Etravirine

Etravirine is an oral second-generation non-nucleoside reverse transcriptase inhibitor that keeps activity against some HIV-1 strains resistant to efavirenz and nevirapine. It is used in treatment-experienced adults and children, always with a boosted protease inhibitor and other active drugs. It needs a meal for absorption and interacts with many drugs. Severe skin reactions occur uncommonly.

Class. Non-nucleoside reverse transcriptase inhibitor.

Mechanism. Binds to a flexible pocket in HIV-1 reverse transcriptase that adapts to many resistance mutations. Several mutations are needed to remove its activity.

Pharmacokinetics. Absorption falls by about 50% when fasting. Highly protein bound; half life about 41 hours. Metabolised by CYP3A4, CYP2C9 and CYP2C19. It induces CYP3A4 and inhibits CYP2C9 and CYP2C19.

Treatment-experienced HIV-1 infection with NNRTI resistance (adults). 200 mg orally twice daily after a meal, with a boosted protease inhibitor (for example darunavir with ritonavir) and other active drugs.

Children (6 years and over). - 16 to under 20 kg: 100 mg twice daily; 20 to under 25 kg: 125 mg twice daily. - 25 to under 30 kg: 150 mg twice daily; 30 kg or more: 200 mg twice daily.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 400 mg daily.

Main alternatives. Dolutegravir-based regimens with a boosted protease inhibitor, depending on the resistance result.

Contraindications. Hypersensitivity.

Serious adverse effects. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (rare), hepatotoxicity, and immune reconstitution syndrome.

Common adverse effects. Rash (usually mild, in the first 6 weeks), nausea, diarrhoea, headache, peripheral neuropathy, and raised lipids.

Interactions. - Do not give with tipranavir, fosamprenavir with ritonavir, atazanavir with ritonavir, unboosted protease inhibitors, efavirenz or nevirapine. - Rifampicin, rifapentine, carbamazepine, phenytoin, phenobarbital and St John’s wort lower levels: avoid. - Dolutegravir needs 50 mg twice daily with etravirine unless a boosted protease inhibitor is also given. - Raises warfarin and clopidogrel effects; adjust; lowers voriconazole and itraconazole levels.

Common prescribing errors. Giving fasting, combining with the wrong protease inhibitor, using it with only one active partner drug, and missing the rifampicin interaction.

Special groups. - Pregnancy: limited data; use when needed. - Breastfeeding: avoid or specialist advice. - Children: weight-banded; tablets can be dispersed in water. - Older adults: usual dose. - Kidney impairment: no adjustment. - Liver impairment: mild to moderate: no adjustment; severe: not studied.

Regional points. Etravirine is used only in third-line programmes in East Africa, and resistance testing to select regimens is rarely available, so access is by specialist panels.

Formulations. Tablets 25 mg, 100 mg and 200 mg.

Administration. Twice daily after a meal; swallow tablets whole or disperse in water and drink at once.

Baseline. Resistance test result, drug history and interaction check, liver tests, hepatitis B and C status, pregnancy test.

Monitoring. Skin at every visit for 6 weeks; liver tests at 4 and 12 weeks and then every 6 months; viral load at 3 months and 6 months.

Stopping thresholds. Stop for severe rash, rash with fever or mucosal involvement, hypersensitivity, or ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for all patients; admission for suspected Stevens-Johnson syndrome.