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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

CNS Toxicity

(Last updated: February 12, 2014; last reviewed: February 12, 2014)

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Table 11a. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Central Nervous System (CNS) Toxicity
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Global CNS Depression LPV/r oral solution (contains both ethanol and propylene glycol as excipients) Onset:
  • 1–6 days after starting LPV/r
Presentation
Neonates/Preterm Infants:
  • Global CNS depression
  • Cardiac toxicity
  • Respiratory complications
Exact frequency unknown, but ethanol and propylene glycol toxicity at therapeutic LPV/r dose reported in premature neonates. Prematurity

Low birth weight

Age <14 days (whether premature or term)
Avoid use of LPV/r until a postmenstrual age of 42 weeks and a postnatal age ≥14 days. Discontinue LPV/r; symptoms should resolve in 1–5 days.

If needed, reintroduction of LPV/r can be considered once outside the vulnerable period.
Neuropsychiatric Symptoms and Other CNS Manifestations
 
EFV Onset:
  • 1–2 days after initiating treatment
  • Most symptoms subside or diminish by 2–4 weeks, but may persist in a minority of patients.
Presentation
May Include One or More of the Following:
  • Dizziness
  • Somnolence
  • Insomnia
  • Abnormal dreams
  • Impaired concentration
  • Psychosis
  • Suicidal ideation
  • Seizures (including absence seizures) or decreased seizure threshold.
Note: Some CNS side effects (e.g., impaired concentration, abnormal dreams, or sleep disturbances) may be more difficult to assess in children.
Variable, depending on age, symptom, assessment method

Children:
  • 24% for any EFV-related CNS manifestations in one case series with 18% requiring drug discontinuation
  • In one report, 4/44 (9%) of young HIV-infected children aged <36 months experienced new onset seizures within 2–9 weeks of initiating EFV, although 2 of them had an alternative cause for the seizures.
Adults:
  • >50% for any CNS manifestations of any severity
  • 2% for EFV-related severe CNS manifestations
Insomnia associated with elevated EFV trough concentration ≥4 mcg/mL

Presence of CYP450 polymorphisms that decrease EFV metabolism (CYP2B6 516 TT genotype)

Prior history of psychiatric illness or use of psychoactive drugs
Administer EFV on an empty stomach, preferably at bedtime.

Use with caution in the presence of psychiatric illness or with concomitant use of psychoactive drugs.

TDM can be considered in the context of a child with mild or moderate toxicity possibly attributable to a particular ARV agent (see Role of Therapeutic Drug Monitoring in Management of Treatment Failure).
Provide reassurance about the likely time-limited nature of symptoms.

Consider EFV trough level if symptoms excessive or persistent. If EFV trough level >4 mcg/mL, consider dose reduction, preferably with expert pharmacologist input or drug substitution.

In a small study, cyproheptadine was shown to reduce short-term incidence of neuropsychiatric effects in adults receiving EFV, but data are lacking in children and no recommendation can be made for its use at this time.

RAL Presentation:
  • Increased psychomotor activity
  • Headaches
  • Insomnia
  • Depression
Children:
  • Increased psychomotor activity reported in one child
Adults:
  • Headache
  • Insomnia (<5% in adult trials)
Elevated RAL concentrations

Co-treatment with TDF or PPI

Prior history of insomnia or depression
Pre-screen for psychiatric symptoms.

Monitor carefully for CNS symptoms.

Use with caution in the presence of drugs that increase RAL concentration.
Consider drug substitution (RAL or co-administered drug) in case of severe insomnia or other neuropsychiatric symptoms.
RPV Presentation:
  • Dizziness
  • Abnormal dreams/nightmare
  • Insomnia
In Adults:
  • 43% all grade neuropsychiatric AE at 96 weeks (mostly Grade 1, causing RPV discontinuation in only one case, significantly lower than EFV)
Prior history of neuropsychiaric illness
Monitor carefully for CNS symptoms.
Consider drug  substitution in case of severe symptoms.
Intracranial Hemorrage TPV Onset:
  • 7–513 days after starting TPV
Children:
  • No cases of ICH reported in children.
Adults:
  • In premarket approval data in adults, 0.23/100 patient-years or 0.04–0.22/100 patient years in a retrospective review of 2 large patient databases.
Unknown; prior history of bleeding disorder or risk factors for bleeding present in most patients in case series reported. Administer TPV with caution in patients with bleeding disorder, known intracranial lesions, or recent neurosurgery. Discontinue TPV if ICH is suspected or confirmed.
Cerebellar Ataxia RAL Onset:
  • As early as 3 days after starting RAL
Presentation:
  • Tremor
  • Dysmetria
  • Ataxia
Two cases reported in adults during post marketing period Unknown; a speculated mechanism may include recent treatment with ATV with residual UGT1A1 enzyme inhibition and increased RAL serum concentration. Use with caution with ATV or other drugs that cause strong inhibition of UGT1A1 enzyme. Consider drug discontinuation. RAL reintroduction can be considered if predisposing factor (e.g., drug-drug interaction) identified and removed.
Key to Acronyms: AE = adverse effect; ARV = antiretroviral; ATV = atazanavir; CNS = central nervous system; CYP = cytochrome P; EFV = efavirenz; ICH = intracranial hemorrhage; LPV/r = ritonavir-boosted lopinavir; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; TDF = tenofovir disoproxyl fumarate; TDM = therapeutic drug monitoring; TPV = tipranavir; UGT = uridine diphosphate-glucurononyl transferase

References

  1. Boxwell D, K. Cao, et al. Neonatal Toxicity of Kaletra Oral Solution—LPV, Ethanol, or Propylene Glycol? Paper Presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI). Boston MA. 2011. Abstract #708
  2. Maggiolo F. Efavirenz: a decade of clinical experience in the treatment of HIV. J Antimicrob Chemother. Nov 2009;64(5):910-928. Available at http://www.ncbi.nlm.nih.gov/pubmed/19767318.
  3. 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. Dec 1 2005;41(11):1648-1653. Available at http://www.ncbi.nlm.nih.gov/pubmed/16267739.
  4. Elzi L, Marzolini C, Furrer H, et al. Treatment modification in human immunodeficiency virus-infected individuals starting combination antiretroviral therapy between 2005 and 2008. Arch Intern Med. Jan 11 2010;170(1):57-65. Available at http://www.ncbi.nlm.nih.gov/pubmed/20065200.
  5. 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. Dec 3 2004;18(18):2391-2400. Available at http://www.ncbi.nlm.nih.gov/pubmed/15622315.
  6. van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with high plasma concentrations and may prevent efavirenz discontinuations. J Acquir Immune Defic Syndr. Oct 1 2009;52(2):240-245. Available at http://www.ncbi.nlm.nih.gov/pubmed/19593159.
  7. van Luin M, Bannister WP, Mocroft A, et al. Absence of a relation between efavirenz plasma concentrations and toxicity-driven efavirenz discontinuations in the EuroSIDA study. Antivir Ther. 2009;14(1):75-83. Available at http://www.ncbi.nlm.nih.gov/pubmed/19320239.
  8. 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. Jan 2 2011;25(1):65-71. Available at http://www.ncbi.nlm.nih.gov/pubmed/21099666.
  9. Nguyen A, Calmy A, Delhumeau C, et al. A randomized crossover study to compare efavirenz and etravirine treatment. AIDS. Jan 2 2011;25(1):57-63. Available at http://www.ncbi.nlm.nih.gov/pubmed/21076278.
  10. 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.
  11. Munoz-Moreno JA, Fumaz CR, Ferrer MJ, et al. Neuropsychiatric symptoms associated with efavirenz: prevalence, correlates, and management. A neurobehavioral review. AIDS Rev. Apr–Jun 2009;11(2):103-109. Available at http://www.ncbi.nlm.nih.gov/pubmed/19529750.
  12. 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. Oct 2010;32(5):579-585. Available at http://www.ncbi.nlm.nih.gov/pubmed/20720517.
  13. Teppler H, Brown DD, Leavitt RY, et al. Long-term safety from the raltegravir clinical development program. Current HIV research. Jan 2011;9(1):40-53. Available at http://www.ncbi.nlm.nih.gov/pubmed/21198432.
  14. Gray J, Young B. Acute onset insomnia associated with the initiation of raltegravir: a report of two cases and literature review. AIDS Patient Care STDS. Sep 2009;23(9):689-690. Available at http://www.ncbi.nlm.nih.gov/pubmed/19663717.
  15. Reiss KA, Bailey JR, Pham PA, Gallant JE. Raltegravir-induced cerebellar ataxia. AIDS. Nov 13 2010;24(17):2757. Available at http://www.ncbi.nlm.nih.gov/pubmed/20980871.
  16. Strehlau R, Martens L, Coovadia A, et al. Absence seizures associated with efavirenz initiation. Pediatr Infect Dis J. Nov 2011;30(11):1001-1003. Available at http://www.ncbi.nlm.nih.gov/pubmed/21633320.
  17. 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. Jun 2010;32(3):273-281. Available at http://www.ncbi.nlm.nih.gov/pubmed/20445485.
  18. 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. Dec 2010;32(6):782-786. Available at http://www.ncbi.nlm.nih.gov/pubmed/20926993.
  19. 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. Nov 2008;22(11):843-850. Available at http://www.ncbi.nlm.nih.gov/pubmed/19025478.
  20. Justice AC, Zingmond DS, Gordon KS, et al. Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage? Clin Infect Dis. Nov 1 2008;47(9):1226-1230. Available at http://www.ncbi.nlm.nih.gov/pubmed/18831696.
  21. 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. Jun 1 2013;27(9):1403-1412. Available at http://www.ncbi.nlm.nih.gov/pubmed/23343913.
  22. Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr. Mar 1 2012;59(3):274-280. Available at http://www.ncbi.nlm.nih.gov/pubmed/22126740.
  23. 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.
  24. 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. Mar 27 2013;27(6):939-950. Available at http://www.ncbi.nlm.nih.gov/pubmed/23211772.
  25. Nachman S, et al. IMPAACT P1066: raltegravir (RAL) safety and efficacy in HIV infected (+) youth two to 18 years of age through week 48. Paper presented at:19th International AIDS Conference; 2012; Washington, DC. Abstract no. TUAB0205.
  26. Madeddu G, Menzaghi B, Ricci E, et al. Raltegravir central nervous system tolerability in clinical practice: results from a multicenter observational study. AIDS. Nov 28 2012;26(18):2412-2415. Available at http://www.ncbi.nlm.nih.gov/pubmed/23032413.
  27. 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. Mar 2013;27(3):146-154. Available at http://www.ncbi.nlm.nih.gov/pubmed/23442031.

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