May/June 2016 

Know your drugs and classes

Treatments for hepatitis C virus (HCV) available in high-income countries today are highly effective, with rates of cure generally greater than 90%. In the years ahead, even more powerful combinations of all-oral anti-HCV drugs, called direct-acting antivirals (DAAs), will become available that can treat all major strains of HCV.

Proteins and enzymes

There are many steps that are needed within an HCV-infected cell so that copies of HCV can be made. These steps involve proteins and enzymes. A combination of drugs that targets multiple proteins and enzymes makes for a more effective regimen than a single drug alone. HCV proteins and enzymes are targets of DAAs and serve as ways to group DAAs. This grouping is also used when sorting strains of HCV that are resistant to DAAs.

Approved DAAs:

NS3 and NS4A

The enzyme called NS3 is part of a vital step in the production of copies of HCV. A protein called NS4A, made by HCV-infected cells, enhances the activity of NS3. Examples of drugs that work by attacking NS3 and/or NS4A include the following:

  • asunaprevir
  • grazoprevir (in Zepatier)
  • paritaprevir (in Holkira Pak)
  • simeprevir (Galexos)

All of the above listed drugs are called protease inhibitors.


The enzyme NS5B is part of another vital step in the creation of copies of HCV. Approved NS5B inhibitors are divided into subclasses such as nukes (sofosbuvir) and non-nukes (dasabuvir; in Holkira Pak).


Researchers are not certain about the role of this protein, but it is critical to the production of HCV. Inhibitors of NS5A include the following:

  • daclatasvir (Daklinza)
  • Ledipasvir (in Harvoni)
  • elbasvir (in Zepatier)
  • ombitasvir (in Holkira Pak)

DAAs in development:

NS5A inhibitors are the most powerful anti-HCV agents. This is why nearly all DAA regimens in clinical trials contain an NS5A inhibitor. Below are examples of NS5A inhibitors under development:

  • Velpatasvir – this drug will not be available by itself. Velpatasvir is being co-formulated (put into one pill) with another drug called sofosbuvir. The combination of both drugs is expected to be approved in North America in the summer of 2016. These drugs are made by Gilead Sciences.
  • MK-8408 – this drug is being tested in combination with other drugs made by Merck in phase II and III clinical trials. If these studies demonstrate high rates of cure, MK-8408 will be made available in one pill together with other drugs from Merck.
  • ABT-530 – this drug will not be available by itself but co-formulated with another experimental agent, ABT-493. Both drugs are made by Abbvie and are in phase III clinical trials.
  • Odalasvir – this drug is being tested in combination with another drug code-named AL-335 (an NS5B inhibitor) and the NS3 inhibitor simeprevir in phase II clinical trials. All three drugs are made by Janssen. It is too early to know if this trio will be successful and if they will be co-formulated.

The advantages of these emerging drugs and combinations are multifold: They are very likely more powerful than existing combinations of DAAs, they can be used in some cases of treatment failure, and they will likely be effective against a broad range of strains of HCV (genotypes 1 through 6). Combinations of emerging therapies may result in shorter duration of treatment for some cases of uncomplicated HCV infection.

—Sean R. Hosein


Gotte M, Feld JJ. Direct-acting antiviral agents for hepatitis C: structural and mechanistic insights. Nature Reviews. Gastroenterology & Hepatology. 2016; in press.