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Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia.
Emery JS, et al.
Am J Gastroenterol 2017

OBJECTIVES: Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection and ranges from being asymptomatic to causing life-threatening vasculitis. In those with symptoms, treatment with pegylated interferon (pegIFN) and ribavirin (RBV) reduces mortality. However, few data are available on the safety and efficacy of antiviral therapy with direct acting antivirals (DAAs) in the treatment of HCV-related cryoglobulinemia.

METHODS: Patients treated for HCV-related cryoglobulinemia with DAA┬▒pegIFN were retrospectively evaluatedat a tertiary care center. Primary outcomes were virological, immunological, and clinical response. Complete (normalization), partial (>50% reduction), or non-response (<50% reduction) were used to describe change in cryocrit or vasculitic manifestations at week 12 post treatment. Side effects, hospitalizations, and decompensating events were recorded.

RESULTS: Eighteen symptomatic and 65 asymptomatic patients were reviewed (61% male, median age 58 years) including 10 with severe/life-threatening vasculitis. Sixty-six (79.5%) patients received pegIFN-free therapy. Sustained virological response (SVR) was attained in 16 (88.9%) symptomatic and 59 (90.8%) asymptomatic patients. Cryoglobulins disappeared in 5 (29.4%) symptomatic and 27 (52.9%) asymptomatic patients. Of symptomatic patients with SVR, clinical response was complete in 7 (38.8%) and partial response in 4 (22.2%). Of the 5 viral relapsers, 1 had a complete response during therapy with no symptomatic recurrence, while the other patients had no clinical response. Among 7 with severe vasculitis, 6 achieved SVR but only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. All four with life-threatening vasculitis required plasmapheresis and three received rituximab. All achieved SVR leading to partial clinical response in two, but no response in two. Skin manifestations (39% reduction) were most likely to completely resolve with lower responses seen in renal (11.2% reduction) and neurological symptoms (11.1%). Eighty-two (98.8%) patients completed therapy, with 19 (22.8%) reporting adverse events. Hospitalization for decompensation or worsening vasculitis occurred in five (6.0%) and four (22.2) patients respectively.

CONCLUSIONS: DAAs resulted in high rates of SVR in patients with cryoglobulinemia. Safety and tolerability were excellent; however, most patients did not have a complete clinical or immunological response, suggesting a delay to clinical response particularly in those with severe/life-threatening vasculitis. Further follow-up will be required to determine if clinical improvement continues after viral clearance.

Expert's Commentary (Dr Jordan Feld, senior author)

The prospect of rapid viral clearance with DAA-based therapy held great promise for the treatment of a virally-mediated disease such as HCV-associated mixed cryoglobulinemic vasculitis. In this single-centre study, Emery and colleagues did indeed show that the presence of cryoglobulins did not impair SVR rates and patients with symptomatic MCV improved with antiviral therapy. However, although the results were encouraging, DAAs were not the panacea that was perhaps anticipated. Of patients who achieved SVR, only 39% had complete resolution of all manifestations of MCV, while an additional 22% saw some improvement. All 4 patients with life-threatening vasculitis required rescue therapy with plasmapheresis and/or rituximab. Unfortunately the most serious complications of MCV (renal and neurological) responded least well to antiviral therapy. While patients continued to improve with extended follow-up, these data suggest that there may be significant delays in clinical and immunological improvement after viral clearance, particularly for patients with more advanced disease. This is important for patients and clinicians to recognize and more importantly, further suggests that we should treat patients with asymptomatic cryoglobulinemia early to prevent development of symptoms that may respond poorly or at least slowly to antiviral therapy.

Jordan Feld MD MPH, University of Toronto, Ontario, Canada