Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: A prospective, controlled pilot study

doi:10.1016/j.dld.2014.05.017

Digestive and Liver Disease

Volume 46, Issue 9, September 2014, Pages 833-837

https://doi.org/10.1016/j.dld.2014.05.017 Get rights and content

Abstract

Background

Mixed cryoglobulinaemia is strongly related to hepatitis C virus infection. Treatment with peg-interferon and ribavirin has been indicated as first-line therapy for mild/moderate hepatitis C virus-related mixed cryoglobulinaemia.

Aim

To evaluate the safety and efficacy of triple boceprevir-based antiviral therapy in patients with or without mixed cryoglobulinaemia previously treated with peg-interferon and ribavirin, and with advanced liver disease.

Methods

Thirty-five hepatitis C virus-positive patients (17 with asymptomatic mixed cryoglobulinaemia, 5 with symptomatic mixed cryoglobulinaemia, and 11 without mixed cryoglobulinaemia) were treated with triple boceprevir-based antiviral therapy.

Results

In 19/22 cryoglobulinaemic subjects (86%), the addition of boceprevir induced cryocrit disappearance. Cryocrit behaviour was related to virological response, with improvement of symptoms upon undetectable viraemia and reappearance after virological breakthrough. The rate of sustained virological response was lower in cryoglobulinaemic patients than in patients without mixed cryoglobulinaemia (23.8% vs 70% respectively, p = 0.01).

Conclusion

Boceprevir-based therapy was safe and effective in cryoglobulinaemic patients. The correlation between direct inhibition of hepatitis C virus replication and clinical improvement in mixed cryoglobulinaemic patients is definitive proof of the key pathogenetic role played by viral replication. Further studies are needed to confirm and clarify the reduced virological response in patients with mixed cryoglobulinaemia.

Introduction

Hepatitis C virus (HCV) infects about 200 million people worldwide, leading to chronic liver disease, cirrhosis, and liver cancer. HCV is able to infect not only hepatocytes, but also lymphatic cells, and leads to B-cell lymphoproliferative disorders (LPDs). A striking association has been shown between HCV and mixed cryoglobulinaemia (MC), a benign, but pre-lymphomatous condition. Indeed, 5–10% of MC patients develop B-cell lymphoma [1], [2].

The cryoglobulins are immune complexes that reversibly precipitate at temperatures lower than 37 °C and consist of IgM with rheumatoid factor activity (mono-oligoclonal in type II MC, or polyclonal in type III MC) and polyclonal IgGs [3].

Most MC patients harbour HCV infection (70–90%) and 40–60% of HCV patients carry MC, including 5–30% with symptoms (mixed cryoglobulinaemia syndrome, MCS) [3]. The clinical impact of cryoglobulinaemia without symptoms is still subject to debate. MCS is a progressive, possibly invalidating syndrome, which is the clinical expression of systemic vasculitis of the small/medium vessels [4]. It has been historically described by Meltzer and Franklin as a triad of purpura, fatigue and arthralgia [5]. MCS symptoms are complex and heterogeneous and reliable classification criteria for the MCS have only been recently published according to the results of an international European study [6], [7].

Different organs and tissues can be affected (mainly skin, joints, kidney, peripheral nerves), justifying the MCS-related multiple and variable symptoms and evolution [1], [8]. These range from skin manifestations (palpable purpura and petechiae most often on the legs, as well as papules, ulcers, and livedo at any skin site) to severe involvement of the kidney, peripheral and central nervous systems [3]. Circulating cryoglobulins, rheumatoid factor and a low C4 represent the serum hallmarks [1].

The treatment of MC changed when the pathogenetic role of HCV became clear. In fact, the eradication of HCV generally coincides with the resolution of MCS; thus, anti-HCV therapy with peg-interferon (Peg-IFN) and ribavirin (RBV) was indicated as the first-line therapeutic option in patients with MCS forms whose severity did not hamper the use of IFN-dependent antiviral therapy (mild to moderate HCV-related MCS) [9], [10]. Recently, triple therapy based on the combination of Peg-IFN, RBV, and a direct-acting antiviral, boceprevir (BOC) or telaprevir, has been indicated as the standard of care for the treatment of HCV-related chronic hepatitis. At present, few data are available regarding patients with HCV-related MCS [11] and no information exists about the correlations between virological response and cryoglobulin production or about the comparison between patients with and without MC in response to triple therapy. In the present study, we evaluated the efficacy and safety of BOC-based antiviral triple therapy in patients with or without MC previously treated with Peg-IFN and RBV, and with advanced liver disease.

Section snippets

Patients and methods

From September 2011 to April 2012, consecutive, HCV-positive, genotype 1 patients were prospectively recruited at the MASVE Center Outpatient Clinic of the University of Florence, to be treated with triple therapy. Enrolment criteria included: HCV genotype 1a or 1b, previous failure of anti-HCV dual treatment with Peg-IFN and RBV and advanced liver disease (F3-F4, METAVIR scoring system, if biopsy was available or a stiffness value >9 kPa evaluated by fibroscan) [12], [13].

All patients received

Results

Thirty-five HCV-positive Caucasian patients were consecutively recruited. These included 27 patients with genotype 1b and 8 with genotype 1a, 19 males (54%), mean age 57.5 years (range 41–71). Two patients were excluded from the comparative analysis: one because of recent rituximab (RTX) treatment and the other one for coexistence of smouldering multiple myeloma.

The remaining 33 patients were divided into three groups as follows: 17 patients in the HCV-MC group (HCV + MC patients without

Discussion

In this pilot study, for the first time we prospectively evaluated the clinical, immunological and virological responses of patients with chronic HCV infection, with or without MC, who were treated with BOC-based triple therapy. Patients without MC were divided into those with or without symptoms. The introduction of a direct-acting antiviral to Peg-IFN + RBV therapy, now considered the first therapeutic option in mild to moderate MCS [9], has important implications for both pathogenesis and

Conflict of interest

None declared.

Acknowledgments

This work was supported by grants from the ‘Associazione Italiana per la Ricerca sul Cancro’ (AIRC) Investigator Grant #1461, “Istituto Toscano Tumori” (ITT), ‘Fondazione Istituto di Ricerche Virologiche Oretta Bartolomei Corsi’, “Ente Cassa di Risparmio di Firenze” and “Fondazione Cassa di Risparmio di Pistoia e Pescia”; LG is supported by 2014 fellowship “Fondazione Umberto Veronesi”; EF is supported by 2014 fellowship “Mario Coppo, Associazione Italiana per lo Studio del Fegato (A.I.S.F)”.

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We performed a longitudinal cohort study between 2011 and 2018 from a single-center French university hospital's database of 15 970 patients screened for MC. Epidemiological, clinical and immunological data of MC were recorded. We evaluated the incidence and evolution of MC before and after the era of DAA agents and compared HCV and non-HCV related MC.
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Direct-acting antivirals have dramatically changed the landscape and the incidence of MC.
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¹: These authors contributed equally to this work.

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Liver, Pancreas and Biliary TractTriple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: A prospective, controlled pilot study

Abstract

Background

Aim

Methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest

Acknowledgments

Seminars in Arthritis and Rheumatism

Molecular Aspects of Medicine

American Journal of Medicine

Autoimmunity Reviews

Digestive and Liver Disease

Hepatology

Journal of Hepatology

Blood

Blood

Journal of Hepatology

Blood

Blood

Blood

Blood

Liver, Pancreas and Biliary Tract
Triple antiviral therapy in hepatitis C virus infection with or without mixed cryoglobulinaemia: A prospective, controlled pilot study