Darunavir

Darunavir is an oral protease inhibitor with a high barrier to resistance, used with a booster (ritonavir or cobicistat) in naive and experienced patients and as a key drug in third-line treatment. It contains a sulphonamide group. Rash, hepatotoxicity and lipid rise are the main concerns, and the booster brings many interactions.

Class. HIV protease inhibitor.

Mechanism. Binds the active site of HIV protease with high affinity, blocking cleavage of viral polyproteins and producing immature virions. Several mutations are needed for resistance.

Pharmacokinetics. Absorption increased by food; plasma levels depend on the booster. Half life about 15 hours when boosted. Metabolised by CYP3A4. Highly protein bound.

HIV-1 infection, treatment-naive or experienced without darunavir mutations (adults). Darunavir 800 mg with ritonavir 100 mg orally once daily with food, combined with other active drugs.

Experienced patients with darunavir resistance mutations. Darunavir 600 mg with ritonavir 100 mg twice daily with food.

Pregnancy. Darunavir 600 mg with ritonavir 100 mg twice daily (levels fall in the second and third trimesters).

Children (3 years and over, 15 kg or more). Weight-banded dosing with ritonavir; 40 kg or more: adult doses.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 1200 mg daily.

Main alternatives. Atazanavir with ritonavir, lopinavir with ritonavir, dolutegravir.

Contraindications. Hypersensitivity; co-administration with the following drugs: amiodarone, dronedarone, flecainide, propafenone, quinidine, ranolazine, lovastatin, simvastatin, lurasidone, pimozide, ergot alkaloids, oral midazolam, triazolam, sildenafil for pulmonary hypertension, colchicine in kidney or liver impairment, and strong inducers (carbamazepine, phenytoin, phenobarbital, rifampicin, St John’s wort).

Serious adverse effects. Hepatotoxicity, severe skin reactions including Stevens-Johnson syndrome, hyperglycaemia and diabetes, pancreatitis (uncommon), and immune reconstitution syndrome.

Common adverse effects. Diarrhoea, nausea, headache, rash (about 10%, usually in the first 4 weeks) and raised lipids.

Interactions. Boosting causes the same interactions as ritonavir; rifampicin is contraindicated with boosted darunavir; hormonal contraceptives may be less effective; statins other than pravastatin or low-dose atorvastatin need adjustment; inhaled or injected corticosteroids may cause adrenal suppression.

Common prescribing errors. Giving without ritonavir or without food, using with rifampicin, and missing the sulphonamide allergy.

Special groups. - Pregnancy: twice daily dose with ritonavir. - Breastfeeding: limited data; compatible with specialist advice. - Children: from 3 years and 15 kg. - Older adults: usual dose; high interaction burden. - Kidney impairment: no adjustment. - Liver impairment: no adjustment in mild to moderate; not advised in severe.

Regional points. In East Africa boosted darunavir is the usual protease inhibitor in third-line regimens with dolutegravir; tuberculosis co-treatment needs rifabutin or a regimen without rifampicin.

Formulations. Tablets 400 mg, 600 mg and 800 mg; oral suspension 100 mg/mL; fixed-dose tablets with cobicistat.

Administration. With food, once daily (800 mg) or twice daily (600 mg), with ritonavir at the same time.

Baseline. Sulphonamide allergy history, drug history and interaction check, liver tests, hepatitis B and C status, lipids, glucose.

Monitoring. Liver tests at 4 and 12 weeks and then every 6 months; lipids and glucose yearly; viral load at 3 and 6 months.

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

Referral and escalation. Specialist review for all third-line patients, for virological failure, and for tuberculosis co-treatment.