PharmacologyTier 1Medical Sciences concept

Direct-acting antiviral mechanisms in hepatitis C (NS3/4A, NS5A, NS5B inhibitors)

Core concept

HCV has a single polyprotein cleaved into structural and non-structural proteins; three of the non-structural proteins are drug targets

Target	Suffix	Agents	Role
NS3/4A protease	-previr	Glecaprevir, grazoprevir, voxilaprevir, paritaprevir	Cleaves the polyprotein; also blocks innate immune signalling
NS5A	-asvir	Velpatasvir, pibrentasvir, ledipasvir, daclatasvir, elbasvir	Replication complex assembly and virion assembly; most potent, picomolar
NS5B polymerase	-buvir	Sofosbuvir (nucleotide, chain terminator), dasabuvir (non-nucleoside)	RNA-dependent RNA polymerase

Combination of two or three classes with non-overlapping resistance profiles -> functional cure
HCV has no latent reservoir and does not integrate - which is why it is curable and HIV and HBV are not

Cure = SVR12 - undetectable HCV RNA 12 weeks after finishing treatment; >95% across regimens
Pangenotypic regimens (no genotyping required in most cases)
- Sofosbuvir/velpatasvir 12 weeks
- Glecaprevir/pibrentasvir 8 weeks (12 in cirrhosis or prior treatment)
- Salvage after DAA failure: sofosbuvir/velpatasvir/voxilaprevir
Sofosbuvir/ledipasvir achieves ~95% SVR12 in genotype 1 - the earlier generation regimen
Renal and hepatic constraints
- Protease inhibitors (-previr) are contraindicated in decompensated cirrhosis (Child-Pugh B/C) - hepatotoxicity
- Sofosbuvir was historically avoided below eGFR 30; glecaprevir/pibrentasvir is the preferred option in severe renal impairment
Interactions - the practical hazard
- Amiodarone + sofosbuvir -> severe symptomatic bradycardia - contraindicated
- Inducers (rifampicin, carbamazepine, phenytoin, St John's wort) cause treatment failure
- Statins - marked exposure increase with protease inhibitors; reduce or withhold
- PPIs reduce ledipasvir absorption
Screen for HBV before starting - HBV reactivation can occur when HCV is suppressed; a boxed warning
Treat, then continue HCC surveillance in cirrhosis - cure does not remove the cancer risk

In Australia, any prescriber (including GPs) can prescribe DAAs on the PBS with remote specialist consultation - a deliberate elimination strategy, and the reason access questions appear
Pre-treatment work-up: HCV RNA, genotype (often unnecessary), fibrosis assessment (FibroScan/APRI/FIB-4), HBV and HIV serology, drug interaction check, pregnancy status
Reinfection is possible after cure - retest people with ongoing risk; cure is not immunity
Decompensated cirrhosis: sofosbuvir/velpatasvir + ribavirin, avoid protease inhibitors, manage in a liver unit
People who inject drugs should be treated - treatment as prevention; active injecting is not a contraindication

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