Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial

Gregory T Everson, Mitchell L Shiffman, John C Hoefs, Timothy R Morgan, Richard K Sterling, David A Wagner, Shannon Lauriski, Teresa M Curto, Anne Stoddard, Elizabeth C Wright, HALT-C Trial Group, Jennifer DeSanto, Marcelo Kugelmas, Carol McKinley, Brenda Easley, Stephanie Shea, Michelle Jaramillo, Muhammad Sheikh, Norah Milne, Choon Park, William Rietkerk, Richard Kesler-West, M Mazen Jamal, Charlotte Hofmann, Paula Smith, Michael C Doherty, Kristin K Snow, Marina Mihova, James E Everhart, Jay H Hoofnagle, Leonard Seeff, Gary L Davis, Guadalupe Garcia-Tsao, Michael Kutner, Stanley M Lemon, Robert P Perillo, Gregory T Everson, Mitchell L Shiffman, John C Hoefs, Timothy R Morgan, Richard K Sterling, David A Wagner, Shannon Lauriski, Teresa M Curto, Anne Stoddard, Elizabeth C Wright, HALT-C Trial Group, Jennifer DeSanto, Marcelo Kugelmas, Carol McKinley, Brenda Easley, Stephanie Shea, Michelle Jaramillo, Muhammad Sheikh, Norah Milne, Choon Park, William Rietkerk, Richard Kesler-West, M Mazen Jamal, Charlotte Hofmann, Paula Smith, Michael C Doherty, Kristin K Snow, Marina Mihova, James E Everhart, Jay H Hoofnagle, Leonard Seeff, Gary L Davis, Guadalupe Garcia-Tsao, Michael Kutner, Stanley M Lemon, Robert P Perillo

Abstract

Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C virus (HCV). We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred and twenty-seven participants in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k(elim)), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, perfused hepatic mass (PHM), and liver and spleen volumes (by single-photon emission computed tomography) were measured. Baseline QLFTs were significantly worse (P = 0.0017 to P < 0.0001) and spleen volumes were larger (P < 0.0001) in the 54 patients who subsequently experienced clinical outcomes. QLFT cutoffs that characterized patients as "low" and "high risk" for clinical outcome yielded hazard ratios ranging from 2.21 (95% confidence interval [CI]: 1.29-3.78) for GEC to 6.52 (95% CI: 3.63-11.71) for CA clearance after oral administration (Cl(oral)). QLFTs independently predicted outcome in models with Ishak fibrosis score, platelet count, and standard laboratory tests. In serial studies, patients with high-risk results for CA Cl(oral) or PHM had a nearly 15-fold increase in risk for clinical outcome. Less than 5% of patients with "low risk" QLFTs experienced a clinical outcome.

Conclusion: QLFTs independently predict risk for future clinical outcomes. By improving risk assessment, QLFTs could enhance the noninvasive monitoring, counseling, and management of patients with chronic HCV.

Trial registration: ClinicalTrials.gov NCT00006164.

Copyright © 2011 American Association for the Study of Liver Diseases.

Figures

Figure 1
Figure 1
Metabolic tests. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For these metabolic tests the high risk tertile had the lowest test results. Survival Probability is freedom from clinical outcome.
Figure 1
Figure 1
Metabolic tests. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For these metabolic tests the high risk tertile had the lowest test results. Survival Probability is freedom from clinical outcome.
Figure 1
Figure 1
Metabolic tests. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For these metabolic tests the high risk tertile had the lowest test results. Survival Probability is freedom from clinical outcome.
Figure 1
Figure 1
Metabolic tests. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For these metabolic tests the high risk tertile had the lowest test results. Survival Probability is freedom from clinical outcome.
Figure 1
Figure 1
Metabolic tests. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For these metabolic tests the high risk tertile had the lowest test results. Survival Probability is freedom from clinical outcome.
Figure 2
Figure 2
Cholate (CA) tests and SPECT liver-spleen scan results. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For CA Cliv, CA Cloral, and PHM the high risk tertile had the lowest test results. For cholate shunt and spleen volume the high risk tertile had the highest test results. Survival Probability is freedom from clinical outcome.
Figure 2
Figure 2
Cholate (CA) tests and SPECT liver-spleen scan results. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For CA Cliv, CA Cloral, and PHM the high risk tertile had the lowest test results. For cholate shunt and spleen volume the high risk tertile had the highest test results. Survival Probability is freedom from clinical outcome.
Figure 2
Figure 2
Cholate (CA) tests and SPECT liver-spleen scan results. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For CA Cliv, CA Cloral, and PHM the high risk tertile had the lowest test results. For cholate shunt and spleen volume the high risk tertile had the highest test results. Survival Probability is freedom from clinical outcome.
Figure 2
Figure 2
Cholate (CA) tests and SPECT liver-spleen scan results. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For CA Cliv, CA Cloral, and PHM the high risk tertile had the lowest test results. For cholate shunt and spleen volume the high risk tertile had the highest test results. Survival Probability is freedom from clinical outcome.
Figure 2
Figure 2
Cholate (CA) tests and SPECT liver-spleen scan results. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For CA Cliv, CA Cloral, and PHM the high risk tertile had the lowest test results. For cholate shunt and spleen volume the high risk tertile had the highest test results. Survival Probability is freedom from clinical outcome.
Figure 2
Figure 2
Cholate (CA) tests and SPECT liver-spleen scan results. Results were divided into tertiles of equal numbers of patients, stratifying results into low (solid line), intermediate (dashed line), or high ranges (dotted and dashed line). Risks for clinical outcomes across tertiles were analyzed by Kaplan-Meier log-rank tests. Cutoffs were defined using the boundary for the high risk tertile. For CA Cliv, CA Cloral, and PHM the high risk tertile had the lowest test results. For cholate shunt and spleen volume the high risk tertile had the highest test results. Survival Probability is freedom from clinical outcome.
Figure 3
Figure 3
Incidence of clinical outcomes in 2 year intervals during serial studies. QLFT cutoffs were determined by prior Kaplan-Meier log-rank tests and ROC analyses. QLFT cutoffs defined two groups of patients, those at high versus low risk for clinical outcome. Patients with high risk QLFT results had an 11 to 30% chance of experiencing clinical outcome within 2 years. Patients with low risk QLFT results had a benign clinical course.
Figure 3
Figure 3
Incidence of clinical outcomes in 2 year intervals during serial studies. QLFT cutoffs were determined by prior Kaplan-Meier log-rank tests and ROC analyses. QLFT cutoffs defined two groups of patients, those at high versus low risk for clinical outcome. Patients with high risk QLFT results had an 11 to 30% chance of experiencing clinical outcome within 2 years. Patients with low risk QLFT results had a benign clinical course.
Figure 3
Figure 3
Incidence of clinical outcomes in 2 year intervals during serial studies. QLFT cutoffs were determined by prior Kaplan-Meier log-rank tests and ROC analyses. QLFT cutoffs defined two groups of patients, those at high versus low risk for clinical outcome. Patients with high risk QLFT results had an 11 to 30% chance of experiencing clinical outcome within 2 years. Patients with low risk QLFT results had a benign clinical course.

Source: PubMed

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