What Are Direct-Acting Antivirals for HCV Treatment?

Reviewed by: HU Medical Review Board | Last reviewed: May 2023

Direct-acting antivirals (DAAs) are a newer class of drugs used to treat hepatitis C. DAAs target specific steps in the hepatitis C virus (HCV) life cycle. DAAs have shorter treatment times, fewer side effects, and higher SVR rates than older drugs. Sustained Virologic Response (SVR) means the hep C virus is not detectable in the blood, or “cured.” DAAs work by targeting the virus directly, making them more effective than older treatments.1-6

How do DAAs work?

HCV is a virus that makes its own proteins to help it grow (replicate). Some of these proteins, or enzymes, are called:1-6

  • NS3/4A protease
  • NS5B RNA-dependent RNA polymerase
  • NS5A protein

DAAs stop these proteins from working so the virus cannot finish its life cycle and grow.

DAAs fall into 4 main types. Each type targets 1 or more of these proteins to stop the hep C virus life cycle and lower the body’s viral load.1,6

Most DAAs are taken in combination with other DAAs to improve how well they work. Ribavirin and peginterferon also are sometimes added to a DAA to improve how it attacks the virus.1,6

Examples of DAAs

NS3/4A protease inhibitors for HCV treatment

NS3/4A protease inhibitors target the NS3/4A protease enzyme. This enzyme is needed for the virus to grow and thrive. These drugs may also weaken the virus in other ways. These drugs are mainly used to treat HCV genotype 1. They may also be used in combination with other HCV drugs to attack the virus from multiple angles.1,3

NS3/4A protease inhibitors approved to treat HCV include:1,3

  • Grazoprevir
  • Paritaprevir
  • Voxileprevir
  • Glecaprevir

Compared to newer HCV medicines, NS3/4As are more complicated to take. They also have more side effects and drug interactions. It is easier for HCV to develop resistance to the NS3/4As than some of the newer drugs.3

NS5B inhibitors

NS5B is an enzyme that is essential for the virus to grow. NS5B inhibitors block this enzyme and stop the virus from replicating. These drugs are generally well-tolerated and are less likely to develop resistance to the virus. NS5Bs also tend to work equally well across many genotypes. NS5B inhibitors used to treat HCV include Sovaldi (sofosbuvir) and Dasabuvir.1

NS5A protein inhibitors

These drugs target the NS5A protein. This is a protein that helps HCV grow. NS5A inhibitors work on all HCV genotypes. However, NS5A inhibitors have different levels of toxicity. HCV may more easily develop resistance to this class of drug. In general, these drugs work better when combined with peginterferon and ribavirin. For genotype 1, NS5As work better when used with other DAAs and ribavirin.3

Generic names of NS5A protein inhibitors include:3

  • Elbasvir
  • Ledipasvir
  • Ombitasvir
  • Velpatasvir
  • Pibrentasvir

Combination DAAs

Many DAAs are not designed to be taken alone. This is because they work better when used in combination with each other. Combination DAAs include:2,6

  • Epclusa (sofosbuvir and velpatasvir)
  • Harvoni (ledipasvir and sofosbuvir)
  • Zepatier (elbasvir and grazoprevir)
  • Mavyret™ (glecaprevir and pibrentasvir)
  • Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir)

Side effects

While DAAs are a huge improvement over the first drugs available for HCV, they do come with potential side effects. Side effects can vary depending on the specific DAA drug you are taking. The most common side effects include:4

  • Headache
  • Fatigue
  • Nausea
  • Diarrhea and abdominal pain
  • Insomnia
  • Nasal drip or sore throat
  • Irritability

Typically, most people can take DAAs without experiencing major side effects or complications. However, because these drugs stimulate an immune reaction, they can also increase the risk of hepatitis B virus (HBV) reactivating. Your doctor should monitor you for HBV and for signs of liver problems before and during treatment with a DAA.2

These are not all the possible side effects of DAA drugs. Talk to your doctor about what to expect or if you experience any changes that concern you during treatment with DAAs.

Things to know about DAAs

The safety of ribavirin-free DAAs has not been tested in people who are pregnant or breastfeeding. DAAs that contain ribavirin can harm an unborn baby. If you or your partner can become pregnant, you should use birth control during treatment and for some time after the last dose of a DAA with ribavirin. You should also not breastfeed during treatment with a DAA with ribavirin and for some time after the last dose. Talk to your doctor about your options for birth control and breastfeeding while taking a DAA with ribavirin.5

Everyone should be tested for liver function, HIV, and HBV before taking DAAs. Anyone taking a DAA should be monitored regularly for signs of liver cancer.5

DAAs interact with many other types of prescription and over-the-counter drugs. Before beginning treatment with a DAA, tell your doctor about all your health conditions and any other drugs, vitamins, or supplements you are taking. This includes over-the-counter drugs.5

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