Results From the HALT-C Trial
Results From the HALT-C Trial
Backgroud: The impact of virologic response on hepatic function has not been previously defined.
Aim: To determine the relationships of quantitative liver function tests (QLFTs) with virological responses to peginterferon (PEG) ± ribavirin (RBV) in patients with chronic hepatitis C and to use serial QLFTs to define the spectrum of hepatic improvement after sustained virological response (SVR).
Methods: Participants (n = 232) were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, had failed prior therapy, had bridging fibrosis or cirrhosis and were retreated with PEG/RBV. All 232 patients had baseline QLFTs; 24 patients with SVR and 68 nonresponders had serial QLFTs. Lidocaine, [24-C]cholate, galactose and Tc-sulfur colloid were administered intravenously; [2,2,4,2-H]cholate, [1-C]methionine, caffeine and antipyrine were administered orally. Clearances (Cl), breath CO2, monoethylglycylxylidide (MEGX), perfused hepatic mass (PHM) and liver volume were measured.
Results: Rates of SVR were 18-26% in patients with good function by QLFTs, but ≤6% in patients with poor function. Hepatic metabolism, measured by caffeine kelim (P = 0.02), antipyrine kelim (P = 0.05) and antipyrine Cl (P = 0.02) and the portal circulation, measured by cholate Cloral (P = 0.0002) and cholate shunt (P = 0.0003) and PHM (P = 0.03) improved after SVR.
Conclusion: Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM.
More than 2.7 million Americans are infected with the hepatitis C virus (HCV); 8000-10 000 die annually due to complications of chronic hepatitis C and the number of Americans infected for 20 or more years will not peak until 2015. As a consequence, the number of patients who will decompensate, advance to hepatocellular carcinoma and need liver transplantation will increase.
Rates of sustained virological response (SVR) with peginterferon/ribavirin treatment of chronic hepatitis C are lower in patients with advanced hepatic fibrosis or cirrhosis. In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, patients with chronic hepatitis C with bridging fibrosis or compensated cirrhosis [Child-Turcotte-Pugh (CTP) ≤6] and prior nonresponse were retreated with peginterferon/ribavirin. In this cohort, SVR after retreatment declined stepwise, from 23% to 9%, with increasing severity of disease, as defined by liver histology and platelet count. Because quantitative liver function tests (QLFTs) measure the continuum of liver impairment, we reasoned that the relationship between SVR and disease severity might be better defined by QLFTs.
Sustained virological response reduces hepatic inflammation, fibrosis and rates of clinical outcomes. The principal clinical manifestations of advanced chronic hepatitis C, such as varices, ascites and encephalopathy are linked to portal hypertension and impaired hepatic function. Beneficial effects of SVR on hepatic fibrosis and clinical outcomes are probably mediated through improvements in the portal circulation and hepatic function - improvements which could be detected by QLFTs, but not by standard laboratory tests.
In this study of retreatment of patients with chronic hepatitis C with peginterferon/ribavirin, we utilized a battery of QLFTs to measure hepatic metabolism, hepatic and portal blood flow, portal-systemic shunting and hepatic parenchymal mass. One goal was to define the relationships between severity of hepatic impairment, as measured by QLFTs and virological responses. In addition, we used serial QLFTs to define hepatic improvement after achievement of SVR.
Abstract and Introduction
Abstract
Backgroud: The impact of virologic response on hepatic function has not been previously defined.
Aim: To determine the relationships of quantitative liver function tests (QLFTs) with virological responses to peginterferon (PEG) ± ribavirin (RBV) in patients with chronic hepatitis C and to use serial QLFTs to define the spectrum of hepatic improvement after sustained virological response (SVR).
Methods: Participants (n = 232) were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, had failed prior therapy, had bridging fibrosis or cirrhosis and were retreated with PEG/RBV. All 232 patients had baseline QLFTs; 24 patients with SVR and 68 nonresponders had serial QLFTs. Lidocaine, [24-C]cholate, galactose and Tc-sulfur colloid were administered intravenously; [2,2,4,2-H]cholate, [1-C]methionine, caffeine and antipyrine were administered orally. Clearances (Cl), breath CO2, monoethylglycylxylidide (MEGX), perfused hepatic mass (PHM) and liver volume were measured.
Results: Rates of SVR were 18-26% in patients with good function by QLFTs, but ≤6% in patients with poor function. Hepatic metabolism, measured by caffeine kelim (P = 0.02), antipyrine kelim (P = 0.05) and antipyrine Cl (P = 0.02) and the portal circulation, measured by cholate Cloral (P = 0.0002) and cholate shunt (P = 0.0003) and PHM (P = 0.03) improved after SVR.
Conclusion: Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM.
Introduction
More than 2.7 million Americans are infected with the hepatitis C virus (HCV); 8000-10 000 die annually due to complications of chronic hepatitis C and the number of Americans infected for 20 or more years will not peak until 2015. As a consequence, the number of patients who will decompensate, advance to hepatocellular carcinoma and need liver transplantation will increase.
Rates of sustained virological response (SVR) with peginterferon/ribavirin treatment of chronic hepatitis C are lower in patients with advanced hepatic fibrosis or cirrhosis. In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, patients with chronic hepatitis C with bridging fibrosis or compensated cirrhosis [Child-Turcotte-Pugh (CTP) ≤6] and prior nonresponse were retreated with peginterferon/ribavirin. In this cohort, SVR after retreatment declined stepwise, from 23% to 9%, with increasing severity of disease, as defined by liver histology and platelet count. Because quantitative liver function tests (QLFTs) measure the continuum of liver impairment, we reasoned that the relationship between SVR and disease severity might be better defined by QLFTs.
Sustained virological response reduces hepatic inflammation, fibrosis and rates of clinical outcomes. The principal clinical manifestations of advanced chronic hepatitis C, such as varices, ascites and encephalopathy are linked to portal hypertension and impaired hepatic function. Beneficial effects of SVR on hepatic fibrosis and clinical outcomes are probably mediated through improvements in the portal circulation and hepatic function - improvements which could be detected by QLFTs, but not by standard laboratory tests.
In this study of retreatment of patients with chronic hepatitis C with peginterferon/ribavirin, we utilized a battery of QLFTs to measure hepatic metabolism, hepatic and portal blood flow, portal-systemic shunting and hepatic parenchymal mass. One goal was to define the relationships between severity of hepatic impairment, as measured by QLFTs and virological responses. In addition, we used serial QLFTs to define hepatic improvement after achievement of SVR.
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