Is HCV RNA analysis at day 7 cost-effective in deciding the duration of therapy in chronic HCV genotype 2/3 infection?
Authors: Martin Lagging, Åsa Alsiö, Kristoffer Hellstrand, Gunnar Norkrans
Journal: Journal of Hepatology (2010)

Viral kinetics for individualized treatment durationsJournal of HepatologyVol. 54Issue 4PreviewReply to Lagging et al.: Full-Text PDF Open Access To the Editor: The recent study by Sarrazin et al. [[1]Sarrazin C. Shiffman M.L. Hadziyannis S.J. Lin A. Colucci G. Ishida H. et al.Definition of rapid virologic response with a highly sensitive real-time PCR-based HCV RNA assay in peginterferon alfa-2a plus ribavirin response-guided therapy.J Hepatol. 2010; 52: 832-838Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar] reported results from a re-analysis of stored sera from two large multicenter randomized trials [2Hadziyannis S.J. Sette Jr., H. Morgan T.R. Balan V. Diago M. Marcellin P. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2771) Google Scholar, 3Shiffman M.L. Suter F. Bacon B.R. Nelson D. Harley H. Sola R. et al.Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3.N Engl J Med. 2007; 357: 124-134Crossref PubMed Scopus (516) Google Scholar], in HCV infected patients treated with peginterferon alfa-2a plus ribavirin. The authors quantified HCV RNA using COBAS Ampliprep/COBAS TaqMan (CAP–CTM), a sensitive real-time PCR-based assay with a limit of detection of ⩽15 IU/ml. Among genotype 2/3 infected patients achieving a rapid virologic response (RVR; defined as HCV RNA <15 IU/ml after 4 weeks of therapy), a sustained viral response (SVR) rate of 83% was noted for patients treated for 16 weeks and 91% for those treated for 24 weeks. These SVR rates were observed in both study arms even when using a stricter definition of undetectable HCV RNA (CAP–CTM). However, when the analysis was limited to patients with a baseline viral load below 800,000 IU/ml, i.e. a third of the patients included, the authors found no statistically significant difference in SVR rates between patients treated for 16 or 24-weeks irrespective of the cut-off used to define RVR. In another recently reported trial with HCV genotype 2/3 infected patients (NORDynamIC; n = 382) treated with peginterferon alfa-2a weekly plus 800 mg ribavirin daily for 12 or 24 weeks, plasma samples were analyzed using the CAP–CTM assay [[4]Lagging M. Langeland N. Pedersen C. Farkkila M. Buhl M.R. Morch K. et al.Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection.Hepatology. 2008; 47: 1837-1845Crossref PubMed Scopus (156) Google Scholar]. It was observed that 12 weeks of treatment overall was significantly inferior to 24 weeks, but that short-term therapy may be acceptable for patients younger than 40 years of age [[4]Lagging M. Langeland N. Pedersen C. Farkkila M. Buhl M.R. Morch K. et al.Randomized comparison of 12 or 24 weeks of peginterferon alpha-2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection.Hepatology. 2008; 47: 1837-1845Crossref PubMed Scopus (156) Google Scholar] as well as for those achieving HCV RNA below 1000 IU/ml by day 7, i.e. immediately prior to the second dose of peginterferon [[5]Lagging M. Langeland N. Pedersen C. Farkkila M. Buhl M.R. Morch K. et al.Weight-adjusted dosing of ribavirin and importance of hepatitis C virus RNA below 1000 IU/mL by day 7 in short-term peginterferon therapy for chronic genotype 2/3 hepatitis C virus infection.Hepatology. 2008; 48: 695Crossref PubMed Scopus (14) Google Scholar]. The analysis of the 136 patients in this trial with baseline viral load below 800,000 IU/ml and a plasma sample available day 29, according to the proposal by Sarrazin et al., revealed a non-significant trend towards slightly higher SVR among patients with HCV RNA <15 IU/ml day 29 treated for 24 weeks (Fig. 1A; p=0.08, Chi square) whereas no such trend was seen among 109 patients achieving below 1000 IU/ml day 7 irrespective of their baseline viral load (Fig. 1B). In contrast, among patients with HCV RNA levels above or equal to 1000 IU/ml day 7, SVR rates were significantly higher in the 24-week study arm irrespective of whether RVR (i.e. <15 IU/ml HCV RNA day 29) was achieved or not (55% vs. 87%, p=0.0002, and 39% vs. 62%, p= 0.01, Chi squared; Fig. 1B). These results imply that a single day 7 analysis of HCV RNA is at least as accurate as an assessment of RVR in deciding whether genotype 2/3-infected patients should receive short-term treatment. Additionally, considering that sampling HCV RNA on day 7 entails only one sampling instead of the two suggested by Sarrazin et al., i.e. baseline and week 4, while identifying approximately as many suitable candidates for short-term therapy, sampling at day 7 is likely to be more cost-effective for patients infected with HCV genotype 2 or 3. Also, the suggested cut-off level of 1000 IU/ml is stably quantifiable by most currently available assays, and is not prone to re-definition as the limits of detection of HCV RNA analyses will further improve over time. Similarly, since it is important that the day 7 HCV RNA sample is drawn immediately prior to the second dose of pegylated interferon, this allows for an additional opportunity to directly observe the patient’s injection technique as well as minimize the risk of sampling variations in relation to the previous dose as is often the case with week 4 HCV RNA determination. However, it is important to consider the intra- and inter-assay variability of real-time PCR based HCV RNA assays [[6]Sarrazin C. Dragan A. Gartner B.C. Forman M.S. Traver S. Zeuzem S. et al.Evaluation of an automated, highly sensitive, real-time PCR-based assay (COBAS Ampliprep/COBAS TaqMan) for quantification of HCV RNA.J Clin Virol. 2008; 43: 162-168Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] as well as differences between methods that persist despite the introduction of WHO standardizations [[7]Vermehren J. Kau A. Gartner B.C. Gobel R. Zeuzem S. Sarrazin C. 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 Microbiol. 2008; 46: 3880-3891Crossref PubMed Scopus (98) Google Scholar], which obviously affect all proposed algorithms based on quantitative HCV RNA determinations, including those at baseline or day 7. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The Swedish Society of Medicine, The Swedish Medical Research Council, The Swedish Society of Microbiology, ALF Funds, and Roche affiliates in the Nordic region supported this study.