Application of response-guided therapy (RGT) rules to the treatment of HCV infection with pegylated interferon-α2a and ribavirin, and direct-acting antivirals (DAAs) such as the NS3/4A protease inhibitors (PIs) boceprevir and telaprevir, relies on the determination of viral genotype and on-treatment HCV RNA level. Currently there are few data available regarding the clinical impact of the analytical differences that exist between different HCV RNA quantification assays on treatment decisions such as those involved in RGT.
Methods
We sought to ascertain the concordance between two HCV RNA quantification assays, the Roche/ High-Pure-System COBAS® TaqMan (CTM) version 2 and Abbott RealTime HCV (ART), and to understand the impact of different assay characteristics on treatment decisions. We evaluated 1,336 specimens collected from 74 patients enrolled in the Phase II CHAMPION-2 study of the investigational DAAs ABT-450 (an acylsulfonamide NS3/4A PI), ABT-072 and ABT-333 (both non-nucleoside NS5B polymerase inhibitors).
Results
HCV RNA level results were highly correlated, but CTM values were higher than those from ART by an average of 0.46 log IU/ml. Use of ART HCV RNA level results led to a higher positive predictive value of week 4 viral load for the achievement of a sustained virological response 24 weeks after the end of treatment (100% versus 87% using the lower limit of detection as the threshold).
Conclusions
This study suggests that HCV viral load assay performance characteristics need to be taken into consideration when managing HCV patients with RGT. Further studies are required to determine whether a consensus HCV RNA level threshold can be established or whether HCV viral load assays with greater sensitivity can increase cure rates with RGT.
References
1.
ShepardC.W., FinelliL., AlterM.J.Global epidemiology of hepatitis C virus infection.Lancet Infect Dis2005; 5: 558–567.
2.
The Global Burden of Hepatitis C Working Group.Global burden of disease (GBD) for hepatitis C.J Clin Pharmacol2004; 44: 20–29.
3.
WiseM., BialekS., FinelliL., BellB.P., SorvilloF.Changing trends in hepatitis C-related mortality in the United States, 1995–2004.Hepatology2008; 47: 1128–1135.
4.
GhanyM.G., StraderD.B., ThomasD.L., SeeffL.B.Diagnosis, management, and treatment of hepatitis C: an update.Hepatology2009; 49: 1335–1374.
5.
JensenD.M., MorganT.R., MarcellinP.Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy.Hepatology2006; 43: 954–960.
6.
FerenciP., LaferlH., ScherzerT.M.Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response.Gastroenterology2008; 135: 451–458.
7.
HarringtonP.R., ZengW., NaegerL.K.Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during boceprevir or telaprevir treatment.Hepatology2012; 55: 1048–1057.
Vertex Pharmaceuticals Incorporated.INCIVEKTM (telaprevir) film coated tablets, for oral use: highlights of prescribing information. (Updated October 2012. Accessed 8 January 2013.) Available from http://pi.vrtx.com/files/uspi_telaprevir.pdf.
10.
JacobsonI.M., MarcellinP., ZeuzemS.Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin.Hepatology2012; 56: 567–575.
11.
ShermanK.E., FlammS.L., AfdhalN.H.Response-guided telaprevir combination treatment for hepatitis C virus infection.N Engl J Med2011; 365: 1014–1024.
12.
ChevaliezS., RodriguezC., PawlotskyJ.M.New virologic tools for management of chronic hepatitis B and C.Gastroenterology2012; 142: 1303–1313.
13.
FarnikH., ZeuzemS.New antiviral therapies in the management of HCV infection.Antivir Ther2012; 17: 771–783.
14.
StedmanC.A.Current prospects for interferon-free treatment of hepatitis C in 2012.J Gastroenterol Hepatol2013; 28: 38–45.
15.
CiesekS., von HahnT., MannsM.P.Second-wave protease inhibitors: choosing an heir.Clin Liver Dis2011; 15: 597–609.
16.
SarrazinC., HézodeC., ZeuzemS., PawlotskyJ-MAntiviral strategies in hepatitis C virus infection.J Hepatol2012; 56Suppl 1: S88–S100.
17.
WedemeyerH., JensenD.M., GodofskyE., ManiN., PawlotskyJ.M., MillerV.Recommendations for standardized nomenclature and definitions of viral response in trials of HCV investigational agents.Hepatology2012; 56: 2398–2403.
18.
LaRueH., RigaliL., Balada-LlasatJ.M., PancholiP.Performance of the Abbott RealTime and Roche Cobas TaqMan hepatitis C virus (HCV) assays for quantification of HCV genotypes.J Clin Microbiol2012; 50: 1769–1772.
19.
LapercheS., BouchardeauF., Andre-GarnierE.Interpretation of real-time PCR results for hepatitis C virus RNA when viral load is below quantification limits.J Clin Microbiol2011; 49: 1113–1115.
20.
PyneM.T., KonnickE.Q., PhansalkarA., HillyardD.R.Evaluation of the Abbott investigational use only RealTime hepatitis C virus (HCV) assay and comparison to the Roche TaqMan HCV analyte-specific reagent assay.J Clin Microbiol2009; 47: 2872–2878.
21.
PisaniG., CristianoK., MarinoF.Quantification of hepatitis C virus (HCV) RNA in a multicenter study: implications for management of HCV genotype 1-infected patients.J Clin Microbiol2009; 47: 2931–2936.
22.
VermehrenJ., KauA., GartnerB.C., GobelR., ZeuzemS., SarrazinC.Differences between two real-time PCR-based hepatitis C virus (HCV) assays (RealTime HCV and Cobas AmpliPrep/Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for RNA detection and quantification.J Clin Microbiol2008; 46: 3880–3891.
23.
TuaillonE., MondainA.M., OttomaniL.Impact of hepatitis C virus (HCV) genotypes on quantification of HCV RNA in serum by COBAS AmpliPrep/COBAS TaqMan HCV test, Abbott HCV RealTime assay [corrected] and VERSANT HCV RNA assay.J Clin Microbiol2007; 45: 3077–3081.
24.
MichelinB.D., MullerZ., StelzlE., MarthE., KesslerH.H.Evaluation of the Abbott RealTime HCV assay for quantitative detection of hepatitis C virus RNA.J Clin Virol2007; 38: 96–100.
25.
HalfonP., BourliereM., PenarandaG., KhiriH., OuzanD.Real-time PCR assays for hepatitis C virus (HCV) RNA quantitation are adequate for clinical management of patients with chronic HCV infection.J Clin Microbiol2006; 44: 2507–2511.
26.
ChevaliezS., Bouvier-AliasM., BrilletR., PawlotskyJ.M.Overestimation and underestimation of hepatitis C virus RNA levels in a widely used real-time polymerase chain reaction-based method.Hepatology2007; 46: 22–31.
27.
ColucciG., FergusonJ., HarkleroadC.Improved COBAS TaqMan hepatitis C virus test (Version 2.0) for use with the High Pure system: enhanced genotype inclusivity and performance characteristics in a multisite study.J Clin Microbiol2007; 45: 3595–3600.
28.
ZitzerH., HeilekG., TruchonK.Second-generation Cobas AmpliPrep/Cobas TaqMan HCV Quantitative Test for viral load monitoring: a novel dual-probe assay design.J Clin Microbiol2013; 51: 571–577.
