30(11):1001-1003. Available at: https://pubmed.ncbi.nlm.nih.gov/21633320.
  43. Teppler H, Brown DD, Leavitt RY, et al. Long-term safety from the raltegravir clinical development program. Curr HIV Res. 2011;9(1):40-53. Available at: https://pubmed.ncbi.nlm.nih.gov/21198432.
  44. Turkova A, Kekitiinwa A, White E, et al. Neuropsychiatric manifestations and sleep disturbances in children and adolescents randomised to dolutegravir-based ART vs standard-of-care in the ODYSSEY trial. Abstract OAB0404. Presented at: 11th IAS Conference on HIV Science 2021. Virtual Conference. Available at: https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(23)00164-5/fulltext
  45. Van de Wijer L, McHaile DN, de Mast Q, et al. Neuropsychiatric symptoms in Tanzanian HIV-infected children receiving long-term efavirenz treatment: a multicentre, cross-sectional, observational study. Lancet HIV. 2019;6(4):e250-e258. Available at: https://pubmed.ncbi.nlm.nih.gov/30770324.
  46. van Dijk JH, Sutcliffe CG, Hamangaba F, Bositis C, Watson DC, Moss WJ. Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings. PLoS One. 2013;8(1):e55111. Available at: https://pubmed.ncbi.nlm.nih.gov/23372824.
  47. Variava E, Sigauke FR, Norman J, et al. Brief report: late efavirenz-induced ataxia and encephalopathy: a case series. J Acquir Immune Defic Syndr. 2017;75(5):577-579. Available at: https://pubmed.ncbi.nlm.nih.gov/28520619.
  48. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212887s005s006lbl.pdf.
  49. Waalewijn H, Turkova A, Rakhmanina N, et al. Optimizing pediatric dosing recommendations and treatment management of antiretroviral drugs using therapeutic drug monitoring data in children living with HIV. Ther Drug Monit. 2019;41(4):431-443. Available at: https://pubmed.ncbi.nlm.nih.gov/31008997.
  50. Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70(5):515-519. Available at: https://pubmed.ncbi.nlm.nih.gov/26262777.
  51. Waters L, Fisher M, Winston A, et al. A Phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS. 2011;25(1):65-71. Available at: https://pubmed.ncbi.nlm.nih.gov/21099666.

Management of Medication Toxicity or Intolerance

Central Nervous System Toxicity

Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity
Table 17a. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Central Nervous System Toxicity
  
  
  
  

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