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Extended report
Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study
  1. David Saadoun1,2,3,4,
  2. Vincent Thibault5,
  3. Si Nafa Si Ahmed6,
  4. Laurent Alric7,
  5. Maxime Mallet8,
  6. Constance Guillaud9,
  7. Hassane Izzedine10,
  8. Aurélie Plaisier11,
  9. Hélène Fontaine12,
  10. Myrto Costopoulos13,
  11. Magali Le Garff-Tavernier13,
  12. Christophe Hezode14,
  13. Stanislas Pol12,
  14. Lucile Musset15,
  15. Thierry Poynard8,
  16. Patrice Cacoub1,2,3,4
  1. 1Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France
  2. 2INSERM, UMR_S 959, Paris, France
  3. 3CNRS, FRE3632, Paris, France
  4. 4Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, AP-HP, Paris, France
  5. 5Groupe Hospitalier Pitié-Salpétrière, Department of Virology, APHP, Paris, France
  6. 6Department of Hepatology, Hôpital Orléans, Orléans, France
  7. 7Department of Internal Medicine-Digestive, Centre hospitalier universitaire Purpan, UMR 152 Toulouse 3 University, Toulouse, France
  8. 8Groupe Hospitalier Pitié-Salpétrière, Department of Hepatology, AP-HP, Paris, France
  9. 9Department of Internal Medicine, Hôpital Henri Mondor, Créteil, France
  10. 10Groupe Hospitalier Pitié-Salpétrière, Department of Nephrology, APHP, Paris, France
  11. 11Department of Hepatology, APHP, Hôpital Beaujon, Clichy, France
  12. 12Department of Hepatology, APHP, Hôpital Cochin, Paris, France
  13. 13Groupe Hospitalier Pitié-Salpétrière, Biological Hematology, APHP, Paris, France
  14. 14Department of Hepatology, APHP, Hôpital Henri Mondor, Créteil, France
  15. 15Groupe Hospitalier Pitié-Salpétrière, Department of Immunology, UF d'Immunochimie et d'autoimmunité, APHP, Paris, France
  1. Correspondence to Dr David Saadoun, Department of Internal Medicine and Clinical Immunology, AP-HP, Hôpital Pitié-Salpêtrière, 83 boulevard de l'hôpital, Paris F-75013, France; david.saadoun{at} and Pr Patrice Cacoub;


Background Hepatitis C virus (HCV) is the aetiological agent for most cases of cryoglobulinaemia vasculitis. Interferon-containing regimens are associated with important side effects and may exacerbate the vasculitis.

Objective To evaluate safety and efficacy of an oral interferon-free regimen, sofosbuvir plus ribavirin, in HCV-cryoglobulinaemia vasculitis.

Patients and methods We enrolled 24 consecutive patients (median age of 56.5 years and 46% of women) with HCV-cryoglobulinaemia vasculitis. Sofosbuvir (400 mg/day) was associated with ribavirin (200–1400 mg/day), for 24 weeks. The primary efficacy end point was a complete clinical response of the vasculitis at the end of treatment (week 24).

Results Main features of HCV-cryoglobulinaemia vasculitis included purpura and peripheral neuropathy (67%), arthralgia (58%), glomerulonephritis (21%) and skin ulcers (12%). Twenty-one patients (87.5%) were complete clinical response at week 24. Complete clinical response was achieved in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16 and one (4.2%) at week 20. The cryoglobulin level decreased from 0.35 (0.16–0.83) at baseline to 0.15 (0.05–0.45) g/L at week 24. The C4 serum level increased from 0.10 (0.07–0.19) to 0.17 (0.09–0.23) g/L at week 24. Seventy-four per cent of patients had a sustained virological response at week 12 post treatment. The most common side effects were fatigue, insomnia and anaemia. Two serious adverse events were observed.

Conclusions Sofosbuvir plus ribavirin combination was associated with a high rate of complete clinical response and a low rate of serious adverse events in HCV-cryoglobulinaemia vasculitis.

  • Systemic vasculitis
  • Infections
  • Autoimmune Diseases

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Hepatitis C virus (HCV) represents a healthcare challenge, with approximately 170 million people chronically infected. Circulating mixed cryoglobulins are detected in 40%–60% of patients chronically infected with HCV whereas overt cryoglobulinaemia vasculitis is observed in only 5%–10% of cases.1–7 It reflects the activation of B cells that generates pathogenic IgM and IgG with rheumatoid factor activity.2 ,8 Cryoglobulinaemia vasculitis leads to clinical manifestations ranging from purpura, arthralgia and fatigue to more serious lesions with neurological and renal involvement.9 ,10 Despite the successes with combination antiviral treatment with or without immunosuppressive drugs, HCV-cryoglobulinaemia vasculitis remains a severe disease with an estimated 5-year survival rate of 75%.2 ,8 ,11–14

Treatment of HCV-cryoglobulinaemia vasculitis remains difficult and should target the downstream B cell arm of autoimmunity and the viral trigger to obtain clinical resolution of symptoms.15–20 Two prospective randomised controlled trials have demonstrated the superiority of rituximab monotherapy as compared with conventional immunosuppressive therapy in patients with HCV-cryoglobulinaemia vasculitis in whom prior antiviral therapy failed to induce disease remission.16 ,19 Rituximab was effective in 71.4%–83% of patients with cryoglobulinaemia vasculitis.16 ,19 However, in the absence of HCV clearance, frequent relapses occurred when B cells re-emerged in the peripheral blood. Repeated rituximab infusions exposed patients to opportunistic infections. Additionally, patients with HCV-cryoglobulinaemia vasculitis treated with HCV first generation protease inhibitor (boceprevir or telaprevir) in combination with peginterferon and ribavirin achieved clinical and sustained virological responses in 66% of cases.21 ,22 Using this latter approach, additional therapy (ie, steroids, plasmapheresis, immunosuppressors) were needed in patients with HCV-cryoglobulinaemia vasculitis with severe organ involvement and/or without sustained virological response. Furthermore, side effects were very frequent.21 ,22

There is an ongoing need to document both the safety of all oral interferon-free, direct-acting antiviral regimens and their effect on HCV-cryoglobulinaemia vasculitis. All oral interferon-free, nucleotide polymerase inhibitor sofosbuvir plus ribavirin have shown high rates of sustained virological responses in chronic HCV infection.23 ,24 This study reports the results from the VASCUVALDIC investigation designed to test the safety and efficacy of sofosbuvir and ribavirin in patients with HCV-cryoglobulinaemia vasculitis.

Patients and methods


The VASCUVALDIC study is an open label prospective study including 24 consecutive patients with active HCV-cryoglobulinaemia vasculitis, recruited between November 2013 and September 2014. To be eligible, the patient must have been at least 18 years of age or older, without any upper age limit, informed and present an active HCV vasculitis defined by a clinically active vasculitis with skin, joint, renal, peripheral nerve, central neurological, digestive, pulmonary and/or cardiac involvement (no histological evidence needed if patient had purpura), and a chronic active HCV infection (positive HCV RNA).

Exclusion criteria included non-active cryoglobulinaemia vasculitis, HIV or active hepatitis B virus (HBV) infection, and current decompensated cirrhosis.

The baseline clinical evaluation included age, gender, any recent weight loss, neurological involvement (peripheral and/or central nervous system), cutaneous involvement (Raynaud's phenomenon, purpura, distal ulcers, skin necrosis), arthralgia, myalgia, gastrointestinal tract involvement, renal involvement (proteinuria, haematuria and glomerular filtration rate (GFR)), and clinical signs of hepatic involvement. All patients had the same follow-up visits every 4 weeks until week 24 and at week 36. The Short Form Health Questionnaire (SF-36) quality of life's scale was performed at day 0 (D0) and weeks 24 and 36. The diagnosis of non-Hodgkin’s lymphoma was based on the WHO criteria.25

The study was performed according to the Declaration of Helsinki, and was approved by the ethic committee of Pitié-Salpêtrière Hospital.

Immunological and virological markers

HCV viral load was quantified using the Abbott HCV RealTime assay (Abbott, Rungis, France) with a lower limit of detection of 12 IU/mL. HCV genotyping was performed by NS5b gene sequencing according to the previously validated consensual method.26 Laboratory evaluation included a complete blood count, serum chemistry profile, alanine aminotransferase (ALT), rheumatoid factor activity, IgM level, C4 fraction of complement and cryoglobulin. Cryoglobulins were measured as previously described27 and classified according to the method described by Brouet et al.28 The estimation of GFR was determined by modification of diet in renal disease study equations. Urine collection was also performed in order to quantify protein excretion. Liver fibrosis was evaluated (by liver biopsy and/or non-invasive tests) according to the previously validated Metavir scoring system.29


The primary endpoint was a complete clinical response of cryoglobulinaemia vasculitis at week 24. The complete clinical response was defined by the improvement of all the affected organs involved at baseline and the absence of clinical relapse. The skin and articular improvement were evaluated clinically (ie, disappearance of purpura and/or ulcers and/or skin necrosis, disappearance of arthralgia and/or arthritis). Renal improvement was evaluated biologically (ie, proteinuria <0.3 g/24 h, disappearance of haematuria and improvement of GFR >20% at week 24 if GFR <60 mL/min/1.73 m2 at diagnosis). Peripheral neurological improvement was evaluated clinically (ie, improvement of pains and paraesthesia by visual analogue scales, improvement of muscular testing in case of motor impairment at baseline) and/or electrophysiologically (ie, improvement of electromyogram abnormalities at week 24 compared with baseline). The neuropathy total symptom score-6 (NTSS-6) was applied to evaluate individual neuropathy sensory symptoms.30 Patients defined as partial clinical responders at week 24 had an improvement in some but not all organs involved at baseline. Patients with no clinical improvement at week 24 were defined as treatment failure.

The secondary endpoints included: (a) a sustained virological response at week-12 follow-up (SVR12); (b) the course of cryoglobulinaemia, C4 complement fraction and ALT; (c) the SF-36 quality of life score at day 0 and week 24 and 36 and (d) the rate and type of side effects during the 36 weeks of follow-up. A sustained virological response was defined by the absence of detectable serum HCV RNA 12 weeks after the end of antiviral therapy; the remaining patients were classified as virological failures. Virological relapse refers to the reappearance of HCV RNA after cessation of antiviral therapy and virological breakthrough if HCV RNA went from undetectable to detectable while still on antiviral therapy.

Study design

Because of the potential of interferon α treatment to exacerbate autoimmune disease states and to induce vasculitis, we decided to use an interferon-free, all-oral combination for the treatment of HCV-cryoglobulinaemia vasculitis. At the time we designed this study, the only available combination of all-oral IFN-free regimen was sofosbuvir plus ribavirin. All patients received antiviral therapy with sofosbuvir 400 mg daily plus ribavirin (200–1400 mg/day orally) for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modification for anaemia were at the investigator's discretion.

Safety assessments

Data on all adverse events were collected prospectively during the follow-up.

Statistical analysis

Data are expressed as the median, IQR for quantitative data and counts and per cent for categorical data. This study was not designed to evaluate formal statistical hypotheses, and no sample-size calculations were performed. Analyses of efficacy, safety and baseline patient characteristics were performed with the intention to treat population, defined as all enrolled patients who received at least one dose of study drugs (sofosbuvir, ribavirin).


Characteristics of the patients with HCV-Cryoglobulinaemia vasculitis

Patient characteristics are detailed in table 1. Twenty-four patients with HCV-cryoglobulinaemia vasculitis, with a median age of 56.5 (IQR, 49.5–66.5 years) were included. Main clinical features of cryoglobulinaemia vasculitis included purpura and peripheral neuropathy (67%), arthralgia (58%), glomerulonephritis (21%), and skin ulcers (12%). Among the 16 patients with peripheral neuropathy three had sensory-motor polyneuropathy, eight had sensory polyneuropathy, and five had sensory-motor multiplex neuropathy. Among the five patients with kidney involvement, four had a renal biopsy showing membranoproliferative glomerulonephritis in all cases. Median (IQR) cryoglobulin level was of 0.36 g/L (0.2–0.8). Eighty per cent of patients had a type II mixed cryoglobulin. Median (IQR) C4 serum level was of 0.10 g/L (0.07–0.19). Fourteen patients (58%) had severe liver fibrosis (ie, a stage 3 or 4 Metavir fibrosis score) and 12 had a Child–Pugh class A cirrhosis. Seven (29.1%) patients were treated with immunomodulatory or immunosuppressive therapy due to kidney involvement (n=2) and/or severe neuropathy (n=2). Rituximab (4 weekly infusions at 375 mg/m2) was used in four cases, in addition with prednisone (50 mg/day progressively tapered) and plasmapheresis in two patients. One patient received seven monthly courses of rituximab (500 mg) plus cyclophosphamide (300 mg daily for 4 days) for a refractory HCV-cryoglobulinaemia vasculitis associated with a B cell lymphoma. This patient received the last course of immunosuppresssors 3 months before starting antiviral therapy with sofosbuvir plus ribavirin. Three patients had plasmapheresis alone (4–17 sessions). Eleven patients (46%) were antiviral treatment naïve, and the remaining 13 (54%) were virological non-responders to a previous antiviral therapy (table 1).

Table 1

Baseline characteristics of the 24 patients with HCV-cryoglobulinaemia vasculitis

Treatment efficacy

The main treatment-related data are summarised in table 2, figures 1 and 2, and online supplementary figure S1. At week 24 (end of antiviral treatment), twenty one (87.5%) patients were complete clinical responders, and three (12.5%) were partial responders. Complete clinical improvement was achieved in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16 and one (4.2%) at week 20. Purpura, skin ulcers and arthralgia disappeared in all cases. Kidney involvement improved in four out of five (80%) patients. The median creatinine level was 89 µmol/L (80–163) at baseline and 85 µmol/L (78–146) at week 24 (figure 2 and online supplementary figure S1). Median GFR was 77.3 mL/min/1.73 m2 (44–90) at baseline and 66.7 mL/min/1.73 m2 (48–87) at week 24. Daily proteinuria decreased from 1.09 (0.6–2.4) to 0.17 (0.07–0.25) g. Haematuria was present in four out of five (80%) at diagnosis and disappeared in all cases at week 24. Peripheral neuropathy improved in 15 out of 16 (94%) cases. The mean NTSS-6 score decreased from 11.9±2.7 to 2.6±2.6. Motor symptoms slightly improved in four out of eight patients.

Table 2

Responses during and after treatment

Figure 1

Kinetics of Hepatitis C virus (HCV) RNA (A), cryoglobulinaemia (B) and C4 serum complement level (C). Data are shown for all patients with HCV-Cryoglobulinaemia vasculitis for whom assessments were available. The limit of detection of HCV RNA level was of 1.08 log10 copies/mL.

Figure 2

Outcome of kidney involvement*. (A) Daily proteinuria. (B) Serum creatinine level. (C) Glomerular filtration rate (GFR). *Data relative to kidney parameters from one patient who was on long-term haemodialysis were not shown.

The cryoglobulin level decreased from 0.35 (0.16–0.83) at baseline to 0.15 (0.05–0.45) g/L at week 24. Disappearance of cryoglobulin was evidenced in 46.1% of cases. The C4 serum level increased from 0.10 (0.07–0.19) to 0.17 (0.09–0.23) g/L at week 24 (table 2 and figure 1). The HCV viral load was <12 IU/mL at week 8 in 20 out of 24 (83.3%) and sustained virological response rate at week 12 post-treatment was of 74%. The ALT level decreased from 48.5 (28–68) to 15.5 (12–20) IU/L. Among patients with virological failure (n=2) or relapse (n=4), five had a liver cirrhosis, all had a virological failure to a previous antiviral therapy including three with peginterferon and ribavirin plus protease inhibitor (telaprevir or boceprevir), and two were infected with HCV genotype 4 (see online supplementary table S1). Among the three patients who received rituximab infusion 1 month before starting antiviral therapy, all achieved SVR12. No difference of outcome was found in patients who received immunosuppressive treatment or not (see online supplementary table S2).

Quality of life

The SF-36 score was assessed at baseline and at week 24 and 36. The physical status score improved by a mean change from baseline of +10% at week 24 and +14% at week 36. The mental status score improved by a mean change from baseline of +4% at week 24 and +7% at week 36.


Table 3 summarises the safety profile of the antiviral therapy. Fourteen patients (54%) experienced at least one side effect. Main side effects of antiviral therapy included fatigue (25%), anaemia (25%), insomnia (21%), infection (17%), nausea, pruritus and alopecia (8%). Antiviral therapy discontinuation was required in two (8%) patients due to hallucination and irritability (n=1) and to a grade 4 anaemia and death (n=1). At the end of follow-up, two deaths occurred in 80 and 89 years old patients with severe impairment of health status and without kidney involvement. One patient died during the course of antiviral therapy, at week 16, while he showed partial clinical improvement and HCV RNA negativity. Death was related to a severe pneumonia in the context of B cell lymphoma (ie, Waldenström's macroglobulinaemia). Monoclonal IgM level was slightly increased before death (7.8 at baseline vs 9.4 g/L at week 13). The remaining patient discontinued antiviral therapy at week 20 because of hallucinations and irritability while he had complete clinical improvement. This patient received erythropoietin during antiviral therapy. He had no evidence of hepatocellular carcinoma or central nervous system vasculitis at this time. He achieved SVR12. Hallucinations and irritability persisted after discontinuation of antiviral therapy. He died in the following weeks of a pulmonary embolism in the context of hepatocellular carcinoma. Infections were reported in four patients, including acute herpes zoster virus infection (n=2), pneumonia (n=1) and prostatitis (n=1). Grade 3 and 4 anaemia was observed in three (12.5%) patients. Thirteen (54%) patients received erythropoietin, and three (12.5%) received blood transfusion.

Table 3

Adverse events


HCV-cryoglobulinaemia vasculitis belongs to one of the non-hepatic indications for the use of HCV nucleotide polymerase inhibitors in USA and in Europe.29 ,31 HCV-cryoglobulinaemia vasculitis is a severe and challenging condition with up to 40% of death in 10 years7 and an overall risk of non-Hodgkin's lymphoma 35 times higher than in the general population.14 The total annual direct medical cost associated with the care of patients with HCV extra hepatic manifestations in USA was estimated to be US$1447 million per year, with a predominant impact of cryoglobulinaemia vasculitis.32 In the present VASCUVALDIC study of a 24-week, interferon-free, all oral antiviral regimen, a rate of 87.5% of complete clinical improvement was observed at the end of therapy among patients with HCV-cryoglobulinaemia vasculitis, with a good safety profile. By comparison, treatment with peginterferon and ribavirin,21 and more recently with first generation protease inhibitors (boceprevir or telaprevir) in combination with peginterferon and ribavirin21 had shown a lower rate of complete clinical improvement and very high rates of side effects. The present study is the first to evaluate the safety and efficacy of direct-acting antiviral therapy in HCV-cryoglobulinaemia vasculitis. Because of the well-known potential of interferon α to exacerbate autoimmune disease states and to induce vasculitis in some patients,33 ,34 we decided to use an interferon-free, all-oral combination. Sofosbuvir plus ribavirin regimen was the only available combination with such profile in 2013 in France.

Our results demonstrate a rapid virological response and clinical improvement. The HCV viral load dropped dramatically within 4 weeks of treatment and 83% of patients had undetectable HCV RNA at week 8; a typical feature found with direct-acting antiviral agents. A rapid clinical improvement of cryoglobulinaemia vasculitis symptoms was simultaneously achieved. However, 40% of patients with renal involvement were also treated with immunosuppressants. A complete clinical improvement was evidenced in 42%, 71% and 87.5% of patients at week 4, 12 and 24, respectively. HCV-related splenic marginal zone lymphoma was effectively treated with direct-acting antiviral agents (faldaprevir, deleobuvir) plus ribavirin in a recent case-report.35 Undetectable HCV RNA was observed at week 4 and haematological complete improvement was achieved within 8 weeks of therapy. These results contrast with those previously reported with the use of first generation protease inhibitors plus peginterferon and ribavirin in patients with HCV-cryoglobulinaemia vasculitis, where only 50% of patients achieved a complete clinical improvement at week 12.21 In a study of patients with HCV-cryoglobulinaemia vasculitis, the rate of sustained virological response was of 23.8% with boceprevir plus peginterferon and ribavirin.36 Immunosuppressive agents are typically indicated for patients with HCV-cryoglobulinaemia vasculitis with severe disease manifestations such as membranoproliferative glomerulonephritis, severe neuropathy and life-threatening complication.2 ,12 Rituximab is used for the control of severe vasculitis lesions while awaiting the generally gradual improvement to antiviral treatments.16 ,19 ,37 In the present study, only 17% of patients required the use of rituximab and glucocorticosteroids associated with antiviral therapy as compared with 43% of those who received first generation protease inhibitors (telaprevir or boceprevir) plus peginterferon and ribavirin (20). In addition, we found no difference in safety or virological/clinical efficacy whether patients received or not glucocorticosteroids or rituximab. Careful assessment of health-related quality of life was performed using a validated questionnaire. The quality of life was improved at the end of therapy (ie, at week 24) and at week 36, in both mental and physical domains, as compared with the values before treatment initiation.

Few data are available in the literature on efficacy of sofosbuvir-based regimen in HCV-infected patients with impaired kidney function. Among the five patients with HCV-cryoglobulinaemia vasculitis with kidney involvement, 80% achieved a complete clinical improvement and all were sustained virological responders at post-treatment week 12.

Treatment of HCV-cryoglobulinaemia vasculitis with telaprevir or boceprevir plus peginterferon and ribavirin has been associated with high rates of treatment discontinuation due to adverse events.21 Severe side effects were observed in 46.6% of cases. Grade 3 and 4 cytopenia occurred in 40% of cases, including haemoglobin levels of less than 8.0 (mg/dL) in 20% of patients.21 Erythropoietin was used in 93% of patients and 46% had blood transfusion.21 By comparison, grade 3 and 4 laboratory abnormalities were observed in only 12.5% of patients with HCV-cryoglobulinaemia vasculitis treated with sofosbuvir and ribavirin. Overall, antiviral therapy discontinuation rate was 34.7% with telaprevir or boceprevir plus peginterferon and ribavirin21 versus 8.3% with sofosbuvir and ribavirin.

This study has some limitations. This was an open label study with no control group. Considering the very high rates of SVR and the very good safety profile previously demonstrated with a combination of sofosbuvir and ribavirin, the use of a control group would have been unethical in a population with a severe life-threatening disease. Some patients were antiviral treatment naïve whereas other had failed to previous therapies.

In conclusion, the VASCUVALDIC study demonstrates for the first time that a combination of an all oral, interferon-free, antiviral therapy can induce very rapid clinical improvement and virological response, and a high rate of complete clinical improvement in cryoglobulinaemia vasculitis. The tolerance was satisfactory with a low rate of serious adverse events. Further studies are warranted to assess whether in patients with HCV-cryoglobulinaemia vasculitis (a) direct acting antiviral agents may reduce the need for glucocorticosteroids and immunosuppressants and (b) safer and more effective regimens, without ribavirin, may increase the response rates.


Authors thank Sofia Honorio-Grand and Marlene Garrido for their help in collecting data and in the preparation of the manuscript. We also thank all patients and their families.


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  • Handling editor Tore K Kvien

  • Contributors Study concept and design: DS, PC. Acquisition of data: DS, VT, SNSA, LA, MM, CG, HI, AP, HF, MC, MLG-T, CH, SP, LM, TP, PC. Analysis and interpretation of data: DS, VT, TP, PC. Drafting of the manuscript: DS, VT, PC. Critical revision of the manuscript for important intellectual content: DS, VT, LA, HF, LM, CH, TP, PC.

  • Funding This work was supported by an unrestricted grant provided by Gilead Science.

  • Competing interests DS has received consulting and lecturing fees from Medimmune, Roche, Servier, Gilead, AstraZeneca and Glaxo Smith Kline. SNSA received consulting and lecturing fees from Abbvie, Bristol Myers Squibb, Gilead, Janssen and Roche. LA received consulting and lecturing fees from Gilead, Bristol Myers Squibb, Janssen, Abbvie, Merck Sharp Dhome, Roche. HF has given lectures and participated to boards for Bristol Myers Squibb, Gilead, Abbvie, Merck Sharp Dohme, Janssen. CH has been adviser and speaker for Abbvie, Bristol Myers Squibb, Gilead, Janssen, and Merck Sharp Dohme. SP, speaker: Glaxo Smith Kline, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Gilead, Roche, Merck Sharp Dohme, Sanofi, Novartis, Vertex, Abbvie; grants : Bristol Myers Squibb, Gilead, Roche, Merck Sharp Dohme; board member : Glaxo Smith Kline, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Gilead, Roche, Merck Sharp Dohme, Sanofi, Novartis, Vertex, and Abbvie. TP is the founder of BioPredictive marketing FibroTest (patent belong to Public Organization APHP). Patrice Cacoub has received consulting and lecturing fees from Abbvie, Astra Zeneca, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen, Merck Sharp Dohme, Roche, Servier and Vifor.

  • Patient consent Obtained.

  • Ethics approval Paris VI University IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.