(Last updated: March 5, 2015; last reviewed: March 5, 2015)
|Adverse Effects||Associated ARVs||Onset / Clinical Manifestations||Estimated Frequency||Risk Factors||Prevention/
|Global CNS Depression||LPV/r oral solution (contains both ethanol and propylene glycol as excipients)
|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 (i.e., postmenstrual age of 42 weeks and a postnatal age ≥14 days).
|Neuropsychiatric Symptoms and Other CNS Manifestations
May Include One or More of the Following:
Variable, depending on age, symptom, assessment method
|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).
|Discontinue EFV if suitable alternative exists
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.
||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.|
||Prior history of neuropsychiaric illness||Monitor carefully for CNS symptoms.||Consider drug substitution in case of severe symptoms.|
||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.|
||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; EEG = electroencephalogram; 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