An in vivo duck hepatitis B virus model recapitulates key aspects of nucleic acid polymer treatment outcomes in chronic hepatitis B patients
Copyright © 2024 Elsevier B.V. All rights reserved..
Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients. A subset of patients achieve functional cure, whereas the others exhibit a moderate response or are non-responders. NAP efficacy has been difficult to recapitulate in animal models, with the duck hepatitis B virus (DHBV) model showing some promise but remaining underexplored for NAP efficacy testing. Here we report on an optimized in vivo DHBV duck model and explore several characteristics of NAP treatment. REP2139 was efficacious in reducing DHBV DNA and DHBsAg levels in approximately half of the treated ducks, whether administered intraperitoneally or subcutaneously. Intrahepatic or serum NAP concentrations did not correlate with efficacy, nor did the appearance of anti-DHBsAg antibodies. Furthermore, NAP efficacy was only observed in experimentally infected ducks, not in endogenously infected ducks (vertical transmission). REP2139 add-on to entecavir treatment induced a deeper and more sustained virological response compared to entecavir monotherapy. Destabilized REP2165 showed a different activity profile with a more homogenous antiviral response followed by a faster rebound. In conclusion, subcutaneous administration of NAPs in the DHBV duck model provides a useful tool for in vivo evaluation of NAPs. It recapitulates many aspects of this class of compound's efficacy in CHB patients, most notably the clear division between responders and non-responders.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:224 |
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| Enthalten in: |
Antiviral research - 224(2024) vom: 21. März, Seite 105835 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Debing, Yannick [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 18.03.2024 Date Revised 18.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.antiviral.2024.105835 |
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| funding: |
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| 245 | 1 | 3 | |a An in vivo duck hepatitis B virus model recapitulates key aspects of nucleic acid polymer treatment outcomes in chronic hepatitis B patients |
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| 520 | |a Nucleic acid polymers (NAPs) are an attractive treatment modality for chronic hepatitis B (CHB), with REP2139 and REP2165 having shown efficacy in CHB patients. A subset of patients achieve functional cure, whereas the others exhibit a moderate response or are non-responders. NAP efficacy has been difficult to recapitulate in animal models, with the duck hepatitis B virus (DHBV) model showing some promise but remaining underexplored for NAP efficacy testing. Here we report on an optimized in vivo DHBV duck model and explore several characteristics of NAP treatment. REP2139 was efficacious in reducing DHBV DNA and DHBsAg levels in approximately half of the treated ducks, whether administered intraperitoneally or subcutaneously. Intrahepatic or serum NAP concentrations did not correlate with efficacy, nor did the appearance of anti-DHBsAg antibodies. Furthermore, NAP efficacy was only observed in experimentally infected ducks, not in endogenously infected ducks (vertical transmission). REP2139 add-on to entecavir treatment induced a deeper and more sustained virological response compared to entecavir monotherapy. Destabilized REP2165 showed a different activity profile with a more homogenous antiviral response followed by a faster rebound. In conclusion, subcutaneous administration of NAPs in the DHBV duck model provides a useful tool for in vivo evaluation of NAPs. It recapitulates many aspects of this class of compound's efficacy in CHB patients, most notably the clear division between responders and non-responders | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antiviral therapy | |
| 650 | 4 | |a Chronic hepatitis B | |
| 650 | 4 | |a Duck hepatitis B virus | |
| 650 | 4 | |a Ducks | |
| 650 | 4 | |a Nucleic acid polymer | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Nucleic Acids |2 NLM | |
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| 700 | 1 | |a Vanrusselt, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Degrauwe, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Silva de Oliveira, Daniel Apolônio |e verfasserin |4 aut | |
| 700 | 1 | |a Kariuki, Christopher Kinyanjui |e verfasserin |4 aut | |
| 700 | 1 | |a Ebwanga, Ebanja Joseph |e verfasserin |4 aut | |
| 700 | 1 | |a Bashir, Shahbaz |e verfasserin |4 aut | |
| 700 | 1 | |a Merckx, Wouter |e verfasserin |4 aut | |
| 700 | 1 | |a Thatikonda, Santhosh Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Rajwanshi, Vivek |e verfasserin |4 aut | |
| 700 | 1 | |a Gohil, Vikrant |e verfasserin |4 aut | |
| 700 | 1 | |a Hong, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Kum, Dieudonné Buh |e verfasserin |4 aut | |
| 700 | 1 | |a Acosta Sanchez, Abel |e verfasserin |4 aut | |
| 700 | 1 | |a Chanda, Sushmita |e verfasserin |4 aut | |
| 700 | 1 | |a Blatt, Lawrence M |e verfasserin |4 aut | |
| 700 | 1 | |a Jekle, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Symons, Julian A |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, David B |e verfasserin |4 aut | |
| 700 | 1 | |a Raboisson, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Tse-I |e verfasserin |4 aut | |
| 700 | 1 | |a Beigelman, Leonid |e verfasserin |4 aut | |
| 700 | 1 | |a Paeshuyse, Jan |e verfasserin |4 aut | |
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