| Summary: | It is unclear whether eradication of hepatitis C virus (HCV) leads to a reduction in the risk of hematologic malignancies. We aimed to determine the impact of sustained virologic response (SVR) induced by either direct‐acting antivirals (DAAs) or interferon (IFN) on the risk of hematologic malignancies. We identified 69,581 patients who initiated antiviral treatment in the Veterans Affairs national health care system from January 1, 1999, to December 31, 2015, including 40,410 (58%) IFN‐only regimens, 4,546 (6.5%) DAA + IFN regimens, and 24,625 (35%) DAA‐only regimens. We retrospectively followed patients to identify incident cases of hematologic malignancies or monoclonal gammopathy of unknown significance (MGUS), a premalignant precursor of multiple myeloma. Among patients treated with IFN, SVR was significantly associated with a reduction in the risk of lymphoma (adjusted hazard ratio [AHR], 0.70; 95% confidence interval [CI], 0.51‐0.97), multiple myeloma (AHR, 0.40; 95% CI, 0.20‐0.77), MGUS (AHR, 0.65; 95% CI, 0.42‐0.99), or all hematologic malignancies and MGUS combined (AHR, 0.67; 95% CI, 0.53‐0.84) over a mean follow‐up of 10.6 years. In contrast, among patients treated with DAA, SVR was not associated with the risk of lymphoma, multiple myeloma, MGUS, or all hematologic malignancies and MGUS combined (AHR, 1.08; 95% CI, 0.66‐1.78) during a mean follow‐up of 2.9 years. Neither IFN‐induced SVR nor DAA‐induced SVR was associated with risk of colon cancer or prostate cancer, which were chosen a priori as comparison/control malignancies. Conclusion: We describe novel strong associations between IFN‐induced SVR and lymphoma, multiple myeloma, MGUS, and all hematologic malignancies combined. Surprisingly, these associations were not observed with DAA‐induced SVR.
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