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

Abstract

The nucleic acid polymer REP 2139 inhibits assembly/secretion of hepatitis B virus (HBV) subviral particles. Previously, REP 2139-Ca and pegylated interferon (pegIFN) in HBV/hepatitis delta virus (HDV) coinfection achieved high rates of HDV RNA and hepatitis B surface antigen (HBsAg) loss/seroconversion in the REP 301 study (NCT02233075). The REP 301-LTF study (NCT02876419) examined safety and efficacy during 3.5 years of follow-up. In the current study, participants completing therapy in the REP 301 study were followed for 3.5 years. Primary outcomes were safety and tolerability, and secondary outcomes were HDV functional cure (HDV RNA target not detected [TND], normal alanine aminotransferase [ALT]), HBV virologic control (HBV DNA ≤2,000 IU/mL, normal ALT), HBV functional cure (HBV DNA TND; HBsAg <0.05 IU/mL, normal ALT), and HBsAg seroconversion. Supplemental analysis included high-sensitivity HBsAg (Abbott ARCHITECT HBsAg NEXT), HBV pregenomic RNA (pgRNA), HBsAg/hepatitis B surface antibody (anti-HBs) immune complexes (HBsAg ICs), and hepatitis B core-related antigen (HBcrAg). Asymptomatic grade 1-2 ALT elevations occurred in 2 participants accompanying viral rebound; no other safety or tolerability issues were observed. During therapy and follow-up, HBsAg reductions to <0.05 IU/mL were also <0.005 IU/mL. HBsAg ICs declined in 7 of 11 participants during REP 2139-Ca monotherapy and in 10 of 11 participants during follow-up. HDV functional cure persisted in 7 of 11 participants; HBV virologic control persisted in 3 and functional cure (with HBsAg seroconversion) persisted in 4 of these participants. Functional cure of HBV was accompanied by HBV pgRNA TND and HBcrAg <lower limit of quantitation. Conclusion: REP 2139-Ca + pegIFN is not associated with long-term safety or tolerability issues. The establishment of HDV functional cure and HBV virologic control/functional cure and HBsAg seroconversion are durable over 3.5 years and may reflect removal of integrated HBV DNA from the liver. Further investigation is warranted in larger studies.

FIG. 1

HDV RNA and HBsAg response during therapy in the REP 301 study and during the extended follow‐up in the REP 301‐LTF study. (A) Individual HDV RNA dynamics during therapy (left) and extended follow‐up in participants with HDV RNA either TND (middle) or >LLOQ (right) at the end of follow‐up are presented. (B,C) Reductions in qHBsAg below 0.05 IU/mL were evaluated by the high‐sensitivity HBsAg NEXT assay. Four participants had HBsAg reported at <0.05 IU/mL at the end of follow‐up by qHBsAg assay; all were confirmed to have HBsAg <0.005 IU/mL at the end of follow‐up by the HBsAg NEXT assay. HDV RNA and qHBsAg values from baseline to F1Y (FW52) have been published.^{( 19 )}Abbreviation: S/Co, signal/cut‐off for positivity.

FIG. 2

Changes in response in the REP 301 and REP 301‐LTF studies. (A) Anti‐HBs, (B) HBsAg IC, and (C) ALT during therapy (left) and in participants maintaining HDV RNA TND (middle) or >LLOQ (right) at the end of the extended follow‐up. Lines in bold during therapy in (A) and (B) indicate the 5 participants who experienced rapid elevations in anti‐HBs following addition of pegIFN. Anti‐HBs and ALT in 3 participants with mild rebounds in HBsAg IC during therapy in (B) are identified in (A) and (C). ALT and anti‐HBs values from baseline to F1Y (FW52) have been published.^{( 19 )}Abbreviation: RLU, relative light unit.

FIG. 3

Changes in response in the REP 301 and REP 301‐LTF studies. (A) HBV DNA, (B) HBV RNA, and (C) HBcrAg during therapy (left) and in participants maintaining HDV RNA TND (middle) or >LLOQ (right) at the end of the extended follow‐up. In (B), total HBV RNA is presented during therapy and HBV pgRNA is presented during follow‐up (middle and right). HBV DNA, total HBV RNA, and HBcrAg from baseline to F1Y (FW52) were previously published.^{( 19 )}