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… Show more
“…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.…”
Finite therapy of HBV/HDV co‐infection with REP 2139‐Ca and pegIFN has good long term safety and is accompanied by high rates of functional cure of HDV, normalization of liver function and additional functional cure of HBV. HBV functional cure is accompanied inactivation / clearance of cccDNA and clearance of integrated HBV DNA.
“…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.…”
Finite therapy of HBV/HDV co‐infection with REP 2139‐Ca and pegIFN has good long term safety and is accompanied by high rates of functional cure of HDV, normalization of liver function and additional functional cure of HBV. HBV functional cure is accompanied inactivation / clearance of cccDNA and clearance of integrated HBV DNA.
“…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.…”
Background
Ropeginterferon alfa-2b is a novel mono-pegylated interferon that has only one major form as opposed to 8–14 isomers of other on-market pegylated interferon, allowing injection every two or more weeks with higher tolerability. It received European Medicines Agency and Taiwan marketing authorization in 2019 and 2020, for treatment of polycythemia vera. This phase I/II study aimed to have preliminary evaluation of safety and efficacy in chronic hepatitis B.
Methods
Thirty-one HBeAg-positive and 31 HBeAg-negative were stratified by HBeAg status and randomized at 1:1:1 ratio to q2w ropeginterferon alfa-2b 350 μg (group 1), q2w 450 μg (group 2) or q1w PEG-IFN alfa-2a 180 μg (group 3). Each patient received 48-week treatment (TW48) and 24-week post-treatment follow-up (FW24).
Results
The baseline demographics were comparable among the three groups, except for mean HBeAg in HBeAg-positive patients (2.90, 2.23, 2.99 log10 S/CO, respectively). Cumulative HBeAg seroconversion rate at follow-up period was 27.3% (3/11), 36.4% (4/11), and 11.1% (1/9) with time to HBeAg seroconversion starting from TW24, TW16, and TW48 in group 1, 2, and 3, respectively. The rate of HBV DNA < 2000 IU/mL and HBsAg levels < 1500 IU/mL at FW24 were comparable in all groups. Ropeginterferon alfa-2b (group 1 & 2) had numerically lower incidence of rash (9.5% and 4.5%) as compared to PEG-IFN alfa-2a (36.8%). Ropeginterferon alfa-2b 350 μg (group 1) had more ALT elevation (38.1%), however the rate was comparable in group 2 (9.1%) and group 3 (10.5%).
Conclusion
In this preliminary study, ropeginterferon alfa-2b, although in only half the number of injections, is as safe and effective as pegylated interferon alfa-2a for chronic hepatitis B.
Graphic abstract
“…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.…”
Antibody-mediated clearance of hepatitis B surface antigen (HBsAg) from the circulation of chronically infected patients (i.e., seroconversion) is usually associated with increased HBV-specific T cell responsiveness. However, a causative link between serum HBsAg levels and impairment of intrahepatic CD8+ T cells has not been established. Here we addressed this issue by using HBV replication-competent transgenic mice that are depleted of circulating HBsAg, via either spontaneous seroconversion or therapeutic monoclonal antibodies, as recipients of HBV-specific CD8+ T cells. Surprisingly, we found that serum HBsAg clearance has only a minimal effect on the expansion of HBV-specific naive CD8+ T cells undergoing intrahepatic priming. It does not alter their propensity to become dysfunctional, nor does it enhance the capacity of IL-2–based immunotherapeutic strategies to increase their antiviral function. In summary, our results reveal that circulating HBsAg clearance does not improve HBV-specific CD8+ T cell responses in vivo and may have important implications for the treatment of chronic HBV infection.
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