Direct acting antivirals

crop_square Key points

  • check_circle Three subclasses: NS3-4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors
  • check_circle Revolutionised HCV treatment with high sustained virologic response rates
  • check_circle DAAs are used in combination depending on HCV genotypes and clinical presentation
  • check_circle Better tolerated than previous interferon-based regimens

crop_square Background and biochemistry

Direct acting antivirals (DAAs) have recently revolutionised the treatment of chronic hepatitis C virus (HCV) infections. Since the introduction of DAA combination therapy in 2014, sustained virologic response (SVR) rates have increased dramatically to around 95%. DAAs have largely replaced interferon-based drug regimens. It should be noted that DAAs are grouped together because they are used in chronic HCV infections and not because of a shared mechanism of action. Indeed, there are three subclasses of DAAs: non-structural protein 3-4A (NS3-4A) protease inhibitors, non-structural protein 5A (NS5A) inhibitors and non-structural protein 5B (NS5B) polymerase inhibitors. The first approved direct acting antiviral was the NS3-4A protease inhibitor boceprevir in 2011. Sofosbuvir, an NS5B inhibitor, received FDA approval in 2013. After highly successful clinical trials, Daclatasvir became the first NS5A inhibitor available in 2015. DAA are never prescribed as monotherapy. Guidelines on anti-HCV combination therapies take into account the HCV genotype and clinical presentation.

crop_square Mechanism of action

NS3-4A protease inhibitors bind to the eponymous protease NS3-4A, which is essential for the HCV life cycle as it cleaves HCV polypeptides into functional viral proteins. Non-structural protein 3 is multifunctional and possesses helicase activity, which may be blocked by NS3-4A inhibitors. This is hypothesised to contribute to the antiviral effect of these drugs.
The mechanism of action of NS5A inhibitors is incompletely understood. NS5A is a multifunctional HCV protein with three structural (I, II, III) four functional domains (A, B, C , D) involved with RNA replication, HCV protein-protein interactions, virion assembly and virion secretion. It is currently unclear to what extend NS5A inhibition affects the various protein functions and how this translates to HCV replication inhibition.
NS5B RNA-dependent RNA polymerase is the key enzyme for HCV replication which catalyses the polymerisation of ribonucleotide triphosphates (rNTPs) into a new RNA strand. Sofosbuvir is a competitive nucleotide NS5B inhibitor and a rNTP analogue. Incorporation into the new RNA strand by NS5B polymerase leads to chain termination. Non-nucleotide NS5B inhibitors bind directly to the polymerase allosteric sites which inhibits its function.
Despite high rates of sustained virologic response rates after DAA treatment in chronic HCV, treatment failures do occur and are linked to so-called resistance-associated substitutions (RAS). The HCV polymerase is error-prone and constantly generates new HCV variants.

crop_square Drugs and spectrum of activity

NS3-4A protease inhibitors
  • Asunaprevir
  • Boceprevir
  • Glecaprevir
  • Grazoprevir
  • Paritaprevir
  • Simeprevir
  • Telaprevir
  • Voxilaprevir

NS5A inhibitors
  • Daclatasvir
  • Elbasvir
  • Ledipasvir
  • Ombitasvir
  • Pibrentasvir
  • Velpatasvir

NS5B polymerase inhibitors
  • Dasabuvir (non-nucleotide)
  • Sofosbuvir (nucleotide)
HCV combination drugs
brand name drugs HCV genotypes
Epclusa sofosbuvir/­velpatasvir all
Harvoni ledipasvir/sofosbuvir 1,4,5,6
Mavyret glecaprevir/pibrentasvir all
Viekira Pak ombitasvir/paritaprevir/
ritonavir and dasabuvir
(+-ribavirin)
1
Vosevi sofosbuvir/velpatasvir/
voxilaprevir
all
Zepatier elbasvir/grazoprevir 1,4

crop_square Pharmacokinetics

Pharmacokinetics of direct acting antivirals (DAAs) are complex due to the distinctly different drug classes in this group. DAAs undergo hepatic metabolization except for ledipasvir. They are usually highly protein bound. NS3-4A inhibitors are mostly metabolised by and induce CYP3A4. NS5A and NS5B inhibitors are metabolised by various cytochrome P450 enzymes. Most DAAs and metabolites are eliminated via faeces. Sofosbuvir is a prodrug whose metabolites are cleared via the kidneys.

crop_square Adverse drug effects

Direct acting antivirals are generally better tolerated than older interferon-based HCV drug regimens. Adverse effects are usually mild but may be serious. NS3-4A inhibitors may cause skin rashes, hyperbilirubinaemia and neutropenia. NS5A inhibitors side effects include gastrointestinal symptoms and fatigue. NS5B inhibitors have been associated with headaches, skin rashes and anaemia. All DAAs may be hepatotoxic and can rarely cause liver failure.