Sofosbuvir

Sofosbuvir is an oral nucleotide inhibitor of the hepatitis C virus NS5B polymerase, the backbone of most direct-acting regimens for chronic hepatitis C. It is active across all genotypes and is used with an NS5A inhibitor (daclatasvir, ledipasvir, velpatasvir). It is well tolerated and cures more than 95% of patients. It carries a boxed warning for hepatitis B reactivation.

Class. Direct-acting antiviral; NS5B nucleotide polymerase inhibitor.

Mechanism. The active triphosphate is incorporated into viral RNA by NS5B polymerase and terminates chain elongation.

Pharmacokinetics. Prodrug taken up by the liver. Half life of the parent about 0.5 hours; the main metabolite (GS-331007) about 27 hours. Excreted mainly by the kidney as the metabolite. It is a P-glycoprotein substrate.

Chronic hepatitis C (adults). 400 mg orally once daily, with food or not, combined as follows.

• With daclatasvir 60 mg once daily for 12 weeks, or 24 weeks in cirrhosis.
• With ledipasvir (fixed 400/90 mg) for genotypes 1, 4, 5 and 6.
• With velpatasvir (fixed 400/100 mg) for all genotypes for 12 weeks.
• With ribavirin for genotype 2 for 12 weeks and genotype 3 for 24 weeks, where other combinations are unavailable.

Children 3 years and over. Weight-banded fixed combinations.

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

Main alternative. Glecaprevir with pibrentasvir.

Contraindications. Hypersensitivity; co-administration with strong P-glycoprotein inducers (rifampicin, rifapentine, carbamazepine, phenytoin, phenobarbital, St John’s wort); amiodarone is avoided.

Serious adverse effects. Hepatitis B reactivation with fulminant hepatitis in co-infected patients, symptomatic bradycardia with amiodarone, and hepatic decompensation in advanced cirrhosis.

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

Interactions. - Amiodarone: severe bradycardia; avoid. - Rifampicin and anticonvulsant inducers: avoid. - Ribavirin adds haemolytic anaemia and teratogenicity. - Boosted protease inhibitors and tenofovir disoproxil fumarate: monitor kidney function.

Common prescribing errors. Not testing for hepatitis B first, giving with rifampicin, giving with amiodarone, and using ribavirin in pregnancy.

Special groups.

• Pregnancy: limited data; avoid unless essential; ribavirin is contraindicated.
• Breastfeeding: limited data.
• Children: weight-banded from 3 years.
• Older adults: usual dose.
• Kidney impairment: usual dose, including eGFR under 30 mL/min and dialysis.
• Liver impairment: usual dose in compensated disease; add ribavirin or extend therapy in decompensated disease, under specialist care.

Regional points. Generic sofosbuvir is available in many African programmes at low cost; genotypes 1 and 4 are most frequent in East Africa, and tuberculosis co-treatment with rifampicin must be completed before sofosbuvir is started.

Formulations. Tablets 400 mg; fixed-dose combinations with ledipasvir and with velpatasvir.

Administration. Once daily with or without food.

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

Monitoring. ALT at 4 weeks; HCV RNA at 12 weeks after the end of treatment (cure); ALT and HBV DNA in hepatitis B co-infection.

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

Referral and escalation. Specialist review for cirrhosis, hepatitis B co-infection, HIV co-infection and treatment failure.