Doravirine

Doravirine is an oral non-nucleoside reverse transcriptase inhibitor with a high barrier to resistance among drugs of its class, activity against common NNRTI-resistant mutants, and little effect on lipids or the central nervous system. It is used with two nucleosides in naive and switching patients. Strong enzyme inducers lower its levels sharply.

Class. Non-nucleoside reverse transcriptase inhibitor.

Mechanism. Binds to HIV-1 reverse transcriptase and blocks DNA synthesis without needing activation. It keeps activity against K103N and Y181C.

Pharmacokinetics. Oral bioavailability about 64%, not affected by food. Half life about 15 hours. Metabolised mainly by CYP3A4; a substrate, not a clinically important inducer or inhibitor.

HIV-1 infection (adults and children 35 kg or more). 100 mg orally once daily, with or without food, with two nucleosides. Duration: lifelong.

With rifabutin. 100 mg twice daily (about 12 hours apart) during rifabutin treatment and for 2 weeks after.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 200 mg daily with rifabutin; otherwise 100 mg daily.

Main alternatives. Efavirenz, rilpivirine, or integrase inhibitor regimens.

Contraindications. Hypersensitivity; co-prescription with rifampicin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, mitotane, enzalutamide and St John’s wort.

Serious adverse effects. Severe skin reactions and hypersensitivity (rare), hepatotoxicity (uncommon), and immune reconstitution syndrome.

Common adverse effects. Nausea, headache, fatigue, dizziness, diarrhoea and abnormal dreams.

Interactions. Strong CYP3A inducers lower levels and are contraindicated; strong inhibitors (ritonavir, azoles) raise levels slightly without a dose change; efavirenz and etravirine should not be given together.

Common prescribing errors. Giving with rifampicin, continuing a single daily dose with rifabutin, and using it without testing for hepatitis B before a lamivudine or tenofovir switch.

Special groups. - Pregnancy: limited data; use only where other agents are unsuitable. - Breastfeeding: no data; avoid. - Children: 35 kg or more at 12 years and over. - Older adults: usual dose. - Kidney impairment: no adjustment at CrCl 10 mL/min or more for the single drug; fixed combinations containing tenofovir disoproxil fumarate are not advised under CrCl 50 mL/min. - Liver impairment: no adjustment in mild to moderate disease.

Regional points. Tuberculosis co-treatment with rifampicin rules it out; access in East African programmes is limited, so it is used mainly in selected patients.

Formulations. Tablet 100 mg; fixed-dose tablet with tenofovir disoproxil fumarate and lamivudine.

Administration. Once daily with or without food.

Baseline. Viral load, CD4 count, resistance result where available, hepatitis B status, creatinine, liver tests, pregnancy test.

Monitoring. Viral load at 3 and 6 months and then every 6 to 12 months; liver tests; lipids yearly.

Stopping thresholds. Stop for severe skin reaction, hypersensitivity, or ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for virological failure and for any need to use rifampicin.