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 chronic HBV infection who were negative for hepatitis B e antigen. METHODS: Following 24 weeks TDF therapy, 40 patients were randomly assigned to groups that received 48 weeks of experimental therapy (TDF þ pegIFN þ REP 2139-Mg or REP 2165-Mg) or 24 weeks of control therapy (TDF þ pegIFN) followed by 48 weeks of 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 þ pegIFN compared with TDF þ 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 were reductions in hepatitis B surface antigen (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 ¼ .299 vs controls) and neutropenia (P ¼ .112 vs controls) were unaffected by NAPs (REP 2139 vs REP 2165). Increases in levels of transaminases were significantly more frequent (P < .001 vs controls) and greater (P ¼ .002 vs controls) in the NAP groups (but did not produce symptoms), correlated with initial decrease in HBsAg, and normalized during therapy and follow-up. During the first 24 weeks of TDF and pegIFN administration, significantly higher proportions of

Persistent Control of Hepatitis B Virus and Hepatitis Delta Virus Infection Following REP 2139-Ca and Pegylated Interferon Therapy in Chronic Hepatitis B Virus/Hepatitis Delta Virus Coinfection

“…The long-term safety of combined treatment with REP 2139 and pegIFN has been demonstrated with a 2-year follow-up in HBeAg-positive chronic HBV infection (17) and a 1-year follow-up in HBeAg-negative chronic HBV infection. (28) The REP 301-LTF study extends this safety envelope to 3.5 years and additionally confirms the long-term stability of both virologic control and functional cure of HBV infection as well as HBsAg seroconversion and functional cure of HDV infection that have been reported. (17,19,28) During the follow-up, the only safety-related observations were mild ALT elevations and thrombocytopenia subsequent to rebound in HBV or HDV infection and were not considered REP 2139 related.…”

Ropeginterferon alfa-2b every 2 weeks as a novel pegylated interferon for patients with chronic hepatitis B

“…Interferon would be the backbone of treatment in patients with chronic hepatitis D. Although most of patients with CHB are under NAs treatment, the unmet medical need is that the rate of HBsAg loss is low. Recent many new clinical trials for hepatitis B combine small molecules or other agents with interferon to maximize the therapeutic efficacy [26][27][28][29][30]. We anticipate a renewed interest in interferon as safe and reliable immunomodulator therapy in combination with emerging anti-HBV regimens.…”

Serum HBsAg clearance has minimal impact on CD8+ T cell responses in mouse models of HBV infection

“…Circulating HBsAg is thought not only to have a negative impact on antigen-specific B cell responses, but also to delete or functionally impair antigen-specific T cells (Zhu et al, 2016). This notion is supported by the observation that HBsAg seroconversion induced by nucleos(t)ide analogues is associated with an increase in the quality and vigor of HBV-specific T cell responses (Boni et al, 2012;Bazinet et al, 2020). Whether these T cell responses are actively unleashed by HBsAg loss (for instance, through cross-presentation of HBsAg-HBsAb immune complexes by professional antigen-presenting cells) or whether HBsAg loss is simply a consequence of such responses is unknown because no studies have yet systematically investigated the impact of extracellular, circulating HBsAg levels on HBV-specific CD8 + T cell responses at the single-cell level.…”