Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha

Abstract

Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. We found a significant association between rs7574865 genotype and CR (P= .004) and loss of HBsAg (P= .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P= .811) or loss of HBsAg (P=.439). In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.