Protease Inhibitors

HIV protease inhibitors block cleavage of viral polyproteins, so newly released virions are immature and non-infectious. Boosted darunavir, atazanavir and lopinavir have a high barrier to resistance and are the main second-line drugs after integrase or nonnucleoside failure. Every current protease inhibitor is boosted with ritonavir or cobicistat.

Pharmacokinetics. Extensively metabolised by CYP3A4, which is why boosters are used, and highly protein bound. Absorption of darunavir and lopinavir tablets improves with food. Atazanavir needs gastric acid.

• Lopinavir with ritonavir: 400 mg/100 mg twice daily. Used in infants and children and in pregnancy when needed. Diarrhoea, hyperlipidaemia, QT and PR prolongation.
• Atazanavir with ritonavir: 300 mg/100 mg once daily with food. Indirect hyperbilirubinaemia and jaundice, nephrolithiasis, PR prolongation. Absorption falls with proton pump inhibitors.
• Darunavir with ritonavir: 800 mg/100 mg once daily with food for patients without darunavir resistance; 600 mg/100 mg twice daily with resistance mutations or in pregnancy. Sulphonamide moiety, so rash. Best tolerated.
• Darunavir with cobicistat: 800 mg/150 mg once daily.

Second-line therapy. After failure of tenofovir, lamivudine and dolutegravir with confirmed viraemia and adherence addressed, switch to a boosted protease inhibitor plus a recycled or new nucleoside backbone, preferably after resistance testing. Darunavir or atazanavir is preferred to lopinavir because of tolerability.

Third-line. Darunavir with dolutegravir and active nucleosides, designed by a specialist after genotype.

Rifampicin. Boosted protease inhibitors are strongly induced. Options: replace rifampicin with rifabutin; or give lopinavir with ritonavir at double dose (800 mg/200 mg twice daily) with close liver monitoring. Other protease inhibitors are not used with rifampicin.

Dose adjustment.

• Kidney: none.
• Liver: lopinavir and darunavir with caution; atazanavir avoided in severe impairment.
• Pregnancy: lopinavir, atazanavir and darunavir are used; darunavir is given twice daily; cobicistat is avoided.
• Children: lopinavir and ritonavir by weight band or body surface area; avoid the oral solution in preterm neonates because of propylene glycol content.

Contraindications. Co-administration with simvastatin, lovastatin, ergot derivatives, oral midazolam, triazolam, pimozide, and St John's wort. Hypersensitivity (sulphonamide for darunavir).

Serious adverse effects. Hepatotoxicity, pancreatitis, dyslipidaemia, insulin resistance and diabetes, lipodystrophy, PR prolongation (atazanavir, lopinavir), and bleeding in haemophilia.

Major interactions. Inhaled or intranasal fluticasone and budesonide can cause Cushing syndrome and adrenal suppression with ritonavir (use beclometasone). Reduced hormonal contraceptive effect. Large rises in levels of ciclosporin, tacrolimus, colchicine, sildenafil, rivaroxaban and many antipsychotics. Warfarin response varies.

Monitoring. Fasting lipids and glucose at baseline and yearly, liver enzymes at 1 and 3 months then 6-monthly, ECG when other QT drugs are used, bilirubin with atazanavir, viral load at 6 months.

Common prescribing errors. Omitting the booster; giving atazanavir with a proton pump inhibitor; using lopinavir once daily with rifampicin; missing statin interactions.

Special groups.

• Breastfeeding: acceptable.
• Older adults: review interactions and cardiovascular risk.