Fostemsavir

Fostemsavir is an oral prodrug of temsavir, an attachment inhibitor with a new target, used in heavily treatment-experienced adults with multidrug-resistant HIV-1 when no other suppressive regimen can be built. It has no cross-resistance with other classes. Temsavir causes QT prolongation at high exposures, and enzyme inducers lower its levels to ineffective values.

Class. HIV-1 attachment inhibitor.

Mechanism. Temsavir binds the gp120 protein of the viral envelope and prevents attachment to the CD4 receptor on host cells.

Pharmacokinetics. Fostemsavir is hydrolysed by alkaline phosphatase to temsavir. Oral bioavailability about 26%, increased by food (extended-release tablet). Half life about 11 hours. Metabolised by esterases and CYP3A4.

Multidrug-resistant HIV-1 infection, heavily treatment-experienced (adults). 600 mg extended-release tablet orally twice daily with other active drugs.

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

Main alternatives. Ibalizumab or enfuvirtide in specialist centres.

Contraindications. Hypersensitivity; co-administration with strong CYP3A inducers (rifampicin, carbamazepine, phenytoin, mitotane, enzalutamide, St John’s wort).

Serious adverse effects. QT prolongation (particularly with other QT drugs or ritonavir or cobicistat boosting), hepatotoxicity in hepatitis B or C co-infection, and immune reconstitution syndrome.

Common adverse effects. Nausea, headache, diarrhoea, fatigue and rash.

Interactions. - Boosters (ritonavir, cobicistat) raise levels without a dose change; monitor the QT interval. - Other QT-prolonging drugs add risk. - Hormonal contraceptives: limit ethinylestradiol to 30 micrograms daily.

Common prescribing errors. Crushing or chewing the tablet, using with rifampicin, and ignoring QT-prolonging drugs.

Special groups. - Pregnancy: limited data. - Breastfeeding: avoid. - Children: not established. - Older adults: usual dose; check the ECG. - Kidney impairment: no adjustment. - Liver impairment: no adjustment in mild to moderate disease; use with care in severe.

Formulations. Extended-release tablets 600 mg.

Administration. With or without food; swallow whole; do not crush, split or chew.

Baseline. ECG, resistance result, liver tests, hepatitis B and C status, drug history for QT drugs and inducers.

Monitoring. ECG when starting QT-prolonging drugs; liver tests; viral load at 3 and 6 months.

Stopping thresholds. Stop for QTc over 500 ms or symptomatic arrhythmia, or for ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for every patient.