Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial

Abstract

Background: 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-(13)C]cholate, galactose and (99m)Tc-sulfur colloid were administered intravenously; [2,2,4,2-(2)H]cholate, [1-(13)C]methionine, caffeine and antipyrine were administered orally. Clearances (Cl), breath (13)CO(2), 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 < or =6% in patients with poor function. Hepatic metabolism, measured by caffeine k(elim) (P = 0.02), antipyrine k(elim) (P = 0.05) and antipyrine Cl (P = 0.02) and the portal circulation, measured by cholate Cl(oral) (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.

Figures

Figure 1

Flow diagram of final outcome of the 232 patients enrolled in the Lead-In Phase of HALT-C and who participated in the QLFT study. The baseline QLFT studies of all 232 patients were used to define the associations of QLFTs with virologic responses. To examine the effect of SVR on hepatic function, we compared serial studies of QLFTs in 24 patients achieving SVR to 68 nonresponders and 12 relapsers randomized to long-term followup without additional treatment.

Figure 2

Panel A: Rates of VR20 declined as caffeine kelim (P=0.0001), antipyrine kelim (P=0.0002), antipyrine Cl (P=0.0002), cholate Cloral (P=0.0003), cholate shunt (P=0.0001), MEGX15min (P=0.01), MEGX30min (P=0.005), methionine breath test (P=0.02), and perfused hepatic mass (P=0.01) worsened. Panel B: Rates of SVR declined as caffeine kelim (P=0.002), antipyrine kelim (P=0.002), antipyrine Cl (P=0.002), cholate Cloral (P=0.003), cholate shunt (P=0.002), methionine breath test (P=0.04), and perfused hepatic mass (P=0.01), MEGX15min (P=0.09), and MEGX30min (P=0.07) worsened. Cholate kelim, cholate Cliv, and galactose elimination capacity, which primarily assess total hepatic blood flow, failed to correlate with either VR20 or SVR (not shown). Abbreviations: Q, quartile; QLFT, quantitative test of liver function; Caff k, rate constant of elimination of caffeine; AP k, rate constant of elimination of antipyrine; AP Cl, clearance of antipyrine; MEGX 15, concentration of monoethylglycylxylidide 15 minutes after administration of lidocaine; MEGX 30, concentration of monoethylglycylxylidide 30 minutes after administration of lidocaine; CA Clo, clearance of orally administered [2,2,4,4-2H] cholate; CA Shunt, cholate shunt; GEC, galactose elimination capacity; MBT, methionine breath test; PHM, perfused hepatic mass

Figure 3

SVR was associated with a 32% increase in cholate Cloral (Panel A), a measure of portal blood flow, and a 26% decrease in cholate shunt (Panel B), a measure of portal-systemic shunting. The dotted line represents one patient with increase in cholate shunt despite SVR – this patient also had the lowest cholate Cloral both at baseline and in followup.

Figure 4

The percentage change between baseline and the followup studies for QLFTs are shown. The black bars depict the changes after sustained virologic response (SVR) and grey bars show the changes in patients with nonresponse (NR). Compared to patients with nonresponse, patients experiencing SVR had significant improvements in caffeine and antipyrine elimination rates (kelim), antipyrine clearance (Cl), clearance of orally administered cholate (Cloral), cholate shunt, and perfused hepatic mass (PHM).