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Hepatitis C Viral RNA Genotype 3 NS5A Drug Resistance

Test code(s) 93325

This is an outdated version of this FAQ. It was effective 02/12/2016 to 08/22/2016.

The current version is available here.

Question 1. What are hepatitis C virus (HCV) NS5A inhibitors?

NS5A inhibitors are antiviral drugs. They are classified as direct acting agents (DAAs) and work by inhibiting the HCV NS5A protein.1,2

Question 2. Which NS5A inhibitors are approved for clinical use to treat HCV genotype 3?

Daklinza® (daclatasvir) was approved by the FDA in July 2014 for use in genotype 3 in combination with the NS5B inhibitor sofosbuvir.3 Additional NS5A inhibitors are currently under FDA review or are undergoing clinical trials.

Question 3. Which method is used to test for HCV NS5A inhibitor resistance?

Quest Diagnostics uses reverse transcription polymerase chain reaction (PCR) and DNA sequencing of HCV genotype 3 NS5A codons 1 to 150. This method detects NS5A inhibitor resistance-associated variants (RAVs), in particular the Y93H mutation, which occurs in <10% of patients with HCV genotype 3.3,4

Question 4. What is the clinical significance of genotype 3 NS5A resistance-associated variants (RAVs)?

NS5A RAVs are associated with a lower sustained virologic response (SVR) in patients with HCV genotype 3 who are being treated with daclatasvir and sofosbuvir for 12 weeks. In a phase 3 clinical trial, patients with a baseline Y93H polymorphism had an SVR of 54%, while those without Y93H had an SVR of 92%.3,5 Among patients with HCV genotype 3 and cirrhosis, 1 in 4 (25%) of those with Y93H achieved an SVR at week 12 compared to 19/28 (68%) of those without Y93H.3,5 In a follow-up study, most patients with cirrhosis and RAVs achieved an SVR when treated for 12 or 16 weeks with sofosbuvir, daclatasvir and ribavirin.6

Other  HCV genotype 3 NS5A RAVs, including A30K/S/T/V and P58R/S, were not associated with a reduced response, however.3,5

Question 5. Is HCV genotype 3 NS5A drug resistance testing recommended before prescribing a daclatasvir-containing regimen?

The AASLD and IDSA guidelines do not currently provide a recommendation regarding NS5A resistance testing in patients with HCV genotype 3.7

However, the guidelines do recommend NS5A resistance testing in certain circumstances for patients with HCV genotype 1 (see FAQ 173). Additionally, the guidelines suggest consultation with an expert in the treatment of HCV infection if uncertainty remains regarding the applicability of NS5A resistance testing.7

Question 6. How are HCV genotype 3 NS5A drug resistance test results reported?


Example 1  
HCV NS5A Subtype:     3a
Daclatasvir Resistance:     PREDICTED
Example 2  
HCV NS5A Subtype:     3a
Daclatasvir Resistance:     NOT PREDICTED


  1. Rupp D, Bartenschlager R. Targets for antiviral therapy of hepatitis C. Semin Liver Dis. 2014;34:9-21.
  2. Kohler JJ, Nettles JH, Amblard F, et al. Approaches to hepatitis C treatment and cure using NS5A inhibitors. Infect Drug Resist. 2014;7:41-56.
  3. Daklinza [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015New York, NY: Bristol-Myers Squibb; 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206843Orig1s000lbl.pdf.
  4. Hernandez D, Zhou N, Ueland J, et al. Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors. J Clin Virol. 2013;57:13-18.
  5. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61:1127-1135.
  6. Leroy V, Angus PW, Bronowicki J-P, et al. All-oral treatment with daclatasvir (DCV) plus sofosbuvir (SOF) plus ribavirin (RBV) for 12 or 16 weeks in HCV genotype (GT) 3-infected patients with advanced fibrosis or cirrhosis: the ALLY-3+ phase 3 study. 2015 Annual Meeting of the American Association for the Study of Liver Diseases; November 13-17, 2015; San Francisco, California. Abstract LB-3.
  7. American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA). Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/. Accessed December 16, 2015.
This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’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.174 Version: 0
Effective 02/12/2016 to present