Cloé Comarmond1, Marlène Garrido2, Stanislas Pol3, Anne-Claire Desbois1, Myrto Costopoulos4, Magali Le Garff-Tavernier4, Si Nafa Si Ahmed5, Laurent Alric6, Hélène Fontaine3, Bertrand Bellier2, Anna Maciejewski2, Michelle Rosenzwajg2, David Klatzmann2, Lucile Musset7, Thierry Poynard8, Patrice Cacoub1, David Saadoun9. 1. Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (département hospitalo-unniversitaire i2B), Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, unité mixte de recherche 7211, Paris, France; INSERM, unité mixte de recherche_S 959, Paris, France; centre national de recherche et de santé, FRE3632, Paris, France; Département de Médecine Interne et Immunologie Clinique, Paris, France. 2. Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (département hospitalo-unniversitaire i2B), Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, unité mixte de recherche 7211, Paris, France; INSERM, unité mixte de recherche_S 959, Paris, France; centre national de recherche et de santé, FRE3632, Paris, France. 3. Department of Hepatology, assistance publique des hôpitaux de Paris, Hôpital Cochin, Paris, France. 4. Biological Hematology, Groupe Hospitalier Pitié-Salpétrière, Paris, France. 5. Department of Hepatology, Hôpital d'Orléans, Orléans, France. 6. Department of Internal Medicine and Digestive Diseases, Centre Hospitalier Universitaire Purpan, unité mixte de recherche 152, institut de recherche pour le développement Toulouse 3 University, Toulouse, France. 7. Department of Immunology, unité fonctionnelle d'Immunochimie et d'Autoimmunité, Groupe Hospitalier Pitié-Salpétrière, Paris, France. 8. Department of Hepatology, unité mixte de recherche_S 938, Institute of Cardiometabolism and Nutrition, assistance publique des hôpitaux de Paris, Groupe Hospitalier Pitié-Salpétrière, Paris, France. 9. Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (département hospitalo-unniversitaire i2B), Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, unité mixte de recherche 7211, Paris, France; INSERM, unité mixte de recherche_S 959, Paris, France; centre national de recherche et de santé, FRE3632, Paris, France; Département de Médecine Interne et Immunologie Clinique, Paris, France. Electronic address: david.saadoun@aphp.fr.
Abstract
BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity. METHODS: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay. RESULTS: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively). CONCLUSIONS: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.
BACKGROUND & AIMS: Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity. METHODS: We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay. RESULTS: Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively). CONCLUSIONS: In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.
Authors: Hashem B El-Serag; Israel C Christie; Amy Puenpatom; Diana Castillo; Fasiha Kanwal; Jennifer R Kramer Journal: Aliment Pharmacol Ther Date: 2019-04-01 Impact factor: 8.171