Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

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Management of Medication Toxicity or Intolerance

CNS Toxicity

Last Updated: April 27, 2017; Last Reviewed: April 27, 2017

References

  1. Food and Drug Administration. FDA Drug Safety Communication: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution. 2011. Available at http://www.fda.gov/Drugs/DrugSafety/ucm246002.htm. Accessed March 10, 2017.
  2. Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis. 2005;41(11):1648-1653. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267739.
  3. 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 http://www.ncbi.nlm.nih.gov/pubmed/15622315.
  4. 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 http://www.ncbi.nlm.nih.gov/pubmed/21099666.
  5. 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 http://www.ncbi.nlm.nih.gov/pubmed/19474465.
  6. 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 http://www.ncbi.nlm.nih.gov/pubmed/20720517.
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  9. 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 http://www.ncbi.nlm.nih.gov/pubmed/21633320.
  10. 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 http://www.ncbi.nlm.nih.gov/pubmed/20445485.
  11. 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 http://www.ncbi.nlm.nih.gov/pubmed/20926993.
  12. Chan-Tack KM, Struble KA, Birnkrant DB. Intracranial hemorrhage and liver-associated deaths associated with tipranavir/ritonavir: review of cases from the FDA's Adverse Event Reporting System. AIDS Patient Care STDS. 2008;22(11):843-850. Available at http://www.ncbi.nlm.nih.gov/pubmed/19025478.
  13. 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 http://www.ncbi.nlm.nih.gov/pubmed/23343913.
  14. 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 http://www.ncbi.nlm.nih.gov/pubmed/23372824.
  15.  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 http://www.ncbi.nlm.nih.gov/pubmed/23211772.
  16. 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.
  17. 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 http://www.ncbi.nlm.nih.gov/pubmed/23032413.
  18. Dabaghzadeh F, Ghaeli P, Khalili H, et al. Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial. AIDS Patient Care STDS. 2013;27(3):146-154. Available at http://www.ncbi.nlm.nih.gov/pubmed/23442031.
  19. 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 http://www.ncbi.nlm.nih.gov/pubmed/24979445.
  20. Mills AM, Antinori A, Clotet B, et al. Neurological and psychiatric tolerability of rilpivirine (TMC278) vs. efavirenz in treatment-naive, HIV-1-infected patients at 48 weeks. HIV Med. 2013;14(7):391-400. Available at http://www.ncbi.nlm.nih.gov/pubmed/23298380.
  21. 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 http://www.ncbi.nlm.nih.gov/pubmed/25192857.
  22. Leutscher PD, Stecher C, Storgaard M, Larsen CS. Discontinuation of efavirenz therapy in HIV patients due to neuropsychiatric adverse effects. Scandinavian Journal of Infectious Diseases. 2013;45(8):645-651. Available at http://www.ncbi.nlm.nih.gov/pubmed/23427878.
  23. Group ES, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard 600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised, double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383(9927):1474-1482. Available at http://www.ncbi.nlm.nih.gov/pubmed/24522178.
  24. 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 http://www.ncbi.nlm.nih.gov/pubmed/25394021.
  25. 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 http://www.ncbi.nlm.nih.gov/pubmed/25850607.
  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 http://www.ncbi.nlm.nih.gov/pubmed/26045359.
  27. 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.
  28. Kheloufi F, Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. AIDS. 2015;29(13):1723-1725. 
  29. Rilpivirine (Edurant) [package insert]. Food and Drug Administration. 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/202022s008lbledt.pdf  
  30. 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 http://www.ncbi.nlm.nih.gov/pubmed/26262777.
  31. Lombaard J, Bunupuradah T. Week 48 safety and efficacy of a rilpivirine (TMC278)-based regimen in HIV-infected treatment-naïve adolescents: PAINT phase II trial. Presented at: 7th International Workshop on HIV Pediatrics. 2015. Vancouver, Canada.
  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 http://www.ncbi.nlm.nih.gov/pubmed/26817882.
  33.  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 http://www.ncbi.nlm.nih.gov/pubmed/26831894.
  34. 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.
  35. 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.
  36. Hauptfleisch MP, Moore DP, Rodda JL. Efavirenz as a cause of ataxia in children. S Afr Med J. 2015;105(10):876. Available at https://www.ncbi.nlm.nih.gov/pubmed/26636156.

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