Genetic Variation in STAT4 Predicts Response to Interferon-α Therapy for Hepatitis B e Antigen-Positive Chronic Hepatitis B

Interferon (IFN)-alpha 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 IFN alpha treatment for hepatitis B e antigen (HBeAg)-positive CHB patients. We studied 466 HBeAg-positive CHB patients who received either IFN alpha-2b (n = 224) or pegylated IFN alpha-2a (n = 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 IFN alpha-2b and pegylated IFN alpha-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 IFN alpha-2b therapy (21.1% versus 37.2%, P = 0.01) and those who received pegylated IFN alpha-2a therapy (18.0% versus 41.2%, P = 9.74 x 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 = 4.15 x 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 IFN alpha therapy for HBeAg-positive CHB patients and may be used for optimizing the treatment of CHB.