Registered clinical trials on CCR antagonists (other than CVC) in patients with NAFLD
ID, registration date (DD/MM/YYYY)*
Title
Design
Arms
Patients (n)
Duration
Primary outcome(s)
ISRCTN31461655, 23/02/2018
A phase IV, open-label pilot study investigating non-invasive markers of hepatic fibrosis in people living with HIV-1 and non-alcoholic fatty liver disease randomized to receiving optimized background therapy (OBT) plus maraviroc or OBT
Multicenter, randomized, open-label, phase 4
MVC (NA mg) vs. No treatment (ART only)
60
24 months
1) Number of participants with adverse events 2) Adherence to MVC treatment (questionnaire) 3) Parameters related to the participation and missing values
EUC-TR2017-003172-32, 06/02/2018
Maraviroc Add-On Therapy for Steatohepatitis in HIV (MASH study)
Multicenter, non-randomized, open-label, phase 2
MVC (150 mg) vs. MVC (300 mg)
30
12 months
Change in hepatic immune cells identified on liver biopsy (immuno-histochemistry)
A Multicentre, 48 Week Randomized Controlled Factorial Trial of Adding Maraviroc and/or Metformin for Hepatic Steatosis in HIV-1-infected Adults on Combination Antiretroviral Therapy (MAVMET)
Multicenter, randomized, open label, phase 2
MVC (NA mg) vs. Metformin (500 mg) vs. MVC (NA mg) + Metformin 500 mg) vs. No treatment (ART only)
90
12 months
Change in percentage of liver fat, measured by MR-PDFF
References are presented in date of registration order (newer to older); ART: antiretroviral treatment; HIV: human immunodeficiency virus; MR-PDFFl: magnetic resonance spectroscopy measuring the hepatic proton density fat fraction; MVC: Maraviroc; NA: not available; OBT: optimized background therapy
Declarations
Author Contributions
MD, KP, AP: design of the review, drafting the manuscript; JK: design of the review, critical revision of the manuscript; SAP: conception and design of the review, drafting and critical revision of the manuscript; all the authors: final approval of the version to publish, agreeing to be accountable for all aspects of the work.
Conflicts of interest
The authors declare that they have no conflicts of interest.
Long MT, Gandhi S, Loomba R. Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease. Metabolism.2020;[Epub ahead of print].[DOI]
Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol.2017;42:92–108. [DOI] [PubMed]
Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease: the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med.2009;9:299–314. [DOI] [PubMed]
Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism.2019;92:82–97. [DOI] [PubMed]
Polyzos SA, Kountouras J, Zavos C, Deretzi G. Nonalcoholic fatty liver disease: multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol.2012;46:272–84. [DOI] [PubMed]
Mintziori G, Polyzos SA. Emerging and future therapies for nonalcoholic steatohepatitis in adults. Expert Opin Pharmacother.2016;17:1937–46. [DOI] [PubMed]
Polyzos SA, Kang ES, Boutari C, Rhee EJ, Mantzoros CS. Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. Metabolism.2020;[Epub ahead of print].[DOI]
Tamura Y, Sugimoto M, Murayama T, Minami M, Nishikaze Y, Ariyasu H, et al. C-C chemokine receptor 2 inhibitor improves diet-induced development of insulin resistance and hepatic steatosis in mice. J Atheroscler Thromb.2010;17:219–28. [DOI] [PubMed]
Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One.2016;11:e0158156. [DOI] [PubMed] [PMC]
Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology.2018;67:1754–67. [DOI] [PubMed] [PMC]
Ratziu V, Sanyal A, Harrison SA, Wong VW, Francque S, Goodman Z, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis: final analysis of the phase 2b CENTAUR study. Hepatology.2020;[Epub ahead of print].[DOI]
Anstee QM, Neuschwander-Tetri BA, Wong VW, Abdelmalek MF, Younossi ZM, Yuan J, et al. Cenicriviroc for the treatment of liver fibrosis in adults with nonalcoholic steatohepatitis: AURORA Phase 3 study design. Contemp Clin Trials.2020;89:105922. [DOI] [PubMed]
Parker R, Weston CJ, Miao Z, Corbett C, Armstrong MJ, Ertl L, et al. CC chemokine receptor 2 promotes recruitment of myeloid cells associated with insulin resistance in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol.2018;314:G483–93. [DOI] [PubMed] [PMC]
Fantuzzi L, Tagliamonte M, Gauzzi MC, Lopalco L. Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders. Cell Mol Life Sci.2019;76:4869–86. [DOI] [PubMed] [PMC]
Chen W, Zhang J, Fan HN, Zhu JS. Function and therapeutic advances of chemokine and its receptor in nonalcoholic fatty liver disease. Therap Adv Gastroenterol.2018;11:1756284818815184. [DOI]
Rot A, von Andrian UH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol.2004;22:891–928. [DOI] [PubMed]
Hughes CE, Nibbs RJB. A guide to chemokines and their receptors. FEBS J.2018;285:2944–71. [DOI] [PubMed] [PMC]
Townsend SA, Newsome PN. Review article: new treatments in non-alcoholic fatty liver disease. Aliment Pharmacol Ther.2017;46:494–507. [DOI] [PubMed]
Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology.2014;147:577–94.e1. [DOI] [PubMed]
Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology.2018;67:1270–83. [DOI] [PubMed]
Saiman Y, Friedman SL. The role of chemokines in acute liver injury. Front Physiol.2012;3:213. [DOI] [PubMed] [PMC]
Tacke F. Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis. Expert Opin Investig Drugs.2018;27:301–11. [DOI]
Lefere S, Devisscher L, Tacke F. Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges. Expert Opin Investig Drugs.2020;29:89–92. [DOI]
Xu L, Kitade H, Ni Y, Ota T. Roles of chemokines and chemokine receptors in obesity-associated insulin resistance and nonalcoholic fatty liver disease. Biomolecules.2015;5:1563–79. [DOI] [PubMed] [PMC]
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest.2006;116:1494–505. [DOI] [PubMed] [PMC]
Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest.2006;116:115–24. [DOI] [PubMed] [PMC]
Kanneganti TD, Dixit VD. Immunological complications of obesity. Nat Immunol.2012;13:707–12. [DOI] [PubMed]
Yao L, Herlea-Pana O, Heuser-Baker J, Chen Y, Barlic-Dicen J. Roles of the chemokine system in development of obesity, insulin resistance, and cardiovascular disease. J Immunol Res.2014;2014:181450. [DOI] [PubMed] [PMC]
Kamei N, Tobe K, Suzuki R, Ohsugi M, Watanabe T, Kubota N, et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem.2006;281:26602–14. [DOI] [PubMed]
Berres ML, Koenen RR, Rueland A, Zaldivar MM, Heinrichs D, Sahin H, et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest.2010;120:4129–40. [DOI] [PubMed] [PMC]
Zimmermann HW, Tacke F. Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis. Inflamm Allergy Drug Targets.2011;10:509–36. [DOI] [PubMed]
Liaskou E, Wilson DV, Oo YH. Innate immune cells in liver inflammation. Mediators Inflamm.2012;2012:949157. [DOI] [PubMed] [PMC]
Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest.2012;122:787–95. [DOI] [PubMed] [PMC]
Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T, Ohnishi H, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology.2010;139:323–34.e7. [DOI] [PubMed] [PMC]
Stienstra R, Saudale F, Duval C, Keshtkar S, Groener JEM, van Rooijen N, et al. Kupffer cells promote hepatic steatosis via interleukin-1β-dependent suppression of peroxisome proliferator-activated receptor alpha activity. Hepatology.2010;51:511–22. [DOI] [PubMed]
Miura K, Yang L, van Rooijen N, Ohnishi H, Seki E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am J Physiol Gastrointest Liver Physiol.2012;302:1310–21. [DOI]
Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut.2012;61:416–26. [DOI] [PubMed]
Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, et al. Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance. Diabetes.2010;59:347–57. [DOI] [PubMed] [PMC]
Lanthier N, Molendi-Coste O, Cani PD, van Rooijen N, Horsmans Y, Leclercq IA. Kupffer cell depletion prevents but has no therapeutic effect on metabolic and inflammatory changes induced by a high-fat diet. FASEB J.2011;25:4301–11. [DOI] [PubMed]
Neokosmidis G, Tziomalos K. Role of cenicriviroc in the management of nonalcoholic fatty liver disease. World J Gastroenterol.2018;24:5415–7. [DOI] [PubMed] [PMC]
Polyzos SA, Slavakis A, Koumerkeridis G, Katsinelos P, Kountouras J. Noninvasive liver fibrosis tests in patients with nonalcoholic fatty liver disease: an external validation cohort. Horm Metab Res.2019;51:134–40. [DOI] [PubMed]
Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology.2016;64:1667–82. [DOI] [PubMed]
Kruger AJ, Fuchs BC, Masia R, Holmes JA, Salloum S, Sojoodi M, et al. Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis. Hepatol Commun.2018;2:529–45. [DOI] [PubMed] [PMC]
Polyzos SA, Perakakis N, Mantzoros CS. Fatty liver in lipodystrophy: a review with a focus on therapeutic perspectives of adiponectin and/or leptin replacement. Metabolism.2019;96:66–82. [DOI] [PubMed]
Thompson M, Chang W, Jenkins H, Flynt A, Gottwald M, Lefebvre E. Improvements in APRI and FIB-4 fibrosis scores correlate with decreases in sCD14 in HIV-1 infected adults receiving cenicriviroc over 48 weeks. Hepatology.2014;60:424A.
Lefebvre E, Gottwald M, Lasseter K, Chang W, Willett M, Smith PF, et al. Pharmacokinetics, safety, and CCR2/CCR5 antagonist activity of cenicriviroc in participants with mild or moderate hepatic impairment. Clin Transl Sci.2016;9:139–48. [DOI] [PubMed] [PMC]
Polyzos SA, Kountouras J, Anastasiadis S, Doulberis M, Katsinelos P. Nonalcoholic fatty liver disease: is it time for combination treatment and a diabetes-like approach?Hepatology. 2018;68:389. [DOI] [PubMed]
Stringer R, Gu J, Pedrosa MC, Woessner R, Ayalasomayajula S, Seyedkazemi S, et al. Tropifexor in combination with cenicriviroc: pharmacokinetics and clinical safety in healthy volunteers plus study design of a phase 2b trial in patients with nonalcoholic steatohepatitis. Hepatology.2018;68:991A.
Polyzos SA, Kountouras J, Mantzoros CS. Obeticholic acid for the treatment of nonalcoholic steatohepatitis: expectations and concerns. Metabolism.2020;104:154144. [DOI] [PubMed]
Venetsanaki V, Karabouta Z, Polyzos SA. Farnesoid X nuclear receptor agonists for the treatment of nonalcoholic steatohepatitis. Eur J Pharmacol.2019;863:172661. [DOI] [PubMed]
Pedrosa M, Seyedkazemi S, Francque S, Sanyal A, Rinella M, Charlton M, et al. A randomized, double-blind, multicenter, phase 2b study to evaluate the safety and efficacy of a combination of tropifexor and cenicriviroc in patients with nonalcoholic steatohepatitis and liver fibrosis: study design of the TANDEM trial. Contemp Clin Trials.2020;88:105889. [DOI] [PubMed]
Pulley SR. CCR5 antagonists: from discovery to clinical efficacy. In: Neote K, Letts GL, Moser B, editors. Chemokine biology–basic research and clinical application. Switzerland: Birkhäuser Basel; 2007; pp. 145–63. [DOI]
Coppola N, Perna A, Lucariello A, Martini S, Macera M, Carleo MA, et al. Effects of treatment with Maraviroc a CCR5 inhibitor on a human hepatic stellate cell line. J Cell Physiol.2018;233:6224–31. [DOI] [PubMed]
Pérez-Martínez L, Pérez-Matute P, Aguilera-Lizarraga J, Rubio-Mediavilla S, Narro J, Recio E, et al. Maraviroc, a CCR5 antagonist, ameliorates the development of hepatic steatosis in a mouse model of non-alcoholic fatty liver disease (NAFLD). J Antimicrob Chemother.2014;69:1903–10. [DOI] [PubMed]
Pérez-Martínez L, Ochoa-Callejero L, Rubio-Mediavilla S, Narro J, Bernardo I, Oteo JA, et al. Maraviroc improves hepatic triglyceride content but not inflammation in a murine nonalcoholic fatty liver disease model induced by a chronic exposure to high-fat diet. Transl Res.2018;196:17–30. [DOI] [PubMed]
Yang SJ, IglayReger HB, Kadouh HC, Bodary PF. Inhibition of the chemokine (C-C motif ) ligand 2/chemokine (C-C motif ) receptor 2 pathway attenuates hyperglycaemia and inflammation in a mouse model of hepatic steatosis and lipoatrophy. Diabetologia.2009;52:972–81. [DOI] [PubMed]
Han YM, Lee YJ, Jang YN, Kim HM, Seo HS, Jung TW, et al. Aspirin improves nonalcoholic fatty liver disease and atherosclerosis through regulation of the PPARδ-AMPK-PGC-1α pathway in dyslipidemic conditions. Biomed Res Int.2020;2020:7806860. [DOI] [PubMed] [PMC]
Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology.2018;67:328–57. [DOI] [PubMed]
EASL, EASD, EASOEASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia.2016;59:1121–40. [DOI] [PubMed]
Sumida Y, Okanoue T, Nakajima A, Japan Study Group of NAFLD (JSG-NAFLD). Phase 3 drug pipelines in the treatment of non-alcoholic steatohepatitis. Hepatol Res.2019;49:1256–62. [DOI] [PubMed]
