Efavirenz

Efavirenz is an oral non-nucleoside reverse transcriptase inhibitor, long used in first-line HIV treatment, now largely replaced by dolutegravir but still used in programmes, in pregnancy where dolutegravir is not suitable, and in some tuberculosis co-treatment. Its main limits are central nervous system effects, rash, liver injury and many enzyme-induction interactions. It has no activity against HIV-2 or hepatitis B.

Class. Non-nucleoside reverse transcriptase inhibitor.

Mechanism. Binds directly to a hydrophobic pocket in HIV-1 reverse transcriptase and inhibits the enzyme without needing activation. A single mutation (for example K103N) causes high-level resistance.

Pharmacokinetics. Oral bioavailability increased by fatty food (avoid). Half life 40 to 55 hours after repeated doses. Metabolised by CYP2B6 and CYP3A4. It induces CYP3A4, CYP2B6 and UGT1A1 and inhibits CYP2C9 and CYP2C19. Slow CYP2B6 metabolisers have higher levels.

HIV-1 infection (adults and adolescents 40 kg or more). - 600 mg orally once daily at bedtime on an empty stomach, with tenofovir and lamivudine. - 400 mg once daily is used in some fixed-dose combinations for adults not on rifampicin. - During rifampicin treatment, 600 mg once daily (no increase).

Children (3 months and over, 3.5 kg and over). - 10 to under 15 kg: 200 mg once daily; 15 to under 20 kg: 250 mg; 20 to under 25 kg: 300 mg. - 25 to under 32.5 kg: 350 mg; 32.5 to under 40 kg: 400 mg; 40 kg or more: 600 mg.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 600 mg daily.

Main alternative. Dolutegravir.

Contraindications. Hypersensitivity; co-administration with voriconazole at usual doses, rilpivirine, elbasvir with grazoprevir, bepridil, cisapride, midazolam, triazolam, pimozide, ergot alkaloids and St John’s wort.

Serious adverse effects. Severe neuropsychiatric events (depression, suicidal thoughts, psychosis), hepatotoxicity, severe rash including Stevens-Johnson syndrome, QT prolongation, and convulsions in people with epilepsy.

Common adverse effects. Dizziness, vivid dreams, insomnia, poor concentration (usually settle in 2 to 4 weeks), rash, nausea, and raised triglycerides and cholesterol.

Interactions. - Dolutegravir: increase to 50 mg twice daily. - Raltegravir, protease inhibitors, rilpivirine, etravirine, bictegravir, maraviroc: levels lowered; avoid or adjust. - Bedaquiline: lowered, so avoid. - Artemether-lumefantrine and other antimalarials: lowered levels. - Methadone: lowered; hormonal contraception: implant efficacy lowered; use an alternative. - Anticonvulsant enzyme inducers lower efavirenz.

Common prescribing errors. Taking with a fatty meal, daytime dosing, not warning about dizziness, and using it with bedaquiline, rilpivirine or implants.

Special groups. - Pregnancy: can be used in any trimester; early neural tube defect concern is not confirmed. - Breastfeeding: compatible. - Children: weight-banded dosing; night-time dosing. - Older adults: usual dose; watch for confusion. - Kidney impairment: no adjustment. - Liver impairment: caution in Child-Pugh A; avoid in B and C.

Regional points. A high proportion of people of African ancestry are slow CYP2B6 metabolisers, which raises central nervous system toxicity at 600 mg and is the reason for the 400 mg dose; tuberculosis co-treatment is common and rifampicin lowers levels only slightly.

Formulations. Tablets 200 mg and 600 mg; capsules 50 mg and 200 mg; oral solution 30 mg/mL; fixed-dose combinations with tenofovir and lamivudine or emtricitabine (600 mg or 400 mg).

Administration. Once daily at bedtime on an empty stomach; avoid heavy meals and alcohol.

Baseline. HIV test, hepatitis B and C status, liver tests, mental health history, pregnancy test, lipids.

Monitoring. Liver tests at 2, 4 and 12 weeks and then every 6 months; mood and sleep; lipids; viral load at 6 months.

Stopping thresholds. Stop for ALT over 3 times the upper limit of normal with symptoms, or over 5 times without; stop for severe rash or suicidal thinking.

Referral and escalation. Specialist review for psychiatric symptoms, severe rash, hepatitis and treatment failure.