title: Direct-Acting Antiviral Therapy Restores Immune Tolerance to Patients With Hepatitis C Virus-Induced Cryoglobulinemia Vasculitis.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.
authors.affiliation: 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.
authors.forename: Cloé
authors.initials: C
authors.lastname: Comarmond
authors.affiliation: 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.
authors.forename: Marlène
authors.initials: M
authors.lastname: Garrido
authors.affiliation: Department of Hepatology, assistance publique des hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: 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.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Desbois
authors.affiliation: Biological Hematology, Groupe Hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Myrto
authors.initials: M
authors.lastname: Costopoulos
authors.affiliation: Biological Hematology, Groupe Hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Le Garff-Tavernier
authors.affiliation: Department of Hepatology, Hôpital d'Orléans, Orléans, France.
authors.forename: Si Nafa
authors.initials: SN
authors.lastname: Si Ahmed
authors.affiliation: 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.affiliation: Department of Hepatology, assistance publique des hôpitaux de Paris, Hôpital Cochin, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Fontaine
authors.affiliation: 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Bellier
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Maciejewski
authors.affiliation: 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.
authors.forename: Michelle
authors.initials: M
authors.lastname: Rosenzwajg
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.affiliation: Department of Immunology, unité fonctionnelle d'Immunochimie et d'Autoimmunité, Groupe Hospitalier Pitié-Salpétrière, Paris, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Musset
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.affiliation: 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.
authors.forename: Patrice
authors.initials: P
authors.lastname: Cacoub
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Saadoun
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016175:B-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015415:Biomarkers / Q000097:blood; D002219:Carbamates; D016022:Case-Control Studies; D003449:Cryoglobulinemia / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D016207:Cytokines / Q000097:blood; D004359:Drug Therapy, Combination; D005260:Female; D006526:Hepatitis C / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D006518:Hepatitis Viruses / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007108:Immune Tolerance / Q000187:drug effects*; D007111:Immunity, Cellular / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D011759:Pyrrolidines; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D000069616:Simeprevir / Q000009:adverse effects / Q000627:therapeutic use*; D000069474:Sofosbuvir / Q000009:adverse effects / Q000627:therapeutic use*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013997:Time Factors; D016896:Treatment Outcome; D014633:Valine / Q000031:analogs & derivatives; D014657:Vasculitis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D002219:Carbamates; D016207:Cytokines; D007093:Imidazoles; D011759:Pyrrolidines; D012254:Ribavirin; D000069616:Simeprevir; D014633:Valine; C549273:daclatasvir; D000069474:Sofosbuvir
keywords: Immune Regulation; Liver Disease; PDCD1; Response To Treatment