Daclatasvir

Daclatasvir is an oral hepatitis C NS5A inhibitor, taken with sofosbuvir as a low-cost, widely generic regimen for chronic infection across genotypes. Its dose changes with enzyme inhibitors and inducers, and several interacting drugs make it unsafe or ineffective. It carries a boxed warning for hepatitis B reactivation.

Class. Direct-acting antiviral; NS5A inhibitor.

Mechanism. Binds NS5A and blocks viral RNA replication and virion assembly. Mutations at positions 31 and 93 reduce susceptibility, especially in genotype 3.

Pharmacokinetics. Absorbed orally; not affected by food. Half life 12 to 15 hours. Metabolised by CYP3A4 and a P-glycoprotein substrate.

Chronic hepatitis C (adults). - Daclatasvir 60 mg orally once daily with sofosbuvir 400 mg once daily for 12 weeks. - Cirrhosis or genotype 3: 24 weeks, or 12 weeks with ribavirin, under specialist care.

Dose adjustment for interactions. - Strong CYP3A inhibitors (atazanavir with ritonavir, clarithromycin, ketoconazole, itraconazole): 30 mg once daily. - Moderate inducers (efavirenz, etravirine, nevirapine, dexamethasone, bosentan): 90 mg once daily.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 90 mg daily.

Main alternative. Sofosbuvir with velpatasvir.

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

Serious adverse effects. Hepatitis B reactivation, symptomatic bradycardia with amiodarone (when combined with sofosbuvir), and decompensation in advanced cirrhosis.

Common adverse effects. Headache, fatigue and nausea.

Interactions. - Strong CYP3A inhibitors need 30 mg once daily, and moderate inducers need 90 mg once daily. - Amiodarone: avoid with sofosbuvir. - Digoxin and statins: levels may rise; monitor.

Common prescribing errors. Not adjusting for atazanavir or efavirenz, using with rifampicin, and omitting a hepatitis B check.

Special groups. - Pregnancy: limited data; avoid unless essential. - Breastfeeding: limited data. - Children: specialist use only. - Older adults: usual dose. - Kidney impairment: no adjustment. - Liver impairment: usual dose; decompensated disease needs specialist care.

Regional points. The combination with sofosbuvir is in use in several African programmes because of generic supply, and in HIV co-infection the antiretroviral partner decides the daclatasvir dose.

Formulations. Tablets 30 mg and 60 mg.

Administration. Once daily with or without food, at the same time as sofosbuvir.

Baseline. HCV RNA, hepatitis B surface antigen and core antibody, HIV test, fibrosis assessment, drug history for inhibitors and inducers.

Monitoring. ALT at 4 weeks; HCV RNA 12 weeks after treatment; heart rate with amiodarone.

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.