Efavirenz

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Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in combination with other antiretrovirals to treat HIV-1. Once a cornerstone of first-line therapy, it has been largely replaced by integrase inhibitors (e.g., Dolutegravir) but remains widely used globally. It is notable for prominent neuropsychiatric side effects and significant drug interactions.[1]

Administration

  • Type: Non-nucleoside reverse transcriptase inhibitor (NNRTI)
  • Dosage Forms: 50 mg, 200 mg capsules; 600 mg tablets
  • Routes of Administration: Oral
  • Common Trade Names: Sustiva; also in fixed-dose combination: Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate)

Adult Dosing

  • 600 mg PO once daily[1]
  • Take on an empty stomach, preferably at bedtime — food increases drug levels and worsens adverse effects; bedtime dosing improves tolerability of CNS symptoms[2]
  • Tablets must be swallowed whole (do not crush or break)
  • With rifampin and weight >50 kg: increase to 800 mg once daily[1]

Pediatric Dosing

  • Approved for patients ≥3 months and ≥3.5 kg; weight-based dosing[1]
  • Consult prescribing information or pediatric ID for weight-band tables
  • Capsule sprinkle method available for patients unable to swallow capsules

Special Populations

Pregnancy Rating

  • Avoid in pregnancy, particularly during the first trimester — primate studies showed neural tube defects (anencephaly, anophthalmia, cleft palate); human data are less definitive but efavirenz remains contraindicated at conception[1]
  • Women of childbearing potential should have a pregnancy test before initiation and use effective contraception during treatment and for 12 weeks after discontinuation (due to the long half-life)[1]
  • Hormonal contraceptives containing progesterone may have decreased effectiveness[1]

Lactation risk

  • Present in human milk; women with HIV should not breastfeed (risk of HIV transmission)[1]

Renal Dosing

  • Adult: No dose adjustment needed (minimal renal excretion; <1% unchanged drug in urine)[2]
    • Highly protein bound; unlikely removed by dialysis
  • Pediatric: No specific adjustment data

Hepatic Dosing

  • Adult: Mild impairment (Child-Pugh A): No dose adjustment, but use with caution[1]
    • Moderate or severe impairment (Child-Pugh B or C): Not recommended (insufficient data; extensively hepatically metabolized)
  • Pediatric: Not studied

Contraindications

  • Allergy to class/drug
  • Coadministration with elbasvir/grazoprevir (Zepatier)[1]
  • Coadministration with drugs highly dependent on CYP3A4/2C9/2C19 where decreased levels cause loss of efficacy (e.g., voriconazole standard dosing) or where efavirenz inhibition causes toxicity

Adverse Reactions

Serious

  • Neuropsychiatric effects: Severe depression (2.4%), suicidal ideation/attempts, psychosis, aggressive behavior, hallucinations, paranoia, mania[1]
  • Hepatotoxicity: Hepatic failure (including fatalities) reported, some in patients without pre-existing liver disease; higher risk with hepatitis B/C co-infection[1]
  • Stevens-Johnson syndrome, erythema multiforme, toxic skin eruptions[1]
  • QTc prolongation — consider alternatives when coadministered with QT-prolonging drugs or in patients at risk for torsades de pointes[1]
  • Seizures (reported in patients with and without history of seizures)[3]
  • Immune reconstitution inflammatory syndrome (IRIS)

Common

  • CNS effects (52%): Dizziness, insomnia, vivid/abnormal dreams, impaired concentration, drowsiness, headache — typically onset days 1–2, improve over 2–4 weeks but may persist[1]
  • Rash (26%; usually mild-to-moderate maculopapular, onset within first 2 weeks; 1.7% discontinuation rate)[1]
  • Nausea, diarrhea
  • Elevated transaminases (higher in hepatitis B/C co-infection)
  • Hyperlipidemia (elevated cholesterol and triglycerides)

Pharmacology

  • Half-life: ~40–55 hours (single dose); ~52–76 hours at steady state (due to autoinduction)[2]
  • Metabolism: Primarily CYP2B6 and CYP3A4; efavirenz is both a CYP3A4/CYP2B6 inducer and a CYP2C9/2C19/3A4 inhibitor at therapeutic concentrations[1]
  • Excretion: ~14–34% in urine (as metabolites); ~16–61% in feces; <1% unchanged drug in urine[2]

Mechanism of Action

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that binds directly to a hydrophobic pocket on HIV-1 reverse transcriptase near the catalytic active site. This induces a conformational change that disrupts enzyme function, blocking RNA-dependent and DNA-dependent DNA polymerase activity. Unlike nucleoside analogs, efavirenz does not require intracellular phosphorylation and does not compete with nucleotide substrates.[1] It has no activity against HIV-2.[2]

Comments

  • Psychiatric emergency pearl: Patients on efavirenz may present to the ED with acute psychiatric symptoms (psychosis, suicidal ideation, severe depression, aggression). These can occur at any time during treatment, not just at initiation. Always check the medication list in psychiatric presentations of HIV+ patients[1]
  • CNS effects vs. intoxication: Efavirenz causes dizziness, drowsiness, impaired concentration, and vivid dreams that can mimic intoxication. Be aware of this in altered mental status presentations
  • False-positive UDS for cannabis: Efavirenz can cause false-positive urine cannabinoid screening tests. Confirm with more specific assay (GC-MS) before attributing a positive result to marijuana use[1]
  • CYP3A inducer: Efavirenz primarily induces CYP3A (unlike PIs which inhibit it) — this decreases levels of many coadministered drugs. Key ED relevance:
    • Decreases levels of: methadone (may precipitate withdrawal), some benzodiazepines, calcium channel blockers, statins, hormonal contraceptives[1]
    • Dose adjustments required when combined with other ARVs (e.g., increases maraviroc dose to 600 mg BID)
  • QTc prolongation: Avoid coadministration with other QT-prolonging agents when possible; obtain ECG if clinical concern[1]
  • Long washout: Half-life of ~40–76 hours means drug effects (including interactions and teratogenic risk) persist for weeks after discontinuation. Women must use contraception for 12 weeks after stopping[1]
  • Overdose: Supportive care; increased neuropsychiatric symptoms expected. Involuntary muscle contractions reported at supratherapeutic doses. No specific antidote; unlikely removed by dialysis (>99% protein bound)[1]

See Also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 Sustiva (efavirenz) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2016.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Efavirenz. StatPearls. NCBI Bookshelf. Updated 2024.
  3. ↑ Efavirenz. Wikipedia. Accessed 2025.
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