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Unique nucleotide sequences of certain regions (eg, 5'-noncoding, core, NS5b) of the hepatitis C virus (HCV) genome allow classification of HCV into 6 major genotypes or clades (1 to 6), based on the most recently proposed HCV genotype nomenclature. In the United States, the most commonly encountered HCV genotypes are 1a and 1b, followed by genotypes 2 and 3. Worldwide geographic distribution, disease outcome, and response to antiviral therapy differ among the genotypes. Therefore, reliable methods for genotype determination are important for proper selection of antiviral therapy and optimal patient management. Infections with HCV genotypes 2 and 3 have better therapeutic response rates (80%-90%) than genotypes 1 and 4 (40%-50%) to previous standard combination therapy (ribavirin plus pegylated interferon alpha-2a or alpha-2b). Duration of such combination therapy is 24 weeks for chronic HCV genotype 2 and 3 infections in patients who show early virologic response (>2 log or 100-fold decrease in HCV RNA or no detectable HCV RNA at week 12 of therapy), while patients with chronic HCV genotype 1 and 4 infections receive a minimum of 48 weeks of such combination therapy if early virologic response is achieved (undetectable HCV RNA at week 4 of therapy).
Therapeutic response rates for HCV genotype 1 infection are improved significantly (80%-90%) when oral direct acting antiviral agents (eg, simeprevir, sofosbuvir, ledispasvir + sofosbuvir, daclatasvir + sofosbuvir, ombitasvir + paritaprevir + ritonavir + dasabuvir) are added or used in lieu of interferon-based combination therapy. However, antiviral resistance can emerge during such combination therapy, and occurrence of such resistance is more frequent with HCV subtype 1a than 1b for simeprevir-treated patients.
The American Association for the Study of Liver Diseases (AASLD) and Infectious Disease Society of America (IDSA) recommendations for testing, managing, and treating hepatitis C are available from URL: http://www.hcvguidelines.org/full-report-view
The following algorithms are available in Special Instructions:
- Testing Algorithm for the Screening and Diagnosis of Hepatitis C
- Chronic Hepatitis C Treatment and Monitoring Algorithm: Interferon-Free Combination Therapy
Determining hepatitis C virus genotype (1 to 5) to guide antiviral therapy in patients with chronic hepatitis C
Differentiating between hepatitis C virus subtypes 1a and 1b
An "Undetected" result indicates the absence of detectable hepatitis C virus (HCV) RNA in the specimen.
An "Indeterminate" result may be due to one or more of the following causes: 1) low HCV RNA level (ie,<500 IU/mL), 2) HCV genotype 6; 3) probe reactivity with multiple HCV genotypes, or 4) variation in patient’s HCV target sequences with mismatches to PCR primers and/or probes. Specimens generating indeterminate results with this assay will be automatically evaluated with the subsequent test HCVGR / Hepatitis C Virus Genotype Resolution, Serum.
A genotype result of "1" without a subtype result may be due to 1 or more of the following causes: 1) low HCV RNA level (ie, <500 IU/mL), 2) probe reactivity with multiple genotype 1 subtypes, or 3) variation in HCV genotype 1 target sequence.
This assay is able to differentiate between HCV subtypes 1a and 1b. However, subtypes are not reported for HCV genotypes 2 to 5 due to limitations of the current genotyping assay in accurately differentiating the various subtypes of these genotypes.
Results with multiple or mixed HCV genotypes (eg, 1, 5; 1a, 2; or 3, 5) may be due to mixed genotype infection or assay probe cross-reactivity. Only those specimens with multiple or mixed genotype results containing genotype 1 but no subtype will be automatically evaluated with the subsequent test HCVGR / Hepatitis C Virus Genotype Resolution, Serum.
This assay should not be used as a screening test for hepatitis C virus (HCV) infection. It should be requested only on specimens obtained from patients confirmed to have HCV RNA levels in serum of > or =500 IU/mL.
An "Undetected" or "Indeterminate" HCV genotype result does not rule-out active HCV infection. Test results should be correlated with routine serologic and molecular-based testing, as well as clinical presentation. Specimens with indeterminate results will be automatically evaluated with the subsequent test HCVGR / Hepatitis C Virus Genotype Resolution, Serum.
Known cross-reactivity between the assay probes and various HCV genotypes limits the ability of this assay to identify multiple HCV genotypes present in a given specimen. Such cross-reactivity or the actual presence of multiple HCV genotypes in the same specimen may result in an "Indeterminate" or multiple / mixed genotype result.
1. Germer JJ, Mandrekar JN, Bendel JL, et al: Hepatitis C virus genotypes in clinical specimens tested at a national reference testing laboratory in the United States. J Clin Microbiol 2011;49:3040-3043
2. American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. Available from URL: http://www.hcvguidelines.org/full-report-view. Accessed August, 2015