Alimentary Pharmacology and Therapeutics Invited Commentaries generation PIs. The majority of studies investigating interferon-based treatment regimens with new DAAs include on-treatment HCV RNA testing as guidance for treatment futility, the optimal treatment duration and/or to predict sustained virological response. This affects the second wave PIs simeprevir and faldaprevir. In the US, stopping rules during simeprevir containing regimens are based on the detection of low level viraemia at certain time points. Preliminary studies suggest that even in patients treated with sofosbuvir and ribavirin dual therapy on-treatment HCV RNA levels can be associated with the risk for treatment failure.6 Finally, it may well be essential to determine the optimal duration of highly potent interferon-free regimens to save treatment costs and ensure that all patients can be treated. Therefore, on-treatment response predictors might be very useful also during future HCV therapies.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
Commentary: what factors are important in diagnosing hepatic fibrosis? M. Kelley & J. J. Feld Toronto Western Hospital Liver Centre, University Health Network, Toronto, ON, Canada. E-mail: [email protected] doi:10.1111/apt.12611
Von Willebrand factor (vWF) is released by activated endothelial cells and is a marker of endothelial dysfunction. Endothelial dysfunction is a fundamental component of increased hepatic vascular tone in cirrhotic livers.1 Previous studies have found vWF-Ag levels to correlate with Child-Pugh score, clinically significant portal hypertension and mortality.2, 3 The study conducted by Maieron et al. examined the utility of vWF-Ag as a marker of liver fibrosis. The authors compared vWF-Ag and a new VITRO score (vWF-Ag/platelets) to other non-invasive fibrosis scores (APRI, FCI, FORNS, FI, Fib-4) in patients with chronic hepatitis C, using liver biopsy as the gold standard. The vWF-Ag and VITRO score were found to be comparable in performance to the other fibrosis scores. As with most serum markers, differentiation between patients with and Aliment Pharmacol Ther 2014; 39: 540-546 ª 2014 John Wiley & Sons Ltd
REFERENCES 1. Elsharkawy AM. Commentary: detection of low level viraemia in telaprevir-based triple therapy for hepatitis C virus. Aliment Pharmacol Ther 2014; 39: 543–4. 2. Maasoumy B, Cobb B, Bremer B, et al. Detection of low HCV viraemia by repeated HCV RNA testing predicts treatment failure to triple therapy with telaprevir. Aliment Pharmacol Ther 2014; 39: 85–92. 3. Harrington PR, Zeng W, Naeger LK. Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during boceprevir or telaprevir treatment. Hepatology 2012; 55: 1048– 57. 4. Pfeiffer KH, Gerber L, Susser S, Vermehren J, Perner D, Sarrazin C. Significant differences between different assays for assessment of HCV RNA undetectability during response guided therapy in patients treated with PEG-Interferon, Ribavirin with or without a protease inhibitor. Hepatology 2012; 56: 560A. 5. Vermehren J, Aghemo A, Pfeiffer KH, et al. Undetectable HCVRNA in telaprevir-treated patients: low concordance between two highly sensitive real-time pcr assays. J Hepatol 2013; 58 (Suppl.): 208. 6. Wyles DL, Nelson DR, Swain MG, et al. On treatment HCV RNA as a predictor of virologic response in sofosbuvircontaining regimens for genotype 2/3 HCV infection: analysis of the FISSION, POSITRON, and FUSION studies. Hepatology 2013; 58: 140A.
without cirrhosis was better than the ability to distinguish earlier stages of fibrosis, likely reflecting that endothelial dysfunction is primarily a response to, or a cause of, portal hypertension, which only occurs with advanced fibrosis or cirrhosis.1 Although vWF-Ag is relatively inexpensive and the score is easy to calculate, this is not a test that is routinely ordered in patients with liver disease, meaning that it may add cost and inconvenience compared to simple fibrosis scores like APRI or FIB-4, which are composed of routine lab values. However, vWF-Ag may provide additional prognostic information, such as the presence of significant portal hypertension and may even predict mortality, which has been less clearly associated with components of the other scores.2, 3 This will clearly require further validation, but would provide a rationale for using this test over others. This study has demonstrated that measurement of vWF-Ag, and particularly the VITRO score, provides yet another non-invasive way to fairly reliably exclude or diagnose cirrhosis. Similar to the other fibrosis scores, its performance would likely improve when combined with another fibrosis measurement, such as transient elastography, which was not performed in this study.4 Ultimately, this test will probably not stand out as a major
545
Invited Commentaries advance on its own, but it is an additional tool and may well prove to be the ‘factor’ that predicts not only cirrhosis but also clinical outcomes.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES
fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment Pharmacol Ther 2014; 39: 331–8. 2. Ferlitsch M, Reiberger T, Hoke M, et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 2012; 56: 1439–47. 3. La Mura V, Reverter JC, Flores-Arroyo A, et al. Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension. Gut 2011; 60: 1133–8. 4. Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142: 1293–302.
1. Maieron A, Salzl P, Peck-Radosavljevic M, et al. Von Willebrand Factor as a new marker for non-invasive assessment of liver
Commentary: what factors are important in diagnosing hepatic fibrosis? Authors’ reply A. Maieron*,† & M. Ferlitsch† *Division of Gastroenterology and Hepatology, Internal Medicine IV, Elisabeth Hospital Linz, Linz, Austria. † Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria. E-mail: [email protected]
although it will increase costs slightly. However, as it may help not only to predict or rule out cirrhosis but also predict clinical outcomes, we believe that the marginal increased costs might be justified. Despite this, there is still a need for further clinical validation for vWF-Ag and VITRO score.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
doi:10.1111/apt.12612
REFERENCES 1
We agree on the comments by Kelley et al. regarding our article.2 So far, vWF-Ag is not part of the daily routine work-up. Many clinics and laboratories have the ability to determine vWF-Ag, and in fact vWF-Ag can be accessed from the same laboratory probe as, for example, an international normalized ratio (INR). Therefore, the addition of vWF-Ag and VITRO score does not augment inconvenience for the patients,
546
1. Kelley M, Feld JJ. Commentary: what factors are important in diagnosing hepatic fibrosis? Aliment Pharmacol Ther 2014; 39: 545–6. 2. Maieron A, Salzl P, Peck-Radosavljevic M, et al. Von Willebrand Factor as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment Pharmacol Ther 2014; 39: 331–8.
Aliment Pharmacol Ther 2014; 39: 540-546 ª 2014 John Wiley & Sons Ltd
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
Commentary: what factors are important in diagnosing hepatic fibrosis? M. Kelley & J. J. Feld Toronto Western Hospital Liver Centre, University Health Network, Toronto, ON, Canada. E-mail: [email protected] doi:10.1111/apt.12611
Von Willebrand factor (vWF) is released by activated endothelial cells and is a marker of endothelial dysfunction. Endothelial dysfunction is a fundamental component of increased hepatic vascular tone in cirrhotic livers.1 Previous studies have found vWF-Ag levels to correlate with Child-Pugh score, clinically significant portal hypertension and mortality.2, 3 The study conducted by Maieron et al. examined the utility of vWF-Ag as a marker of liver fibrosis. The authors compared vWF-Ag and a new VITRO score (vWF-Ag/platelets) to other non-invasive fibrosis scores (APRI, FCI, FORNS, FI, Fib-4) in patients with chronic hepatitis C, using liver biopsy as the gold standard. The vWF-Ag and VITRO score were found to be comparable in performance to the other fibrosis scores. As with most serum markers, differentiation between patients with and Aliment Pharmacol Ther 2014; 39: 540-546 ª 2014 John Wiley & Sons Ltd
REFERENCES 1. Elsharkawy AM. Commentary: detection of low level viraemia in telaprevir-based triple therapy for hepatitis C virus. Aliment Pharmacol Ther 2014; 39: 543–4. 2. Maasoumy B, Cobb B, Bremer B, et al. Detection of low HCV viraemia by repeated HCV RNA testing predicts treatment failure to triple therapy with telaprevir. Aliment Pharmacol Ther 2014; 39: 85–92. 3. Harrington PR, Zeng W, Naeger LK. Clinical relevance of detectable but not quantifiable hepatitis C virus RNA during boceprevir or telaprevir treatment. Hepatology 2012; 55: 1048– 57. 4. Pfeiffer KH, Gerber L, Susser S, Vermehren J, Perner D, Sarrazin C. Significant differences between different assays for assessment of HCV RNA undetectability during response guided therapy in patients treated with PEG-Interferon, Ribavirin with or without a protease inhibitor. Hepatology 2012; 56: 560A. 5. Vermehren J, Aghemo A, Pfeiffer KH, et al. Undetectable HCVRNA in telaprevir-treated patients: low concordance between two highly sensitive real-time pcr assays. J Hepatol 2013; 58 (Suppl.): 208. 6. Wyles DL, Nelson DR, Swain MG, et al. On treatment HCV RNA as a predictor of virologic response in sofosbuvircontaining regimens for genotype 2/3 HCV infection: analysis of the FISSION, POSITRON, and FUSION studies. Hepatology 2013; 58: 140A.
without cirrhosis was better than the ability to distinguish earlier stages of fibrosis, likely reflecting that endothelial dysfunction is primarily a response to, or a cause of, portal hypertension, which only occurs with advanced fibrosis or cirrhosis.1 Although vWF-Ag is relatively inexpensive and the score is easy to calculate, this is not a test that is routinely ordered in patients with liver disease, meaning that it may add cost and inconvenience compared to simple fibrosis scores like APRI or FIB-4, which are composed of routine lab values. However, vWF-Ag may provide additional prognostic information, such as the presence of significant portal hypertension and may even predict mortality, which has been less clearly associated with components of the other scores.2, 3 This will clearly require further validation, but would provide a rationale for using this test over others. This study has demonstrated that measurement of vWF-Ag, and particularly the VITRO score, provides yet another non-invasive way to fairly reliably exclude or diagnose cirrhosis. Similar to the other fibrosis scores, its performance would likely improve when combined with another fibrosis measurement, such as transient elastography, which was not performed in this study.4 Ultimately, this test will probably not stand out as a major
545
Invited Commentaries advance on its own, but it is an additional tool and may well prove to be the ‘factor’ that predicts not only cirrhosis but also clinical outcomes.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. REFERENCES
fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment Pharmacol Ther 2014; 39: 331–8. 2. Ferlitsch M, Reiberger T, Hoke M, et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 2012; 56: 1439–47. 3. La Mura V, Reverter JC, Flores-Arroyo A, et al. Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension. Gut 2011; 60: 1133–8. 4. Castera L. Noninvasive methods to assess liver disease in patients with hepatitis B or C. Gastroenterology 2012; 142: 1293–302.
1. Maieron A, Salzl P, Peck-Radosavljevic M, et al. Von Willebrand Factor as a new marker for non-invasive assessment of liver
Commentary: what factors are important in diagnosing hepatic fibrosis? Authors’ reply A. Maieron*,† & M. Ferlitsch† *Division of Gastroenterology and Hepatology, Internal Medicine IV, Elisabeth Hospital Linz, Linz, Austria. † Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria. E-mail: [email protected]
although it will increase costs slightly. However, as it may help not only to predict or rule out cirrhosis but also predict clinical outcomes, we believe that the marginal increased costs might be justified. Despite this, there is still a need for further clinical validation for vWF-Ag and VITRO score.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
doi:10.1111/apt.12612
REFERENCES 1
We agree on the comments by Kelley et al. regarding our article.2 So far, vWF-Ag is not part of the daily routine work-up. Many clinics and laboratories have the ability to determine vWF-Ag, and in fact vWF-Ag can be accessed from the same laboratory probe as, for example, an international normalized ratio (INR). Therefore, the addition of vWF-Ag and VITRO score does not augment inconvenience for the patients,
546
1. Kelley M, Feld JJ. Commentary: what factors are important in diagnosing hepatic fibrosis? Aliment Pharmacol Ther 2014; 39: 545–6. 2. Maieron A, Salzl P, Peck-Radosavljevic M, et al. Von Willebrand Factor as a new marker for non-invasive assessment of liver fibrosis and cirrhosis in patients with chronic hepatitis C. Aliment Pharmacol Ther 2014; 39: 331–8.
Aliment Pharmacol Ther 2014; 39: 540-546 ª 2014 John Wiley & Sons Ltd
