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Pharmacology · Hepatitis C direct-acting antivirals

Sofosbuvir + velpatasvir !

A pangenotypic pill for hepatitis C that WHO recommends; it cures most patients without the need to know the genotype.

Updated 2026-11-01

  • Class: Hepatitis C direct-acting antivirals
  • Enzyme: Hepatitis C virus NS5B polymerase (sofosbuvir) and NS5A protein (velpatasvir)
  • ATC code: J05AP55
  • WHO Model List of Essential Medicines

The figure shows the active diphosphate-level metabolite of sofosbuvir in the hepatitis C NS5B polymerase; no structure of NS5A with velpatasvir is available.

Target in 3D: Hepatitis C virus NS5B polymerase (sofosbuvir) and NS5A protein (velpatasvir). PDB structure 4WTG (RCSB PDB, public domain). View the structure at RCSB PDB

Mechanism of action

Two antivirals in one tablet. Sofosbuvir, a nucleotide prodrug, is converted to a uridine triphosphate analogue that NS5B incorporates into viral RNA, stopping the chain. Velpatasvir binds NS5A, a protein needed to build the replication complex and assemble new virions. Together they act on all genotypes with a high barrier to resistance.

  1. Sofosbuvir triphosphate stops RNA synthesis by NS5B
  2. Velpatasvir blocks NS5A
  3. Replication complex and virion assembly fail
  4. Viral RNA becomes undetectable: cure

Pharmacokinetics

Absorption
Oral; velpatasvir needs gastric acid, so acid-reducing drugs lower its absorption
Metabolism
Sofosbuvir is activated in the liver and ends as the inactive metabolite GS-331007
Elimination
GS-331007 by the kidneys (filtration and tubular secretion)
Half-life
GS-331007 about 25 hours; velpatasvir about 15 hours

Indications

  • Chronic hepatitis C of any genotype (1 to 6), with or without compensated cirrhosis, in adults and children from 3 years Viral hepatitis →
  • Decompensated cirrhosis, combined with ribavirin Cirrhosis →

Adverse effects

Common

  • Headache
  • Fatigue
  • Nausea
  • Insomnia

Contraindications

  • When combined with ribavirin, the contraindications of ribavirin apply (pregnancy, among others)

Key interactions

Rifampicin, carbamazepine, phenytoin, St John's wort (strong inducers)
Lower both drug levels; not recommended
Antacids, H2 blockers, proton pump inhibitors
Less velpatasvir absorption: antacids are separated by 4 hours and proton pump inhibitors are generally avoided
Amiodarone
Severe symptomatic bradycardia
Tenofovir disoproxil
Higher tenofovir levels: kidney monitoring

What is monitored

  • HBsAg and anti-HBc before starting; liver tests during and after
  • HCV RNA 12 weeks after treatment ends (sustained virological response)
  • INR in people on warfarin and glucose in diabetes, as liver function improves
  • Haemoglobin when ribavirin is added

Administration and safety

  • One tablet a day
  • Medicine list reviewed for amiodarone, inducers and acid-reducing drugs
  • Antacids taken at least 4 hours apart

Nursing care

  • Review all medicines, including over-the-counter antacids and herbal products
  • Teach to report slow pulse, dizziness or fainting
  • Encourage completing all the weeks of treatment
  • Explain that cure does not protect against reinfection

Pregnancy and breastfeeding

Human data are lacking; animal studies showed no harm. With ribavirin it is contraindicated in pregnancy.

Test yourself

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

Why is sofosbuvir-velpatasvir called pangenotypic?

It is active against hepatitis C genotypes 1 to 6.

Why are proton pump inhibitors a problem with this combination?

Velpatasvir needs gastric acid to dissolve; higher gastric pH lowers its absorption.

What is added in decompensated cirrhosis?

Ribavirin.

Which test defines cure after treatment?

Undetectable HCV RNA 12 weeks after the end of treatment (sustained virological response).

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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: DailyMed - SOFOSBUVIR AND VELPATASVIR tablet, film coated (DailyMed (U.S. National Library of Medicine), 2026); Hepatitis C (World Health Organization, 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026); eEML - Electronic Essential Medicines List (World Health Organization, 2025).

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Representative model, for educational purposes only.