Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naïve to Nucleos(t)ide Therapy

Abstract Background & Aims Nucleic acid polymers (NAPs) inhibit assembly and secretion of hepatitis B virus (HBV) subviral particles. We performed an open-label, phase 2 study of the safety and efficacy of the NAPs REP 2139 or REP 2165 combined with tenofovir disoproxil fumarate (TDF) and pegylated interferon alfa-2a (pegIFN) in patients with negative chronic HBV infection who were negative for HB e antigen (HBeAg). Methods Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF + pegIFN + REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF + pegIFN) followed by 48 weeks experimental therapy. Patients were then followed for a treatment-free period of 48 weeks. Primary outcomes were the safety and tolerability of REP 2139-Mg or REP 2165-Mg in combination with TDF + pegIFN compared to TDF + pegIFN alone through the first 48 weeks of therapy and subsequently throughout 48 weeks of NAP-based combination therapy (treatment weeks 24-72 in the experimental group and weeks 48-96 in the control group). Secondary outcomes reductions in HBsAg in control and experimental groups over the first 48 weeks of the study and throughout 48 weeks of combination therapy and virologic control (HBsAg positive, HBV DNA below 2000 IU/mL, normal level of alanine aminotransferase) or functional cure (HBsAg below 0.05 IU/mL, HBV DNA target not detected, normal level of alanine aminotransferase) after removal of all therapy. Results Levels of HBsAg, anti-HBs, and HBV DNA did not differ significantly between the groups given REP 2139 vs REP 2165. PegIFN-induced thrombocytopenia (P=.299 vs controls) and neutropenia (P=.112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P Conclusions In a phase 2 randomized trial, we found that addition of NAPs to TDF + pegIFN did not alter tolerability and significantly increased rates of HBsAg loss and HBsAg seroconversion during therapy and functional cure after therapy. Clinicaltrials.gov no: NCT02565719.