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Hepatitis C Viral RNA Genotype 1 NS5A Drug-resistance

Test code(s) 92447, 93871, 93873

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?

Ledipasvir was approved by the Food and Drug Administration in October 2014 as a component of HARVONI® (sofosbuvir and ledipasvir).3

Ombitasvir was approved as a component of VIEKIRA PAK® (ombitasvir, paritaprevir, ritonavir, and dasabuvir) in December 2014.4

Daklinza® (daclatasvir) was approved by the FDA in July 2014.5

Elbasvir was approved by the FDA in January 2016 as a component of Zepatier® (grazoprevir and elbasvir).6

Velpatasvir was approved by the FDA in June 2016 as a component of EPCLUSA® (sofosbuvir + velpatasvir).7 Additional NS5A inhibitors are currently under FDA review or are undergoing clinical trials.

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

Quest Diagnostics uses reverse transcription polymerase chain reaction (PCR) and DNA sequencing of genotype 1 NS5A codons 1 to 150. This method detects NS5A inhibitor resistance-associated variants (RAVs), including those identified at positions 28, 30, 31, 58, and 93 on the NS5A gene. The RAVs include Y93H, which is associated with reduced susceptibility to all approved NS5A inhibitors.8

Question 4. Is HCV genotype 1 NS5A drug-resistance testing recommended before prescribing an NS5A inhibitor-containing regimen to patients requiring retreatment?

Yes, in certain circumstances. The American Association for the Study of Liver Diseases(AASLD) and Infectious Diseases Society of America(IDSA) guidelines recommend: "For patients with cirrhosis or other patients who require retreatment urgently, testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below."9 Additionally, the guidelines suggest consultation with an expert in the treatment of HCV infection if uncertainty remains regarding the applicability of NS5A RAV testing.9

Question 5. Is HCV genotype 1 NS5A drug-resistance testing recommended before prescribing an NS5A inhibitor-containing regimen to treatment-naïve patients?

Yes, testing for NS5A RAVs at positions 28, 30, 31, and 93 is recommended prior to initiation of Zepatier® therapy for patients with HCV genotype 1a.6,9 In addition, NS5A testing prior to initiation of daclatasvir plus sofosbuvir therapy should be considered for patients with genotype 1a and cirrhosis.5

Naturally occurring NS5A RAVs conferring moderate to high levels of resistance have been found at a low prevalence in HCV genotype 1a and 1b patients.10,11 However, the impact of these baseline variants on treatment efficacy with combination DAA regimens in other circumstances may be limited and further studies are warranted.3,4,12

The AASLDand IDSAguidelines suggest consultation with an expert in the treatment of HCV infection if uncertainty remains regarding the applicability of NS5A RAV testing.9

Question 6. How are HCV genotype 1 NS5A drug-resistance test results reported?

Example 1

 

 

HCV NS5A Subtype:

1a

 

Daclatasvir Resistance:

PROBABLE

Ledipasvir Resistance:

PROBABLE

Ombitasvir Resistance:

PROBABLE

Elbasvir Resistance:

PROBABLE

Velpatasvir Resistance:

PROBABLE

MUTATIONS DETECTED

Y93H

 

 

 

 

Example 2

 

 

HCV NS5A Subtype:

1a

 

Daclatasvir Resistance:

PROBABLE

Ledipasvir Resistance:

PROBABLE

Ombitasvir Resistance:

NOT PREDICTED

Elbasvir Resistance:

PROBABLE

Velpatasvir Resistance:

NOT PREDICTED

MUTATIONS DETECTED

L31M

 

 

 

 

Example 3

 

 

HCV NS5A Subtype:

1b

 

Daclatasvir Resistance:

NOT PREDICTED

Ledipasvir Resistance:

NOT PREDICTED

Ombitasvir Resistance:

NOT PREDICTED

Elbasvir Resistance:

NOT PREDICTED

Velpatasvir Resistance:

NOT PREDICTED

MUTATIONS DETECTED

NONE

 

Question 7. Which options does Quest Diagnostics offer for HCV genotype 1 NS5A drug-resistance testing?

Quest Diagnostics will be offering the following NS5A drug testing options:

  • Test code 92447, Hepatitis C Viral RNA Genotype 1 NS5A Drug-resistance
  • Test code 93871, Hepatitis C Viral RNA Genotype, LiPA with Reflex to HCV NS5A Drug-resistance

If the HCV genotype is 1a, NS5A drug-resistance test will be performed at additional charge.

  • Test code 93873, Hepatitis C Viral RNA, Quantitative Real-Time PCR with Reflexes

If the HCV RNA is ≥300 IU/mL, the genotype (LiPA) test will be performed at additional charge. If the HCV genotype is 1a, the NS5A drug-resistance test will be performed at additional charge.

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. HARVONI® [package insert]. Foster City, CA: Gilead; 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205834s000lbl.pdf
  4. VIEKIRA PAK® [package insert]. Chicago, IL: Abbvie Incorporated; 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206619lbl.pdf
  5. Daklinza® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2016.             http://packageinserts.bms.com/pi/pi_daklinza.pdf
  6. Zepatier® [package insert]. Merck Sharpe & Dohme Corp.; 2016. http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf
  7. EPCLUSA® [package insert]. Gilead; Foster City, CA; 6/2016. http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208341s000lbl.pdf
  8. Lontok, E, Harrington, P, Howe, A, et al. Hepatitis C virus drug-resistance-associated substitutions: State of the art summary. Hepatology. 2015;62:1623-1632.
  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 28, 2016.
  10. 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. Antiviral Ther. 2014;20:81-85.
  11. Dietz J, Susser S, Berkowski C, et al. Consideration of viral resistance for optimization of direct antiviral therapy of hepatitis C virus genotype 1-infected patients. PLoS One. 2015;10:e0134395.
  12. Cento V, Chevaliez S, Federico Perno C. Resistance to direct-acting antiviral agents: clinical utility and significance. Curr Opin HIV AIDS. 2015;10:381-389.
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.173 Version: 3
Version 3 effective 08/22/2016 to present
Version 2 effective 03/26/2016 to 08/22/2016
Version 1 effective 02/29/2016 to 03/25/2016
Version 0 effective 02/12/2016to 02/28/2016