Ledipasvir

Ledipasvir is an oral hepatitis C NS5A inhibitor available only in a fixed-dose tablet with sofosbuvir. It is used for genotypes 1, 4, 5 and 6, with high cure rates over 8 to 12 weeks. It needs acidic gastric conditions for absorption, so acid suppression lowers its levels.

Class. Direct-acting antiviral; NS5A inhibitor.

Mechanism. Binds the viral NS5A protein, which is needed for RNA replication and virion assembly, and blocks replication. Mutations such as Y93H reduce susceptibility.

Pharmacokinetics. Absorbed orally; not affected by food. Half life about 47 hours. Excreted mainly in faeces unchanged. It is a P-glycoprotein substrate.

Chronic hepatitis C, genotypes 1, 4, 5 and 6 (adults).

• One tablet orally once daily containing ledipasvir 90 mg and sofosbuvir 400 mg.
• Duration: 12 weeks; 8 weeks for non-cirrhotic, treatment-naive genotype 1 with HCV RNA under 6 million IU/mL.
• Compensated cirrhosis with previous treatment: 24 weeks, or 12 weeks with ribavirin.

Children 3 years and over. Weight-banded: under 17 kg 33.75/150 mg; 17 kg to under 35 kg 45/200 mg; 35 kg or more 90/400 mg once daily.

Loading dose, maintenance dose and titration. Not applicable. Maximum: one tablet daily.

Main alternative. Sofosbuvir with velpatasvir.

Contraindications. Hypersensitivity; co-administration with rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort, and rosuvastatin.

Serious adverse effects. Hepatitis B reactivation, symptomatic bradycardia with amiodarone, and decompensation in advanced cirrhosis.

Common adverse effects. Fatigue, headache, nausea and insomnia.

Interactions. - Proton pump inhibitors: omeprazole up to 20 mg simultaneously; H2 blockers at the same time or 12 hours apart; antacids 4 hours apart. - Tenofovir disoproxil fumarate: levels of tenofovir rise; monitor kidney function. - Amiodarone: avoid. - Rosuvastatin: contraindicated.

Common prescribing errors. High-dose acid suppression, using with amiodarone, and not testing for hepatitis B.

Special groups. - Pregnancy: limited data; avoid unless essential. - Breastfeeding: limited data. - Children: weight-banded from 3 years. - Older adults: usual dose. - Kidney impairment: usual dose. - Liver impairment: usual dose in compensated disease; decompensated disease needs ribavirin and specialist care.

Formulations. Fixed-dose tablet 90/400 mg; lower-strength tablets and granules for children.

Administration. Once daily with or without food.

Baseline. HCV RNA, genotype, hepatitis B surface antigen and core antibody, HIV test, fibrosis assessment, creatinine, pregnancy test.

Monitoring. ALT at 4 weeks; HCV RNA 12 weeks after treatment; kidney function if on tenofovir.

Stopping thresholds. Stop for jaundice, hepatic decompensation, or ALT over 3 times the upper limit of normal with symptoms, or over 5 times without.

Referral and escalation. Specialist review for cirrhosis, co-infection and failure.