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Interferon (IFN)-a is a first-line therapy for chronic hepatitis B (CHB) patients but only initiates a response in a minority of patients. A genetic variant, rs7574865 in STAT4, was recently reported to be associated with risk of developing CHB and hepatitis B virus-related hepatocellular carcinoma. We aimed to determine whether this variant is associated with the response to IFNa treatment for hepatitis B e antigen (HBeAg)-positive CHB patients. We studied 466 HBeAg-positive CHB patients who received either IFNa-2b (n 5 224) or pegylated IFNa-2a (n 5 242) therapy for 48 weeks and were followed for an additional 24 weeks. The rate of sustained virologic response (SVR), defined as HBeAg seroconversion along with hepatitis B virus DNA level <2000 copies/mL at week 72, was compared among patients with different genotypes of rs7574865. After 48 weeks of treatment and 24 weeks off treatment, the SVR rates in the IFNa-2b and pegylated IFNa-2a therapy groups were 30.4% and 28.9%, respectively. Compared to the rs7574865 GT/TT genotype, the GG genotype (a risk factor of CHB and hepatitis B virus-related hepatocellular carcinoma) was significantly associated with a reduced SVR rate in both patients who received IFNa-2b therapy (21.1% versus 37.2%, P 5 0.01) and those who received pegylated IFNa-2a therapy (18.0% versus 41.2%, P 5 9.74 3 10 -5 ). In joint analysis of the 466 patients, the GG genotype was associated with an approximately half SVR rate compared to the GT/TT genotype (19.3% versus 39.1%, P 5 4.15 3 10 -6 ). A multivariate logistic regression model including rs7574865 and clinical variables showed that rs7574865 was the most significant factor for the prediction of SVR. Conclusion: STAT4 rs7574865 is a reliable predictor of response to IFNa therapy for HBeAg-positive CHB patients and may be used for optimizing the treatment of CHB. (HEPATOLOGY 2016;63:1102-1111 C hronic hepatitis B (CHB) continues to be a major global health issue with more than 350 million cases worldwide and is a significant cause of cirrhosis and hepatocellular carcinoma (HCC).(1) Interferon (IFN)-a (standard and pegylated [PEG] forms) and nucleos(t)ide analogues are

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