Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-γ1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis

Pockros, Paul J.; Jeffers, Lennox J.; Afdhal, Nezam H.; Goodman, Zachary; Nelson, David R.; Gish, Robert G.; Reddy, K. Rajender; Reindollar, Robert; Rodrı́guez-Torres, Maribel; Sullivan, Sarah; Blatt, Lawrence M.; Faris-Young, Sima

doi:10.1002/hep.21561

Cited by 105 publications

(61 citation statements)

References 30 publications

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“…28 A total of 502 patients met entry criteria and were randomized, and 488 received at least one dose of the study drug. Of those, 162 received placebo, 169 received 100 g IFN-␥ 1b 3 times weekly, and 157 received 200 g IFN-␥ 1b 3 times weekly.…”

Section: Resultsmentioning

confidence: 99%

“…28 Patients recruited into the study had clinically compensated chronic hepatitis C refractory to standard IFN-␣-based therapy, and they were required to have an adequate liver biopsy, evaluated by the central pathologist (Z.G. ), showing marked bridging fibrosis or cirrhosis, stages 4 to 6 of the Ishak score.…”

Section: Methodsmentioning

confidence: 99%

“…The opportunity to study fibrosis change by morphometric image analysis was made available by a clinical trial of interferon gamma-1b (IFN-␥ 1b) for the treatment of advanced fibrosis attributable to chronic hepatitis C. 28 IFN-␥ 1b is a cytokine that has shown promise as an antifibrotic agent because of its effects on hepatic stellate cells in vitro, from animal studies showing regression of fibrosis, and from studies of human idiopathic pulmonary fibrosis. A placebo-controlled trial was designed to study the safety and efficacy of IFN-␥ 1b in patients with chronic hepatitis C resistant to interferon alpha-based therapy and with marked fibrosis or cirrhosis on liver biopsy.…”

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Progression of fibrosis in advanced chronic hepatitis C

et al. 2007

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Fibrosis progression in chronic liver disease has usually been evaluated by liver biopsy using insensitive semiquantitative numerical scores. An alternative to this is to measure fibrous tissue quantitatively using morphometric image analysis. The aim of this study was to quantify fibrosis progression in a cohort of patients with treatment-refractory chronic hepatitis C enrolled in a placebo-controlled clinical trial of interferon gamma-1b (IFN-␥ 1b) for the treatment of advanced hepatic fibrosis. We used morphometry to quantify the amount of fibrous tissue in liver biopsies performed at baseline and after 48 weeks in 245 patients who had paired unfragmented, adequate-sized specimens and correlated the results with clinical and laboratory parameters. Eighty-seven patients were treated with placebo and 158 with IFN-␥ 1b. No effect of the drug on fibrosis was found in the trial, and so data from all 245 patients were combined for analysis. At baseline, 78% had cirrhosis; 22%, bridging fibrosis. The mean morphometrically determined collagen content increased by 58% between baseline and 48 weeks. There were statistically significant but weak correlations of fibrosis with platelet count, albumin, bilirubin, INR, and hyaluronic acid; however, changes in these did not correlate with or predict changes in fibrosis in the liver biopsy. Conclusion: In advanced chronic hepatitis C, fibrosis increases at a rapid pace that can only be detected by morphometry. This technique can be used in future therapeutic trials of agents to inhibit fibrosis progression. (HEPATOLOGY 2007;45:886-894.)

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Progression of fibrosis in advanced chronic hepatitis C

et al. 2007

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“…216 Based on this lesson, it is clear that trials in such cirrhotic patients will need to be lengthy, with the use of more sensitive and specific biomarkers that do not rely on biopsy alone. 217 Further progress in understanding, diagnosing, and treating hepatic fibrosis will continue to rely on the exploration of fundamental mechanisms of fibrogenesis, which is certain to lead to a meaningful impact on the prognosis of patients with chronic liver disease. Contributions of activated stellate cells and other fibrogenic cell types to hepatic fibrosis.…”

Section: Clinical and Translational Implicationsmentioning

confidence: 99%

Mechanisms of Hepatic Fibrogenesis

2008

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Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, posttranscriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.The field of hepatic fibrosis is flourishing thanks to continued experimental advances complemented by exciting progress in the treatment of chronic liver disease. 1 Control of chronic hepatitis B and C by antiviral therapies has established that advanced fibrosis can regress in association with improved clinical outcomes, 2-4 thereby intensifying enthusiasm to uncover the mechanistic basis for hepatic fibrogenesis and its attenuation. At the same time, simple paradigms defining the cellular sources of extracellular matrix (ECM), and the roles of cytokines and paracrine interactions among resident liver cells and inflammatory cells have yielded a more nuanced understanding of how the liver responds to injury. These advances have had a collateral benefit towards understanding fibrosis in other organs, particularly the pancreas. 5 Thus, a review of the mechanisms underlying hepatic fibrosis is not only timely, but is more clinically relevant than ever. This article focuses on recent advances in the field, building on established principles from earlier reviews 6,7 while weaving in their clinical relevance, but also emphasizing the molecular subtleties that have emerged through continued progress in the field. General PrinciplesFibrosis, or scarring of the liver, is a wound-healing response that engages a range of cell types and mediators to encapsulate injury. Although even acute injury will activate mechanisms of fibrogenesis, the sustained signals associated with chronic liver disease caused by infection, Cirrhosis, the most advanced stage ...

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“…18,23,24 Furthermore, treatment with IFN-γ was shown to ameliorate liver fibrosis in patients with hepatitis B viral or HCV infection, 25,26 but a recent clinical trial showed that IFN-γ treatment had no beneficial effect in patients with advanced liver disease. 27 The difference between these studies may be due to the selection of patients with differing stages of liver disease. It is possible that IFN-γ may have beneficial effects when treating early stages of liver fibrosis but not the later stage of cirrhosis.…”

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confidence: 99%