Hepatitis C Drugs Meet Resistance Issues

April 24, 2017
Rodger D. MacArthur, MD

Merin Varghese, MD

Resistance-associated variants limit the activity of some drugs, but HIV infection treatment may offer some guidance.

In the treatment of the hepatitis C virus (HCV), it should come as no surprise that resistance-associated variants (RAVs)-pre-existing or selected during treatment-would limit the activity of some drugs. After all, there is a wealth of knowledge about the importance of baseline, transmitted, and regimen-selected resistance mutations after the almost 30 years antiretroviral drugs have been available to treat HIV.

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In fact, one of the principles of treating HIV infection is to use drugs from at least 2 classes, both to increase the potency of the treatment regimen and to make resistance less likely to develop during the course of therapy. Of course, the “modern” era of treating HCV with the direct acting antiviral agents is only about 2 years old. Consequently, only recently have we begun to appreciate the role resistance plays in HCV treatment.

FDA-approved HCV Drugs and Drug Combinations

The 8 drugs or drug combinations that are FDA approved to treat patients with HCV fall into the following 4 classes:

1. NS3/4A protease inhibitors: grazoprevir (a component of Zepatier™), paritaprevir (a component of Technivie™ and Viekira Pak™), and simeprevir (Olysio™).

2. NS5A inhibitors: daclatasvir (Daklinza™), elbasvir (a component of Zepatier™), ledipasvir (a component of Harvoni™), ombitasvir (a component of Technivie™ and Viekira Pak™), and velpatasvir (a component of Epclusa™).

3.NS5B nucleot(s)ide polymerase inhibitors: sofosbuvir (Solvaldi™ and a component of Harvoni™).

4.NS5B non-nucleoside polymerase inhibitors: dasabuvir (a component of Viekira Pak™).

Next: Drugs Categorized by Intrinsic Barriers

Drugs Categorized by Intrinsic Barriers

These 4 classes can be categorized by their intrinsic barrier to the development of resistance:

Very low: NS5B non-nucleoside polymerase inhibitors.

Low: NS5A inhibitors, NS3/4A protease inhibitors.

High: NS5B nucleot(s)ide polymerase inhibitors.

Note that differences are likely among the drugs in each class on how limiting RAVs will be on their activity.

What We Do Know About the Role of Resistance

These drugs have been approved for too short a time for there to be a full appreciation of the role resistance will play in the treatment of HCV. So what do we know to date?

• About 10% to 15% of genotype 1 NS5A-naive persons will have detectable RAVs at baseline.

• Patients of genotype 1a seem to have a 5-fold reduction in activity of the NS5A inhibitors if these RAVs are present at baseline.

• In the C-EDGE trial, HCV-infected patients treated with elbasvir/grazoprevir (Zepatier™) with detectable RAVs at baseline had a sustained virologic response rate at 12 weeks (SVR12) of only 58%, compared with a 99% SVR12 for patients who did not have detectable baseline RAVs.

• Treating HCV-infected patients of genotype 1a with a 16-week course of therapy with the addition of ribavirin if Zepatier™ is chosen as the treatment regimen is recommended by the American Association for the Study of Liver Disease.

• In the ASTRAL-1 trial, the presence of baseline RAVs did not have an impact on SVR12 rates in persons of genotypes 1a or 1b when treated with Epclusa™.

• In the ASTRAL-1 and ASTRAL-2 trials, the presence of baseline NS5A or NS5B RAVs was not associated with lower SVR12 rates in HCV-infected persons of genotype 2 treated with Epclusa™.

• In the ASTRAL-3 trial, HCV-infected persons of genotype 3 had a somewhat lower SVR12 response to therapy with Epclusa™ (88% vs 97%) if they had NS5A RAVs detected at baseline.

• In the ALLY-3 trial, HCV-infected persons of genotype 3 had a substantially reduced SVR12 response rate to therapy with Daklinza™ (54% vs 92%) if they had NS5A RAVs detected at baseline.

Next: A Baseline Resistance Test Before Therapy

Obtain a Baseline Resistance Test Before Initiating Therapy

In summary, detectable NS5A RAVs in persons of genotype 1a limit the activity of Zepatier™ when used for 12 weeks. Persons of HCV genotype 3 with detectable baseline RAVs show a reduced response to therapy when treated with Epclusa™ or Daklinza™ for 12 weeks.

Consequently, obtaining a baseline resistance test prior to initiating therapy in persons of genotypes 1 (especially 1a) and 3 seems prudent. How the presence of relevant RAVs limits the activity of drugs other than Zepatier™, Epclusa™, and Daklinza™ is unclear given the paucity of existing data from relevant clinical trials.


Coming soon, the final part of this Special Report on Hepatitis C and Primary Care, a post-test to assess your knowledge of the latest developments in hepatitis C patient care. Watch your email for eNewsletters from Patient Care and visit our homepage at www.patientcareonline.com to check for updates.

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