What Are Direct-Acting Antivirals for HCV Treatment?

Direct-acting antivirals (DAAs) are a relatively new class of medication that acts to target specific steps in the HCV viral life cycle. The goals of DAAs are to shorten the length of therapy, minimize side effects, target the virus itself, and improve sustained virologic response (SVR) rate. HCV is an RNA virus that makes its own structural and non-structural proteins that help it replicate and assemble new virions.1 Some of these crucial particles, or enzymes, include the NS3/4A protease, the NS5B RNA-dependent RNA polymerase, and the NS5A protein.

DAAs fall under four major categories that target one or more of these proteins and enzymes in order to halt the viral life cycle and diminish viral load. As a class, these are typically well tolerated, however, because their purpose is to stimulate certain immune reactions they can also increase the risk of HBV reactivation. Before starting a DAA medication, as well as during treatment, your doctor should monitor you for HBV activity as well as for signs that may indicate a problem with your liver.2 Many DAAs are taken in combination with one another or with other medications including ribavirin or peginterferon to improve efficacy and SVR rates.

NS3/4A Protease Inhibitors for HCV treatment

This class of DAAs works to inhibit the NS3/4A protease enzyme, which is required for viral replication and post-translational processing (the making of mature virus particles). Additionally, these inhibitors may act in other ways, including weakening the induction of interferons. This means NS3/4A protease inhibitors can act in more than one way to combat HCV. This class was started with treatments like telaprevir and boceprevir, which were taken with ribavirin or peginterferon, and used to treat HCV genotype 1. Now, this class still mainly treats genotype 1, however, other medications with fewer side effects and greater efficacies have risen to take their place. These treatments include grazoprevir, paritaprevir, and simeprevir (Olysio). These medications are also used in combination with other DAAs to further enhance their efficacy and indications. One side effect to note from this group is the increased risk of photosensitivity and rash.

NS5B RNA-Dependent RNA Polymerase Inhibitors for HCV treatment

This group contains two different classes within it—NS5B nucleoside polymerase inhibitors and NS5B non-nucleoside polymerase inhibitors. This group works to inhibit enzymes at the post-translational stage of the virus’ life cycle, in other words to prevent the virus from fully maturing and replicating. The structure of these enzymes is highly similar across many different HCV genotypes, meaning these medications are indicated for a wider range of individuals with HCV. NS5B nucleoside polymerase inhibitors are less susceptible to resistance, and have a similar efficacy rate across many genotypes. This class includes sofosbuvir (Sovaldi) and is typically well tolerated, with the main side effects coming from peginterferon or ribavirin taken in addition to the medication. The NS5B non-nucleoside polymerase inhibitors are less potent and more genotype-specific than their NS5B nucleoside counterpart. They are usually used as an adjunct therapy to heighten the effects of other DAAs, and include dasabuvir.

NS5A Protein Inhibitors for HCV treatment

This group targets the NS5A protein, an HCV protein involved in the assembly of new virus particles, as well as the replication of the virus itself. The exact mechanism by which the NS5A protein completes these processes is unknown. NS5A inhibitors are effective across all genotypes, however, they have variable toxicity and a low barrier to resistance. Prominent NS5A protein inhibitors are daclatasvir (Daklinza), elbasivr, ledipasvir, ombitasvir, and velpatasvir. In general, the efficacy of these medications is stronger when used in combination with peginterferon and ribavirin. For genotype 1 specifically, this class has a higher rate of SVR when used with other DAAs as well as with or without ribavirin.3

Combinations of DAAs for HCV treatment

As mentioned earlier, many of these DAAs are not designed to be taken alone, or have stronger efficacy or SVR rates when used in combination with one another.2 Currently available combination medications include:

  • Epclusa (sofosbuvir and velpatasvir)
  • Harvoni (ledipasvir and sofosbuvir)
  • Technivie (ombitasvir, paritaprevir, and ritonavir)
  • Viekra Pak and Viekira Pak XR (dasabuvir, ombitasvir, paritaprevir, and ritonavir)
  • Zepatier (elbasvir and grazoprevir)
Written by: Casey Hribar | Last reviewed: August 2017.
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