Therapy with direct antiviral drugs in patients with HCVassociated cryoglobulinemic vasculitis – is it always possible to achieve complete clinical and immunological responses after the virus eradication?

Background. The use of direct acting antiviral drugs (DAАs) leads to the achievement of a stable virological response (SVR) in 95–100 % of patients with HCV-associated cryoglobulinemic vasculitis (HCV-CV). However, in some patients, despite the eradication of the virus, clinical and immunological markers of vasculitis still remain.

The aim: to evaluate clinical and immunological responses in patients with HCV-CV in comparison with patients with "asymptomatic" HCV- associated cryoglobulinemia (HCV- СG) after achieving SVR with the help of DAАs with long-term dynamic observation (12 months).

Patients and Methods: The study included 45 patients: 23 with HCV-CV and 22 with "asymptomatic" HCV-CG, who underwent antiviral therapy with DAAs. Clinical-immunological, virological data were evaluated: before treatment, 12 weeks (3 months) and 48 weeks (12 months) after the end of treatment.

Results: After a course of DAAs, SVR was diagnosed in all 45 (100 % of patients). In patients with HCV-CV, an immunological response (complete and partial) was observed by week 12 (SVR₁₂) – in 56.5 % and by week 48 (SVR₄₈) – in 73.9 % patients. In 6 patients (26.1 %), the immunological response was not achieved by SVR₄₈. The rate of complete and partial clinical response 12 weeks after the end of treatment at the SVR₁₂ period in patients with HCV-CV was 65.2 %, to the time of SVR₄₈ amounted to 78.3 % patients. In 5 (21.7 %) individual manifestations of CV persisted and/or relapsed. In patients with HCV-CG, the frequency of complete and partial immunological responses after DAAs therapy was 77.3 % – by SVR₁₂ and 86.3 % – by SVR₄₈, respectively. No response was observed in 3 patients and it was characterized by trace-level of cryoglobulinemia.

Conclusion: In most patients with HCV-CV eradication of HCV with help of DAAs leads to the achievement of clinical and immunological remission of the disease. However, in 20 % of patients manifestations of HCV-CV persist / recur immediately after the end of treatment or later relapses are observed. Based on these observations, patients with HCV-CV, especially those with severe underlying skin and kidney disease, are required long-term monitoring after SVR is achieved.

1. Bonacci M., Lens S., Mariño Z. et al. Long-Term Outcomes of Patients With HCV- Associated Cryoglobulinemic Vasculitis After Virologic Cure. Gastroenterology 2018; 155 (2): 311–315. https://doi.org/10.1053/j.gastro.2018.04.024

2. Bonacci M, Lens S, Londoño MC, Mariño Z, Cid MC, RamosCasals M, et al. Virologic, clinical, and immune response outcomes of patients with hepatitis C virus-associated cryoglobulinemia treated with direct-acting antivirals. Clin Gastroenterol Hepatol 2017;15:575–83. https://doi.org/10.1016/j.cgh.2016.09.158

3. Cacoub P, Vautier M, Desbois AC et al. Effectiveness and cost of hepatitis C virus cryoglobulinaemia vasculitis treatment: From interferon-based to direct-acting antivirals era. Liver International 2017; 37(12): 1805–1813. https://doi.org/10.1111/liv.13465

4. Emery JS, Kuczynski M, La D et al. Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia. American Journal of Gastroenterology 2017; 112(8): 1298–1308. https://doi.org/10.1038/ajg.2017.49

5. Artemova M, Abdurakhmanov D, Ignatova T et al. Persistent hepatitis C virus- associated cryoglobulinemic vasculitis following virus eradication after direct-acting antiviral therapy. Hepatology 2017; 65(5):1770–1771. https://doi.org/10.1002/hep.28981

6. Gradnani L, Cerretelli G, Lorini S et al. Interferon-free therapy in hepatitis C virus mixed cryoglobulinemia: prospective, controlled, clinical and quality of life analysis. Alimentary Pharm and Therapeutics 2018;48:440–450 https://doi.org/10.1111/apt.14845

7. Gragnani L, Lorini S, Marri S, Basile U, Santarlasci V, Monti M et al. Hematological and Genetic Markers in the Rational Approach to Patients With HCV Sustained Virological Response With or Without Persisting Cryoglobulinemic Vasculitis. Hepatology 2021; 74(3):1164–1173. https://doi.org/10.1002/hep.31804

8. Ferri C, Ramos-Casals M, Zignego AL, Arcaini L, Roccatello D, Antonelli A et al. International diagnostic guidelines for patients with HCV-related extrahepatic manifestations. A multidisciplinary expert statement. Autoimmun Rev 2016;15:1145–1160. https://doi.org/10.1016/j.autrev.2016.09.006

9. Pellicano R, Leone N, Maiocco IA et al. Chronic HCV hepatopathy and cryoglobulinemia. The associated clinical spectrum. Minerva Med 1999; 90(1-2):1–5

10. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol 2017;66:153–194. https://doi.org/10.1016/j.jhep.2016.09.001

11. Zignego AL, Ramos-Casals M, Ferri C, Saadoun D, Arcaini L, Roccatello D et al. International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement. Autoimmun Rev 2017;16:523–541. https://doi.org/10.1016/j.autrev.2017.03.004

12. Ignatova TM, Lysenko (Kozlovskaya) LV, Gordovskay NB et al. Hepatitis C virus-associated cryoglobulinemic vasculitis: A 20- year experience with treatment. Ter arh 2017;5:46–52 (In Russ.) doi: 10.17116/terarkh201789546-52

13. Pozzato G, Mazzaro C, Artemova M et al. Direct-acting antiviral agents for hepatitis C virus-mixed cryoglobulinaemia: dissociated virological and haematological responses. British Journal of Haematology 2020;191:775–783. https://doi.org/10.1111/bjh.17036

14. Comarmond C, Garrido M, Pol S et al. Direct-acting antiviral therapy restores immune tolerance to patients with hepatitis C virus-induced cryoglobulinemia vasculitis. Gastroenterology 2017; 152: 2052–2062. https://doi.org/10.1053/j.gastro.2017.02.037

15. Visentini M, Conti V, Cagliuso M et al. Persistence of a Large Population of Exhausted Monoclonal B cells in Mixed Cryoglobuliemia After the Eradication of Hepatitis C Virus Infection. Journal of Clinical Immunology 2012;32(4):729–735. https://doi.org/10.1007/s10875-012-9677-0

16. Arcaini L, Besson C, Frigeni M et al. Interferon-free antiviral treatment in B-cell lymphoproliferative disorders associated with hepatitis C virus infection. Blood 2016;128(21):2527–2532. https://doi.org/10.1182/blood-2016-05-714667