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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: March 1, 2016; last reviewed: March 1, 2016)

Table 12a. Antiretroviral-Therapy-Associated Adverse Effects and Management Recommendations—Central Nervous System 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 (e.g., abnormal EEG, altered state of consciousness, somnolence)
  • Non-CNS-associated toxicity may include cardiac toxicity and respiratory complications.
Exact frequency of ethanol and propylene glycol-associated toxicity unknown in neonates receiving LPV/r oral solution. 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 (i.e., postmenstrual age of 42 weeks and a postnatal age ≥14 days).
Neuropsychiatric Symptoms and Other CNS Manifestations
EFV Onset:
  • 1–2 days after initiating treatment
  • Many symptoms subside or diminish by 2–4 weeks, but may persist in a significant proportion of patients. In one report, 37% experienced persistent symptoms at 12 months and in another, half of discontinuations occurred after 12 months.
Presentation (May Include One or More of the Following)
Neuropsychiatric Symptoms:
  • Abnormal dreams
  • Psychosis
  • Suicidal ideation or attempted/completed suicide
  • Seizures (including absence seizures) or decreased seizure threshold
Other CNS Manifestations:
  • Dizziness
  • Somnolence
  • Insomnia or poor sleep quality
  • Impaired concentration
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 1 case series with 18% requiring drug discontinuation
  • 9% incidence of new-onset seizures reported in 1 study in children aged <36 months, in two of the children the seizures had alternative causes.

Adults:
  • 30% incidence for any CNS manifestations of any severity.
  • 6% incidence for EFV-related severe CNS manifestations including suicidality. However, evidence is conflicting about whether EFV use increases the incidence of suicidality.
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 including depression or suicidal thoughts 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).
Obtain EFV trough concentration if symptoms excessive or persistent. If EFV trough concentrationl >4 mcg/mL, strongly consider drug substitution if suitable alternative exists. Alternatively, consider dose reduction with repeat TDM and dose adjustment (with expert pharmacologist input).

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.
RPV Presentation
Neuropsychiatric Symptoms:
  • Depressive disorders
  • Suicidal ideation
  • Abnormal dreams/nightmare
Other CNS Manifestations:
  • Headache
  • Dizziness
  • Insomnia
In Adults:
  • CNS/neuropsychiatric adverse events of all severity grades were reported in 43% of patients at 96 weeks (mostly Grade 1). Depressive disorders of all severity grades were reported in 9% of patients, and were severe requiring RPV discontinuation in 1% of patients.
In Children:
  • Depressive disorders of all severity grades were reported in 19.4% of pediatric patients aged 12 years to 17 years. Severe depressive disorders were reported in 5.6% of patients, including a suicide attempt in 1 subject.
Prior history of neuropsychiaric illness Monitor carefully for depressive disorders and other CNS symptoms. Consider drug substitution in case of severe symptoms.
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
Prescreen 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.
DTG Onset:
  • 7–30 days after initiating drug
Presentation: Neuropsychiatric Symptoms:
  • Depression or exacerbation of preexisting depression
  • Anxiety
  • Suicidal ideation attempt, behavior, or completion
Other CNS Manifestations (Generally Mild):
  • Insomnia
  • Dizziness
  • Headache
  • Adults:
    • Exact frequency of neuropsychiatric symptoms is unknown; case reports of 4 adult patients. Headache, insomnia, and dizziness are common, reported in up to 10% of patients. Less than 1% patients experienced more severe symptoms.
    Pre-existing depression or other psychiatric illness Use with caution in the presence of psychiatric illness especially depression. For severe neuropsychiatric symptoms, consider discontinuation of DTG if suitable alternative exists. 

    Discontinuation resulted in resolution of neuropsychiatric symptom in 3 out of 4 patients (in the 4th patient, symptoms resolved slowly despite DTG continuation).

    For mild symptoms, continue DTG and counsel patient that symptoms will likely resolve with time.
    Intracranial Hemorrhage 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 py or 0.04–0.22/100 py 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: ARV = antiretroviral; ATV = atazanavir; CNS = central nervous system; CYP = cytochrome P; DTG = dolutegravir; EEG = electroencephalogram; EFV = efavirenz; ICH = intracranial hemorrhage; LPV/r = ritonavir-boosted lopinavir; PPI = proton pump inhibitor; py = patient years; RAL = raltegravir; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate; TDM = therapeutic drug monitoring; TPV = tipranavir; UGT = uridine diphosphate-glucurononyl transferase

                                                                                                 

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