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To the Editor:

We read with interest the article by Ghany et al. 1 that describes an update to the treatment of hepatitis C virus (HCV) genotype 1 infection after the approval of the NS3/4A serine protease inhibitors boceprevir and telaprevir. The trials for both drugs relied on HCV RNA results to make decisions about shortening or extending treatment (response-guided therapy [RGT]). In the article, the term “undetectable” was referred to “as defined in the package insert as <10-15 IU/mL.” However, physicians need to know that quantitative polymerase chain reaction (PCR) viral load assays have a lower limit of quantification (LLOQ). HCV RNA detectable below the LLOQ is described as detected but, by definition, cannot be quantified. Thus, PCR results beneath the LLOQ can reported as <LLOQ, detected or <LLOQ, undetected. A result <LLOQ, undetected should be referred as target not detected (TND), which means that no PCR amplification or detection can be achieved, indicating absence of HCV RNA. The limit of sensitivity for detection of HCV RNA that cannot be quantified is the limit of detection (LOD) that is established as HCV RNA detected at a rate of ≥95%. 2 Based on this, HCV RNA would be undetected 5% of the time.

The boceprevir and telaprevir phase 3 trials measured HCV RNA with the COBAS® TaqMan® HCV Test, v2.0 for use with the High Pure System (Roche Molecular Systems Inc., Branchburg, NJ). This assay has an overall LOD across multiple samples and genotypes of 20 IU/mL and an LLOQ of 25 IU/mL. 3 The genotype 1 LOD differs by plasma or serum and can range between 10 and 15 IU/mL. Therefore, any result between 1 and 24 will be reported as “<25 IU/mL, detected.” Similarly, if the HCV RNA is <10-15 IU/mL but detected, the result will also be reported as “<25 IU/mL, detected.” Only a TND result will be reported if no virus is detectable.

The prescribing information for both antivirals states that for assessing RGT, an “undetectable” HCV RNA result is required and a “detectable but below limit of quantification” HCV RNA result should not be considered equivalent to an “undetectable HCV RNA result.” 4, 5 Given that an “undetectable” result is required for RGT with boceprevir or telaprevir and should not be considered equivalent to a result of “<25 IU/mL, detected,” the term “undetectable” should therefore be defined as a result that is TND rather than the assay LOD, or <10-15 IU/mL.

References

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  • 1
    Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. HEPATOLOGY 2011; 54: 1433-1444.
  • 2
    Clinical and laboratory standards institute. Protocols for determination of limits of detection and limits of quantification; Approved guideline. CLSI document EP17-A. CLSI: Wayne, PA 2008.
  • 3
    COBAS Taqman HCV Test v.2 for use with the High Pure System. Package insert, November 2010. Document Rev 1.0.
  • 4
    VICTRELIS (boceprevir) prescribing information 2011. Available at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.
  • 5
    INCIVIK (telaprevir) prescribing information 2011. Available at: http://pi.vrtx.com/files/uspi_telaprevir.pdf.

Bryan Cobb Ph.D.*, Regis A. Vilchez M.D., Ph.D.*, * Roche Molecular Systems, Inc., Pleasanton, CA.