Combination therapies are emerging as promising strategies for achieving functional cures in patients with chronic hepatitis B (HBV). Recent data from Phase II trials highlight the potential of novel antiviral agents and immunomodulators to induce sustained reductions in hepatitis B surface antigen (HBsAg), a key marker of HBV infection.
Xalnesiran Plus Immunomodulators
The Phase II Piranga trial (NCT04225715), published in the New England Journal of Medicine, evaluated the efficacy of xalnesiran, a novel N-acetyl-d-galactosamine–conjugated small interfering RNA molecule, in combination with immunomodulators in patients with chronic HBV infection who had achieved virologic suppression with nucleoside or nucleotide analog (NA) therapy. The trial included 159 patients randomly assigned to one of five groups:
- Xalnesiran 100 mg (n = 30)
- Xalnesiran 200 mg (n = 30)
- Xalnesiran 200 mg + ruzotolimod 150 mg (n = 34)
- Xalnesiran 200 mg + pegylated interferon alfa-2a 180 μg (n = 30)
- NA monotherapy (n = 35)
The primary efficacy endpoint was HBsAg loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks following the end of treatment. The results showed that the combination of xalnesiran with pegylated interferon alfa-2a resulted in the highest rate of HBsAg loss, with 23% of patients achieving the primary endpoint, compared to 0% in the NA monotherapy group. HBsAg seroconversion occurred in 20% of participants in the xalnesiran plus pegylated interferon alfa-2a group, versus 0% in the NA monotherapy group.
However, the study authors noted that HBsAg loss with or without seroconversion was only observed in patients with a screening HBsAg level below 1000 IU per milliliter, and that "erosion of this response was observed during the follow-up period."
VTP-300 and Nivolumab Combination
Another promising approach involves the use of immunotherapeutic agents to stimulate the immune response against HBV. New data from the ongoing HBV003 clinical trial demonstrate the ability of VTP-300 combined with low-dose nivolumab to stimulate immune response and induce sustained reductions in hepatitis B surface antigen (HBsAg) meeting functional cure criteria. VTP-300 is an immunotherapeutic candidate consisting of an initial dose using the ChAdOx vector and a secondary dose(s) using the MVA vector, both encoding multiple HBsAg, including full-length surface, modified polymerase, and core antigens.
The data, presented at The Liver Meeting 2024 from the American Association for the Study of Liver Diseases (AASLD), included 40 participants with HBsAg < 200 IU/mL at screening who had reached day 169 and were assessed for nucleos(t)ide analogue (NUC) discontinuation. Of these patients, 8 had complete HBsAg loss and 2 met the criteria for functional cure, defined by AASLD as sustained HBsAg loss and hepatitis B virus DNA <LLOQ for 6 months off-treatment.
"The data we are seeing with VTP-300 is unique because they indicate a durable loss of HBsAg in participants, including two who met the criteria for functional cure," said Chun-Jen Liu, MD, PhD, an investigator on HBV003 and director of the Hepatitis Research Center and Clinical Trial Center at National Taiwan University Hospital.
The HBV003 trial is designed to assess different dosing regimens of VTP-300 in combination with low-dose nivolumab, an anti-PD-1 monoclonal antibody. All groups received ChAdOx on day 1. Groups 1 and 2 received MVA with nivolumab on day 29, and group 2 was dosed again with MVA and nivolumab on day 85. Group 3 received only MVA on day 29, nivolumab on day 36, and a conditional second MVA dose on day 85 to evaluate anti-PD-1 inhibition timing. The conditional MVA dose was administered if participants had HBsAg ≥10 IU/mL.
The Need for Further Research
While these results are encouraging, challenges remain in achieving durable HBsAg loss and functional cure in all patients with chronic HBV. The Piranga trial identified limitations in efficacy in patients with high HBsAg levels, while the HBV003 trial is ongoing and requires further follow-up to assess the long-term durability of response. Combination regimens containing checkpoint inhibitors are being explored in chronic hepatitis B, including a liver-targeted locked nucleic acid that degrades programmed death ligand 1 expressionand is being evaluated in combination with xalnesiran in other groups of the Piranga platform trial.
