Activity of nucleic acid polymers in rodent models of HBV infection

Schöneweis, Katrin; Motter, Neil E.; Roppert, Pia Luise; Lu, Mengji; Wang, Baoju; Roehl, Ingo; Glebe, Dieter; Yang, Dongliang; Morrey, John D.; Roggendorf, Michael; Vaillant, Andrew

doi:10.1016/j.antiviral.2017.10.022

Cited by 18 publications

(15 citation statements)

References 56 publications

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“…The molecular targets underlying the antiviral effects of NAPs have not yet been elucidated; however, the remarkable similarities between SVP and high‐density lipoprotein (HDL) suggest that HDL metabolism may be somehow involved in SVP morphogenesis. Interestingly, an absence of antiviral activity of NAPs has been recently reported in rodent models of HBV infection . This study hypothesized that the differences in HDL metabolism in mice and woodchucks, as compared to ducks and humans, may contribute to the absence of anti‐HBV activity of NAPs in rodent species.…”

Section: Discussionsupporting

confidence: 62%

“…Interestingly, an absence of antiviral activity of NAPs has been recently reported in rodent models of HBV infection. (32) This study hypothesized that the differences in HDL metabolism in mice and woodchucks, as compared to ducks and humans, may contribute to the absence of anti-HBV activity of NAPs in rodent species. The apolipoproteins involved in lipid metabolism may be also involved in the assembly of SVPs and may be targeted by NAPs, thus interfering with SVP assembly and secretion without affecting normal apolipoprotein metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks

et al. 2018

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Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)‐infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV‐infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti‐DHBsAg antibodies were monitored by enzyme‐linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow‐up by immunohistochemistry. On‐treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (>3 log) and cccDNA (>2 log), which were tightly correlated with the clearance of DHBsAg in the liver. Conclusion: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (Hepatology 2018;67:2127‐2140).

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks

et al. 2018

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“…This difference could be the result of an immune response, although, thus far REP 2139 has not been shown to augment the host immune response to HDV 8,10,11 . Unfortunately, the effects of NAPs observed in humans were not reproduced in rodent models 14 , so alternative methods are needed to determine whether NAPs do affect the immune system and then models could be developed to incorporate such a response.…”

Section: Discussionmentioning

confidence: 99%

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

Shekhtman

Cotler

Hershkovich

et al. 2020

Sci Rep

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Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) for its assembly and release. Current HBV treatments are only marginally effective against HDV because they fail to inhibit HBsAg production/secretion. However, monotherapy with the nucleic acid polymer REP 2139-Ca is accompanied by rapid declines in both HBsAg and HDV RNA. We used mathematical modeling to estimate HDV-HBsAg-host parameters and to elucidate the mode of action and efficacy of REP 2139-Ca against HDV in 12 treatment-naive HBV/HDV co-infected patients. The model accurately reproduced the observed decline of HBsAg and HDV, which was simultaneous. Median serum HBsAg half-life (t 1/2) was estimated as 1.3 [0.9-1.8] days corresponding to a pretreatment production and clearance of ~10 8 [10 7.7-10 8.3 ] IU/day. The HDV-infected cell loss was estimated to be 0.052 [0.035-0.074] days −1 corresponding to an infected cell t 1/2 = 13.3 days. The efficacy of blocking HBsAg and HDV production were 98.2 [94.5-99.9]% and 99.7 [96.0-99.8]%, respectively. In conclusion, both HBsAg production and HDV replication are effectively inhibited by REP 2139-Ca. Modeling HBsAg kinetics during REP 2139-Ca monotherapy indicates a short HBsAg half-life (1.3 days) suggesting a rapid turnover of HBsAg in HBV/ HDV co-infection. Chronic hepatitis B virus (HBV) and hepatitis D virus (HDV) co-infection affects an estimated 15-40 million persons worldwide 1,2 and is the most aggressive form of viral hepatitis 3. Therapy with pegylated interferon-α2a (pegIFN) is suboptimal in controlling HDV infection 4,5 and no other therapies are approved for the treatment of HDV. HDV requires hepatitis B surface antigen (HBsAg) for assembly and release. While the large isoform (L-HBsAg) is not requisite for HDV assembly and release, it is necessary for infectivity 6. Drugs that directly target HDV and reduce HDV levels are in development 7 , however the only anti-HBV treatment that affects HBsAg production is the nucleic acid polymer (NAP) REP 2139-Ca, which is accompanied by declines in both HBsAg and HDV RNA 8-11. Therefore, analyzing antiviral response during REP 2139-Ca monotherapy provides a unique opportunity to examine HBsAg production and clearance rates in HBV/HDV co-infected patients and to obtain a deeper understanding of REP 2139-Ca mode of action and efficacy against HDV. The aim of this study was to analyze the kinetics of HBV DNA, HBsAg, ALT and HDV RNA during REP 2139-Ca monotherapy and investigate the dynamics of HDV RNA and HBsAg using mathematical modelling.

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“…Nucleic acid polymers (NAPs) ( Figure 1 , Table 1 ) use phosphorothioated oligonucleotides to target apolipoprotein interactions involved in the assembly and release of HBV subviral particles (SVPs), which are made up of HBsAg. These work in a sequence independent manner to block SVP formation inside infected hepatocytes and their subsequent secretion [ 65 , 66 ]. As SVPs account for greater than 99.99% of HBsAg in the blood, NAPs constitute an effective means of clearing HBsAg from the serum of patients with chronic HBV infection [ 67 ].…”

Section: Direct Acting Antiviralsmentioning

confidence: 99%

New Approaches to the Treatment of Chronic Hepatitis B

Alexopoulou

Vasilieva

Karayiannis

2020

JCM

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The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

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Activity of nucleic acid polymers in rodent models of HBV infection

Cited by 18 publications

References 56 publications

Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks

Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks

Modelling hepatitis D virus RNA and HBsAg dynamics during nucleic acid polymer monotherapy suggest rapid turnover of HBsAg

New Approaches to the Treatment of Chronic Hepatitis B

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