| 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 of at least 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)
CNS side effects may be more difficult to detect in children because neurologic symptoms such as impaired concentration, sleep disturbances, or behavior disorders may be difficult to assess.
|
Variable, depending on age, symptom, assessment method
Children:
24% for any EFV related CNS manifestations in one case series with 18% requiring drug discontinuation
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.
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 discontinuation.
|
| |
RAL |
Presentation:
Increased psychomotor activity, headaches, insomnia, depression |
Children:
Psychomotor activity reported in one child
Adults:
Headache, insomnia (<5% in adult trials)
|
Elevated RAL concentrations
Prior history of insomnia or depression
|
Use with caution in the presence of drugs that increase RAL concentration |
Consider drug discontinuation in case of severe insomnia. |
| 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, 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 (such as drug-drug interaction) identified and removed. |