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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
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.
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

  • 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.
  • >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
  • Increased psychomotor activity reported in one child
  • 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
  • No cases of ICH reported in children.
  • 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
  • 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


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