What offers the best prediction of sustained virologic response during combination therapy with interferon and ribavirin: Viral dynamics, viral levels at certain time points, or a combination of both?
Authors: Ola Weiland
Journal: Journal of Hepatology (2009)

Positive and negative prediction of sustained virologic response at weeks 2 and 4 of treatment with albinterferon alfa-2b or peginterferon alfa-2a in treatment-naïve patients with genotype 1, chronic hepatitis CJournal of HepatologyVol. 51Issue 1PreviewAlbinterferon alfa-2b is a novel, long-acting, fusion polypeptide that is dosed q2wk or q4wk. The predictive value of early virologic response during albinterferon alfa-2b or peginterferon alfa-2a treatment was investigated in interferon-naïve patients with genotype 1, chronic hepatitis C. Full-Text PDF Methods to predict the final outcome have been sought and continuously refined during the evolution of standard of care (SOC) treatment for chronic hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin.It was realised early on that genotype and viral load were baseline factors of major importance for achieving a final sustained virologic response (SVR), and that ribavirin was needed in combination with interferon to improve the results [[1]Reichard O. Norkrans G. Fryden A. Braconier J.H. Sonnerborg A. Weiland O. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group.Lancet. 1998; 351: 83-87Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar]. In the pivotal studies evaluating pegylated interferon and ribavirin treatment, it was noted that genotypes 2 and 3 were "easy to treat" and that patients with these genotypes responded much better than patients with "difficult to treat" genotypes 1 and 4 [2Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 3Hadziyannis 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 (2740) Google Scholar, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar]. Thus, patients with the "easy to treat" genotypes 2 and 3 responded with high SVR rates (overall 80%), substantially higher than patients with the "difficult to treat" genotypes 1 and 4 (some 50%) [2Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar]. A landmark study refined the treatment length so that SOC for genotype 2 and 3 was set at 24 weeks, whereas genotypes 1 and 4 needed 48 weeks' treatment [[3]Hadziyannis 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 (2740) Google Scholar]. In addition to genotype, other baseline factors influence the SVR rate, such as gender, extent of fibrosis, age at onset of the disease and race besides genotype and viral load [2Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 3Hadziyannis 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 (2740) Google Scholar, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar].When the viral kinetics during treatment were studied, it was noted that the viral decline during initial interferon treatment was much more pronounced for genotypes 2 and 3 than for genotype 1 [5Neumann A.U. Lam N.P. Dahari H. Davidian M. Wiley T.E. Mika B.P. et al.Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.J Infect Dis. 2000; 182: 28-35Crossref PubMed Scopus (206) Google Scholar, 6Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar]. The viral decline could be split into at least two phases with an initial very rapid 1st phase reduction during the first days of treatment reflecting a direct antiviral effect of IFN. The slower 2nd phase decline is considered to represent the elimination of infected hepatocytes and typically begins at day 3–4 [5Neumann A.U. Lam N.P. Dahari H. Davidian M. Wiley T.E. Mika B.P. et al.Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.J Infect Dis. 2000; 182: 28-35Crossref PubMed Scopus (206) Google Scholar, 6Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar]. It was also noted that the viral decay was IFN dose-dependant and steeper with higher doses. Overall, genotype 1 patients had a 1 log decline in HCV RNA levels during the 1st phase, whereas genotype 2 and 3 infections had a 3 log decline, reflecting that these genotypes are easier to treat.The presently used time points utilized to decide whether treatment should be stopped or continued are treatment weeks 4, 12 and 24. They constitute the basis for guidelines used for treatment of chronic HCV infection [7Läkemedelsbehandling av kronisk hepatit C hos vuxna och barn – uppdaterad rekommendation. Information från Läkemedelsverket (Information from the Swedish medical Product Agency) 2008;6:14–26.Google Scholar, 8Ferenci P. Fried M.W. Shiffman M.L. Smith C.I. Marinos G. Goncales F.L. et al.Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.J Hepatol. 2005; 43: 425-433Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar]. Patients with rapid viral response (RVR) meaning HCV RNA negativity already by treatment week 4 can be treated for a shorter-than-standard treatment. This means 24 weeks for genotype 1 and 12-16 weeks for genotypes 2 and 3, a treatment duration which offers nearly the same results as treatment lasting 48 and 24 weeks, respectively [9Dalgard O. Bjoro K. Ring-Larsen H. Bjornsson E. Holberg-Petersen M. Skovlund E. et al.Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.Hepatology. 2008; 47: 35-42Crossref PubMed Scopus (193) Google Scholar, 10Ferenci P. Laferl H. Scherzer T.M. Gschwantler M. Maieron A. Brunner H. et al.Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C ype 1 and 4 patients with rapid virological response.Gastroenterology. 2008; 135: 451-458Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 11Jensen 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 (460) Google Scholar, 12Lagging 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 (155) Google Scholar, 13Mangia A. Minerva N. Bacca D. Cozzolongo R. Agostinacchio E. Sogari F. et al.Determinants of relapse after a short (12 weeks) course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection.Hepatology. 2009; 49: 358-363Crossref PubMed Scopus (64) Google Scholar, 14Zeuzem S. Buti M. Ferenci P. Sperl J. Horsmans Y. Cianciara J. et al.Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.J Hepatol. 2006; 44: 97-103Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar]. How long patients with genotypes 2 or 3 who do not achieve RVR should be treated is not well defined, but patients who achieve RVR will have higher SVR rates than those who do not, also when treated with shorter-than-standard treatment schedules irrespective of genotype [14Zeuzem S. Buti M. Ferenci P. Sperl J. Horsmans Y. Cianciara J. et al.Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.J Hepatol. 2006; 44: 97-103Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 15Lagging 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, 16Weiland O. Hollander A. Mattsson L. Glaumann H. Lindahl K. Schvarcz R. et al.Lower-than-standard dose peg-IFN alfa-2a for chronic hepatitis C caused by genotype 2 and 3 is sufficient when given in combination with weight-based ribavirin.J Viral Hepat. 2008; 15: 641-645Crossref PubMed Scopus (23) Google Scholar]. For genotype 1 infections which respond less favourably to treatment, guidelines on when to stop treatment that will not be successful are needed.Today, a stopping rule is generally applied in patients who fail to achieve early viral response (EVR), meaning at least a 2 log drop of HCV RNA levels from baseline treatment week 12. This is advocated since the negative predictive value (NPV) is over 95% and very few patients who continue treatment will achieve SVR [[2]Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar]. Patients with EVR who have genotype 1 infection and become HCV RNA negative for the first time at treatment week 24, so called slow viral response, will achieve higher SVR rates if treatment is prolonged to 72 weeks [17Pearlman B.L. Ehleben C. Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders.Hepatology. 2007; 46: 1688-1694Crossref PubMed Scopus (223) Google Scholar, 18Sanchez-Tapias J.M. Diago M. Escartin P. Enriquez J. Romero-Gomez M. Barcena R. et al.Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment.Gastroenterology. 2006; 131: 451-460Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 19Berg T. von Wagner M. Nasser S. Sarrazin C. Heintges T. Gerlach T. et al.Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar].It is obvious that the earlier a patient becomes HCV RNA negative during treatment the higher the likelihood to achieve SVR [[8]Ferenci P. Fried M.W. Shiffman M.L. Smith C.I. Marinos G. Goncales F.L. et al.Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.J Hepatol. 2005; 43: 425-433Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar]. In fact, the viral decline and slope during the 2nd phase HCV RNA decline might be used to predict response and calculate the time needed for treatment to achieve SVR. A single standard IFN dose can be used to calculate the likelihood of a non-response: Jessner et al. measured the viral load within 24 h after one dose of 5 or 10 MU interferon alfa-2b in 29 consecutive patients with chronic HCV infection caused by genotype 1. A 24 h viral load decline of less than 70% of baseline after 5 MU interferon was the best pre-treatment measure to identify non-responders (specificity 100%, n = 10, 95% CI 74-100, sensitivity 83% (15/18), 59–96) [[20]Jessner W. Gschwantler M. Steindl-Munda P. Hofer H. Watkins-Riedel T. Wrba F. et al.Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study.Lancet. 2001; 358: 1241-1242Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. Furthermore, Drusano and Preston calculated that a negative HCV RNA test in serum for at least 36 weeks was needed to obtain SVR with 90% probability during SOC treatment of genotype 1 infections [[21]Drusano G.L. Preston S.L. A 48-week duration of therapy with pegylated interferon alpha 2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype-1 hepatitis C virus.J Infect Dis. 2004; 189: 964-970Crossref PubMed Scopus (79) Google Scholar]. This has been further refined by Lindh et al., who from data obtained in a pilot study, suggested that the calculated HCV RNA slope can be used to decide the length of SOC treatment that is needed to obtain SVR [[22]Lindh M. Alestig E. Arnholm B. Eilard A. Hellstrand K. Lagging M. et al.Response prediction and treatment tailoring for chronic hepatitis C virus genotype 1 infection.J Clin Microbiol. 2007; 45: 2439-2445Crossref PubMed Scopus (17) Google Scholar]. These authors found a strong correlation between the 2nd phase slope and SVR. Patients with a slope steeper than 0.7 log units/week obtained SVR in 95% and those with a slope between 0.35 and 0.7 log units/week in 64%, whereas patients with slopes below 0.35 log units/week all became non-SVR patients with SOC treatment [[22]Lindh M. Alestig E. Arnholm B. Eilard A. Hellstrand K. Lagging M. et al.Response prediction and treatment tailoring for chronic hepatitis C virus genotype 1 infection.J Clin Microbiol. 2007; 45: 2439-2445Crossref PubMed Scopus (17) Google Scholar].In this issue of the Journal, Neumann et al. have utilized the HCV RNA decline and HCV RNA levels at different time points during combination treatment with albinterferon alfa-2b or peginterferon alfa-2a and ribavirin to calculate the positive and negative predictive value of SVR with a linear exhaustive search algorithm [[23]Neumann A.U. Pianko S. Zuezem S. Yoshida E.M. Benhamou Y. Mishan M. et al.Positive and negative prediction of sustained virologic response at weeks 2 and 4 of treatment with albinterferon alfa-2b or peginterferon alfa-2a in treatment-naïve patients with genotype 1, chronic hepatitis C.J Hepatol. 2009; 51: 21-28Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. The authors claim that improved SVR prediction was possible when both the HCV RNA reduction (VD) and levels of HCV RNA (VL) treatment week 2 and 4 were used in this algorithm. For these calculations they used the results from 368 patients (80%) treated per protocol or treated until discontinuation due to non-response in the four-armed study [[23]Neumann A.U. Pianko S. Zuezem S. Yoshida E.M. Benhamou Y. Mishan M. et al.Positive and negative prediction of sustained virologic response at weeks 2 and 4 of treatment with albinterferon alfa-2b or peginterferon alfa-2a in treatment-naïve patients with genotype 1, chronic hepatitis C.J Hepatol. 2009; 51: 21-28Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. As expected, most patients with a larger initial viral decline (VD) week 2 and 4 achieved SVR whereas those with low VD failed to do so. The authors used an exhaustive search computer program to identify the thresholds of VD and viral load (VL) at weeks 0, 2, 4, 6, 8 and 12 and their combinations.Overall, the VL thresholds were better for NPV calculations than VD, whereas the latter were better for a positive prediction of SVR than VL.The best NPV for SVR was obtained when VD and VL data were combined. Hence, at treatment week 4, a VL > 5.5 log10 IU/mL and VD < 2 log10 IU/mL provided a 100% NPV in all treatment arms.Patients who the authors claimed to have rapid initial viral response (RIVR) meaning VD >2 log10 IU/mL treatment week 2 had a high PPV for SVR (88–97%) comparable to figures found for RVR (a negative HCV RNA treatment week 4) and included a larger group at an earlier time point than RVR. By using the less stringent threshold VD >3 log10 IU/mL at week 4, a PPV of 88–94% was seen in one-third to half of the number of patients.To complicate the calculations further, the authors used a sequential prediction algorithm from weeks 2, 4 and 12 and divided the response patterns into 4 categories: rapid initial virologic response, partial initial virologic response, no initial virologic response and low initial virologic response. Some 28–35% of the patients could, however, not be properly classified and for these patients assessment of complete EVR is still needed for prediction of SVR.Overall, the authors found that by integrating VD and VL data obtained sequentially at weeks 2 and 4, totally 65–72% of the patients in the four treatment arms demonstrated high PPV or NPV. These patients could be identified already by treatment week 4.What are the implications of these findings? Are they likely to be used on a daily basis for deciding when to stop or continue treatment during SOC treatment for chronic HCV infection? Probably not, since most clinicians would find them too cumbersome and difficult to use. They do, however, indicate that VD and VL data during the first 4 weeks of treatment in patients with genotype 1, particularly when combined, can be used to categorize patients in different response groups, and indicate the possibility that a subgroup who have a very small chance to respond to SOC during 48 weeks treatment can stop treatment already at week 4. This is at an earlier time point than treatment week 12 used in the currently operating guidelines, and can save unnecessary adverse events and costs for society [7Läkemedelsbehandling av kronisk hepatit C hos vuxna och barn – uppdaterad rekommendation. Information från Läkemedelsverket (Information from the Swedish medical Product Agency) 2008;6:14–26.Google Scholar, 24Anonymous. NIH consensus development conference statement:management of hepatitis C 2002 (June 10–12, 2002). Hepatology 2002;36(Suppl. 1):S3–S20.Google Scholar]. This, however, needs to be confirmed in a larger prospective study, which is not likely to be performed since the addition of STAT-C drugs to SOC treatment offers a promise to increase the RVR rates in genotype 1 from some 10–15% of today to 80–100%, making shorter treatment schedules possible [[25]Soriano V. Peters M.G. Zeuzem S. New therapies for hepatitis C virus infection.Clin Infect Dis. 2009; 48: 313-320Crossref PubMed Scopus (151) Google Scholar].A favourable outcome of treatment is, however, also to a very large extent dependent on a good compliance of the patients to the treatment length and to ribavirin and peg-IFN doses given, as indicated by the 80/80/80 rule [[26]McHutchison J.G. Manns M. Patel K. Poynard T. Lindsay K.L. Trepo C. et al.Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1061-1069Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar].In summary, the results of the study by Neumann et al. indicate that VD data can be used to calculate PPV better than VL determinations at certain time points, and that the combination of VD and VL data can do this even better. These calculations, however, are likely to be regarded as complicated and expensive and not practical for the every day care of patients. Calculations of the VD or the 2nd phase slope during the initial 4 weeks of treatment might, however, offer a possibility to individualize the treatment duration for genotype 1 patients, from the categorized 24, 48 or 72 weeks' treatment used today based on RVR or EVR, to more flexible treatment periods spanning from 24 to 72 weeks. Methods to predict the final outcome have been sought and continuously refined during the evolution of standard of care (SOC) treatment for chronic hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin. It was realised early on that genotype and viral load were baseline factors of major importance for achieving a final sustained virologic response (SVR), and that ribavirin was needed in combination with interferon to improve the results [[1]Reichard O. Norkrans G. Fryden A. Braconier J.H. Sonnerborg A. Weiland O. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group.Lancet. 1998; 351: 83-87Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar]. In the pivotal studies evaluating pegylated interferon and ribavirin treatment, it was noted that genotypes 2 and 3 were "easy to treat" and that patients with these genotypes responded much better than patients with "difficult to treat" genotypes 1 and 4 [2Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 3Hadziyannis 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 (2740) Google Scholar, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar]. Thus, patients with the "easy to treat" genotypes 2 and 3 responded with high SVR rates (overall 80%), substantially higher than patients with the "difficult to treat" genotypes 1 and 4 (some 50%) [2Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar]. A landmark study refined the treatment length so that SOC for genotype 2 and 3 was set at 24 weeks, whereas genotypes 1 and 4 needed 48 weeks' treatment [[3]Hadziyannis 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 (2740) Google Scholar]. In addition to genotype, other baseline factors influence the SVR rate, such as gender, extent of fibrosis, age at onset of the disease and race besides genotype and viral load [2Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar, 3Hadziyannis 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 (2740) Google Scholar, 4Manns M.P. McHutchison J.G. Gordon S.C. Rustgi V.K. Shiffman M. Reindollar R. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5873) Google Scholar]. When the viral kinetics during treatment were studied, it was noted that the viral decline during initial interferon treatment was much more pronounced for genotypes 2 and 3 than for genotype 1 [5Neumann A.U. Lam N.P. Dahari H. Davidian M. Wiley T.E. Mika B.P. et al.Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.J Infect Dis. 2000; 182: 28-35Crossref PubMed Scopus (206) Google Scholar, 6Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar]. The viral decline could be split into at least two phases with an initial very rapid 1st phase reduction during the first days of treatment reflecting a direct antiviral effect of IFN. The slower 2nd phase decline is considered to represent the elimination of infected hepatocytes and typically begins at day 3–4 [5Neumann A.U. Lam N.P. Dahari H. Davidian M. Wiley T.E. Mika B.P. et al.Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.J Infect Dis. 2000; 182: 28-35Crossref PubMed Scopus (206) Google Scholar, 6Neumann A.U. Lam N.P. Dahari H. Gretch D.R. Wiley T.E. Layden T.J. et al.Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.Science. 1998; 282: 103-107Crossref PubMed Scopus (1889) Google Scholar]. It was also noted that the viral decay was IFN dose-dependant and steeper with higher doses. Overall, genotype 1 patients had a 1 log decline in HCV RNA levels during the 1st phase, whereas genotype 2 and 3 infections had a 3 log decline, reflecting that these genotypes are easier to treat. The presently used time points utilized to decide whether treatment should be stopped or continued are treatment weeks 4, 12 and 24. They constitute the basis for guidelines used for treatment of chronic HCV infection [7Läkemedelsbehandling av kronisk hepatit C hos vuxna och barn – uppdaterad rekommendation. Information från Läkemedelsverket (Information from the Swedish medical Product Agency) 2008;6:14–26.Google Scholar, 8Ferenci P. Fried M.W. Shiffman M.L. Smith C.I. Marinos G. Goncales F.L. et al.Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.J Hepatol. 2005; 43: 425-433Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar]. Patients with rapid viral response (RVR) meaning HCV RNA negativity already by treatment week 4 can be treated for a shorter-than-standard treatment. This means 24 weeks for genotype 1 and 12-16 weeks for genotypes 2 and 3, a treatment duration which offers nearly the same results as treatment lasting 48 and 24 weeks, respectively [9Dalgard O. Bjoro K. Ring-Larsen H. Bjornsson E. Holberg-Petersen M. Skovlund E. et al.Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response.Hepatology. 2008; 47: 35-42Crossref PubMed Scopus (193) Google Scholar, 10Ferenci P. Laferl H. Scherzer T.M. Gschwantler M. Maieron A. Brunner H. et al.Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C ype 1 and 4 patients with rapid virological response.Gastroenterology. 2008; 135: 451-458Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 11Jensen 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 (460) Google Scholar, 12Lagging 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 (155) Google Scholar, 13Mangia A. Minerva N. Bacca D. Cozzolongo R. Agostinacchio E. Sogari F. et al.Determinants of relapse after a short (12 weeks) course of antiviral therapy and re-treatment efficacy of a prolonged course in patients with chronic hepatitis C virus genotype 2 or 3 infection.Hepatology. 2009; 49: 358-363Crossref PubMed Scopus (64) Google Scholar, 14Zeuzem S. Buti M. Ferenci P. Sperl J. Horsmans Y. Cianciara J. et al.Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.J Hepatol. 2006; 44: 97-103Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar]. How long patients with genotypes 2 or 3 who do not achieve RVR should be treated is not well defined, but patients who achieve RVR will have higher SVR rates than those who do not, also when treated with shorter-than-standard treatment schedules irrespective of genotype [14Zeuzem S. Buti M. Ferenci P. Sperl J. Horsmans Y. Cianciara J. et al.Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia.J Hepatol. 2006; 44: 97-103Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar, 15Lagging 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, 16Weiland O. Hollander A. Mattsson L. Glaumann H. Lindahl K. Schvarcz R. et al.Lower-than-standard dose peg-IFN alfa-2a for chronic hepatitis C caused by genotype 2 and 3 is sufficient when given in combination with weight-based ribavirin.J Viral Hepat. 2008; 15: 641-645Crossref PubMed Scopus (23) Google Scholar]. For genotype 1 infections which respond less favourably to treatment, guidelines on when to stop treatment that will not be successful are needed. Today, a stopping rule is generally applied in patients who fail to achieve early viral response (EVR), meaning at least a 2 log drop of HCV RNA levels from baseline treatment week 12. This is advocated since the negative predictive value (NPV) is over 95% and very few patients who continue treatment will achieve SVR [[2]Fried M.W. Shiffman M.L. Reddy K.R. Smith C. Marinos G. Goncales F.L. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5861) Google Scholar]. Patients with EVR who have genotype 1 infection and become HCV RNA negative for the first time at treatment week 24, so called slow viral response, will achieve higher SVR rates if treatment is prolonged to 72 weeks [17Pearlman B.L. Ehleben C. Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis c genotype 1-infected slow responders.Hepatology. 2007; 46: 1688-1694Crossref PubMed Scopus (223) Google Scholar, 18Sanchez-Tapias J.M. Diago M. Escartin P. Enriquez J. Romero-Gomez M. Barcena R. et al.Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment.Gastroenterology. 2006; 131: 451-460Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 19Berg T. von Wagner M. Nasser S. Sarrazin C. Heintges T. Gerlach T. et al.Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin.Gastroenterology. 2006; 130: 1086-1097Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar]. It is obvious that the earlier a patient becomes HCV RNA negative during treatment the higher the likelihood to achieve SVR [[8]Ferenci P. Fried M.W. Shiffman M.L. Smith C.I. Marinos G. Goncales F.L. et al.Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin.J Hepatol. 2005; 43: 425-433Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar]. In fact, the viral decline and slope during the 2nd phase HCV RNA decline might be used to predict response and calculate the time needed for treatment to achieve SVR. A single standard IFN dose can be used to calculate the likelihood of a non-response: Jessner et al. measured the viral load within 24 h after one dose of 5 or 10 MU interferon alfa-2b in 29 consecutive patients with chronic HCV infection caused by genotype 1. A 24 h viral load decline of less than 70% of baseline after 5 MU interferon was the best pre-treatment measure to identify non-responders (specificity 100%, n = 10, 95% CI 74-100, sensitivity 83% (15/18), 59–96) [[20]Jessner W. Gschwantler M. Steindl-Munda P. Hofer H. Watkins-Riedel T. Wrba F. et al.Primary interferon resistance and treatment response in chronic hepatitis C infection: a pilot study.Lancet. 2001; 358: 1241-1242Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. Furthermore, Drusano and Preston calculated that a negative HCV RNA test in serum for at least 36 weeks was needed to obtain SVR with 90% probability during SOC treatment of genotype 1 infections [[21]Drusano G.L. Preston S.L. A 48-week duration of therapy with pegylated interferon alpha 2b plus ribavirin may be too short to maximize long-term response among patients infected with genotype-1 hepatitis C virus.J Infect Dis. 2004; 189: 964-970Crossref PubMed Scopus (79) Google Scholar]. This has been further refined by Lindh et al., who from data obtained in a pilot study, suggested that the calculated HCV RNA slope can be used to decide the length of SOC treatment that is needed to obtain SVR [[22]Lindh M. Alestig E. Arnholm B. Eilard A. Hellstrand K. Lagging M. et al.Response prediction and treatment tailoring for chronic hepatitis C virus genotype 1 infection.J Clin Microbiol. 2007; 45: 2439-2445Crossref PubMed Scopus (17) Google Scholar]. These authors found a strong correlation between the 2nd phase slope and SVR. Patients with a slope steeper than 0.7 log units/week obtained SVR in 95% and those with a slope between 0.35 and 0.7 log units/week in 64%, whereas patients with slopes below 0.35 log units/week all became non-SVR patients with SOC treatment [[22]Lindh M. Alestig E. Arnholm B. Eilard A. Hellstrand K. Lagging M. et al.Response prediction and treatment tailoring for chronic hepatitis C virus genotype 1 infection.J Clin Microbiol. 2007; 45: 2439-2445Crossref PubMed Scopus (17) Google Scholar]. In this issue of the Journal, Neumann et al. have utilized the HCV RNA decline and HCV RNA levels at different time points during combination treatment with albinterferon alfa-2b or peginterferon alfa-2a and ribavirin to calculate the positive and negative predictive value of SVR with a linear exhaustive search algorithm [[23]Neumann A.U. Pianko S. Zuezem S. Yoshida E.M. Benhamou Y. Mishan M. et al.Positive and negative prediction of sustained virologic response at weeks 2 and 4 of treatment with albinterferon alfa-2b or peginterferon alfa-2a in treatment-naïve patients with genotype 1, chronic hepatitis C.J Hepatol. 2009; 51: 21-28Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. The authors claim that improved SVR prediction was possible when both the HCV RNA reduction (VD) and levels of HCV RNA (VL) treatment week 2 and 4 were used in this algorithm. For these calculations they used the results from 368 patients (80%) treated per protocol or treated until discontinuation due to non-response in the four-armed study [[23]Neumann A.U. Pianko S. Zuezem S. Yoshida E.M. Benhamou Y. Mishan M. et al.Positive and negative prediction of sustained virologic response at weeks 2 and 4 of treatment with albinterferon alfa-2b or peginterferon alfa-2a in treatment-naïve patients with genotype 1, chronic hepatitis C.J Hepatol. 2009; 51: 21-28Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. As expected, most patients with a larger initial viral decline (VD) week 2 and 4 achieved SVR whereas those with low VD failed to do so. The authors used an exhaustive search computer program to identify the thresholds of VD and viral load (VL) at weeks 0, 2, 4, 6, 8 and 12 and their combinations. Overall, the VL thresholds were better for NPV calculations than VD, whereas the latter were better for a positive prediction of SVR than VL. The best NPV for SVR was obtained when VD and VL data were combined. Hence, at treatment week 4, a VL > 5.5 log10 IU/mL and VD < 2 log10 IU/mL provided a 100% NPV in all treatment arms. Patients who the authors claimed to have rapid initial viral response (RIVR) meaning VD >2 log10 IU/mL treatment week 2 had a high PPV for SVR (88–97%) comparable to figures found for RVR (a negative HCV RNA treatment week 4) and included a larger group at an earlier time point than RVR. By using the less stringent threshold VD >3 log10 IU/mL at week 4, a PPV of 88–94% was seen in one-third to half of the number of patients. To complicate the calculations further, the authors used a sequential prediction algorithm from weeks 2, 4 and 12 and divided the response patterns into 4 categories: rapid initial virologic response, partial initial virologic response, no initial virologic response and low initial virologic response. Some 28–35% of the patients could, however, not be properly classified and for these patients assessment of complete EVR is still needed for prediction of SVR. Overall, the authors found that by integrating VD and VL data obtained sequentially at weeks 2 and 4, totally 65–72% of the patients in the four treatment arms demonstrated high PPV or NPV. These patients could be identified already by treatment week 4. What are the implications of these findings? Are they likely to be used on a daily basis for deciding when to stop or continue treatment during SOC treatment for chronic HCV infection? Probably not, since most clinicians would find them too cumbersome and difficult to use. They do, however, indicate that VD and VL data during the first 4 weeks of treatment in patients with genotype 1, particularly when combined, can be used to categorize patients in different response groups, and indicate the possibility that a subgroup who have a very small chance to respond to SOC during 48 weeks treatment can stop treatment already at week 4. This is at an earlier time point than treatment week 12 used in the currently operating guidelines, and can save unnecessary adverse events and costs for society [7Läkemedelsbehandling av kronisk hepatit C hos vuxna och barn – uppdaterad rekommendation. Information från Läkemedelsverket (Information from the Swedish medical Product Agency) 2008;6:14–26.Google Scholar, 24Anonymous. NIH consensus development conference statement:management of hepatitis C 2002 (June 10–12, 2002). Hepatology 2002;36(Suppl. 1):S3–S20.Google Scholar]. This, however, needs to be confirmed in a larger prospective study, which is not likely to be performed since the addition of STAT-C drugs to SOC treatment offers a promise to increase the RVR rates in genotype 1 from some 10–15% of today to 80–100%, making shorter treatment schedules possible [[25]Soriano V. Peters M.G. Zeuzem S. New therapies for hepatitis C virus infection.Clin Infect Dis. 2009; 48: 313-320Crossref PubMed Scopus (151) Google Scholar]. A favourable outcome of treatment is, however, also to a very large extent dependent on a good compliance of the patients to the treatment length and to ribavirin and peg-IFN doses given, as indicated by the 80/80/80 rule [[26]McHutchison J.G. Manns M. Patel K. Poynard T. Lindsay K.L. Trepo C. et al.Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1061-1069Abstract Full Text Full Text PDF PubMed Scopus (952) Google Scholar]. In summary, the results of the study by Neumann et al. indicate that VD data can be used to calculate PPV better than VL determinations at certain time points, and that the combination of VD and VL data can do this even better. These calculations, however, are likely to be regarded as complicated and expensive and not practical for the every day care of patients. Calculations of the VD or the 2nd phase slope during the initial 4 weeks of treatment might, however, offer a possibility to individualize the treatment duration for genotype 1 patients, from the categorized 24, 48 or 72 weeks' treatment used today based on RVR or EVR, to more flexible treatment periods spanning from 24 to 72 weeks.