Long term effectiveness of DAA therapy in patients with chronic HCV and Mixed Cryoglobulinemic Syndrome

Background: Mixed cryoglobulinemia is the most frequent extrahepatic HCV-induced disorder. Promising data exists on the effectiveness and safety of direct-acting antiviral (DAA) therapy, but prospective, long-term posttreatment follow-up studies are lacking. Using data from the prospective multicentric PITER cohort we aimed to evaluate the clinical effect of DAA therapy following viral eradication. Methods: Patients with cryoglobulins and symptoms before antiviral treatment were prospectively followed-up during and after treatment collecting clinical data in a dedicated eCRF. Results: Of the 458 patients who had a Cryoglobulinemic Syndrome (mean age:63; SD 11 years; 64% female; 33% with liver cirrhosis) and were treated with DAAs from 2014-2017, the SVR was 96%. At the end of treatment, the clinical responses were: Full Complete (disappearance of all symptoms) in 12%; Complete (improvement of all symptoms) in 20%; Partial (improvement in ≥50% of symptoms) in 23%; Non Response (improvement in less than 50% or persistence of all symptoms) in 45%. In 402 patients a follow-up (mean:561 days SD 308) was available after the SVR. At the end of the follow-up the clinical responses were: Full Complete in 27%, Complete in 29%, Partial in 22% and Non Response in 18%. A new appearance of symptoms (Clinical Relapse) was observed in 15 (3.7%) patients. After SVR a complete disappearance of cryoglobulins was achieved in 73%, in 19% a significant reduction of cryocrit was observed, in the remaining 8% of patients cryocrit values did not change significantly. Nephropathy was the only independent factor associated to Non Response by Cox Regression analysis (HR:2.8; CI:95%:1.4-5.4). Presence of cryoglobulins following the SVR was the only independent predictor of Clinical Relapse (HR:28; 95% CI 3-249). Among the 150 patients in whom four points (every 6 months) of clinical evaluation were available, fluctuations in the clinical response (from Non Response to Full Complete Response and vice versa in the different time points) were observed in 72% of patients. Conclusion: DAA therapy induces a high virologic and clinical response. However a follow-up evaluation of Symptomatic HCV-Cryoglobulinemic patients is necessary because a fluctuating pattern is observed in clinical response during follow-up in a consistent proportion of cases