The Role of Direct-Acting Antivirals (DAAs) in Hepatitis C Virus-Associated Lymphoproliferative Disorders
by
, , , and
Cesare Mazzaro
1,*,†, 
Riccardo Bomben
1,*,†,
Laura Gragnani
2
,
Marcella Visentini
3,
Paolo Agostinis
4,
Silvia Marri
5,
Anna Linda Zignego
5
and
Valter Gattei
1 1
Clinical and Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
2
Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
3
Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
4
Department of Internal Medicine, Hospital of Tolmezzo, 33028 Tolmezzo, Italy
5
Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cancers 2026, 18(15), 2501; https://doi.org/10.3390/cancers18152501
Submission received: 5 May 2026
/
Revised: 1 July 2026
/
Accepted: 3 August 2026
/
Published: 4 August 2026
(This article belongs to the Special Issue Development of Hepatitis C Virus-Related Cancers)
Simple Summary
Hepatitis C is widely known as a liver disease, but it can also affect the immune system and contribute to the development of disorders caused by the abnormal growth of certain white blood cells. These conditions include mixed cryoglobulinemia, a disorder that can damage blood vessels and organs, and some forms of lymphoma, a cancer of the immune system. Growing evidence shows that long-term infection with the hepatitis C virus plays a direct role in the development of these diseases. The introduction of modern antiviral treatments has dramatically improved the ability to eliminate the virus, with high cure rates and few side effects. Clearing the infection often leads to improvement of immune-related complications and can even cause some slow-growing lymphomas to regress. These findings support early treatment of hepatitis C and highlight the importance of integrating antiviral therapy into the care of patients with hepatitis C-related blood and immune disorders.
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, affecting approximately 50 million people worldwide. An estimated 15–30% of individuals with chronic HCV infection progress to cirrhosis, which may subsequently develop into hepatocellular carcinoma. Beyond liver disease, HCV is associated with a broad spectrum of extrahepatic manifestations, particularly mixed cryoglobulinemia (MC) and B-cell non-Hodgkin lymphoma (B-NHL). Persistent viral infection induces chronic antigenic stimulation of B lymphocytes, a key pathogenic mechanism underlying the progression from MC to overt B-NHL. These observations have important therapeutic implications and support the use of antiviral therapy as a cornerstone of treatment. The efficacy of direct-acting antivirals (DAAs) has been well established in patients with HCV-related MC and cryoglobulinemic vasculitis. Several studies have shown that DAAs achieve sustained virologic response rates exceeding 90%, often approaching 100% in contemporary cohorts. Viral eradication is frequently associated with clinical and immunological improvement, as well as regression of cryoglobulinemia. Encouraging outcomes have also been reported in patients with HCV-associated indolent B-NHL, particularly marginal zone lymphoma, although confirmation in larger studies with longer follow-up is needed. In patients with HCV-positive aggressive lymphomas, DAAs have been safely administered in combination with immunochemotherapy, yielding promising results. This review summarizes the current evidence on HCV-associated MC and B-NHL and discusses the impact of DAA therapy on the clinical course and management of these disorders.
