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Direct Acting Antivirals for Hepatitis C

Updated January 15, 2016.

Hepatitis C Treatment – Up Through 2011

Hepatitis C infection is a somewhat common co-infection that occurs alongside HIV. This is, in part, because high risk activities for HIV may also be high-risk for hepatitis C. For example, sharing needles is a major route of infection for both viruses. Hepatitis C can also be sexually transmitted, although that’s rare in people who are not infected with HIV or other STDs.

Hepatitis C has been around for a long time. However, until relatively recently there were few effective methods of treatment. Historically the major treatment regimen was a long course of pegylated interferon and ribavirin. However, these treatments had a significant problem. They combined an only moderate ability to elicit a sustained virological response with significant side effects. For example, one study found that as many as a quarter of people taking interferon developed major depressive episodes due to the treatment regimen.

 The drugs were also contraindicated in individuals with advanced liver or kidney disease. That meant that many people with hepatitis C weren’t even eligible to take them.

In addition, the drugs were least effective against the most common types of hepatitis C. Genotype 1 was historically difficult to treat with pegylated interferon and ribavirin. The treatment regimen worked slightly better with genotypes 2 and 3, but those types were also less common. The combination of poor efficacy and high intolerance were driving forces for the development of interferon-free methods of hepatitis C treatment.

The Rise of Direct Acting Antivirals for Hepatitis C Treatment

The first direct acting antivirals (DAAs) started to hit the market in 2011. Direct acting antivirals got their name by targeting specific proteins involved in viral replication. The release of these DAAs, boceprevir and telaprevir, revolutionized the treatment of hepatitis C by shortening treatment courses dramatically. However, these protease inhibitors needed to be used in combination with interferon and ribavirin. There were also still many cases in which they didn’t work.

Second generation DAAs included simeprevir, another protease inhibitor. It worked better than the first generation DAAs but was susceptible to some of the same resistance mutations. (This is similar to problems with drug resistance in HIV.)  However, there were also new classes of DAAs being released. For example sofosbuvir is a polymerase inhibitor. It has many fewer side effects than the protease inhibitors, although, like them, it was also released to be used in combination with a shortened course of interferon and ribavirin.

Getting Rid of Interferon

In 2010, the first study was published showing that treatments that didn’t include interferon might be effective against hepatitis C. Given the serious side effects and limitations of interferon, this research was incredibly exciting. However, it would be a few years before interferon-free treatments would actually reach the market. In 2013, sofosbuvir in combination with ribavirin was approved for use in genotype 2 and 3 patients. It could also be used in patients who were ineligible for treatment with interferon, although it was less effective.

In the future, it may be possible to get rid of ribavirin treatment as well. Combinations of two or more classes of DAA have shown impressive efficacy in several clinical trials. (Furthermore, as with HIV treatment, it looks like using a multi-drug combination reduces the development of resistance.) It’s an exciting time. The development of shorter, less toxic courses of treatment could vastly improve the availability and acceptability of treatment for hepatitis C both in the United States and around the world.

A partial list of DAAs that have either been released or are under development include:

First and second generation protease inhibitors

  • boceprevir – first generation protease inhibitor
  • telaprevir – first generation protease inhibitor
  • simeprevir – second generation protease inhibitor

NS5B nucleotide polymerase inhibitors

  • sofosbuvir –  NS5B nucleotide polymerase inhibitor
  • mericitabine – NS5B nucleotide polymerase inhibitor

NS5B non-nucleoside polymerase inhibitors

  • GS-9669 – NS5B non-nucleoside polymerase inhibitor
  • dasabuvir – NS5B non-nucleoside polymerase inhibitor

NS3/4A protease inhibitors

  • danoprevir –  NS3/4A protease inhibitor
  • asunaprevir – NS3/4A protease inhibitor

Complication complex inhibitors

  • daclatasvir – NS5A complication complex inhibitor

Replication complex inhibitors

  • ledipasvir – NS5A replication complex inhibitor

For the most recently updated information about Hepatitis C treatment, check out the American Association for the Study of Liver Diseases guidelines at http://hcvguidelines.org/

American Association for the Study of Liver Diseases (2014), HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. Accessed 12/20/15 from http://www.hcvguidelines.org/

Centers for Disease Control. (2015, October 15) Hepatitis C FAQs for the Public Accessed 12/20/15 from: http://www.cdc.gov/hepatitis/hcv/cfaq.htm

Kohli A, Shaffer A, Sherman A, Kottilil S. Treatment of hepatitis C: a systematic review. JAMA. 2014 Aug 13;312(6):631-40. doi: 10.1001/jama.2014.7085.

Udina M, Castellví P, Moreno-España J, Navinés R, Valdés M, Forns X, Langohr K, Solà R, Vieta E, Martín-Santos R. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012 Aug;73(8):1128-38. doi: 10.4088/JCP.12r07694.

Yau AH, Yoshida EM. Hepatitis C drugs: the end of the pegylated interferon era and the emergence of all-oral interferon-free antiviral regimens: a concise review. Can J Gastroenterol Hepatol. 2014 Sep;28(8):445-51.