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Hepatitis C Viral RNA Genotype 3 NS5A Drug Resistance

Test code(s) 93325

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 Velpatasvir, a pangenotypic NS5A inhibitor included in the medication EPCLUSA®(sofosbuvir + velpatasvir), was approved by the FDA in June 2016.4 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 3.5,6

Question 4. What is the clinical significance of genotype 3 NS5A resistance-associated variants (RAVs) for patients treated with a daclatasvir-containing regimen?

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%.3,7 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.3,7 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.8

Question 5. What is the clinical significance of genotype 3 NS5A resistance-associated variants (RAVs) for patients treated with a velpatasvir-containing regimen?

NS5A RAVs are associated with a lower sustained virologic response (SVR) in patients with HCV genotype 3 who are being treated with velpatasvir and sofosbuvir for 12 weeks. In a phase 3 clinical trial, the SVR rate was 88% for patients with any NS5A RAVs at baseline, 84% for patients with Y93H at baseline, and 97% for patients without baseline RAVs.10 For all 10 genotype 3a patients with virologic failure, Y93H was observed at the time of failure.4

Question 6. Is HCV genotype 3 NS5A drug resistance testing recommended before prescribing a daclatasvir-containing or a velpatasvir-containing regimen?

The AASLD and IDSA guidelines currently recommend NS5A drug resistance testing for cirrhotic patients. If the NS5A Y93H mutation is present, ribavirin along with sofosbuvir and either daclatasvir or velpatasvir is recommended.9

Question 7. What is the recommended HCV viral load for NS5A resistance testing?

We recommend specimens being submitted for NS5A resistance testing have an HCV RNA level of at least 1,000 IU/mL. The assay may fail at lower viral loads.

Question 8. How are HCV genotype 3 NS5A drug resistance test results reported?

Example 1

 

 

HCV NS5A Subtype:

3a

 

Daclatasvir Resistance:

PROBABLE

Velpatasvir Resistance:

PROBABLE

MUTATIONS DETECTED

Y93H

 
     

Example 2

 

 

HCV NS5A Subtype:

3a

 

Daclatasvir Resistance:

NOT PREDICTED

Velpatasvir Resistance:

NOT PREDICTED

MUTATIONS DETECTED

NONE

 

References

  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]. Bristol-Myers Squibb Company; New York, NY; 2/2016. http://packageinserts.bms.com/pi/pi_daklinza.pdf
  4. EPCLUSA®[package insert]. Gilead; Foster City, CA; 6/2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208341s000lbl.pdf
  5. 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.
  6. McCormick AL, Wang L, Garcia-Diaz A, et al. Prevalence of baseline polymorphisms for potential resistance to NS5A inhibitors in drug-naive individuals infected with hepatitis C genotypes 1-4. Antivir Ther. 2015;20:81-85.
  7. 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.
  8. Leroy V, Angus P, Bronowicki JP, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology. 2016;63:1430-1441.
  9. 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 July 25, 2016.
  10. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015;373:2608-2617.
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.174 Version: 1
Version 1 effective 08/22/2016 to present
Version 0 effective 02/12/2016 to 08/22/2016