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Hepatitis C Viral RNA NS3 Drug Resistance

Test code(s) 90924

This is an outdated version of this FAQ. It was effective 11/24/2015 to 08/22/2016.

The current version is available here.

Question 1. What are hepatitis C virus (HCV) NS3 protease inhibitors?

NS3 protease inhibitors are antiviral drugs. They are classified as direct acting agents (DAAs) and work by inhibiting the HCV NS3a protease.1-3 Clinical studies have shown that when NS3 protease inhibitors are combined with other DAAs, a high proportion of patients achieve a sustained virologic response (SVR).10

Question 2. Which NS3 protease inhibitors are approved for clinical use?

Boceprevir (Victrelis®) and telaprevir (Incivek®) were approved by the FDA in 2011 for the treatment of HCV genotype 1 patients.4,5 Boceprevir and telaprevir are no longer recommended for clinical use in the U.S.10 Simeprevir (Olysio) was approved by the FDA in November 2013 for the same patient group.6 Paritaprevir was approved as a component of VIEKIRA PAK® (ombitasvir, paritaprevir, ritonavir and dasabuvir ) in December 2014.7 Additional NS3 protease inhibitors are currently undergoing clinical trials.

Question 3. What methods are available to test for HCV NS3 protease inhibitor resistance?

A genotypic assay that uses reverse transcription of HCV genotype 1 RNA, followed by PCR amplification and DNA sequencing of the NS3 gene, can detect mutations associated with NS3 protease inhibitor resistance. Such mutations include the R155K mutation in HCV genotype 1a and the A156S mutation in HCV genotype 1b. These and other mutations result in resistance to some or all NS3 protease inhibitors.8,9

Question 4. What is the Q80K polymorphism?

The Q80K polymorphism is a naturally occurring amino acid substitution of glutamine to lysine at NS3 codon 80. It is found in 30% to 50% of HCV genotype 1a infected patients and in 0.5% of genotype 1b patients.6 Clinical studies have shown that when cirrhotic patients with HCV genotype 1a have this polymorphism at baseline, the efficacy of simeprevir in combination sofosbuvir is substantially reduced.10 Consequently, alternative therapy should be considered for such patients.10

Question 5. Is NS3 genotype testing required before prescribing an NS3 protease inhibitor-containing antiviral regimen?

NS3 genotype testing is strongly recommended before prescribing simeprevir for patients with cirrhosis and HCV genotype 1a infection or for patients who urgently require retreatment.10 Alternative therapy should be considered for these patients when genotype testing reveals presence of the Q80K polymorphism.10

Question 6. How are HCV NS3 drug resistance genotype test results reported?

The HCV subtype (1a or 1b) and predicted resistance to boceprevir, paritaprevir, and simeprevir are reported. The mutations detected, including the Q80K polymorphism, are also reported.

Example 1

HCV NS3 Subtype:              1a

Boceprevir Resistance:      NOT PREDICTED

Telaprevir Resistance:        NOT PREDICTED

Simeprevir Resistance:        NOT PREDICTED

MUTATIONS DETECTED:   Q80K

Example 2

HCV NS3 Subtype:              1a

Boceprevir Resistance:      PREDICTED

Telaprevir Resistance:        PREDICTED

Simeprevir Resistance:        PREDICTED

MUTATIONS DETECTED:   V36M, R155K

Example 3

HCV NS3 Subtype:               1b

Boceprevir Resistance:       NOT PREDICTED

Telaprevir Resistance:         NOT PREDICTED

Simeprevir Resistance:        NOT PREDICTED

MUTATIONS DETECTED:    NONE

 

References
  
  1. Pawlotsky JM. Treatment of chronic hepatitis C: current and future. Curr Top Microbiol Immunol. 2013;369:321-342.
  2. Sarrazin C, Hézode C, Zeuzem S, et al. Antiviral strategies in hepatitis C virus infection. J Hepatol. 2012;56(suppl 1):S88-S100.
  3. You DM, Pockros PJ. Simeprevir for the treatment of chronic hepatitis C. Expert Opin Pharmacother. 2013;14:2581-2589.
  4. Boceprevir [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.       http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202258lbl.pdf.
  5. Telaprevir [package insert]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; 2011.       http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/201917lbl.pdf.
  6. Simeprevir [package insert]. Titusville, NJ: Janssen Therapeutics; 2013.       http://www.janssentherapeutics.com/shared/product/olysio/prescribing-information.pdf.
  7. VIEKIRA PAK® [package insert]. Chicago, IL: Abbvie Incorporated; 2014. http://www.abbvie.com/content/dam/abbviecorp/us/desktop/contentrooms/downloads/ProductFactsheet_ViekiraPak_US.pdf.
  8. Pawlotsky JM. Treatment failure and resistance with direct-acting antiviral drugs against hepatitis C virus. Hepatology. 2011;53:1742-1751.
  9. Cento V, Chevaliez S, Perno CF. Resistance to direct-acting antiviral agents: clinical utility and significance. Curr Opin HIV AIDS. 2015;10:381-389.
  10. Recommendations for Testing, Managing, and Treating Hepatitis C. AASLD and IDSA; 2015. http://www.hcvguidelines.org/full-report-view.
This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
Document FAQS.132 Version: 3
Version 3 effective 11/24/2015 to present
Version 2 effective 07/08/2015 to 11/23/2015
Version 1 effective 03/12/2014 to 07/07/2015
Version 0 effective 01/09/2014 to 03/11/2014