Test Catalog

Test ID: HCVDR    
Hepatitis C Virus Genotypic Antiviral Drug Resistance, Serum

Useful For Suggests clinical disorders or settings where the test may be helpful

Detection and identification of codon substitutions in the hepatitis C virus (HCV) NS3, NS5A, and NS5B genomic regions that confer resistance to current direct-acting antiviral (DAA) drugs used for treatment of chronic hepatitis C infection due to HCV genotype 1a, 1b, or 3 (any subtype)

 

Guiding initiation or change of antiviral drug combinations for the treatment of chronic HCV infection

 

This assay should not be used as a screening test for HCV infection.

 

This test should not be ordered for HCV infection due to genotype 2, 4, 5, or 6.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

See Chronic Hepatitis C Treatment and Monitoring Algorithm: Direct Antiviral Agent (DAA) Combination in Special Instructions.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Interferon-free, direct-acting antiviral (DAA) drug combination therapy is now a standard of care for patients with chronic hepatitis C virus (HCV) infection. However, poor compliance with therapy and the existence of pretreatment antiviral drug resistance may compromise efficacy of such drug therapy. Naturally occurring (preexisting) or treatment-induced mutations in the viral genomic sequences that are targets of such antiviral agents can lead to antiviral resistance and therapeutic failure. Clinical trials and postmarketing studies of DAA therapy indicated that preexisting, resistance-associated substitutions (RAS) in the relevant HCV genomic regions of certain genotypes or emergence of certain RAS during DAA therapy can lead to treatment failure. Per current recommendations from the FDA and professional society practice guidelines (see table below and Clinical Reference section), use of certain FDA-approved DAA drugs for treating chronic HCV due to genotypes 1a, 1b, and 3 (any subtype) requires pretreatment testing for RAS in the relevant HCV genomic regions to guide selection of optimal DAA combination therapy.

 

DAA target region

HCV genotype

1a

1b

3 (any subtype)

HCV NS3

Glecaprevir(a)

Grazoprevir(b)

Voxilaprevir(c)

Glecaprevir(a)

Grazoprevir(b)

Voxilaprevir(c)

Glecaprevir(a)

Voxilaprevir(c)

HCV NS5A

Daclatasvir(d)

Elbasvir(b)

Ledipasvir(e)

Pibrentasvir(a)

Velpatasvir(c,f)

Daclatasvir(d)

Elbasvir(b)

Ledipasvir(e)

Pibrentasvir(a)

Velpatasvir(c,e)

Daclatasvir(d)

Pibrentasvir(a)

Velpatasvir(c,e)

HCV NS5B

Sofosbuvir(c,e,f,g)

Sofosbuvir(c,e,f,g)

Sofosbuvir(c,f,g)

Trade names of DAA:

(a) Mavyret = Glecaprevir + Pibrentasvir

(b) Zepatier = Elbasvir + Grazoprevir

(c) Vosevi = Sofosbuvir + Velpatasvir + Voxilaprevir

(d) Daklinza = Daclatasvir

(e) Harvoni = Ledipasvir + Sofosbuvir

(f) Epclusa = Sofosbuvir + Velpatasvir

(g) Sovaldi = Sofosbuvir

 

Antiviral drug RAS in the relevant HCV genomic regions can be detected and identified genotypically using either Sanger sequencing or next-generation sequencing (NGS) methods. Amino acid changes deemed as RAS are predicted by the NS3, NS5A, and NS5B sequences of the patient's HCV strain by comparing them to the expected amino acid at relevant codon positions within a wild-type HCV reference sequence. DAA drug resistance may be predicted for each drug based on the relevant RAS present in the HCV sequences found in the patient's serum. Prediction of HCV antiviral drug resistance in this NGS assay is based on a combination of FDA-approved prescribing information for the drug and professional society practice guidelines (see table above and Clinical Reference section).

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Interpretive report

Interpretation Provides information to assist in interpretation of the test results

Interpretation of antiviral drug resistance in this assay is based on a detection threshold of 10% of resistance-associated hepatitis C virus (HCV) variants present in the patient's serum specimen (ie, minimum 10% frequency of such variants).

 

This assay will confirm the patient's HCV genotype, with possible genotype results generated as 1a; 1b; 1, no subtype; 2a; 2b; 2, no subtype; 3a; 3, no subtype; 4a; 4, no subtype; 5a; 6a; 6, no subtype. However, analysis of resistance-associated substitutions (RAS) and prediction of antiviral drug resistance are restricted only to HCV genotype test results of 1a, 1b, 3a, or 3 no subtype.

 

Inconclusive result indicates that testing failed, likely due to presence of inhibitory substances in the submitted serum specimen. A new serum specimen should be collected and submitted for retesting if clinically indicated.

 

Indeterminate result is due to presence of atypical HCV genomic sequences, such as a recombinant HCV strain comprised of genomic sequences from multiple genotypes, preventing definitive determination of the HCV genotype.

 

Unable to genotype indicates that the assay is unable to reliably determine antiviral resistance because of either low HCV viral load (ie, <50,000 IU/mL) or ambiguous or incomplete HCV target sequences generated with the assay.

 

Predicted resistance means that the RAS detected have been reported to be associated with reduction in susceptibility to the specific direct-acting antiviral (DAA) drug.

 

Possible resistance means that the RAS detected may be associated with a reduction in susceptibility to the specific DAA drug due to possible cross-resistance within the same drug class. Current peer-reviewed, published reports do not have sufficient data to definitively rule out antiviral resistance to the drug.

 

Not predicted means that no RAS were detected and no resistance to the specific DAA drug is predicted for patient's HCV strain.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

A patient's response to antiviral therapy depends on multiple factors, including the patient's hepatitis C virus (HCV) genotype, characteristics of the infecting viral strain, patient compliance with the prescribed drug therapy, patient's access to adequate care, drug pharmacokinetics, and drug-drug interactions. Drug-resistance test results should be interpreted only in conjunction with clinical presentation and other laboratory markers when making therapeutic decisions.

 

Absence of resistance to a drug does not rule out the presence of reservoirs of direct-acting antiviral (DAA)-resistant HCV in the infected patient.

 

An HCV genotypic drug resistance test is not a direct measure of antiviral drug resistance. Although genotypic testing can detect resistance-associated substitutions (RAS) in the relevant HCV genomic regions, the clinical significance of these RAS requires careful interpretation to predict drug susceptibility. This assay's ability to amplify the HCV target sequences and detect RAS may be limited when the serum HCV viral load is less than 50,000 IU/mL due to HCV strain diversity. Serum specimens submitted for this test should contain a minimum of 50,000 IU/mL of HCV RNA.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Pawlotsky JM: Hepatitis C virus resistance to direct-acting antiviral drugs in interferon-free regimens. Gastroenterology 2016;151:70-86

2. Wyles DL, Luetkemeyer AF: Understanding hepatitis C virus drug resistance: clinical implications for current and future regimens. Top Antivir Med 2017;25(3):103-109

3. Sorbo MC, Cento V, Di Maio VC, et al: Hepatitis C virus drug resistance associated substitutions and their clinical relevance: update 2018. Drug Resist Updat 2018;37:17-39

4. Wyles DL: Resistance to DAAs: When to look and when it matters. Curr HIV/AIDS Rep 2017;14:229-237

5. European Association for the Study of the Liver: EASL recommendations on treatment of hepatitis C 2018. J Hepatol 2018;69:461-511

6. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America: HCV guidance: recommendations for testing, managing, and treating hepatitis C. Accessed November 2018. Available at: www.hcvguidelines.org/evaluate/resistance

Special Instructions Library of PDFs including pertinent information and forms related to the test