title: Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis.
abstract: Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n = 32) or 24 weeks (n = 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie University of Paris 06, Unité Médicale de Recherche 7211, Inflammation-Immunopathology-Biotherapy Department (Département Hospitalo Universitaire Inflammation, Immunopathology and Biotherapy), Paris, France; INSERM, Unité Médicale de Recherche_S 959, Paris, France; Centre National de la Recherche Scientifique, FRE3632, Paris, France; Department of Internal Medicine and Clinical Immunology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Electronic address: david.saadoun@aphp.fr.
authors.forename: David
authors.initials: D
authors.lastname: Saadoun
authors.affiliation: Université Paris Descartes, Assistance Publique Hôpitaux de Paris, Unité d'Hépatologie, Hôpital Cochin, INSERM U-1223 et USM20, Institut Pasteur, Paris, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Pol
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie University of Paris 06, Unité Médicale de Recherche 7211, Inflammation-Immunopathology-Biotherapy Department (Département Hospitalo Universitaire Inflammation, Immunopathology and Biotherapy), Paris, France; INSERM, Unité Médicale de Recherche_S 959, Paris, France; Centre National de la Recherche Scientifique, FRE3632, Paris, France; Department of Internal Medicine and Clinical Immunology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Ferfar
authors.affiliation: Department of Internal Medicine-Digestive, Centre Hospitalier Universitaire Purpan, Unité Médicale de Recherche 152 Toulouse 3 University, Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Alric
authors.affiliation: Department of Hepatology, Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hezode
authors.affiliation: Department of Hepatology, Hôpital Orléans, Orléans, France.
authors.forename: Si Nafa
authors.initials: SN
authors.lastname: Si Ahmed
authors.affiliation: Department of Internal Medicine, Centre Hospitalier Universitaire Brest, Brest, France.
authors.forename: Luc
authors.initials: L
authors.lastname: de Saint Martin
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie University of Paris 06, Unité Médicale de Recherche 7211, Inflammation-Immunopathology-Biotherapy Department (Département Hospitalo Universitaire Inflammation, Immunopathology and Biotherapy), Paris, France; INSERM, Unité Médicale de Recherche_S 959, Paris, France; Centre National de la Recherche Scientifique, FRE3632, Paris, France; Department of Internal Medicine and Clinical Immunology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Cloé
authors.initials: C
authors.lastname: Comarmond
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie University of Paris 06, Unité Médicale de Recherche 7211, Inflammation-Immunopathology-Biotherapy Department (Département Hospitalo Universitaire Inflammation, Immunopathology and Biotherapy), Paris, France; INSERM, Unité Médicale de Recherche_S 959, Paris, France; Centre National de la Recherche Scientifique, FRE3632, Paris, France; Department of Internal Medicine and Clinical Immunology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Bouyer
authors.affiliation: Department of Immunology, UF d'Immunochimie et d'Autoimmunité, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Musset
authors.affiliation: Department of Hepatology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Poynard
authors.affiliation: Department of Biostatistics and Medical Data Processing, INSERM U717, Hôpital Saint-Louis, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Resche Rigon
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie University of Paris 06, Unité Médicale de Recherche 7211, Inflammation-Immunopathology-Biotherapy Department (Département Hospitalo Universitaire Inflammation, Immunopathology and Biotherapy), Paris, France; INSERM, Unité Médicale de Recherche_S 959, Paris, France; Centre National de la Recherche Scientifique, FRE3632, Paris, France; Department of Internal Medicine and Clinical Immunology, Assistance Publique Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. Electronic address: patrice.cacoub@aphp.fr.
authors.forename: Patrice
authors.initials: P
authors.lastname: Cacoub
mesh_terms: D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000737:chemistry; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry; D002219:Carbamates; D003449:Cryoglobulinemia / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D003450:Cryoglobulins / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D006526:Hepatitis C / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007075:Immunoglobulin M / Q000032:analysis; D007378:Interleukins / Q000032:analysis; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011759:Pyrrolidines; D054380:Receptors, CXCR5 / Q000032:analysis; D017464:Receptors, Complement 3d / Q000032:analysis; D000069474:Sofosbuvir / Q000009:adverse effects / Q000627:therapeutic use*; D000072230:Sustained Virologic Response; D050378:T-Lymphocytes, Regulatory; D058504:Th17 Cells; D014633:Valine / Q000031:analogs & derivatives; D014657:Vasculitis / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D000098546:Interleukin-21
chemical_list: D000998:Antiviral Agents; C095085:CXCR5 protein, human; D002219:Carbamates; D003450:Cryoglobulins; D007093:Imidazoles; D007075:Immunoglobulin M; D007378:Interleukins; D011759:Pyrrolidines; D054380:Receptors, CXCR5; D017464:Receptors, Complement 3d; D014633:Valine; C549273:daclatasvir; D000098546:Interleukin-21; D000069474:Sofosbuvir
keywords: Autoimmunity; Cryoglobulinemia Vasculitis; DAA; Treg Cell