Viral kinetics for individualized treatment durations
Authors: Christoph Sarrazin
Journal: Journal of Hepatology (2010)

Is HCV RNA analysis at day 7 cost-effective in deciding the duration of therapy in chronic HCV genotype 2/3 infection?Journal of HepatologyVol. 54Issue 4PreviewTo the Editor: The recent study by Sarrazin et al. [1] reported results from a re-analysis of stored sera from two large multicenter randomized trials [2,3], 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. Full-Text PDF Open Access Reply to Lagging et al.: The shortening of treatment duration is the most important aim for improving antiviral therapy in patients with chronic hepatitis C. The new direct antiviral agents currently in development should allow an increasing number of patients to benefit from shortened treatment durations and consequently to significantly increase the number of patients who are willing and able to receive antiviral therapy. Algorithms for abbreviated treatment durations established for the current standard of care are mainly based on viral kinetics. In addition, while not visible in smaller studies [1von Wagner M. Huber M. Berg T. Hinrichsen H. Rasenack J. Heintges T. et al.Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C.Gastroenterology. 2005; 129: 522-527Abstract Full Text Full Text PDF PubMed Google Scholar, 2Mangia A. Santoro R. Minerva N. Ricci G.L. Carretta V. Persico M. et al.Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3.N Engl J Med. 2005; 352: 2609-2617Crossref PubMed Scopus (604) Google Scholar] all large studies have shown that in patients with high baseline viral load, higher relapse rates were observed, although they become HCV RNA negative at time points that are identical to those reported in patients with a low baseline viral load [3Jensen D.M. Morgan T.R. Marcellin P. Pockros P.J. Reddy K.R. Hadziyannis S.J. et al.Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy.Hepatology. 2006; 43: 954-960Crossref PubMed Scopus (465) Google Scholar, 4Diago M. Shiffman M.L. Bronowicki J.P. Zeuzem S. Rodriguez-Torres M. Pappas S.C. et al.Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40 KD) plus ribavirin.Hepatology. 2010; 51: 1897-1903Crossref PubMed Scopus (57) Google Scholar]. Thus, in the NORDynamIC study reported by Lagging et al., baseline viral load may not be a significant predictor of relapse in patients with virologic response at day 7 because of the limited number of patients investigated [[5]Lagging M. Alsiö A. Hellstrand K. Norkrans G. Is HCV RNA analysis at day 7 cost-effective in deciding the duration of therapy in chronic hepatitis genotype 2/3 infection?.J Hepatol. 2011; 54: 836-837Abstract Full Text Full Text PDF Scopus (8) Google Scholar]. However, it may also be that the selection of patients for shortened treatment very early on during therapy (i.e. day 7) and the application of a viral cut-off level (i.e. 1000 IU/ml) rather than undetectable HCV RNA, allow for a response to be predicted independent of baseline viral load. This has to be explored in future studies. However, while the assessment of virologic response very early during therapy may indeed have the potential of very high positive predictive values of sustained virologic response, the number of patients benefitting may decline (i.e. 109 vs. 136 patients in the NORDynamIC trial). In addition, practical, pharmacokinetic, and technical problems may arise: (1) it is essential to take an early assessment of viral kinetic measurements of HCV RNA viral load from blood drawn exactly at day 7 and directly before the next PEG-interferon injection because viral load may fluctuate significantly during the initial phase of viral decline. This may be less of a problem 4 weeks after initiation of antiviral therapy. Indeed, in our study we found that when retesting a large number of samples at week 4, undetectable HCV RNA and viral levels below 15 IU/ml had identical predictive values for sustained virologic response in genotype 1 and 2/3 infected patients [[6]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]. (2) Differences may be present between the two pegylated interferons alfa 2a and 2b because of different pharmacokinetics (65 vs. a 28 h elimination half-life, respectively). For pegylated interferon alfa 2b, a more step-wise viral decline is well known. After one week of therapy a flat or even slightly increasing viral load kinetics may be seen while a more continuous viral decline is observed with pegylated interferon alfa 2a. With identical rapid virologic response rates for both pegylated interferons at week 4 of treatment (IDEAL study 11.4% vs. 11.9% for pegylated interferon alfa 2a vs. 2b, respectively) [[7]McHutchison J.G. Lawitz E.J. Shiffman M.L. Muir A.J. Galler G.W. McCone J. et al.Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.N Engl J Med. 2009; 361: 580-593Crossref PubMed Scopus (1126) Google Scholar] algorithms with later assessments of virologic response may be better applicable for these differences. (3) Finally, despite standardization of IU HCV RNA viral loads measured with different commercially available assays, these are not comparable and this is already a problem for the determination of low vs. high baseline viral load. For a measurement at day 7 as proposed by Lagging et al., for example 1000 IU/ml by the Cobas TaqMan assay in genotype 1, 2, 3 infected patients equals approximately 300, 1000, and 600 IU/ml by realtime HCV and 300, 600, and 500 IU/ml by the bDNA assay [8Chevaliez S. Bouvier-Alias M. Brillet R. Pawlotsky J.M. Overestimation and underestimation of hepatitis C virus RNA levels in a widely used real-time polymerase chain reaction-based method.Hepatology. 2007; 46: 22-31Crossref PubMed Scopus (123) Google Scholar, 9Michelin B.D. Muller Z. Stelzl E. Marth E. Kessler H.H. Evaluation of the Abbott RealTime HCV assay for quantitative detection of hepatitis C virus RNA.J Clin Virol. 2007; 38: 96-100Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 10Vermehren J. Kau A. Gartner B.C. Gobel R. Zeuzem S. Sarrazin C. Differences between two real-time PCR based assays (RealTime HCV, Cobas AmpliPrep/Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for HCV RNA detection and quantification.J Clin Microbiol. 2008; 46: 3880-3891Crossref PubMed Scopus (98) Google Scholar, 11Sarrazin C. Gärtner B. Sizmann D. Babiel R. Mihm U. Hofmann W.P. et al.Comparison of conventional PCR with real-time PCR and branched DNA-based assays for hepatitis C virus RNA quantification and clinical significance for genotypes 1 to 5.J Clin Microbiol. 2006; 44: 729-737Crossref PubMed Scopus (85) Google Scholar]. Moreover, a significant intra- and inter-assay variability especially for lower viral loads (0.04–0.13 log10 SD) may make it difficult to establish a general and precise rule with just one HCV RNA measurement taken early during therapy [[10]Vermehren J. Kau A. Gartner B.C. Gobel R. Zeuzem S. Sarrazin C. Differences between two real-time PCR based assays (RealTime HCV, Cobas AmpliPrep/Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for HCV RNA detection and quantification.J Clin Microbiol. 2008; 46: 3880-3891Crossref PubMed Scopus (98) Google Scholar]. Herein, determination of undetectable HCV RNA levels with a highly sensitive assay may be superior because all new assays have lower detection limits between 5 and 10 IU/ml (Cobas TaqMan, realtime HCV, TMA). All these parameters have to be taken into account for the current standard of care. In the era of direct antiviral agents that display strong antiviral activities, highly individualized and tailored treatment durations will be established. The determination of virologic response with or without additional parameters (baseline viral load, IL28B polymorphisms etc.) very early during therapy (i.e. between day 3 and week 4) will most likely be required for the selection of super responders that may benefit from very short treatments (24 weeks or shorter for genotype 1 and perhaps even below 12–16 weeks for genotype 2/3 infected patients). 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.