Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents

Abstract

Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events.

Conclusion: SVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.

Figure 1. Change in cryoglobulin levels over time in patients treated with sofosbuvir-based direct-acting antiviral therapy

Patients who achieved SVR12 are shown with solid lines. The two patients who relapsed are shown with dashed lines. The first data-point at time 0 shows the baseline pre-treatment cryoglobulin percent measurement for each of the 9 patients with serial cryoglobulin percent measured. The second data-point shows the nadir and the time-to-nadir in days since initiating therapy. The final data-point for each patient shows the cryoglobulins percentage at last follow-up visit. Three patients did not have repeat cryoglobulins measured after initiating treatment and are excluded from this figure.

Figure 2. Serum creatinine and proteinuria trends in 7 cases of HCV-MCS with renal involvement

Serum creatinine (hollow squares) and proteinuria (dark circles, panels A,C,G) values obtained 3 months prior to direct-acting antiviral therapy initiation, through treatment period (gray) and through last follow-up visit. Patients 1–6 (panels A-F) achieved SVR12. Patient 7 (Panel G) relapsed four weeks after completing therapy. Abbreviations: SOF=sofosbuvir, SIM = simeprevir, RBV = ribavirin. SVR12 = sustained virological response 12 weeks after completion of therapy.