BACKGROUND & AIMS: Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA)>6 log IU/mL or cirrhosis have a reduced probability of a sustained-virologic response (SVR). We examined the relation between bHCV-RNA, cirrhosis, and SVR with a mathematical model that includes the critical-drug efficacy (epsilonc; the efficacy required for a drug to clear HCV), the infection-rate constant (beta), and the percentage of HCV-infected hepatocytes (pi). METHODS: The relation between baseline factors and SVR was evaluated in 1000 in silico HCV-infected patients, generated by random assignment of realistic host and viral kinetic parameters. Model predictions were compared with clinical data from 170 noncirrhotic and 75 cirrhotic patients. RESULTS: The ranges chosen for beta and the viral production rate (p) resulted in bHCV-RNA levels that were in agreement with the distribution observed in US patients. With these beta and p values, higher bHCV-RNA levels led to higher epsilonc, resulting in lower SVR rates. However, higher beta values resulted in lower bHCV-RNA levels but higher pi and (epsilonc), predicting lower rates of SVR. Cirrhotic patients had lower bHCV-RNA levels than noncirrhotic patients (P=.013), and more had bHCV-RNA levels<6 log IU/mL (P<.001). Even cirrhotic patients with lower bHCV-RNA levels had lower SVR rates. An increase in beta could explain the results observed in cirrhotic patients. CONCLUSIONS: Our model predicts that higher bHCV-RNA levels lead to higher epsilonc, reducing the chance of achieving SVR; cirrhotic patients have lower SVR rates because of large pi values, caused by increased rates of hepatocyte infection.
BACKGROUND & AIMS:Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA)>6 log IU/mL or cirrhosis have a reduced probability of a sustained-virologic response (SVR). We examined the relation between bHCV-RNA, cirrhosis, and SVR with a mathematical model that includes the critical-drug efficacy (epsilonc; the efficacy required for a drug to clear HCV), the infection-rate constant (beta), and the percentage of HCV-infected hepatocytes (pi). METHODS: The relation between baseline factors and SVR was evaluated in 1000 in silico HCV-infectedpatients, generated by random assignment of realistic host and viral kinetic parameters. Model predictions were compared with clinical data from 170 noncirrhotic and 75 cirrhoticpatients. RESULTS: The ranges chosen for beta and the viral production rate (p) resulted in bHCV-RNA levels that were in agreement with the distribution observed in US patients. With these beta and p values, higher bHCV-RNA levels led to higher epsilonc, resulting in lower SVR rates. However, higher beta values resulted in lower bHCV-RNA levels but higher pi and (epsilonc), predicting lower rates of SVR. Cirrhoticpatients had lower bHCV-RNA levels than noncirrhotic patients (P=.013), and more had bHCV-RNA levels<6 log IU/mL (P<.001). Even cirrhoticpatients with lower bHCV-RNA levels had lower SVR rates. An increase in beta could explain the results observed in cirrhoticpatients. CONCLUSIONS: Our model predicts that higher bHCV-RNA levels lead to higher epsilonc, reducing the chance of achieving SVR; cirrhoticpatients have lower SVR rates because of large pi values, caused by increased rates of hepatocyte infection.
Authors: Martin Lagging; Ana I Romero; Johan Westin; Gunnar Norkrans; Amar P Dhillon; Jean-Michel Pawlotsky; Stefan Zeuzem; Michael von Wagner; Francesco Negro; Solko W Schalm; Bart L Haagmans; Carlo Ferrari; Gabriele Missale; Avidan U Neumann; Elke Verheij-Hart; Kristoffer Hellstrand Journal: Hepatology Date: 2006-12 Impact factor: 17.425
Authors: Hari S Conjeevaram; Michael W Fried; Lennox J Jeffers; Norah A Terrault; Thelma E Wiley-Lucas; Nezam Afdhal; Robert S Brown; Steven H Belle; Jay H Hoofnagle; David E Kleiner; Charles D Howell Journal: Gastroenterology Date: 2006-08 Impact factor: 22.682
Authors: Harel Dahari; Marian Major; Xinan Zhang; Kathleen Mihalik; Charles M Rice; Alan S Perelson; Stephen M Feinstone; Avidan U Neumann Journal: Gastroenterology Date: 2005-04 Impact factor: 22.682
Authors: Gregory T Everson; John C Hoefs; Leonard B Seeff; Herbert L Bonkovsky; Deepa Naishadham; Mitchell L Shiffman; Jeffrey A Kahn; Anna S F Lok; Adrian M Di Bisceglie; William M Lee; Jules L Dienstag; Marc G Ghany; Chihiro Morishima Journal: Hepatology Date: 2006-12 Impact factor: 17.425
Authors: Sampa Pal; Margaret C Shuhart; Lisa Thomassen; Scott S Emerson; Tao Su; Nathan Feuerborn; John Kae; David R Gretch Journal: J Virol Date: 2006-03 Impact factor: 5.103
Authors: Harel Dahari; Evaldo S Affonso de Araujo; Bart L Haagmans; Thomas J Layden; Scott J Cotler; Antonio A Barone; Avidan U Neumann Journal: J Hepatol Date: 2010-05-27 Impact factor: 25.083