A Semi-mechanistic Model to Characterize the Long-Term Dynamics of Hepatitis B Virus Markers During Treatment With Lamivudine and Pegylated Interferon
© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics..
Antiviral treatments against hepatitis B virus (HBV) suppress viral replication but do not eradicate the virus, and need therefore to be taken lifelong to avoid relapse. Mathematical models can be useful to support the development of curative anti-HBV agents; however, they mostly focus on short-term HBV DNA data and neglect the complex host-pathogen interaction. This work aimed to characterize the effect of treatment with lamivudine and/or pegylated interferon (Peg-IFN) in 1,300 patients (hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative) treated for 1 year. A mathematical model was developed incorporating two populations of infected cells, namely I 1 , with a high transcriptional activity, that progressively evolve into I 2 , at a rate δ tr , representing cells with integrated HBV DNA that have a lower transcriptional activity. Parameters of the model were estimated in patients treated with lamivudine or Peg-IFN alone (N = 894), and the model was then validated in patients treated with lamivudine plus Peg-IFN (N = 436) to predict the virological response after a year of combination treatment. Lamivudine had a larger effect in blocking viral production than Peg-IFN (99.4-99.9% vs. 91.8-95.1%); however, Peg-IFN had a significant immunomodulatory effect, leading to an enhancement of the loss rates of I 1 (×1.7 in HBeAg-positive patients), I 2 (> ×7 irrespective of HBeAg status), and δ tr (×4.6 and ×2.0 in HBeAg-positive and HBeAg-negative patients, respectively). Using this model, we were able to describe the synergy of the different effects occurring during treatment with combination and predicted an effect of 99.99% on blocking viral production. This framework can therefore support the optimization of combination therapy with new anti-HBV agents.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:113 |
|---|---|
| Enthalten in: |
Clinical pharmacology and therapeutics - 113(2023), 2 vom: 01. Feb., Seite 390-400 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
El Messaoudi, Selma [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
2T8Q726O95 |
|---|
| Anmerkungen: |
Date Completed 26.01.2023 Date Revised 26.02.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/cpt.2798 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM349218676 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM349218676 | ||
| 003 | DE-627 | ||
| 005 | 20231226042113.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/cpt.2798 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1164.xml |
| 035 | |a (DE-627)NLM349218676 | ||
| 035 | |a (NLM)36408671 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a El Messaoudi, Selma |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A Semi-mechanistic Model to Characterize the Long-Term Dynamics of Hepatitis B Virus Markers During Treatment With Lamivudine and Pegylated Interferon |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 26.01.2023 | ||
| 500 | |a Date Revised 26.02.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics. | ||
| 520 | |a Antiviral treatments against hepatitis B virus (HBV) suppress viral replication but do not eradicate the virus, and need therefore to be taken lifelong to avoid relapse. Mathematical models can be useful to support the development of curative anti-HBV agents; however, they mostly focus on short-term HBV DNA data and neglect the complex host-pathogen interaction. This work aimed to characterize the effect of treatment with lamivudine and/or pegylated interferon (Peg-IFN) in 1,300 patients (hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative) treated for 1 year. A mathematical model was developed incorporating two populations of infected cells, namely I 1 , with a high transcriptional activity, that progressively evolve into I 2 , at a rate δ tr , representing cells with integrated HBV DNA that have a lower transcriptional activity. Parameters of the model were estimated in patients treated with lamivudine or Peg-IFN alone (N = 894), and the model was then validated in patients treated with lamivudine plus Peg-IFN (N = 436) to predict the virological response after a year of combination treatment. Lamivudine had a larger effect in blocking viral production than Peg-IFN (99.4-99.9% vs. 91.8-95.1%); however, Peg-IFN had a significant immunomodulatory effect, leading to an enhancement of the loss rates of I 1 (×1.7 in HBeAg-positive patients), I 2 (> ×7 irrespective of HBeAg status), and δ tr (×4.6 and ×2.0 in HBeAg-positive and HBeAg-negative patients, respectively). Using this model, we were able to describe the synergy of the different effects occurring during treatment with combination and predicted an effect of 99.99% on blocking viral production. This framework can therefore support the optimization of combination therapy with new anti-HBV agents | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Lamivudine |2 NLM | |
| 650 | 7 | |a 2T8Q726O95 |2 NLM | |
| 650 | 7 | |a Interferon-alpha |2 NLM | |
| 650 | 7 | |a Hepatitis B e Antigens |2 NLM | |
| 650 | 7 | |a DNA, Viral |2 NLM | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Polyethylene Glycols |2 NLM | |
| 650 | 7 | |a 3WJQ0SDW1A |2 NLM | |
| 650 | 7 | |a Recombinant Proteins |2 NLM | |
| 700 | 1 | |a Lemenuel-Diot, Annabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Gonçalves, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Guedj, Jérémie |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Clinical pharmacology and therapeutics |d 1960 |g 113(2023), 2 vom: 01. Feb., Seite 390-400 |w (DE-627)NLM000015318 |x 1532-6535 |7 nnns |
| 773 | 1 | 8 | |g volume:113 |g year:2023 |g number:2 |g day:01 |g month:02 |g pages:390-400 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/cpt.2798 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 113 |j 2023 |e 2 |b 01 |c 02 |h 390-400 | ||