The Role of Antiviral Treatment in Hepatitis C Virus (HCV)-Driven Monoclonal Gammopathies
Authors: Rodríguez García Alba , Linares María , Mennesson Nicolas , Pérez-Revilla Alfredo , Sanchez Ricardo , Leivas Alejandra , Fernández Rafael Alonso , Bigot-Corbel Edith , Hermouet Sylvie , Martinez-Lopez Joaquin 
Published: November 2019

INTRODUCTION: Recently, new understanding of monoclonal gammopathy pathogenesis highlighted possible disease initiation by viral infection in subsets of patients, notably by hepatitis C virus (HCV). If the infectious pathogen targeted by the monoclonal Ig could be eliminated at the monoclonal gammopathy of undetermined significance (MGUS) stage, chronic antigen-stimulation could disappear, leading in turn to the disappearance of the monoclonal Ig. Here we report a series of patients with monoclonal gammopathy and HCV infection, whose disease prognosis clearly improved, even reached complete remission, after antiviral treatment.
METHODS: Nine patients diagnosed with MGUS (n=6) or multiple myeloma (MM) (n=3) after HCV infection were included in the study and classified into two groups: patients who received antiviral treatment, and patients who did not receive anti-viral treatment. Disease status was monitored by the quantification of the monoclonal immunoglobulin (mc Ig) level. The HCV burden was determined by RT-qPCR. Each patient's mc Ig was isolated from polyclonal immunoglobulins by agarose gel electrophoresis and mc Ig purity was evaluated by isoelectric focusing. The multiplex infectious antigen microarray (MIAA) was used to analyze the reactivity of serum immunoglobulins and of monoclonal Ig against commercially available antigens and/or lysates from different microorganisms. The INNO-LIA™ HCV Score assay (Fujirebio) was used to analyze the reactivity of monoclonal Ig to HCV proteins.
RESULTS: Regarding patients treated with antiviral drugs (4 MGUS, 2 MM), mc Ig levels in serum decreased after antiviral treatment. MGUS patients remained in a stable status without disease progression. After antiviral treatment, one MM patient who was in third relapse achieved complete remission with minimal residual disease negativity. As expected, the HCV load decreased after antiviral therapy to undetectable levels. Serum samples from patients were reactive against antigens of various viruses and other microorganisms, but analysis of the specificity of recognition of the purified mc Ig of each patient revealed that it targeted HCV, either the core protein (C1, C2), NS3, or NS4.
In contrast, for patients who did not receive antiviral treatment (2 MGUS, 1 MM), MGUS and MM disease progressed and the mc Ig level remained stable or increased. Serum samples from these patients were reactive against various viruses and other microorganisms, but their mc Ig did not recognize HCV proteins.
CONCLUSION: In this study of monoclonal gammopathies where the mc Ig targeted HCV, successful HCV eradication with antivirals resulted in improvement of MGUS and MM disease as well as of hepatitis C. Our findings suggest that for HCV-positive individuals who were infected before being diagnosed with MGUS or MM, a causal relationship exists between HCV infection and the development of MGUS and MM, and both MGUS and MM patients infected with HCV may benefit from early anti-HCV therapy.

Disclosures
No relevant conflicts of interest to declare.