Atazanavir

Atazanavir is an oral protease inhibitor given once daily with ritonavir or cobicistat. It has a modest effect on lipids, but causes indirect hyperbilirubinaemia, sometimes with jaundice, and rarely kidney stones. It needs gastric acid for absorption. It is a common second-line protease inhibitor in public programmes.

Class. HIV protease inhibitor.

Mechanism. Binds the active site of HIV protease, blocking cleavage of viral polyproteins. The I50L mutation reduces susceptibility.

Pharmacokinetics. Absorption increased by food and needs low gastric pH. Half life about 7 hours unboosted and 11 hours boosted. Metabolised by CYP3A4. It inhibits UGT1A1 (causing raised indirect bilirubin).

HIV-1 infection (adults). Atazanavir 300 mg with ritonavir 100 mg orally once daily with food, with two nucleosides or other active drugs.

With efavirenz in naive patients. Atazanavir 400 mg with ritonavir 100 mg once daily.

Pregnancy (third trimester, with tenofovir disoproxil fumarate or an H2 blocker). Atazanavir 400 mg with ritonavir 100 mg once daily.

Unboosted dose. 400 mg once daily with food, only in naive patients who cannot take ritonavir and are not on tenofovir.

Children. Weight-banded: 15 kg to under 35 kg 200 mg with ritonavir 100 mg once daily; 35 kg or more 300 mg with ritonavir 100 mg once daily.

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

Main alternatives. Darunavir or lopinavir with ritonavir.

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, irinotecan, and strong inducers (carbamazepine, phenytoin, phenobarbital, rifampicin, St John’s wort); proton pump inhibitors in experienced patients.

Serious adverse effects. Jaundice from indirect hyperbilirubinaemia (not liver injury, but it can cause stopping), PR interval prolongation, nephrolithiasis and kidney injury, hepatotoxicity, severe skin reactions, and diabetes.

Common adverse effects. Jaundice or scleral icterus, nausea, headache, rash and raised lipids.

Interactions. - Acid suppression lowers levels: avoid proton pump inhibitors; H2 blockers 12 hours apart; antacids 2 hours before or 1 hour after. - Tenofovir disoproxil fumarate lowers atazanavir, so boost it. - Efavirenz and nevirapine lower levels; rifampicin is contraindicated. - Drugs prolonging PR or QT intervals add risk.

Common prescribing errors. Using a proton pump inhibitor, giving without ritonavir with tenofovir, and treating isolated bilirubin rise as liver failure.

Special groups. - Pregnancy: acceptable; the higher dose is used in the third trimester with tenofovir or an H2 blocker. - Breastfeeding: limited data. - Children: weight-banded capsules; avoid under 3 months. - Older adults: usual dose. - Kidney impairment: no adjustment; avoid unboosted in dialysis. - Liver impairment: mild: usual dose; Child-Pugh B: reduce (unboosted 300 mg); C: avoid.

Regional points. Atazanavir with ritonavir is a common second-line protease inhibitor in East African programmes in a heat-stable fixed-dose tablet; jaundice is frequently the reason for non-adherence, so counselling is essential.

Formulations. Capsules 150 mg, 200 mg and 300 mg; fixed-dose tablets with ritonavir (300/100 mg) and with cobicistat.

Administration. With food, at the same time as ritonavir; swallow whole.

Baseline. Liver tests with bilirubin, creatinine, ECG if on QT drugs, lipids, glucose, drug history.

Monitoring. Liver tests and bilirubin at 4 and 12 weeks and then every 6 months; kidney function; viral load at 3 and 6 months.

Stopping thresholds. Stop for severe rash, ALT over 3 times the upper limit of normal with symptoms, or over 5 times without; consider a switch for intolerable jaundice.

Referral and escalation. Specialist review for virological failure, kidney stones and PR prolongation.