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Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis

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Abstract

Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.

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Funding

This study was supported by Grants from Instituto de Salud Carlos III (ISCIII) (Grant numbers PI17CIII/00003 and PI20CIII/00004 to SR, and PI19CIII/00009 to IM). The study was also funded by the RD16CIII/0002/0002 project as part of the Plan Nacional R + D + I and co-funded by ISCIII- Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER). DSC is supported through Fundación SEIMC-GESIDA by a fellowship award from Fundación ONCE ‘Oportunidad al Talento, 2019/20’ co-financed by Fondo Social Europeo (202001FONCE1).

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Conceptualization: SR and IM. Data curation: DSC and IM. Funding acquisition: SR and IM. Investigation: DSC, SR, and IM. Supervision and visualization: SR and IM. Writing—original draft preparation: DSC, SR, and IM. Writing—review and editing: DSC, SR, and IM. All authors have read and approved the final manuscript.

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Correspondence to Salvador Resino or Isidoro Martinez.

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The authors, DSC, SR, and IM, declare that they have no conflicts of interest.

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Sepulveda-Crespo, D., Resino, S. & Martinez, I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 81, 419–443 (2021). https://doi.org/10.1007/s40265-020-01458-x

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