Hepatitis C Direct Acting Antivirals

Direct acting antivirals block essential hepatitis C virus proteins and cure over 95 percent of infections after 8 to 12 weeks of oral treatment. Cure is defined as undetectable HCV RNA 12 weeks after the end of treatment (sustained virological response).

Classification. NS5B polymerase inhibitors (sofosbuvir), NS5A inhibitors (velpatasvir, daclatasvir, ledipasvir, pibrentasvir), NS3/4A protease inhibitors (glecaprevir, voxilaprevir), and ribavirin as an adjunct.

• Sofosbuvir 400 mg with velpatasvir 100 mg once daily for 12 weeks; pangenotypic.
• Sofosbuvir 400 mg with daclatasvir 60 mg once daily for 12 weeks; 24 weeks or added ribavirin in cirrhosis, particularly genotype 3. Daclatasvir 30 mg with strong CYP3A4 inhibitors and 90 mg with efavirenz or strong inducers.
• Glecaprevir 300 mg with pibrentasvir 120 mg once daily with food for 8 weeks without cirrhosis, 12 weeks with compensated cirrhosis.
• Sofosbuvir 400 mg with ledipasvir 90 mg once daily for 12 weeks (genotypes 1, 4, 5 and 6).
• Sofosbuvir, velpatasvir and voxilaprevir for 12 weeks after previous direct acting antiviral failure, under specialist direction.
• Ribavirin 1,000 mg (under 75 kg) or 1,200 mg (75 kg or more) daily in two divided doses when used with sofosbuvir and velpatasvir in decompensated cirrhosis.

Differences. Pangenotypic regimens remove the need for genotyping, which is useful where testing is unavailable. Protease inhibitors are contraindicated in decompensated cirrhosis.

• Pre-treatment checks: HCV RNA, fibrosis stage (elastography or FIB-4), HBsAg and anti-HBc, HIV status, creatinine, pregnancy test, and full drug history.
• Compensated disease: sofosbuvir with velpatasvir or glecaprevir with pibrentasvir.
• Decompensated cirrhosis: sofosbuvir with velpatasvir plus ribavirin for 12 weeks, under specialist care.
• HIV coinfection: same regimens; check antiretroviral interactions.
• Retreatment: specialist only.

Selection. No need to withhold treatment for active drug use. Defer treatment in pregnancy until after delivery.

Contraindications. Amiodarone with sofosbuvir (severe bradycardia). Strong inducers: rifampicin, carbamazepine, phenytoin and St John's wort. Glecaprevir and voxilaprevir in decompensated cirrhosis. Ribavirin in pregnancy and in the male partners of pregnant women.

Adverse effects. Fatigue, headache, nausea, insomnia. Reactivation of hepatitis B, which needs monitoring and treatment in HBsAg positive patients. Ribavirin: haemolytic anaemia, teratogenicity, cough, rash.

Interactions.

• Efavirenz and nevirapine lower velpatasvir exposure; avoid.
• Tenofovir disoproxil exposure rises with velpatasvir; monitor creatinine.
• Dolutegravir has no important interaction.
• Proton pump inhibitors reduce velpatasvir absorption; avoid, or if essential limit to omeprazole 20 mg or equivalent taken 4 hours after velpatasvir with food. Antacids need a 4-hour gap.
• Atorvastatin and rosuvastatin levels rise with glecaprevir and pibrentasvir.
• Warfarin dose may need change as liver function improves; antidiabetic doses may need reducing.

Special groups.

• Pregnancy: not routinely given; ribavirin contraindicated.
• Breastfeeding: limited data.
• Children: sofosbuvir with velpatasvir and glecaprevir with pibrentasvir are licensed from 3 years with weight-based dosing.
• Kidney impairment: sofosbuvir-based regimens may be used with creatinine clearance under 30 mL/min with caution; glecaprevir with pibrentasvir needs no adjustment.
• Liver impairment: avoid protease inhibitors in Child-Pugh B and C.
• Regional: generic sofosbuvir-based regimens are often supplied through national programmes.

Monitoring. ALT and HCV RNA at the end of treatment and 12 weeks after. Continue hepatocellular carcinoma ultrasound every 6 months in cirrhosis after cure.

Referral and escalation. Cirrhosis, decompensation, treatment failure, kidney failure, transplant recipients, and complex drug interactions need specialist review.