Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Management of Medication Toxicity or Intolerance

CNS Toxicity

Last Updated: April 14, 2020; Last Reviewed: April 14, 2020


  1. Arenas-Pinto A, Grund B, Sharma S, et al. Increased risk of suicidal behaviour with use of efavirenz: results from the START trial. Presented at: 21st International AIDS Conference. 2016. Durban, South Africa.
  2. Bracchi M, Pagani N, et al. Multicentre open-label pilot study of switching from efavirenz to dolutegravir for central nervous system (CNS) toxicity. Abstract # P209. Presented at: HIV Drug Therapy. 2016. Glasgow, Scotland. Available at:
  3. Briand C, Dollfus C, Faye A, et al. Efficacy and tolerance of dolutegravir-based combined ART in perinatally HIV-1-infected adolescents: a French multicentre retrospective study. J Antimicrob Chemother. 2017;72(3):837-843. Available at:
  4. Cabrera Figueroa S, Fernandez de Gatta M, Hernandez Garcia L, et al. The convergence of therapeutic drug monitoring and pharmacogenetic testing to optimize efavirenz therapy. Ther Drug Monit. 2010;32(5):579-585. Available at:
  5. Cattaneo D, Ripamonti D, Baldelli S, Cozzi V, Conti F, Clementi E. Exposure-related effects of atazanavir on the pharmacokinetics of raltegravir in HIV-1-infected patients. Ther Drug Monit. 2010;32(6):782-786. Available at:
  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:
  7. 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:
  8. 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:
  9. 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:
  10. Rilpivirine [package insert]. Food and Drug Administration. 2018. Available at:
  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:
  12. 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:
  13. García-Navarro C, Jiménez de Ory S, Navarro Gómez ML, et al. Sleep disturbances in a cohort of HIV-infected children and adolescents on antiretroviral treatment. Presented at: 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA.
  14. Group ES, Carey D, Puls R, et al. Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15(7):793-802. Available at:
  15. 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:
  16. 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:
  17. 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:
  18. 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:
  19. Lombaard J, Bunupuradah T. Week 48 safety and efficacy of a rilpivirine (TMC278)-based regimen in HIV-infected treatment-naive adolescents: PAINT Phase II trial. Presented at: 7th International Workshop on HIV Pediatrics. 2015. Vancouver, Canada.
  20. 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:
  21. 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:
  22. 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:
  23. Mollan KR, Tierney C, Eron JJ, et al. Composite CYP2B6/CYP2A6 genotype and risk for suicidality among HIV-infected individuals randomly assigned to initiate efavirenz-containing regimens in AIDS Clinical Trials Group studies. Presented at: 21st International AIDS Conference. 2016. Durban, South Africa.
  24. Nachman S, et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through week 48. Abstract no. TUAB0205. Presented at: 19th International AIDS Conference. 2012. Washington, DC.
  25. 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:
  26. 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. 2016;95(3):e2480. Available at:
  27. 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:
  28. 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:
  29. Quercia R, Roberts J. Psychiatric adverse events from the DTG ART-naive Phase 3 clinical trials. Abstract # P210. Presented at: HIV Drug Therapy. 2016. Glasgow, Scotland. Available at:
  30. Rakhmanina NY, van den Anker JN, Soldin SJ, van Schaik RH, Mordwinkin N, Neely MN. Can therapeutic drug monitoring improve pharmacotherapy of HIV infection in adolescents? Ther Drug Monit. 2010;32(3):273-281. Available at:
  31. Reiss KA, Bailey JR, Pham PA, Gallant JE. Raltegravir-induced cerebellar ataxia. AIDS. 2010;24(17):2757. Available at:
  32. 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:
  33. 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:
  34. 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:
  35. Teppler H, Brown DD, Leavitt RY, et al. Long-term safety from the raltegravir clinical development program. Current HIV Res. 2011;9(1):40-53. Available at:
  36. Todd S, Rafferty P, Walker E, et al. Early clinical experience of dolutegravir in an HIV cohort in a larger teaching hospital. Int J STD AIDS. 2017:956462416688127. Available at:
  37. 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:
  38. 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:
  39. Viswanathan P, Baro E, Soon G, Sherwat A, Struble KA. Neuropsychiatric adverse events associated with integrase strand transfer inhibitors. Presented at: Conference on Retroviruses and Opportunistic Infections. 2017. Seattle, Washington.
  40. Walmsley S, Baumgarten A, Berenguer J, et al. 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. Available at:
  41. 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:
  42. 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:
  43. 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:
  44. 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:
  45. 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:
  46. Burman RJ, Wilmshurst JM, Gebauer S, Weise L, Walker KG, Donald KA. Seizures in children with HIV infection in South Africa: a retrospective case control study. Seizure. 2019;65:159-165. Available at:
  47. 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:
  48. Hoffmann C, Llibre JM. Neuropsychiatric Adverse events with dolutegravir and other integrase strand transfer inhibitors. AIDS Rev. 2019;21(1):4-10. Available at:

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