Clinical Pearls & Morning Reports
Published March 17, 2021
Unequivocal data support a causal relationship between chronic hepatitis C virus (HCV) infection and certain disorders, including cryoglobulinemic vasculitis, lymphoma, cardiovascular diseases, insulin resistance, and type 2 diabetes. The recent availability of direct-acting antiviral agents that are safe and effective has provided an opportunity to eradicate HCV in most patients, with major implications for the effective management of both hepatic and nonhepatic consequences of the viral infection. Read the NEJM Review Article here.
Q: Is HCV infection the leading cause of mixed cryoglobulinemic vasculitis?
A: In the era before the introduction of direct-acting antiviral agents (in 2011), infection with HCV was identified as the leading cause of mixed cryoglobulinemic vasculitis. HCV-associated mixed cryoglobulinemic vasculitis was linked to substantial morbidity and mortality. In the era after the introduction of these agents, autoimmune disorders (systemic lupus erythematosus and Sjögren’s syndrome) and B-cell cancers have become the main causes of mixed cryoglobulinemic vasculitis. Most recent studies using direct-acting antiviral agents have shown low mortality rates, which is a major advance as compared with the rates previously published with interferon-alfa–based treatment.
Q: Can HCV-associated cryoglobulinemia persist after treatment with direct-acting antiviral agents?
A: Persistent cryoglobulinemia after treatment with direct-acting antiviral agents is not uncommon in daily practice. The cryoglobulin level usually decreases within a few months after direct-acting antiviral agents have been withdrawn. However, long-term, complete clearance of cryoglobulin is reported in only 29 to 66% of cases, reflecting the persistence of a B-lymphocyte clone in a substantial percentage of patients. Long-term follow-up of such patients is crucial, particularly in order to monitor them for the appearance of B-cell non-Hodgkin’s lymphoma (B-NHL).
A: The overall risk that B-NHL will develop in patients who have chronic HCV infection with cryoglobulinemia is about 35 times as high as the risk in the general population, or 12 times as high if nonaggressive lymphomas are excluded. HCV-associated lymphomas are predominantly marginal-zone lymphomas, with diffuse large B-cell lymphoma (DLBCL) and lymphoplasmacytic lymphoma observed less frequently. HCV-associated DLBCL usually develops from an indolent lymphoma. Among patients with transformed DLBCL, those with HCV infection are younger, have more advanced disease, are more likely to have gastrointestinal and bone marrow involvement, and have a lower 2-year survival rate than HCV-negative patients.
A: Many studies have shown that all-oral, direct-acting antiviral therapy is associated with a complete or partial remission in patients with HCV-associated B-NHL (both low- and high-grade lymphomas), with rates of progression-free survival at 1 year ranging from 75 to 100%. These studies had some limitations, such as their retrospective nature, heterogeneity in direct-acting antiviral regimens and timing after chemotherapy, possible selection bias, and relatively short follow-up. A recent meta-analysis of studies comparing 317 patients who had HCV-associated B-NHL with controls (HCV-negative patients with B-NHL) showed an association between a sustained virologic response and progression-free survival (odds ratio for progression-free survival, 9.34; 95% confidence interval [CI], 4.90 to 17.79). International guidelines have prioritized treatment with direct-acting antiviral agents in HCV-infected patients with B-NHL, and recent data suggest that early treatment may be preferable for all patients, whether they have indolent or aggressive B-NHL.