Early Antiviral Therapy Reduces the Risk of Lymphoma in Patients With Chronic Hepatitis C Infection

Tung-Hung Su; Chun-Jen Liu; Tai-Chung Tseng; Shih-Wan Chou; Chen-Hua Liu; Hung-Chih Yang; Shang-Ju Wu; Pei-Jer Chen; Ding-Shinn Chen; Chi-Ling Chen; Jia-Horng Kao


Aliment Pharmacol Ther. 2019;49(3):331-339. 

In This Article

Abstract and Introduction


Background: Chronic hepatitis C infection is linked to lymphoma development.

Aim: To investigate whether antiviral therapy prevents the risk of HCV-related lymphoma.

Methods: Patients diagnosed with chronic hepatitis C were retrieved from the Taiwan National Health Insurance Research Database during 2004-2012. We included patients who received pegylated interferon and ribavirin (PegIFN/RBV) antiviral therapy for ≥24 weeks (PegIFN/RBV cohort) or hepatoprotectants for ≥90 days without antiviral therapy (HCV-untreated cohort). Both cohorts were matched by age, sex, and comorbidities through propensity scores and followed for newly diagnosed lymphoma or non-Hodgkin's lymphoma (NHL).

Results: In total, 24 133 patients were included in both the PegIFN/RBV and HCV-untreated cohort. The lymphoma incidence was significantly higher in the untreated than in the treated cohort (66.48 vs 43.34 per 100 000 person-years, P = 0.029). After adjusting for confounders, the patients who received PegIFN/RBV therapy were at a lower risk of developing lymphoma compared with the untreated patients (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.43–0.96, P = 0.030). Moreover, this beneficial effect was mainly observed in patients with chronic hepatitis C <60 years old with a relative risk reduction of 51% for all lymphoma (HR: 0.49, 95% CI: 0.29–0.82, P = 0.007) and 48% for non-Hodgkin's lymphoma (HR: 0.52, 95% CI: 0.30–0.91, P = 0.022). The risk of all lymphoma or non-Hodgkin's lymphoma development after antiviral therapy was lowered to that of subjects without HCV.

Conclusions: PegIFN/RBV-based antiviral therapy significantly reduced the risk of lymphoma, especially non-Hodgkin's lymphoma; the reduction was mostly among patients <60 years old. Early antiviral therapy for chronic hepatitis C is suggested.


Hepatitis C virus (HCV) infection is a global health threat with 170 million people infected with chronic hepatitis C (CHC) worldwide. In addition to hepatocellular carcinoma (HCC), CHC is associated with various extrahepatic manifestations, such as chronic kidney disease, insulin resistance, and a spectrum of lymphoproliferative disorders.[1]

Lymphoid neoplasms, including non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL), multiple myeloma (MM), acute lymphoblastic lymphoma, and chronic lymphocytic leukaemia are a heterogeneous group of malignancies accounting for approximately 4% of cancer worldwide, and the incidence is increasing.[2] Studies have demonstrated that HCV infection increases the risk of mixed cryoglobulinemia,[3] which is associated with a 35-fold increased risk of NHL.[4] Subsequent epidemiological studies in Sweden have reported an increased NHL risk in people with HCV infection compared with those without the infection (standardised incidence ratio: 1.89, 95% confidence interval [CI]: 1.10–3.03),[5] which has also been shown in the United States (hazard ratio [HR]: 1.28, 95% CI: 1.12–1.45, P < 0.001).[6] Our recent population-based cohort study also found that HCV infection is associated with an increased risk of either lymphoid neoplasms (HR: 2.30, 95% CI: 1.55–3.43, P < 0.0001) or NHL (HR: 2.00, 95% CI: 1.27–3.16, P = 0.003) in Taiwanese patients.[7]

Studies showing HCV eradication linked to the regression of lymphoma or a lower risk of lymphoma may strengthen the aetiological role of HCV infection in lymphoma. In two small-scale studies,[8,9] Hermine et al reported that interferon treatment could regress splenic lymphoma with villous lymphocytes in nine patients with CHC, whereas a subsequent viral relapse led to lymphoma recurrence.[8] Vallisa et al reported that the haematologic responses of HCV-related low-grade B cell NHL in 13 patients with CHC were associated with the clearance or decrease in the serum HCV viral load following pegylated interferon and ribavirin (PegIFN/RBV) therapy.[9] A Japanese study compared 2708 patients receiving conventional interferon-based therapy with 501 untreated patients. The overall risk of malignant lymphoma after interferon therapy was not reduced (log-rank P = 0.12); however, patients with sustained virological response (SVR) had a lowered risk of lymphoma compared with those without SVR (P = 0.02).[10] Because lymphoma is uncommon, these studies, which had relatively small sample sizes,[8,9] could not convincingly show whether curing HCV reduced the risk of lymphoma. Therefore, we conducted a population-based cohort study to investigate the risk of lymphoma in patients with CHC following PegIFN/RBV antiviral therapy in comparison with a matched untreated cohort with HCV.