The Effects of Angiotensin Blocking Agents on the Progression of Liver Fibrosis in the HALT-C Trial Cohort
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Therapies that can slow the progression of liver fibrosis in chronic liver disease are needed. Evidence suggests that the renin-angiotensin system (RAS) contributes to inflammation and fibrosis in chronic liver disease. Both animal and limited human studies have shown that RAS inhibition with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor-1 [AT-1] blockers (ARBs) has antifibrogenic properties.
In this study, we evaluated the effects of continuous ACEi/ARB use for 3.5 years on histological liver fibrosis progression in the HALT-C Trial cohort.
In the HALT-C Trial, subjects with chronic hepatitis C and advanced hepatic fibrosis (Ishak stage ≥3) underwent serial liver biopsies at baseline, 1.5 years, and 3.5 years after randomization. The primary outcome was a ≥2-point increase in Ishak fibrosis score in at least one of the two serial biopsies. Sixty-six subjects were continuously taking ACEi/ARBs over the observation period, 126 were taking other antihypertensive medications, and 343 subjects took no antihypertensive medications.
The three groups were similar in baseline fibrosis scores, and the two groups being treated with antihypertensives were taking a similar number of antihypertensive medications. Fibrosis progression occurred in 33.3% of the ACEi/ARB group, 32.5% of the other antihypertensive medications group, and in 25.7% of subjects taking no antihypertensive medications. No significant associations between ≥2-point increases in fibrosis scores and continuous ACEi/ARB use were apparent at either 1.5 or 3.5 years in diabetes-adjusted and unadjusted odds ratios.
ACEi/ARB therapy did not retard the progression of hepatic fibrosis.
KeywordsRenin–angiotensin system ACE inhibitors Angiotensin receptor blockers Liver fibrosis Hypertension Diabetes
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Hepatitis C Long-term Treatment Against Cirrhosis
Sustained virologic response
This study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center and Clinical and Translational Science Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. Additional funding to conduct this study was supplied by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement (CRADA) with the National Institutes of Health. In addition to the authors of this manuscript, the following individuals were instrumental in the planning, conduct and/or care of patients enrolled in this study at each of the participating institutions as follows: University of Massachusetts Medical Center, Worcester, MA: (Contract N01-DK-9-2326) Gyongyi Szabo, MD, Barbara F. Banner, MD, Maureen Cormier, RN, Donna Giansiracusa, RN. University of Connecticut Health Center, Farmington, CT: (Grant M01RR-06192) Herbert L. Bonkovsky, MD, Gloria Borders, RN, Michelle Kelley, RN, ANP. Saint Louis University School of Medicine, St Louis, MO: (Contract N01-DK-9-2324) Adrian M. Di Bisceglie, MD, Bruce Bacon, MD, Brent Neuschwander-Tetri, MD, Elizabeth M. Brunt, MD, Debra King, RN. Massachusetts General Hospital, Boston, MA: (Contract N01-DK-9-2319, Grant M01RR-01066; Grant 1 UL1 RR025758-01, Harvard Clinical and Translational Science Center) Andrea E. Reid, MD, Atul K. Bhan, MD, Wallis A. Molchen, David P. Lundmark. University of Colorado Denver, School of Medicine, Aurora, CO: (Contract N01-DK-9-2327, Grant M01RR-00051, Grant 1 UL1 RR 025780-01), Gregory T. Everson, MD, Thomas Trouillot, MD, Marcelo Kugelmas, MD, S. Russell Nash, MD, Jennifer DeSanto, RN, Carol McKinley, RN. University of California—Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Timothy R. Morgan, MD, John C. Hoefs, MD, John R. Craig, MD, M. Mazen Jamal, MD, MPH, Muhammad Sheikh, MD, Choon Park, RN. University of Texas Southwestern Medical Center, Dallas, TX: (Contract N01-DK-9-2321, Grant M01RR-00633, Grant 1 UL1 RR024982-01, North and Central Texas Clinical and Translational Science Initiative) William M. Lee, MD, Thomas E. Rogers, MD, Peter F. Malet, MD, Janel Shelton, Nicole Crowder, LVN, Rivka Elbein, RN, BSN, Nancy Liston, MPH. University of Southern California, Los Angeles, CA: (Contract N01-DK-9-2325, Grant M01RR-00043) Karen L. Lindsay, MD, MMM, Sugantha Govindarajan, MD, Carol B. Jones, RN, Susan L. Milstein, RN. University of Michigan Medical Center, Ann Arbor, MI: (Contract N01-DK-9-2323, Grant M01RR-00042, Grant 1 UL1 RR024986, Michigan Center for Clinical and Health Research) Anna S. Lok, MD, Robert J. Fontana, MD, Joel K. Greenson, MD, Pamela A. Richtmyer, LPN, CCRC, R. Tess Bonham, BS. Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Mitchell L. Shiffman, MD, Richard K. Sterling, MD, MSc, Melissa J. Contos, MD, A. Scott Mills, MD, Charlotte Hofmann, RN, Paula Smith, RN. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD: Marc G. Ghany, MD, T. Jake Liang, MD, David Kleiner, MD, PhD, Yoon Park, RN, Elenita Rivera, RN, Vanessa Haynes-Williams, RN. National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: James E. Everhart, MD, Leonard B. Seeff, MD, Patricia R. Robuck, PhD, Jay H. Hoofnagle, MD, Elizabeth C. Wright, PhD. University of Washington, Seattle, WA: (Contract N01-DK-9-2318) Chihiro Morishima, MD, David R. Gretch, MD, PhD, Minjun Chung Apodaca, BS, ASCP, Rohit Shankar, BC, ASCP, Natalia Antonov, M. Ed. New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Kristin K. Snow, MSc, ScD, Anne M. Stoddard, ScD, Teresa M. Curto, MSW, MPH. Armed Forces Institute of Pathology, Washington, DC: Zachary D. Goodman, MD, PhD. Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perrillo, MD.
Conflict of interest
Financial relationships of the authors with Hoffmann-La Roche, Inc., are as follows: R. T. Chung receives research support. Authors with no financial relationships related to this project are: B. K. Abu Dayyeh, M. Yang, and J. L. Dienstag.