Pharmacokinetic Boosters in HIV Therapy

Pharmacokinetic boosters are drugs given in small doses to inhibit CYP3A4 and slow the metabolism of a partner antiretroviral, raising its exposure and lengthening its half-life. Ritonavir and cobicistat are the two agents. Boosting allows once-daily dosing, lower doses and higher barriers to resistance, but it creates many drug interactions.

Mechanism.

• Ritonavir: potent mechanism-based inhibitor of CYP3A4 and CYP2D6, also inhibits P-glycoprotein. At boosting doses it also induces CYP1A2, CYP2B6, CYP2C9, CYP2C19 and glucuronidation.
• Cobicistat: selective CYP3A inhibitor with no antiviral activity and no enzyme induction. It also inhibits P-glycoprotein, BCRP, OATP1B1, OATP1B3 and MATE1, which raises creatinine by 0.1 to 0.15 mg/dL without a true fall in filtration.

• Ritonavir: 100 mg once or twice daily with darunavir (800 mg daily) or atazanavir (300 mg daily); in lopinavir 400 mg/100 mg tablets twice daily. Gastrointestinal upset, perioral paraesthesia, lipids, hepatotoxicity.
• Cobicistat: 150 mg once daily with darunavir 800 mg or atazanavir 300 mg, or in fixed-dose combinations with elvitegravir.
• Differences: cobicistat is not advised in pregnancy (low exposure in the second and third trimesters), and it cannot overcome the induction by rifampicin. Ritonavir induces enzymes, so it can lower levels of ethinylestradiol, warfarin, methadone and some anticonvulsants.

Protease inhibitors. Ritonavir is the booster of choice in pregnancy, when rifamycins are co-prescribed, and where long experience matters. Cobicistat gives a single-tablet convenience in people not pregnant and not taking rifampicin.

Other uses. Ritonavir boosts nirmatrelvir for COVID-19 (short course, with interaction review).

Interactions that need action.

• Contraindicated: simvastatin, lovastatin, ergot derivatives, oral midazolam, triazolam, pimozide, amiodarone (avoid), sildenafil for pulmonary hypertension, St John's wort.
• Corticosteroids: fluticasone, budesonide and triamcinolone cause Cushing syndrome and adrenal suppression with ritonavir or cobicistat; use beclometasone or prednisolone.
• Colchicine: reduce dose or avoid in kidney or liver impairment.
• Immunosuppressants: ciclosporin, tacrolimus and sirolimus need large reductions and levels.
• Anticoagulants: rivaroxaban and apixaban levels rise; avoid or reduce; warfarin response varies.
• Hormonal contraception: efficacy reduced; use a non-hormonal or higher-dose alternative.
• Rifampicin and rifabutin: rifampicin lowers booster and partner levels sharply; rifabutin needs a reduced dose with boosters, set by a specialist.

Dose adjustment.

• Kidney: none.
• Liver: ritonavir avoided in severe impairment.
• Children: ritonavir booster dose by weight.

Serious adverse effects. Hepatotoxicity, pancreatitis, hyperlipidaemia, insulin resistance, QT and PR prolongation with some partners, and Cushing syndrome with steroid interactions.

Monitoring. Fasting lipids and glucose yearly, liver enzymes at 1 and 3 months, then 6-monthly, creatinine (cobicistat shift of 0.1 to 0.15 mg/dL is expected), and a full medicines review at each visit including over-the-counter and herbal products.

Common prescribing errors. Forgetting the booster in the prescription; treating cobicistat-related creatinine rise as kidney injury; omitting a check of every new drug (including inhaled steroids and antifungals); using cobicistat in pregnancy.

Special groups.

• Pregnancy: ritonavir is used; avoid cobicistat.
• Breastfeeding: ritonavir acceptable.
• Older adults: polypharmacy increases the risk of serious interactions.

Referral and escalation. Seek pharmacist or HIV specialist review before adding any new drug in a patient on a boosted regimen.