Mathematical investigation of HBeAg seroclearance

Kadelka, Sarah; Ciupe, Stanca M.

doi:10.3934/mbe.2019382

Cited by 8 publications

(10 citation statements)

References 74 publications

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“…The average clearance rates of circulating HBeAg d E = 1.05 ± 0.52 per day, correspond to HBeAg life-spans ranging between 15.8 hours and 2.7 days, about one order of magnitude lower than those reported by Loomba et al for HBsAg [54]. The decreased HBeAg life-span predicted by our model may be correlated with the emergence of immune events and/or mutation in the core/precore regions [39] during ARC-520 treatment. Since we have no data on these events, we did not account for them in our model.…”

Section: Resultssupporting

confidence: 49%

“…The decay rate of HBsAg is bounded between 0 < d S < 200 per day, containing previous estimates ranging between 0.057 to 0.58 per day [54,55]. In previous modeling work [39,56] HBeAg decay rate d E was set to 0.3 per day. We allow for a larger range 0 < d E < 200 per day, corresponding to half-lives greater than 5 minutes.…”

Section: The Unknown Parameters Are Parmmentioning

confidence: 99%

“…In this study, we developed mathematical models that best reproduce observed HBV DNA, HBsAg and HBeAg kinetics following a single dose of ARC-520 in five HBeAg-positive patients from the Heparc-2001 study. Mathematical models of hepatitis B infection have been used to study the dynamics of acute, chronic, and occult HBV infections [20][21][22][23][24], anti-HBV therapy [14,[25][26][27][28][29][30], cell-to-cell transmission [31] , intracellular interactions [31][32][33], cellular immune responses [21,25,[34][35][36], antibody-mediated immune responses [11,33,37], HBeAg [33,38,39], and HBeAb [33] dynamics. We build on previous modeling work, consider the interaction between HBV DNA, HBsAg and HBeAg titers in the presence of a single dose RNAi-based therapy, and use the model to run in silico experiments to predict individual contributions of different drug effects on 2/23 the dynamics for HBsAg titers.…”

Section: Introductionmentioning

confidence: 99%

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Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection

Ciupe

Dahari

Kadelka

2020

Preprint

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Reaching hepatitis B surface antigen (HBsAg) loss (called functional cure) with approved treatment with pegylated interferon-α (IFN) and/or nucleos(t)ide analogues (NAs) in chronic hepatitis B virus (HBV) infected patients is suboptimal. The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum HBV DNA, HBsAg and hepatitis B e antigen (HBeAg) in chimpanzees and small animals. A recent clinical study (Heparc-2001) showed reduction of serum HBV DNA, HBeAg and HBsAg in HBeAg-positive patients treated with a single dose of ARC-520 and daily NA (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a a multi-compartmental pharmacokinetic-pharamacodynamic model and calibrated it with measured HBV data. We showed that the time-dependent ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1-4 months. The combined ARC-520 and entecavir effect on HBV DNA is constant over time, with efficacy of more than 99.8%. HBV DNA loss is entecavir mediated and the strong but transient HBsAg and HBeAg decays are solely ARC-520 mediated. We added complexity to the model in order to reproduce current long-term therapy outcomes with NAs by considering the tradeoff between hepatocyte loss and hepatocyte division, and used it to make in-silico long-term predictions for virus, HBsAg and HBeAg titer dynamics. These results may help assess ongoing RNAi drug development for hepatitis B virus infection.Author summaryWith about 300 million persons infected worldwide and 800,000 deaths annually, chronic infection with hepatitis B virus (HBV) is a major public health burden with high endemic areas around the world. Current treatment options focus on removing circulating HBV DNA but are suboptimal in removing hepatitis B s- and e-antigens. ARC-520, a RNA interference drug, had induced substantial hepatitis B s- and e- antigen reductions in animals and patients receiving therapy. We study the effect of ARC-520 on hepatitis B s- and e-antigen decline by developing mathematical models for the dynamics of intracellular and serum viral replication, and compare it to patient HBV DNA, hepatitis B s- and e-antigen data from a clinical trial with one ARC-520 injection and daily nucleoside analogue therapy. We examine biological parameters describing the different phases of HBV DNA, s-antigen and e-antigen decline and rebound after treatment initiation, and estimate treatment effectiveness. Such approach can inform the RNA interference drug therapy.

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Section: Resultssupporting

confidence: 49%

Section: The Unknown Parameters Are Parmmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection

Ciupe

Dahari

Kadelka

2020

Preprint

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“…The average clearance rates of circulating HBeAg d E = 1.05 ± 0.52 per day, correspond to HBeAg life-spans ranging between 59 . The decreased HBeAg life-span predicted by our model may be correlated with the emergence of immune events and/or mutation in the core/precore regions 44 during ARC-520 treatment. Since we have no data on these events, we did not account for them in our model.…”

Section: Resultsmentioning

confidence: 80%

“…The decay rate of HBsAg is bounded between 0 < d S < 200 per day, containing previous estimates ranging between 0.057 to 0.58 per day 59,60 . In previous modeling work 44,61 HBeAg decay rate d E was set to 0.3 per day. We allow for a larger range 0 < d E < 200 per day, corresponding to half-lives greater than 5 minutes.…”

mentioning

confidence: 99%

Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection

Kadelka

Dahari

Ciupe

2021

Sci Rep

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The RNA interference (RNAi) drug ARC-520 was shown to be effective in reducing serum hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in HBeAg-positive patients treated with a single dose of ARC-520 and daily nucleosidic analogue (entecavir). To provide insights into HBV dynamics under ARC-520 treatment and its efficacy in blocking HBV DNA, HBsAg, and HBeAg production we developed a multi-compartmental pharmacokinetic–pharamacodynamic model and calibrated it with frequent measured HBV kinetic data. We showed that the time-dependent single dose ARC-520 efficacies in blocking HBsAg and HBeAg are more than 96% effective around day 1, and slowly wane to 50% in 1–4 months. The combined single dose ARC-520 and entecavir effect on HBV DNA was constant over time, with efficacy of more than 99.8%. The observed continuous HBV DNA decline is entecavir mediated, the strong but transient HBsAg and HBeAg decays are ARC-520 mediated. The modeling framework may help assess ongoing RNAi drug development for hepatitis B virus infection.

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Within-Host Viral Growth and Immune Response Rates Predict Foot-and-Mouth Disease Virus Transmission Dynamics for African Buffalo

Macdonald,

Gulbudak,

Beechler

et al. 2024

The American Naturalist

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Infectious disease dynamics operate across biological scales: pathogens replicate within hosts, but transmit among hosts and populations. Functional changes in the pathogen-host interaction thus generate cascading effects from molecular to landscape scales. We investigated within-host dynamics and among-host transmission of three strains of foot-and-mouth disease viruses (FMDVs) in their wildlife host, African buffalo. We combined data on viral dynamics and host immune responses with mathematical models to ask (i) How do viral and immune dynamics vary among FMDV strains? (SAT1, 2, 3); (ii) Which viral and immune parameters determine viral fitness within hosts?; and (iii) How do within-host dynamics relate to virus transmission among hosts? Our data reveal contrasting within-host dynamics among viral strains. However, SAT2 elicited more rapid and effective immune responses than SAT1 and SAT3. Within-host viral fitness was overwhelmingly determined by variation among hosts in immune response activation rates against FMDVs, but not by variation among individual hosts in viral growth rate. By contrast, our analyses investigating across-scale linkages indicate that viral replication rate in the host correlates with transmission rates among buffalo; and that adaptive immune activation rate determines the infectious period. Together, these parameters define the basic reproductive number, R 0 , of the virus, suggesting that viral invasion potential may be predictable from within-host dynamics. Future work should test the generality of these findings by including additional FMDV strains, and create a multi-scale model to link within-host and between-host dynamics explicitly.

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Mathematical investigation of HBeAg seroclearance

Cited by 8 publications

References 74 publications

Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection

Understanding the antiviral effects of RNAi-based therapy on chronic hepatitis B infection

Understanding the antiviral effects of RNAi-based therapy in HBeAg-positive chronic hepatitis B infection

Within-Host Viral Growth and Immune Response Rates Predict Foot-and-Mouth Disease Virus Transmission Dynamics for African Buffalo

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