Glecaprevir Pibrentasvir

Glecaprevir with pibrentasvir is an oral fixed-dose pangenotypic hepatitis C regimen: a protease inhibitor plus an NS5A inhibitor, taken as three tablets once daily for 8 weeks in most patients. It is the usual alternative for retreatment and for severe kidney disease, since it needs no kidney adjustment. It is contraindicated in decompensated cirrhosis.

Class. Direct-acting antivirals; NS3/4A protease inhibitor (glecaprevir) and NS5A inhibitor (pibrentasvir).

Mechanism. Glecaprevir blocks the viral NS3/4A protease and prevents polyprotein cleavage; pibrentasvir blocks NS5A. Together they stop replication across genotypes 1 to 6.

Pharmacokinetics. Absorption increased by food. Half life 6 hours (glecaprevir) and 13 hours (pibrentasvir). Excreted mainly in bile and faeces. Both are P-glycoprotein and BCRP substrates and inhibitors.

Chronic hepatitis C, all genotypes (adults and adolescents 12 years and over). Three tablets (each glecaprevir 100 mg and pibrentasvir 40 mg; 300/120 mg in total) orally once daily with food. - 8 weeks: treatment-naive, no cirrhosis; or compensated cirrhosis (all genotypes). - 12 weeks: after treatment failure with an NS5A inhibitor or sofosbuvir, or in some experienced patients. - 16 weeks: genotype 3, previously treated.

Children 3 years and over. Weight-banded dosing.

Loading dose, maintenance dose and titration. Not applicable. Maximum: 300/120 mg daily.

Main alternative. Sofosbuvir with velpatasvir.

Contraindications. Hypersensitivity; Child-Pugh B or C (moderate or severe liver impairment); co-administration with atazanavir, rifampicin, carbamazepine, phenytoin, phenobarbital, St John’s wort, and dabigatran etexilate.

Serious adverse effects. Hepatitis B reactivation, hepatic decompensation or failure in patients with unrecognised advanced liver disease, and severe skin reactions (rare).

Common adverse effects. Headache, fatigue and nausea.

Interactions. - Atorvastatin and simvastatin: avoid; lower the dose of other statins. - Ethinylestradiol contraceptives: ALT rises; monitor. - Ritonavir-boosted protease inhibitors, cobicistat and efavirenz: avoid. - Digoxin: reduce the dose.

Common prescribing errors. Using in Child-Pugh B or C, taking without food, and giving with atazanavir or rifampicin.

Special groups. - Pregnancy: limited data. - Breastfeeding: limited data. - Children: weight-banded from 3 years. - Older adults: usual dose. - Kidney impairment: no adjustment, including dialysis. - Liver impairment: contraindicated in Child-Pugh B and C.

Formulations. Tablets 100/40 mg; pellets for children.

Administration. Three tablets once daily, taken together with food, swallowed whole.

Baseline. HCV RNA, hepatitis B surface antigen and core antibody, HIV test, fibrosis assessment and Child-Pugh class, creatinine, pregnancy test.

Monitoring. ALT at 4 weeks; HCV RNA 12 weeks after treatment; ALT and HBV DNA in hepatitis B co-infection.

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, retreatment, co-infection and kidney failure.