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[Pharmacology](https://durgical.com/en/pharmacology/) · Class

# Hepatitis C direct-acting antivirals

Oral combinations that cure more than 95% of people with hepatitis C in a few weeks. They block three viral proteins: NS3/4A, NS5A and NS5B.

Updated 2026-11-01

## What they are

Oral drugs that act directly on hepatitis C virus proteins and, combined, cure more than 95% of people, usually in 12 to 24 weeks (WHO). Pangenotypic combinations (sofosbuvir-velpatasvir, glecaprevir-pibrentasvir) work against all genotypes, which makes testing and treatment simpler. Generic versions have made the course cheap in many low- and middle-income countries. There is no vaccine against hepatitis C.

## Mechanism of action

Each group blocks a different step of viral replication. NS5B polymerase inhibitors (sofosbuvir, a nucleotide) are built into the new viral RNA and stop it. NS5A inhibitors (velpatasvir, ledipasvir, pibrentasvir, daclatasvir) block a protein needed to build the replication complex and assemble virions. NS3/4A protease inhibitors (glecaprevir, grazoprevir, voxilaprevir) prevent the cutting of the viral polyprotein into working proteins. Two or three groups are combined so that resistance does not appear.

Target: HCV NS5B polymerase, NS5A protein and NS3/4A protease

## Key points

- Test for hepatitis B before starting: HBV can reactivate during or after treatment, sometimes with liver failure.
- Sofosbuvir with amiodarone can cause severe, even fatal, bradycardia.
- Strong P-gp or CYP3A inducers (rifampicin, carbamazepine, St John's wort) lower their levels and are avoided.
- Velpatasvir and ledipasvir need gastric acid: antacids, H2 blockers and proton pump inhibitors reduce their absorption.
- NS3/4A protease inhibitors (glecaprevir, voxilaprevir) are contraindicated in decompensated cirrhosis.

## Drugs in this class

- [**Sofosbuvir** The backbone of most hepatitis C regimens. It blocks the virus's RNA polymerase and is always combined with another… Hepatitis C virus NS5B RNA polymerase](https://durgical.com/en/pharmacology/sofosbuvir/)
- [**Sofosbuvir + velpatasvir** A pangenotypic pill for hepatitis C that WHO recommends; it cures most patients without the need to know the genotype. Hepatitis C virus NS5B polymerase (sofosbuvir) and NS5A protein (velpatasvir)](https://durgical.com/en/pharmacology/sofosbuvir-velpatasvir/)
- [**Ledipasvir + sofosbuvir** A single-tablet hepatitis C combination for genotypes 1, 4, 5 and 6. It joins an NS5A inhibitor with the NS5B… Hepatitis C virus NS5A protein (ledipasvir) and NS5B polymerase (sofosbuvir)](https://durgical.com/en/pharmacology/ledipasvir-sofosbuvir/)
- [**Glecaprevir + pibrentasvir** A pangenotypic hepatitis C combination of an NS3/4A protease inhibitor and an NS5A inhibitor, taken with food. Hepatitis C virus NS3/4A protease (glecaprevir) and NS5A protein (pibrentasvir)](https://durgical.com/en/pharmacology/glecaprevir-pibrentasvir/)

## Others in the class

- Daclatasvir
- Ravidasvir
- Elbasvir-grazoprevir
- Sofosbuvir-velpatasvir-voxilaprevir

## Test yourself

Think of the answer, then tap the question to see it.

## Which three hepatitis C proteins do direct-acting antivirals target?

The NS3/4A protease, the NS5A protein and the NS5B RNA polymerase.

## What test is done before any direct-acting antiviral, and why?

Hepatitis B testing (HBsAg, anti-HBc): HBV can reactivate as hepatitis C is cleared.

## Which antiarrhythmic must not be combined with sofosbuvir?

Amiodarone: the combination can cause severe symptomatic bradycardia.

## What does «pangenotypic» mean?

Active against all hepatitis C genotypes, so treatment can start without genotyping.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [Hepatitis C](https://www.who.int/news-room/fact-sheets/detail/hepatitis-c) (World Health Organization, 2026); Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed., ch. 63 (McGraw Hill, 2023); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=J05AP) (WHO Collaborating Centre for Drug Statistics Methodology, 2026); [eEML - Electronic Essential Medicines List](https://list.essentialmeds.org/) (World Health Organization, 2025).

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