|
1
|
Boivin‐Champeaux C, Velez de Mendizabal N, Jones A, Balsitis S, Schmidt S, Feigelman JS, Azeredo FJ. Disease Progression Mathematical Modeling With a Case Study on Hepatitis B Virus Infection. CPT Pharmacometrics Syst Pharmacol 2025; 14:420-434. [PMID: 39731346 PMCID: PMC11919268 DOI: 10.1002/psp4.13298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 12/10/2024] [Accepted: 12/12/2024] [Indexed: 12/29/2024] Open
Abstract
Chronic Hepatitis B presents a significant health and socioeconomic burden. The risk of hepatocellular carcinoma remains elevated although treatments are available. Achieving an optimal treatment regimen necessitates a deep comprehension of the dynamic relationship between the virus and its host across disease states. This tutorial elucidates essential considerations for establishing a disease modeling platform to facilitate informed decision-making in hepatitis B treatment strategies. We review several published models of varying complexity and describe the context that motivated each model's structure and assumptions. Several of the models are made available in an interactive RShiny app to demonstrate the influence of model choice and sensitivity to the choice of parameter values.
Collapse
Affiliation(s)
- Clémence Boivin‐Champeaux
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of PharmacyUniversity of FloridaOrlandoFloridaUSA
| | | | - Aksana Jones
- Clinical Pharmacology and PharmacometricsGilead SciencesFoster CityCaliforniaUSA
| | - Scott Balsitis
- Research Discovery VirologyGilead SciencesFoster CityCaliforniaUSA
| | - Stephan Schmidt
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of PharmacyUniversity of FloridaOrlandoFloridaUSA
| | - Justin S. Feigelman
- Clinical Pharmacology and PharmacometricsGilead SciencesFoster CityCaliforniaUSA
| | - Francine Johansson Azeredo
- Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of PharmacyUniversity of FloridaOrlandoFloridaUSA
| |
Collapse
|
|
2
|
Goyal A, Liao LE, Perelson AS. Within-host mathematical models of hepatitis B virus infection: Past, present, and future. ACTA ACUST UNITED AC 2019; 18:27-35. [PMID: 31930181 DOI: 10.1016/j.coisb.2019.10.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Mathematical modeling has been instrumental in enhancing our understanding of the viral dynamics of hepatitis B virus (HBV) infection. We give a primer on HBV infection in humans and a brief overview of the development of within-host mathematical models of HBV infection. In the last decade, models have advanced from considering chronic HBV infections under therapy to the pathogenesis of infection. We also summarize estimates of key viral dynamic parameters that have varied greatly among studies, and show that they impact model predictions. Future directions for mathematical modeling of HBV infection are proposed to better understand emerging therapies, the HBV life cycle, predicting cure, and the mechanisms involved in the immune response to HBV infection.
Collapse
Affiliation(s)
- Ashish Goyal
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico, 87545, USA
| | - Laura E Liao
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico, 87545, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, P.O. Box 1663, Los Alamos, New Mexico, 87545, USA
| |
Collapse
|
|
3
|
Abstract
Hepatitis B virus infection is the cause of liver diseases such as cirrhosis and liver cancer. Understanding the host-virus mechanisms that mediate virus pathogenesis can help design better preventive measures for disease control. Mathematical models have been used alongside experimental data to provide insight into the role of immune responses during the acute and chronic hepatitis B infections as well as virus dynamics following administration of combined drug therapy. In this paper, we review several modeling studies on virus-host interactions during acute infection, the virus-host characteristics responsible for transition to chronic disease, and the efficacy and optimal control measures of drug therapy. We conclude by presenting our opinion on the future directions of the field.
Collapse
Affiliation(s)
- Stanca M Ciupe
- Department of Mathematics, Virginia Tech, Blacksburg, VA, USA
| |
Collapse
|
|
4
|
Li M, Zu J. The review of differential equation models of HBV infection dynamics. J Virol Methods 2019; 266:103-113. [PMID: 30716348 DOI: 10.1016/j.jviromet.2019.01.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 12/30/2018] [Accepted: 01/24/2019] [Indexed: 12/21/2022]
Abstract
Understanding the infection and pathogenesis mechanism of hepatitis B virus (HBV) is very important for the prevention and treatment of hepatitis B. Mathematical models contribute to illuminate the dynamic process of HBV replication in vivo. Therefore, in this paper we review the viral dynamics in HBV infection, which may help us further understand the dynamic mechanism of HBV infection and efficacy of antiviral treatment. Firstly, we introduce a family of deterministic models by considering different biological mechanisms, such as, antiviral therapy, CTL immune response, multi-types of infected hepatocytes, time delay and spatial diffusion. Particularly, we briefly describe the stochastic models of HBV infection. Secondly, we introduce the commonly used parameter estimation methods for HBV viral dynamic models and briefly discuss how to use these methods to estimate unknown parameters (such as drug efficacy) through two specific examples. We also discuss the idea and method of model identification and use a specific example to illustrate its application. Finally, we propose three new research programs, namely, considering HBV drug-resistant strain, coupling within-host and between-host dynamics in HBV infection and linking population dynamics with evolutionary dynamics of HBV diversity.
Collapse
Affiliation(s)
- Miaolei Li
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, PR China
| | - Jian Zu
- School of Mathematics and Statistics, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, PR China.
| |
Collapse
|
|
5
|
Friedman A, Siewe N. Chronic hepatitis B virus and liver fibrosis: A mathematical model. PLoS One 2018; 13:e0195037. [PMID: 29634771 PMCID: PMC5892900 DOI: 10.1371/journal.pone.0195037] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 03/15/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a liver disorder that can result in cirrhosis, liver failure and hepatocellular carcinoma. HBV infection remains a major global health problem, as it affects more 350 million people chronically and kills roughly 600,000 people annually. Drugs currently used against HBV include IFN-α that decreases viremia, inflammation and the growth of liver fibrosis, and adefovir that decreases the viral load. Each of these drugs can have severe side-effects. In the present paper, we consider the treatment of chronic HBV by a combination of IFN-α and adefovir, and raise the following question: What should be the optimal ratio between IFN-α and adefovir in order to achieve the best 'efficacy' under constraints on the total amount of the drugs; here the efficacy is measured by the reduction of the levels of inflammation and of fibrosis? We develop a mathematical model of HBV pathogenesis by a system of partial differential equations (PDEs) and use the model to simulate a 'synergy map' which addresses the above question.
Collapse
Affiliation(s)
- Avner Friedman
- Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
| | - Nourridine Siewe
- National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, United States of America
| |
Collapse
|
|
6
|
Sun D, Liu F. Modeling and Control of a Delayed Hepatitis B Virus Model with Incubation Period and Combination Treatment. Interdiscip Sci 2017; 10:375-389. [PMID: 29260504 DOI: 10.1007/s12539-017-0275-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 11/16/2017] [Accepted: 11/18/2017] [Indexed: 12/21/2022]
Abstract
In this paper, a hepatitis B virus (HBV) model with an incubation period and delayed state and control variables is firstly proposed. Furthermore, the combination treatment is adopted to have a longer-lasting effect than mono-therapy. The equilibrium points and basic reproduction number are calculated, and then the local stability is analyzed on this model. We then present optimal control strategies based on the Pontryagin's minimum principle with an objective function not only to reduce the levels of exposed cells, infected cells and free viruses nearly to zero at the end of therapy, but also to minimize the drug side-effect and the cost of treatment. What's more, we develop a numerical simulation algorithm for solving our HBV model based on the combination of forward and backward difference approximations. The state dynamics of uninfected cells, exposed cells, infected cells, free viruses, CTL and ALT are simulated with or without optimal control, which show that HBV is reduced nearly to zero based on the time-varying optimal control strategies whereas the disease would break out without control. At last, by the simulations, we prove that strategy A is the best among the three kinds of strategies we adopt and further comparisons have been done between model (1) and model (2).
Collapse
Affiliation(s)
- Deshun Sun
- Control and Simulation Center, Harbin Institute of Technology, Harbin, 15008, China
| | - Fei Liu
- Control and Simulation Center, Harbin Institute of Technology, Harbin, 15008, China.
| |
Collapse
|
|
7
|
Tewari D, Mocan A, Parvanov ED, Sah AN, Nabavi SM, Huminiecki L, Ma ZF, Lee YY, Horbańczuk JO, Atanasov AG. Ethnopharmacological Approaches for Therapy of Jaundice: Part II. Highly Used Plant Species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae Families. Front Pharmacol 2017; 8:519. [PMID: 28848436 PMCID: PMC5554347 DOI: 10.3389/fphar.2017.00519] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 07/24/2017] [Indexed: 12/18/2022] Open
Abstract
In many developing countries, jaundice is the common symptom of hepatic diseases which are a major cause of mortality. The use of natural product-based therapies is very popular for such hepatic disorders. A great number of medicinal plants have been utilized for this purpose and some facilitated the discovery of active compounds which helped the development of new synthetic drugs against jaundice. However, more epidemiological studies and clinical trials are required for the practical implementation of the plant pharmacotherapy of jaundice. The focus of this second part of our review is on several of the most prominent plants used against jaundice identified in the analysis performed in the first part of the review viz. Andrographis paniculata (Burm.f.) Nees, Silybum marianum (L.) Gaertn., Terminalia chebula Retz., Glycyrrhiza glabra L. and some species of genus Phyllanthus. Furthermore, we discuss their physiological effects, biologically active ingredients, and the potential mechanisms of action. Some of the most important active ingredients were silybin (also recommended by German commission), phyllanthin and andrographolide, whose action leads to bilirubin reduction and normalization of the levels of relevant serum enzymes indicative for the pathophysiological status of the liver.
Collapse
Affiliation(s)
- Devesh Tewari
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun UniversityNainital, India
| | - Andrei Mocan
- Department of Pharmaceutical Botany, “Iuliu Haţieganu” University of Medicine and PharmacyCluj-Napoca, Romania
- ICHAT and Institute for Life Sciences, University of Agricultural Sciences and Veterinary MedicineCluj-Napoca, Romania
| | - Emil D. Parvanov
- Division BIOCEV, Institute of Molecular Genetics, Academy of Sciences of the Czech RepublicPrague, Czechia
| | - Archana N. Sah
- Department of Pharmaceutical Sciences, Faculty of Technology, Kumaun UniversityNainital, India
| | - Seyed M. Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical SciencesTehran, Iran
| | - Lukasz Huminiecki
- Institute of Genetics and Animal Breeding of the Polish Academy of SciencesJastrzebiec, Poland
| | - Zheng Feei Ma
- School of Medical Sciences, Universiti Sains MalaysiaKota Bharu, Malaysia
- Department of Public Health, Xi’an Jiaotong-Liverpool UniversitySuzhou, China
| | - Yeong Yeh Lee
- School of Medical Sciences, Universiti Sains MalaysiaKota Bharu, Malaysia
| | - Jarosław O. Horbańczuk
- Institute of Genetics and Animal Breeding of the Polish Academy of SciencesJastrzebiec, Poland
| | - Atanas G. Atanasov
- Institute of Genetics and Animal Breeding of the Polish Academy of SciencesJastrzebiec, Poland
- Department of Pharmacognosy, University of ViennaVienna, Austria
- Department of Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of ViennaVienna, Austria
| |
Collapse
|
|
8
|
Understanding the Complex Patterns Observed during Hepatitis B Virus Therapy. Viruses 2017; 9:v9050117. [PMID: 28534812 PMCID: PMC5454429 DOI: 10.3390/v9050117] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/21/2017] [Accepted: 05/02/2017] [Indexed: 01/16/2023] Open
Abstract
Data from human clinical trials have shown that the hepatitis B virus (HBV) follows complex profiles, such as bi-phasic, tri-phasic, stepwise decay and rebound. We utilized a deterministic model of HBV kinetics following antiviral therapy to uncover the mechanistic interactions behind HBV dynamics. Analytical investigation of the model was used to separate the parameter space describing virus decay and rebound. Monte Carlo sampling of the parameter space was used to determine the virological, pharmacological and immunological factors that separate the bi-phasic and tri-phasic virus profiles. We found that the level of liver infection at the start of therapy best separates the decay patterns. Moreover, drug efficacy, ratio between division of uninfected and infected cells, and the strength of cytotoxic immune response are important in assessing the amount of liver damage experienced over time and in quantifying the duration of therapy leading to virus resolution in each of the observed profiles.
Collapse
|
|
9
|
Nakabayashi J. The intracellular dynamics of hepatitis B virus (HBV) replication with reproduced virion "re-cycling". J Theor Biol 2016; 396:154-62. [PMID: 26924390 DOI: 10.1016/j.jtbi.2016.02.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Revised: 02/02/2016] [Accepted: 02/05/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a causative agent of hepatitis. Clinical outcome of hepatitis type B depends on the viral titer observed in the peripheral blood of the patient. In the chronic hepatitis patient, production of HBV virion remains low level. On the other hand, the viral load prominently increases in fulminant hepatitis patient as compared with that in the chronic hepatitis patient. We previously proposed a mathematical model describing the intracellular dynamics of HBV replication. Our model clarified that there are two distinguishable replication patterns of HBV named "arrested" and "explosive" replication. In the arrested replication, the amount of virion newly reproduced from an infected cell remains low level, while the amount of virion extremely increases in the explosive replication. Viral load is drastically changed by slight alteration of expression ratio of 3.5kb RNA to 2.4kb mRNA of HBV. Though our model provided the switching mechanism determining the replication pattern of HBV, HBV dynamics is determined by not only the expression pattern of viral genes. In this study, "recycling" of HBV virion in the replication cycle is investigated as a new factor affecting the intracellular dynamics of HBV replication. A part of newly produced virion of HBV is reused as a core particle that is a resource of HBV replication. This recycling of HBV virion lowers the threshold for the explosive replication when waiting time for the next cycle of the replication is large. It is seemingly contradicting that prominent production of HBV is caused by large recycling rate and small release rate of HBV virion from infected cell to extracellular space. But the recycling of HBV virion can contribute to the positive feedback cycle of HBV replication for the explosive replication to accumulate the core particle as a resource of HBV replication in an infected cell. Accumulation of core particle in the infected cell can be risk factor for the exacerbation of hepatitis rather than rapid release of HBV virion from the infected cell.
Collapse
Affiliation(s)
- Jun Nakabayashi
- Bioinformatics Laboratory, Advanced Medical Research Center, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa 2360004, Japan.
| |
Collapse
|
|
10
|
Su Y, Sun D. Optimal control of anti-HBV treatment based on combination of Traditional Chinese Medicine and Western Medicine. Biomed Signal Process Control 2015. [DOI: 10.1016/j.bspc.2014.09.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
|
|
11
|
Bertacchi D, Zucca F, Foresti S, Mangioni D, Gori A. Combination versus sequential monotherapy in chronic HBV infection: a mathematical approach. MATHEMATICAL MEDICINE AND BIOLOGY-A JOURNAL OF THE IMA 2014; 32:383-403. [PMID: 25398978 DOI: 10.1093/imammb/dqu022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 10/12/2014] [Indexed: 11/12/2022]
Abstract
Sequential monotherapy is the most widely used therapeutic approach in the treatment of hepatitis B virus (HBV) chronic infection. Unfortunately, under therapy, in some patients the hepatitis virus mutates and gives rise to variants which are drug resistant. We wonder whether those patients would have benefited from the choice of combination therapy instead of sequential monotherapy. To study the action of these two therapeutic approaches and to explain the emergence of drug resistance, we propose a stochastic model for the infection within a patient who is treated with two drugs, either sequentially or contemporaneously, and who, under the first kind of therapy develops a strain of the virus which is resistant to both drugs. Our stochastic model has a deterministic approximation which is a slight modification of a classic three-strain model. We discuss why stochastic simulations are more suitable than the study of the deterministic approximation, when modelling the rise of mutations (this is mainly due to the amplitude of the stochastic fluctuations). We run stochastic simulations with suitable parameters and compare the time when, under the two therapeutic approaches, the resistant strain first reaches detectability in the serum viral load. Our results show that the best choice is to start an early combination therapy, which allows one to stay drug resistance free for a longer time and in many cases leads to viral eradication.
Collapse
Affiliation(s)
- Daniela Bertacchi
- Università di Milano-Bicocca Dipartimento di Matematica e Applicazioni, Via Cozzi 53, 20125 Milano, Italy
| | - Fabio Zucca
- Dipartimento di Matematica, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy
| | - Sergio Foresti
- Division of Infectious Diseases Department of Internal Medicine, 'San Gerardo' Hospital, Università di Milano-Bicocca, 20900 Monza, Italy
| | - Davide Mangioni
- Division of Infectious Diseases Department of Internal Medicine, 'San Gerardo' Hospital, Università di Milano-Bicocca, 20900 Monza, Italy
| | - Andrea Gori
- Division of Infectious Diseases Department of Internal Medicine, 'San Gerardo' Hospital, Università di Milano-Bicocca, 20900 Monza, Italy
| |
Collapse
|
|
12
|
Leung NWY, Herrmann E, Lau GKK, Chan HLY, So TMK, Zeuzem S, Dong Y, Trylesinski A, Naoumov NV. Early Viral Kinetics with Telbivudine, Tenofovir or Combination of Both in Immunotolerant Patients with Hepatitis B e Antigen-Positive Chronic Hepatitis B. Infect Dis Ther 2014; 3:191-202. [PMID: 25228496 PMCID: PMC4269624 DOI: 10.1007/s40121-014-0039-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Indexed: 01/05/2023] Open
Abstract
Introduction Viral kinetics has proved useful in understanding antiviral potency, determining antiviral profiles and optimizing treatment strategy. Methods This was a randomized, open-label study comparing the viral kinetics in 46 hepatitis B e antigen-positive patients during 12-week treatment with telbivudine monotherapy, tenofovir monotherapy or the combination of telbivudine plus tenofovir. A standard biphasic mathematical model was used to compare hepatitis B virus (HBV) DNA decay parameters. Results Forty-six patients received telbivudine (n = 16), tenofovir (n = 14) or telbivudine plus tenofovir (n = 16). From baseline to Week 12, the mean (SD) reduction in HBV DNA levels was not significantly different between treatment groups: −3.9 (0.9) log10 copies/mL in telbivudine group, −4.2 (0.7) log10 copies/mL in tenofovir group, and −4.4 (1.0) log10 copies/mL in combination group. No significant difference was observed among the three groups for viral clearance rate per day (0.97, 1.02, and 0.88, respectively) or for infected cell loss rate per day (0.04, 0.05, and 0.05, respectively). Antiviral efficiency in blocking viral production was similar in the monotherapy groups (median; 99.7% in telbivudine group and 99.4% in tenofovir group), but was slightly better and more homogeneous in the combination treatment group than in the monotherapy groups: mean (SD), 99.1% (0.8%) and 98.8% (1.6%), respectively (Wald–Wolfowitz test; P = 0.038). All treatments were well tolerated and no serious adverse event was reported during the study. Of the 46 patients in the safety population, 23 experienced adverse events. Most of the adverse events were not suspected to be related to the study drug by the investigators. Conclusion Monotherapy with telbivudine or tenofovir showed similar antiviral effectiveness in HBV DNA reduction and viral kinetics of HBV DNA decay. Efficiency in blocking viral production was slightly improved in the combination treatment group compared to the monotherapy groups. Electronic supplementary material The online version of this article (doi:10.1007/s40121-014-0039-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Nancy W Y Leung
- , 1501 Melbourne Plaza, 33 Queen's Road Central, Hong Kong S.A.R., China.
| | - Eva Herrmann
- Johann Wolfgang Goethe University Frankfurt Department of Medicine, Institute of Biostatistics and Mathematical Modeling, Theodor-Stern-Kai 7, Frankfurt am Main, Germany
| | - George K K Lau
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong S.A.R., China
| | - Tokutei M K So
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong S.A.R., China
| | - Stefan Zeuzem
- Klinikum der Johann Wolfgang Goethe-Universitaet, Frankfurt am Main, Germany
| | - Yu Dong
- Novartis Pharma AG, Basel, Switzerland
| | | | | |
Collapse
|
|
13
|
Su Y, Zhao L, Min L. Analysis and simulation of an Adefovir anti-hepatitis B virus infection therapy immune model with alanine aminotransferase. IET Syst Biol 2013; 7:205-13. [PMID: 24067421 DOI: 10.1049/iet-syb.2012.0054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B virus (HBV) infection models and anti-HBV infection therapy models have been set up to understand and explain clinical phenomena. Many of these models have been proposed based on Zeuzem et al. and Nowak et al.'s basic virus infection model (BVIM). Some references have pointed out that the basic infection reproductive number of the BVIM is biologically questionable and gave the modified models with standard mass action incidences. This study describes one anti-HBV therapy immune model with alanine aminotransferase (ALT) based on standard mass action incidences. There are two basic infection reproductive numbers R0 and R1 in the model. It is proved that if R0 < 1 and R1 < 1, the disease free equilibrium is locally and globally asymptotically stable, respectively. For the endemic equilibrium, simulation shows that if R1 > 1, it may be also globally asymptotically stable. Simulations based on clinical data of HBV DNA and ALT can explain some clinical phenomena. Simulations of the correlation between liver cells, HBV DNA, cytotoxic T lymphocytes and ALT are also given.
Collapse
|
|
14
|
Mathematical modeling of triphasic viral dynamics in patients with HBeAg-positive chronic hepatitis B showing response to 24-week clevudine therapy. PLoS One 2012; 7:e50377. [PMID: 23209728 PMCID: PMC3508925 DOI: 10.1371/journal.pone.0050377] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2012] [Accepted: 10/19/2012] [Indexed: 12/18/2022] Open
Abstract
Background Modeling of short-term viral dynamics of hepatitis B with traditional biphasic model might be insufficient to explain long-term viral dynamics. The aim was to develop a novel method of mathematical modeling to shed light on the dissociation between early and long-term dynamics in previous studies. Methods We investigated the viral decay pattern in 50 patients from the phase III clinical trial of 24-week clevudine therapy, who showed virological response and HBsAg decline. Immune effectors were added as a new compartment in the model equations. We determined some parameter values in the model using the non-linear least square minimization method. Results Median baseline viral load was 8.526 Log10copies/mL, and on-treatment viral load decline was 5.683 Log10copies/mL. The median half-life of free virus was 24.89 hours. The median half-life of infected hepatocytes was 7.39 days. The viral decay patterns were visualized as triphasic curves with decreasing slopes over time: fastest decay in the first phase; slowest in the third phase; the second phase in between. Conclusions In the present study, mathematical modeling of hepatitis B in patients with virological response and HBsAg decline during 24-week antiviral therapy showed triphasic viral dynamics with direct introduction of immune effectors as a new compartment, which was thought to reflect the reduction of clearance rate of infected cells over time. This modeling method seems more appropriate to describe long-term viral dynamics compared to the biphasic model, and needs further validation.
Collapse
|
|
15
|
Antiviral therapy using a fuzzy controller optimized by modified evolutionary algorithms: a comparative study. Neural Comput Appl 2012. [DOI: 10.1007/s00521-012-1146-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
16
|
Abstract
Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma result in 1.2 million deaths per year, making CHB the 10th leading cause of mortality worldwide. The natural history of CHB is variable and complex. The past decade witnessed important developments for the therapy of hepatitis B and marked the new era of oral therapy. The ultimate goal of CHB therapy is to arrest the progression of liver injury and to prevent the development of liver failure and hepatocellular carcinoma. Currently, six agents are approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical, and histological benefits for both HBeAg positive and negative CHB. There are, however, limitations in spite of their efficacy. The significant side-effect profile of interferon, for example, limits its long-term use. The approved oral agents are tolerable with prolonged use but drug resistance could limit long-term monotherapy. To date, combination therapy with nucleoside analogue and pegylated interferon or two nucleos(t)ide analogues given for one year does not show superiority in durability of response compared to monotherapy. Ongoing research effort is critical to identify the ideal hepatitis B therapy that is safe, effective, and produces durable response with a finite course of therapy. It is equally important to conduct a well designed, prospective natural history study to identify predictors of disease progression. This will accurately guide treatment strategy for this important disease.
Collapse
Affiliation(s)
- Daryl T-Y Lau
- Associate Professor of Medicine, Harvard Medical School (HMS), Director of Translational Liver Research, Beth Israel Deaconess Medical Center, HMS Liver Center, Division of Gastroenterology, Department of Medicine, 110 Francis Street, Suite 4A, Boston, MA 02215.
| | | |
Collapse
|
|
17
|
Lau GKK, Leung N. Forty-eight weeks treatment with clevudine 30 mg qd versus lamivudine 100 mg qd for chronic hepatitis B infection: a double-blind randomized study. THE KOREAN JOURNAL OF HEPATOLOGY 2011; 16:315-20. [PMID: 20924215 PMCID: PMC3304600 DOI: 10.3350/kjhep.2010.16.3.315] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Clevudine is a pyrimidine analogue with potent activity against hepatitis B virus (HBV) replication in vitro. In a previous pivotal phase III clinical study, 24 weeks treatment with clevudine 30 mg has been shown to profoundly suppress HBV replication and normalize serum alanine aminotransferase level. METHODS In this study, we compare the efficacy and safety of clevudine (30 mg daily) versus lamivudine (100 mg daily) for 48 weeks in treatment-naive chronic hepatitis B e antigen (HBeAg) positive patients. RESULTS Ninety-two chronic HBeAg positive patients were randomized to receive clevudine 30 mg daily or lamivudine 100 mg daily in a 1:1 ratio. The clevudine group demonstrated greater viral suppression at week 48 when compared with the lamivudine group (median reduction: 4.27 vs. 3.17 log(10) copies/ml at week 48, p<0.0001). At week 48, serum HBV DNA level was below 300 copies/mL in 73% and 40% in the clevudine and lamivudine groups, respectively (p=0.001). HBeAg seroconversion occurred in 18% of patients in the clevudine group versus 12% in the lamivudine group at week 48. Lamivudine-resistant mutations were detected in 11 (24%) patients in the lamivudine group, who showed viral rebound during lamivudine therapy but no resistance was found in the clevudine group during 48-week treatment period. CONCLUSIONS A 48-week dosing with clevudine 30 mg daily was superior to lamivudine 100 mg daily in suppressing HBV replication, with no emergence of viral breakthrough in patients with HBeAg positive chronic hepatits B.
Collapse
Affiliation(s)
- George K K Lau
- Clinical Trial Center, LKS Faculty of Medicine, The University of Hong Kong, Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China.
| | | |
Collapse
|
|
18
|
Wang K, Tan W, Tang Y, Deng G. Numerical diagnoses of superinfection in chronic hepatitis B viral dynamics. Intervirology 2011; 54:349-56. [PMID: 21242660 DOI: 10.1159/000321454] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Accepted: 09/15/2010] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVES Fluctuation profile has been observed in chronic hepatitis B patients who are untreated or interrupt therapy. A mathematical model and its parameters could be used to diagnose the assumption of superinfection of hepatocytes and to understand the causes for the spontaneous fluctuation pattern of HBV DNA loads in chronically infected patients. METHODS We propose a new conceptual model in terms of chemical kinetics, which is based on the assumption that hepatocytes can be superinfected with hepatitis B virus (HBV). Minimizing the sum of squares of the deviations, we fitted the model to the HBV DNA trajectories from clinical data and obtained the model parameters. RESULTS The model with the fitted parameters can capture the tendency of HBV DNA trajectories. The mean value of the fitted number of virions that enter a single hepatocyte at the beginning stage of an invasion is 2.10 ± 0.18. The dynamics patterns may correlate with the clinical phenotypes of patients and the value of clinical parameters, such as α-fetoprotein, hepatitis B e-antigen, hepatitis B e-antibody, total bilirubin and alanine transaminase. CONCLUSIONS The superinfection scenario is possible in HBV infection and it may induce HBV DNA fluctuation in the host.
Collapse
Affiliation(s)
- Kaifa Wang
- Department of Medical Device and Equipment, School of Biomedical Engineering and Medical Imaging, Chongqing, P.R. China
| | | | | | | |
Collapse
|
|
19
|
Nakabayashi J, Sasaki A. A mathematical model of the intracellular replication and within host evolution of hepatitis type B virus: Understanding the long time course of chronic hepatitis. J Theor Biol 2010; 269:318-29. [PMID: 21070786 DOI: 10.1016/j.jtbi.2010.10.024] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Revised: 09/29/2010] [Accepted: 10/21/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) causes acute and chronic liver disease. Especially, chronic hepatitis is a major risk factor of liver cirrhosis and hepatocellular carcinoma. Viral kinetics of HBV observed in peripheral blood is quite different depending on the clinical course of hepatitis. But the relationship between the intracellular replication dynamics and clinical course of HBV infection is unclear. Further it is very difficult to predict the long time course of hepatitis because the nature of HBV is changed by mutation within host with high mutation rate. We investigate the intracellular replication dynamics and within host evolution of HBV by using a mathematical model. Two different intracellular replication patterns of HBV, "explosive" and "arrested", are switched depending on the viral gene expression pattern. In the explosive replication, prominent growth of HBV is observed. On the other hand, the virion production is restricted in the arrested replication. It is suggested that the arrested and explosive replication is associated with chronic hepatitis and exacerbation of hepatitis respectively. It is shown by our evolutionary simulation that the exacerbation of hepatitis is caused by the emergence of explosive genotype of HBV from arrested genotype by mutation during chronic hepatitis. It is also shown that chronic infection without exacerbation is maintained by short waiting time for virion release and superinfection with arrested genotype. It is suggested that extension of waiting time for virion release and existence of uninfected hepatocyte in the liver may become risk factors for the exacerbation of hepatitis.
Collapse
Affiliation(s)
- Jun Nakabayashi
- Department of Evolutionary Study of Biosystems, The Graduate University for Advanced Studies (SOKENDAI), Hayama, Kanagawa 240-0193, Japan.
| | | |
Collapse
|
|
20
|
Ribeiro RM, Germanidis G, Powers KA, Pellegrin B, Nikolaidis P, Perelson AS, Pawlotsky JM. Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections. J Infect Dis 2010; 202:1309-18. [PMID: 20874517 DOI: 10.1086/656528] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B infection has a presentation and clinical course that is divergent from that of HBeAg‐positive infection. The former usually presents with lower viral levels but faster progression to liver disease. We sought to better understand the balance between replication and the immune response against hepatitis B virus (HBV). METHODS Viral kinetics in 50 HBeAg‐negative patients under various treatment protocols with interferon α and/or nucleoside or nucleotide analogs was analyzed. HBV DNA level was measured frequently and the data fitted to a viral dynamic model. A meta‐analysis of all published studies of viral kinetics in HBeAg‐positive and HBeAg‐negative infection was also conducted. RESULTS We found that the clearance of both HBV virions and infected cells was significantly faster in HBeAg‐negative infection than in HBeAg‐positive infection. In HBeAg‐negative infection, there was also a negative correlation between baseline HBV DNA levels and infected cell half‐life, suggesting that the higher the viral load the faster the turnover of infected cells. CONCLUSIONS These results reveal the dual role played by the immune response in maintaining lower viral levels and inducing faster turnover of infected cells, the latter of which may be responsible for the more aggressive nature of HBeAg‐negative infection.
Collapse
Affiliation(s)
- Ruy M Ribeiro
- Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Qesmi R, Wu J, Wu J, Heffernan JM. Influence of backward bifurcation in a model of hepatitis B and C viruses. Math Biosci 2010; 224:118-25. [PMID: 20085774 DOI: 10.1016/j.mbs.2010.01.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2009] [Revised: 01/04/2010] [Accepted: 01/11/2010] [Indexed: 10/20/2022]
Abstract
In the 1990 s, liver transplantation for hepatitis B and C virus (HBV and HCV) related-liver diseases was a very controversial issue since recurrent infection of the graft was inevitable. Significant progress has been made in the prophylaxis and treatment of recurrent hepatitis B/C (or HBV/HCV infection) after liver transplantation. In this paper, we propose a mathematical model of ordinary differential equations describing the dynamics of the HBV/HCV and its interaction with both liver and blood cells. A single model is used to describe infection of either virus since the dynamics in-host (infected of the liver) are similar. Analyzing the model, we observe that the system shows either a transcritical or a backward bifurcation. Explicit conditions on the model parameters are given for the backward bifurcation to be present. Consequently, we investigate possible factors that are responsible for HBV/HCV infection and assess control strategies to reduce HBV/HCV reinfection and improve graft survival after liver transplantation.
Collapse
Affiliation(s)
- Redouane Qesmi
- Department of Mathematics and Statistics, York University, Toronto, Ontario, Canada.
| | | | | | | |
Collapse
|
|
22
|
Yang J, Cai T, Lou GQ. Anti-hepatitis B virus treatment guided by long-term virus kinetics stepwise tracing. J Gastroenterol Hepatol 2009; 24:1008-16. [PMID: 19220675 DOI: 10.1111/j.1440-1746.2008.05759.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Biphasic modeling of viral kinetics provided valuable information to rapidly assess potential antiviral regimens during the beginning of therapy, but has not been performed over the long term. METHODS In 11 chronic hepatitis B patients with lamivudine treated per day, the model with delay time was applied to examine phase transition and analyze viral kinetics parameters. RESULTS Viral decay conformed to a biphasic mode during the first 4 weeks, with the complex profile appeared in the later period. Lamivudine treatment resulted in a mean log hepatitis B virus (HBV)-DNA decline of 1.77 +/- 0.55 after 4 weeks and 3.79 +/- 1.70 log after 24 weeks. The median effectiveness of blocking viral replication was 96% (range, 89-99%). The median rate of free virus clearance and infected cell loss was 1.1/day and 0.03/day, respectively. Through phase transition determination and stepwise modeling process, viral kinetics were evaluated for complex decay profile during long-term therapy. Moreover, with the abnormal kinetics tracked, an occasion of add-on combined therapy was developed to treat patients with emerging virus mutants. CONCLUSION The present study using mathematical modeling of viral decay may be a useful approach to evaluate optimal individualized therapy for HBV infection in a continuous long-term manner.
Collapse
Affiliation(s)
- Jin Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, China
| | | | | |
Collapse
|
|
23
|
Lewin SR, Ribeiro RM, Avihingsanon A, Bowden S, Matthews G, Marks P, Locarnini SA, Ruxrungtham K, Perelson AS, Dore GJ. Viral dynamics of hepatitis B virus DNA in human immunodeficiency virus-1-hepatitis B virus coinfected individuals: similar effectiveness of lamivudine, tenofovir, or combination therapy. Hepatology 2009; 49:1113-21. [PMID: 19115219 PMCID: PMC2720274 DOI: 10.1002/hep.22754] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
UNLABELLED Following treatment of hepatitis B virus (HBV) infection with nucleos(t)ide reverse transcriptase inhibitors (NRTIs), there is a biphasic clearance of HBV, similar to that seen following treatment of human immunodeficiency virus-1 (HIV-1) and hepatitis C virus. Little is known about the impact of combination NRTIs and HIV-1 coinfection on HBV viral kinetic parameters following the initiation of HBV-active highly active antiretroviral therapy (HAART). HIV-1-HBV coinfected patients (n = 21) were enrolled in a viral kinetics substudy of the Tenofovir in HIV-1-HBV Coinfection study (TICO). TICO was a randomized (1:1:1) trial of tenofovir disoproxil fumarate (TDF, 300 mg) versus lamivudine (LMV, 300 mg) versus TDF/LMV within an efavirenz based HAART regimen initiated in HIV-1-HBV coinfected antiretroviral naïve individuals in Thailand. HBV DNA was measured frequently over the first 56 days. To fit the viral load data, we used a model of HBV kinetics that allows the estimation of treatment effectiveness, viral clearance and infected cell loss. We observed a biphasic decline in HBV DNA in almost all patients. We did not observe any significant differences in HBV viral dynamic parameters between the three treatments groups. Overall, median (interquartile range) HBV treatment effectiveness was 98% (95%-99%), median HBV virion half-life was 1.2 days (0.5-1.4 days), and median infected cell half-life was 7.9 days (6.3-11.0 days). When we compared hepatitis B e antigen (HBeAg)-positive and HBeAg-negative individuals, we found a significantly longer infected cell half-life in HBeAg-positive individuals (6.2 versus 9.0 days, P = 0.02). CONCLUSION HBV viral dynamic parameters are similar following anti-HBV NRTI monotherapy and dual combination therapy in the setting of HIV-1-HBV coinfection. HIV-1 coinfection has minimal effect on HBV viral dynamics, even in the setting of advanced HIV-1-related immunosuppression.
Collapse
Affiliation(s)
- Sharon R Lewin
- Infectious Diseases Unit, Alfred Hospital, Melbourne, Australia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
24
|
Sypsa V, Hatzakis A. Modelling of viral dynamics in hepatitis B and hepatitis C clinical trials. Stat Med 2009; 27:6505-21. [PMID: 18951370 DOI: 10.1002/sim.3457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
In the recent years, studies of hepatitis B (HBV) and hepatitis C virus (HCV) dynamics have drawn great attention as they provide insight into the process of virus elimination/production and of infected cells decay during antiviral treatment. Estimates of viral dynamic parameters may be used to determine the lifetime of HCV/HBV virions and of infected cells, to estimate how long patients need to be treated and to evaluate antiviral therapies. The implementation of viral dynamics studies is difficult because they involve an intensive blood-sampling schedule and subsequent viral load quantification. In the majority of these studies, a model proposed by Neumann et al. (Science 1998; 282:103-107) is used under various assumptions, such as ignoring the delay in initial viral load decay, assuming time-constant treatment efficacy in reducing virion production and/or complete blocking of new infections, etc. However, only recently the effect of some of these assumptions on the estimated parameters has been evaluated. In this paper we provide a detailed review of the model, its underlying assumptions as well as the assumptions usually made by researchers during the design and analysis of viral dynamics studies. Then, we investigate the effect of these assumptions on the estimated parameters using simulations and draw useful conclusions concerning the analysis of these studies. Real data examples from a clinical trial on hepatitis B are provided as illustrations.
Collapse
Affiliation(s)
- Vana Sypsa
- Department of Hygiene and Epidemiology, Athens University Medical School, M. Asias 75, Athens 11527, Greece.
| | | |
Collapse
|
|
25
|
Starkey JL, Chiari EF, Isom HC. Hepatitis B virus (HBV)-specific short hairpin RNA is capable of reducing the formation of HBV covalently closed circular (CCC) DNA but has no effect on established CCC DNA in vitro. J Gen Virol 2009; 90:115-26. [PMID: 19088280 DOI: 10.1099/vir.0.004408-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) covalently closed circular (CCC) DNA is the source of HBV transcripts and persistence in chronically infected patients. The novel aspect of this study was to determine the effect of RNA interference (RNAi) on HBV CCC DNA when administered prior to establishment of HBV replication or during chronic HBV infection. HBV replication was initiated in HepG2 cells by transduction with HBV baculovirus. Subculture of HBV-expressing HepG2 cells at 10 days post-transduction generates a system in which HBV replication is ongoing and HBV is expressed largely from CCC DNA, thus simulating chronic HBV infection. HepG2 cells were transduced with short hairpin RNA (shRNA)-expressing baculovirus prior to initiation of HBV replication or during chronic HBV replication, and the levels of HBV RNA, HBV surface antigens (HBsAg) and replicative intermediates (RI), extracellular (EC) and CCC DNA species were measured. HBsAg, HBV RNA and DNA levels were markedly reduced until day 8 whether cells were transduced with shRNA prior to or during a chronic infection; however, the CCC DNA species were only affected when shRNA was administered prior to initiation of infection. We conclude that RNAi may have a therapeutic value for controlling HBV replication at the level of RI and EC DNA and for reducing establishment of CCC DNA during HBV infection. Our data support previous findings demonstrating the stability of HBV CCC DNA following antiviral therapy. This study also reports the development of a novel HBV baculovirus subculture system that can be used to evaluate antiviral effects on chronic HBV replication.
Collapse
Affiliation(s)
- Jason L Starkey
- Department of Microbiology and Immunology, Milton S. Hershey Medical Center, The Penn State University College of Medicine, Hershey, PA 17033, USA
| | | | | |
Collapse
|
|
26
|
Dahari H, Shudo E, Ribeiro RM, Perelson AS. Modeling complex decay profiles of hepatitis B virus during antiviral therapy. Hepatology 2009; 49:32-8. [PMID: 19065674 PMCID: PMC3712859 DOI: 10.1002/hep.22586] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED Typically, hepatitis B virus (HBV) decays in patients under therapy in a biphasic manner. However, more complex decay profiles of HBV DNA (e.g., flat partial response, triphasic, and stepwise), for which we have no clear understanding, have also been observed in some treated patients. We recently introduced the notion of a critical drug efficacy, epsilon(c), such that if overall drug efficacy, epsilon(tot), is higher than the critical drug efficacy (i.e., epsilon(tot) > epsilon(c)) then viral levels will continually decline on therapy, while if epsilon(tot) < epsilon(c), then viral loads will initially decline but will ultimately stabilize at a new set point, as seen in flat partial responders. Using the idea of critical efficacy and including hepatocyte proliferation in a viral kinetic model, we can account for these complex HBV DNA decay profiles. The model predicts that complex profiles such as those exhibiting a plateau or shoulder phase, as well as a class of stepwise declines, occur only in patients in whom the majority of hepatocytes are infected before therapy. CONCLUSION We show via kinetic modeling how a variety of HBV DNA decay profiles can arise in treated patients.
Collapse
Affiliation(s)
- Harel Dahari
- Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612
| | - Emi Shudo
- Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, New Mexico 87545
| | - Ruy M. Ribeiro
- Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, New Mexico 87545
| | - Alan S. Perelson
- Theoretical Biology and Biophysics, MS-K710, Los Alamos National Laboratory, New Mexico 87545,Corresponding author: Address: Theoretical Biology and Biophysics, MS-K710, T-10, Los Alamos National Laboratory, New Mexico 87545. Tel: (505)- 667-6829; Fax: (505) – 665-3493;
| |
Collapse
|
|
27
|
Leung N, Peng CY, Hann HW, Sollano J, Lao-Tan J, Hsu CW, Lesmana L, Yuen MF, Jeffers L, Sherman M, Min A, Mencarini K, Diva U, Cross A, Wilber R, Lopez-Talavera J. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir. Hepatology 2009; 49:72-79. [PMID: 19065670 DOI: 10.1002/hep.22658] [Citation(s) in RCA: 136] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
UNLABELLED This study was undertaken to compare the early antiviral activity and viral kinetic profiles of entecavir (ETV) versus adefovir (ADV) in hepatitis B e antigen positive nucleoside-naïve adults with chronic hepatitis B (CHB). Sixty-nine nucleoside-naïve CHB patients with baseline HBV DNA of 10(8) copies/mL or more were randomized 1:1 to open-label treatment with entecavir 0.5 mg/day or adefovir 10 mg/day for a minimum of 52 weeks. The primary efficacy analysis compared mean reduction in HBV DNA at week 12 adjusted for baseline levels using linear regression. Entecavir was superior to adefovir for mean change from baseline in HBV DNA at week 12 (-6.23 log(10) copies/mL versus -4.42 log(10) copies/mL, respectively; mean difference -1.58 log(10) copies/mL; P < 0.0001). Both drugs demonstrated biphasic viral kinetics, with a first phase of rapid decline lasting 10 days. A significant difference favoring ETV was reached at day 10 (day 10 ETV-ADV difference estimate: -0.66 log(10) copies/mL; 95% CI [-0.30, -0.01]). Early virological response was found to be predictive of subsequent virological response, with those having lower HBV DNA levels at day 10 being more likely to achieve HBV DNA of less than 300 copies/mL at week 48. In addition, there was considerably less variability in the extent of HBV DNA reductions in patients treated with entecavir versus adefovir. Both the mean decrease in serum HBV DNA and the proportion of patients achieving HBV DNA less than 300 copies/mL were greater in entecavir-treated than adefovir-treated patients at weeks 2, 4, 8, 12, 24, and 48. At week 48, one (3%) ETV-treated versus 15 (47%) ADV-treated patients had HBV DNA of 10(5) copies/mL or more. Both antivirals were well tolerated. CONCLUSION Entecavir therapy resulted in earlier and superior reduction in HBV DNA compared with adefovir in nucleoside-naïve HBeAg-positive patients with CHB.
Collapse
Affiliation(s)
- Nancy Leung
- Alice Ho Miu Ling Nethersole Hospital, Taipo, Hong Kong SAR, China.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Mihm U, Chan HLY, Zeuzem S, Chim AML, Hui AY, Wong VWS, Sung JJY, Herrmann E. Virodynamic Predictors of Response to Pegylated Interferon and Lamivudine Combination Treatment of Hepatitis B e Antigen-Positive Chronic Hepatitis B. Antivir Ther 2008. [DOI: 10.1177/135965350801300812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background Early identification of non-responders to interferon-α and development of stopping rules are needed in patients with chronic hepatitis B to reduce treatment-related costs and morbidity. Methods In total, 47 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B received pegylated interferon-α2b for 8 weeks, lamivudine plus pegylated interferon-α2b combination therapy for 24 weeks and lamivudine monotherapy for 28 weeks. Sustained virological response was defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA<105 copies/ml at the end of treatment and after 52 weeks of follow-up. The early HBV DNA data from the first 12 weeks of therapy were fitted by a viral kinetic model. Results Cutoff values for prediction of sustained virological response were defined as a rate of infected cell loss δ≥0.005 per day (negative predictive value [NPV] 100% and positive predictive value [PPV] 33.3%) and log values of the area under the mathematically predicted HBV DNA curve between baseline and week 12 of therapy ≤8.9 log10 copies/ml x days (NPV 100% and PPV 50%). By the latter cutoff, 25/36 (69.4%) patients without sustained virological response could be identified after 12 weeks of therapy. Conclusions In the present study, mathematical modelling of viral dynamics allowed prediction of sustained virological response after 12 weeks of therapy. Virodynamic predictors for sustained virological response should be further validated. The area under the mathematically predicted HBV DNA curve seems a promising candidate for potential cutoff values as it summarizes the influence of baseline HBV DNA and treatment effects.
Collapse
Affiliation(s)
- Ulrike Mihm
- Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany
| | - Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Stefan Zeuzem
- Medizinische Klinik I, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany
| | - Angel Mei-Ling Chim
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Alex Yui Hui
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Joseph Jao-Yiu Sung
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China
| | - Eva Herrmann
- Fachbereich Medizin, Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany
| |
Collapse
|
|
29
|
Asselah T, Lada O, Boyer N, Martinot M, Marcellin P. [Treatment of chronic hepatitis B]. ACTA ACUST UNITED AC 2008; 32:749-68. [PMID: 18775613 DOI: 10.1016/j.gcb.2008.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SUMMARY In recent years, marked progress has been made in the treatment of chronic hepatitis B. Several agents have been approved: interferon alpha-(IFN), pegylated interferon alpha2a (PEG-IFN alpha2a), lamivudine, adefovir, entecavir, telbivudine and recently, tenofovir. Each drug has advantages and limitations. IFN and PEG-IFN alpha2a have the advantage of inducing a sustained virologic response after a defined, limited course of treatment. However, these drugs are only effective in a minority of patients and have frequent side effects. Analogues have the advantage of being administered orally, with good safety profiles and a potent antiviral effect. However, these drugs need to be administered indefinitely since withdrawal of therapy is generally associated with reactivation, and a sustained response is uncommon except in HBeAg positive patients who develop HBe seroconversion. In case of HBe seroconversion, therapy should usually be continued for at least another 24 weeks. The efficacy of lamivudine is limited by the emergence of lamivudine-resistant HBV. Adefovir is associated with a moderate incidence of resistance but its antiviral effect is not optimal. Entecavir has shown to be more effective with a favourable safety profile and a low incidence of resistance. Telbivudine is more potent and has a lower rate of resistance than lamivudine but the resistance rate is significantly higher than other approved drugs. Tenofovir has a potent antiviral effect with a good resistance profile. The future of chronic hepatitis B therapy appears to be different drug combinations. Normally the advantage of drug combinations versus monotherapy should be additive or synergistic antiviral effects and a decrease in viral resistance. Unfortunately, there are few data available and none of the evaluated analogue combinations have been shown to be better than monotherapy. The only combination which has shown a synergistic effect is of pegylated interferon alpha2a with lamivudine. Therefore, combinations of pegylated interferon with the most potent analogues need to be evaluated. The ultimate goal of therapy is HBsAg seroconversion which is more often observed with interferon. Indeed, quantification of serum HBsAg will be a useful tool to predict the treatment outcome. More potent drugs and new combinations as well as understanding the mechanisms of viral resistance should be evaluated to improve the efficacy of treatment.
Collapse
Affiliation(s)
- T Asselah
- Pôle des Maladies de l'Appareil Digestif, Service d'Hépatologie, Inserm U773 CRB3, Université Denis-Diderot-Paris-VII, Hôpital Beaujon, Clichy, France.
| | | | | | | | | |
Collapse
|
|
30
|
Kumar M, Sarin SK. Pharmacology, clinical efficacy and safety of lamivudine in hepatitis B virus infection. Expert Rev Gastroenterol Hepatol 2008; 2:465-95. [PMID: 19072396 DOI: 10.1586/17474124.2.4.465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Lamivudine was the first nucleoside analog for the treatment of chronic hepatitis B (CHB). It is well-tolerated and induces a decrease in serum HBV DNA levels associated with normalization of serum alanine aminotransferase levels. However, a sustained response with hepatitis B 'e' antigen to anti-hepatitis B e seroconversion is obtained in a smaller proportion of patients and hepatitis B surface antigen loss is exceptional. The response is maintained during therapy, and needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reappearance of the virus. However, mutations can be induced in long-term treatment.
Collapse
Affiliation(s)
- Manoj Kumar
- Department of Gastroenterology, Academic Block, GB Pant Hospital, New Delhi-110002, India.
| | | |
Collapse
|
|
31
|
Kumar M, Sarin SK. Systematic review: combination therapies for treatment-naïve chronic hepatitis B. Aliment Pharmacol Ther 2008; 27:1187-209. [PMID: 18373730 DOI: 10.1111/j.1365-2036.2008.03695.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND There is a renewed interest in use of combination therapies in treatment-naïve chronic hepatitis B (CHB) because of limitations of monotherapies. AIM To discuss the current status of combination therapies in treatment-naïve CHB. METHODS PubMed search was done using 'combination', 'sequential' and 'chronic hepatitis B' as the search terms. RESULTS The two most popular combination therapies include 'combination of nucleos(t)ide analogues' and 'combination of interferons and nucleos(t)ide analogues'. Combination therapies using two nucleos(t)ide analogues do not lead to higher long-term efficacy. However, addition of a nucleos(t)ide analogue with a good resistance profile to a nucleos(t)ide analogue with a lower genetic barrier to resistance decreases the risk of emergent resistance to the latter. Greater sustained virological, biochemical and seroconversion rates are observed with addition of lamivudine to conventional interferon, but pegylated-interferon monotherapy is equally effective as combination with lamivudine. Again, resistance to lamivudine is lower with its combination with interferons. CONCLUSIONS The answer to the question whether hepatitis B can be treated better with combination or monotherapy remains largely unknown. Additional trials are warranted of combination therapies of peginterferon and potent nucleos(t)ide analogues or therapies with the combined use of nucleos(t)ide analogues or immunomodulators.
Collapse
Affiliation(s)
- M Kumar
- Department of Gastroenterology, G.B. Pant Hospital, Affiliated to the University of Delhi, New Delhi, India
| | | |
Collapse
|
|
32
|
Hui CK, Zhang HY, Bowden S, Locarnini S, Luk JM, Leung KW, Yueng YH, Wong A, Rousseau F, Yuen KY, Naoumov NN, Lau GKK. 96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B. J Hepatol 2008; 48:714-20. [PMID: 18207280 DOI: 10.1016/j.jhep.2007.10.013] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Revised: 10/08/2007] [Accepted: 10/11/2007] [Indexed: 12/12/2022]
Abstract
BACKGROUND/AIMS In order to prevent the occurrence of drug-resistant mutants associated with treatment for chronic hepatitis B virus (HBV) infection, combination therapy is being developed. To determine the efficacy of adefovir dipivoxil (ADV) plus emtricitabine (FTC) combination therapy in chronic HBV infection. METHODS Thirty treatment-nai ve, HBeAg-positive patients were randomized to combination ADV plus FTC (n=14) or ADV plus placebo monotherapy (n=16) for 96 weeks. HBV DNA was measured by polymerase chain reaction. Treatment was stopped in those with HBeAg seroconversion. RESULTS The median decrease in HBV DNA at week 96 was higher in the combination group (-5.30 vs. -3.98 log(10)copies/ml, p=0.05). More patients in the combination group had normalization of alanine aminotransaminase and HBV DNA<300 copies/ml at week 96 when compared with the monotherapy group [11 of the 14 patients (78.6%) vs. 6 of the 16 patients (37.5%), p=0.03]. However, HBeAg seroconversion at week 96 was similar in the 2 groups [2/14 (14.3%) vs. 4/16 (25.0%), p=NS]. No ADV or FTC resistance was detected at week 96. In those with HBeAg seroconversion, 50.0% had post-treatment relapse. CONCLUSIONS Combination ADV plus FTC resulted in more potent suppression of HBV DNA over 96 weeks of therapy.
Collapse
Affiliation(s)
- Chee-Kin Hui
- Department of Microbiology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Abstract
Chronic hepatitis C is a major contributor to cirrhosis and hepatocellular cancer worldwide, justifying the considerable research effort aimed at understanding the disease and refining its treatment. As a result, significant therapeutic advances have been made in the last decade, particularly with regard to the development of pegylated interferons and ribavirin. This review will discuss the physical properties, pharmacokinetics, viral kinetics and side-effect profiles of the different treatment options and how they have improved, culminating in the use of pegylated interferon and ribavirin combination therapy as the current standard of care.
Collapse
Affiliation(s)
- Graham Foster
- Queen Mary Hospital, University of London, London, UK
| | | |
Collapse
|
|
34
|
Pegylated Interferons: Clinical Applications in the Management of Hepatitis C Infection. HEPATITIS C VIRUS DISEASE 2008. [PMCID: PMC7122148 DOI: 10.1007/978-0-387-71376-2_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
|
|
35
|
Rudin D, Shah SM, Kiss A, Wetz RV, Sottile VM. Interferon and lamivudine vs. interferon for hepatitis B e antigen-positive hepatitis B treatment: meta-analysis of randomized controlled trials. Liver Int 2007; 27:1185-93. [PMID: 17919229 PMCID: PMC2156150 DOI: 10.1111/j.1478-3231.2007.01580.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
AIMS To compare interferon monotherapy with its combination with lamivudine for hepatitis B e antigen (HBeAg)-positive hepatitis B treatment. METHODS Two independent researchers identified pertinent randomized controlled trials. The trials were evaluated for methodological quality and heterogeneity. Rates of sustained virological and biochemical responses, and HBeAg clearance and seroconversion were used as primary efficacy measures. Quantitative meta-analyses were conducted to assess differences between groups for conventional and pegylated interferon, and overall. RESULTS Greater sustained virological, biochemical and seroconversion rates were observed with addition of lamivudine to conventional [odds ratio (OR)=3.1, 95% confidence intervals (CI) (1.7-5.5), P<0.0001, OR=1.8, 95% CI (1.2-2.7), P=0.007 and OR=1.8, 95% CI (1.1-2.8), P=0.01 respectively], although not pegylated [OR=1.1, 95% CI (0.5-2.3), P=0.8, OR=1.0, 95% CI (0.7-1.3), P=0.94, and OR=0.9, 95% CI (0.6-1.2), P=0.34 respectively] interferon-alpha, with no significant affect on HBeAg clearance rates [OR=1.6, 95% CI (0.9-2.7), P=0.09, and OR=0.8, 95% CI (0.6-1.1), P=0.26 respectively]. Excluding virological response (P<0.001), pegylated interferon monotherapy and conventional interferon and lamivudine combination therapy were similarly efficacious (P>0.05), with the former studied in harder to treat patients, as evidenced by the superior virological response observed with conventional as compared with pegylated interferon monotherapy (P<0.0001). CONCLUSION In comparable populations, pegylated interferon monotherapy is likely to be equally or more efficacious than conventional interferon and lamivudine combination therapy, thus constituting the treatment of choice, with no added benefit with lamivudine addition. However, when conventional interferon is used, its combination with lamivudine should be considered.
Collapse
Affiliation(s)
- Dan Rudin
- Department of Internal Medicine, Staten Island University Hospital, Staten Island, NY 10305, USA.
| | - Sooraj M Shah
- Department of Internal Medicine, Staten Island University HospitalStaten Island, NY, USA
| | - Alexander Kiss
- Department of Research Design and Biostatistics, Sunnybrook Health Sciences CenterToronto, ON, Canada,Institute for Clinical Evaluative SciencesToronto, ON, Canada
| | - Robert V Wetz
- Department of Internal Medicine, Staten Island University HospitalStaten Island, NY, USA
| | - Vincent M Sottile
- Department of Gastroenterology, Staten Island University HospitalStaten Island, NY, USA
| |
Collapse
|
|
36
|
Lau GKK, Cooksley H, Ribeiro RM, Powers KA, Shudo E, Bowden S, Hui CK, Anderson J, Sorbel J, Mondou E, Rousseau F, Lewin S, Perelson AS, Locarnini S, Naoumov NV. Impact of Early Viral Kinetics on T-Cell Reactivity during Antiviral Therapy in Chronic Hepatitis B. Antivir Ther 2007. [DOI: 10.1177/135965350701200513] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Background The patterns of hepatitis B viral dynamics during different antiviral therapies and the associated changes in HBV-specific T-cell reactivity are not well defined. Methods We investigated the impact of early viral load decline on virus-specific T-cell reactivity in 30 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B randomized to monotherapy with adefovir dipivoxil (ADV) or in combination with emtricitabine (ADV/FTC). Viral kinetics were analysed by mathematical modelling. T-cell reactivity to HBV core and/or surface antigens and natural killer T cell frequency were tested longitudinally, baseline to week 48, using EliSPOT assays and/or flow cytometry. Results Mathematical modelling of early HBV kinetics identified two subsets of patients: 11 fast responders (undetectable viraemia by week 12; eight on ADV/FTC three on ADV) and 19 slow responders who remained viremic (six on ADV/FTC 13 on ADV). The rate of infected hepatocyte loss was higher in fast than in slow responders ( P=0.0007), and correlated inversely with pre-treatment levels of intrahepatic covalently closed circular HBV DNA. The frequency of HBV core-specific CD4+ T-cells increased significantly only in fast responders, peaking between week 16 and 24, while the HBV surface-specific CD4+ T-cells increased in both subsets. These changes in CD4+ T-cell reactivity were transient however, and no increase in HBV-specific CD8+ T-cells was observed. By week 48, HBeAg seroconversion occurred only in 3/30 (10%) patients. Conclusions Early viraemia clearance facilitates recovery of virus-specific CD4+ T-cell reactivity, but appears insufficient to establish clinically relevant antiviral immunity.
Collapse
Affiliation(s)
- George KK Lau
- Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China
| | - Helen Cooksley
- Institute of Hepatology, University College London, London, WC1E, UK
| | | | - Kimberly A Powers
- Los Alamos National Laboratory, Los Alamos, USA
- Department of Biostatistics, University of North Carolina, Chapel Hill, Chapel Hill NC, USA
| | - Emi Shudo
- Los Alamos National Laboratory, Los Alamos, USA
| | - Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Victoria, Australia
| | - Chee-Kin Hui
- Department of Medicine, Queen Mary Hospital, Hong Kong SAR, China
| | - Jane Anderson
- Triangle Pharmaceuticals, Inc/Gilead Sciences Inc, Durham, NC, USA
| | - Jeff Sorbel
- Triangle Pharmaceuticals, Inc/Gilead Sciences Inc, Durham, NC, USA
| | - Elsa Mondou
- Victorian Infectious Diseases Reference Laboratory, Victoria, Australia
| | - Franck Rousseau
- Triangle Pharmaceuticals, Inc/Gilead Sciences Inc, Durham, NC, USA
| | - Sharon Lewin
- Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia
| | | | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory, Victoria, Australia
| | - Nikolai V Naoumov
- Institute of Hepatology, University College London, London, WC1E, UK
| |
Collapse
|
|
37
|
Rizzetto M, Zoulim F. Viral Hepatitis. TEXTBOOK OF HEPATOLOGY 2007:819-956. [DOI: 10.1002/9780470691861.ch9a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
38
|
Ciupe SM, Ribeiro RM, Nelson PW, Perelson AS. Modeling the mechanisms of acute hepatitis B virus infection. J Theor Biol 2007; 247:23-35. [PMID: 17428501 PMCID: PMC1994818 DOI: 10.1016/j.jtbi.2007.02.017] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2006] [Revised: 02/27/2007] [Accepted: 02/28/2007] [Indexed: 12/18/2022]
Abstract
Mathematical models have been used to understand the factors that govern infectious disease progression in viral infections. Here we focus on hepatitis B virus (HBV) dynamics during the acute stages of the infection and analyze the immune mechanisms responsible for viral clearance. We start by presenting the basic model used to interpret HBV therapy studies conducted in chronically infected patients. We then introduce additional models to study acute infection where immune responses presumably play an important role in determining whether the infection will be cleared or become chronic. We add complexity incrementally and explain each step of the modeling process. Finally, we validate the model against experimental data to determine how well it represents the biological system and, consequently, how useful are its predictions. In particular, we find that a cell-mediated immune response plays an important role in controlling the virus after the peak in viral load.
Collapse
Affiliation(s)
| | - Ruy M. Ribeiro
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545
| | - Patrick W. Nelson
- Dept. of Mathematics, University of Michigan, 5860 E. Hall, Ann Arbor, MI 48109
| | - Alan S. Perelson
- Santa Fe Institute, 1399 Hyde Park Rd., Santa Fe, NM, 87507
- Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545
- Correspondence: Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM 87545, , Phone: 505-667-6829, Fax: 505-665-3493
| |
Collapse
|
|
39
|
Panos GZ, Lampropoulos KM, Angelousi AG, Charatsis GG, Falagas ME. Lamivudine and famciclovir treatment in HIV patients with acute hepatitis B virus infection and hepatitis B reactivation. J Clin Gastroenterol 2007; 41:222-3. [PMID: 17245225 DOI: 10.1097/01.mcg.0000212614.89584.32] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
|
|
40
|
Thomas T, Foster G. Nanomedicines in the treatment of chronic hepatitis C--focus on pegylated interferon alpha-2a. Int J Nanomedicine 2007; 2:19-24. [PMID: 17722508 PMCID: PMC2673816 DOI: 10.2147/nano.2007.2.1.19] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Nanotechnology is the application of nanotechnology within medicine. An illustration of this is the use of pegylation as a means of modifying naturally occurring proteins which may have clinical applications, in order to improve the pharmacodynamics of the protein resulting in an effective medication. An example of this is pegylated interferon. The purpose of this review is to examine the chemistry, clinical pharmacology, pharmacokinetics, pharmacodynamics, and clinical studies with 40 kDa pegylated interferon to illustrate the general principles of pegylated biological proteins. The use in clinical practice is reviewed along with the evidence for both efficiacy, safety, and advantages over standard interferon.
Collapse
Affiliation(s)
- Thea Thomas
- Specialist Registrar in Gastroenterology, University College London Hospital NHS Trust, London
| | - Graham Foster
- Queen Marys School of Medicine, Barts and The London NHS Trust, London
| |
Collapse
|
|
41
|
Hollinger FB, Lau DTY. Hepatitis B: the pathway to recovery through treatment. Gastroenterol Clin North Am 2006; 35:895-931. [PMID: 17129820 DOI: 10.1016/j.gtc.2006.10.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Affiliation(s)
- F Blaine Hollinger
- Department of Medicine, Eugene B. Casey Hepatitis Research Center and Diagnostic Laboratory, Baylor College of Medicine, One Baylor Plaza, BCM-385, Houston, TX 77030-3498, USA.
| | | |
Collapse
|
|
42
|
ter Borg MJ, van Zonneveld M, Zeuzem S, Senturk H, Akarca US, Simon C, Hansen BE, Haagmans BL, de Man RA, Schalm SW, Janssen HLA. Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. Hepatology 2006; 44:721-7. [PMID: 16941701 DOI: 10.1002/hep.21302] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
In chronic hepatitis B, it is difficult to predict an early therapeutic response. We investigated the viral decline during therapy with pegylated interferon alpha-2b (PEG-IFN) with or without lamivudine in 266 HBeAg-positive chronic hepatitis B patients. In patients treated with PEG-IFN and lamivudine, a uniform biphasic viral decline pattern was found during therapy and there were no marked differences in viral load between those who lost HBeAg at the end of follow-up (response) or not. In contrast, those treated with PEG-IFN monotherapy exhibited different viral decline patterns. A delayed decline of at least two log from baseline HBV DNA after week 4 but before week 32 was associated with the highest response rate (63%). In comparison, response was 52% for patients with an early decline (week 0-4), 38% for a late decline (week 32-52), 27% for a posttreatment decline (week 52-78) and 11% for patients with no substantial decline. The HBsAg loss was 22% in the delayed decline pattern compared to 4% for those with early decline and none for other decline patterns. In conclusion, different patterns of decline in viral load during treatment with PEG-IFN monotherapy were associated with different rates of HBeAg and HBsAg loss at the end of follow-up. Since there was a considerable response, even in patients with a late or posttreatment decline pattern, prediction of response based on viral decline during the first months of therapy was difficult.
Collapse
Affiliation(s)
- Martijn J ter Borg
- Department of Gastroenterology and Hepatology, Erasmus Medical Center Rotterdam, The Netherlands
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Abstract
Hepatitis B is a major public health problem in the world today. Since 1985, the number of reported cases has declined as a direct result of universal immunization of neonates, vaccination of at-risk populations, lifestyle or behavioral changes in high-risk groups, refinements in the screening of blood donors, and the use of virally inactivated or genetically engineered products in patients with bleeding disorders. New and potent antiviral agents being developed and evaluated provide hope and optimism for those who are chronically infected with hepatitis B virus. Prevention remains the most effective strategy in the global management of hepatitis B virus. Universal immunization programs prevent hepatitis B virus transmission and circumvent acute and chronic infection.
Collapse
Affiliation(s)
- F Blaine Hollinger
- Department of Medicine, Eugene B. Casey Hepatitis Research Center and Diagnostic Laboratory, Baylor College of Medicine, One Baylor Plaza, BCM-385, Houston, TX 77030-3498, USA.
| | | |
Collapse
|
|
44
|
Xiao X, Shao SH, Chou KC. A probability cellular automaton model for hepatitis B viral infections. Biochem Biophys Res Commun 2006; 342:605-10. [PMID: 16487938 DOI: 10.1016/j.bbrc.2006.01.166] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2006] [Accepted: 01/31/2006] [Indexed: 01/12/2023]
Abstract
The existing models of hepatitis B virus (HBV) infection dynamics are based on the assumption that the populations of viruses and cells are uniformly mixed. However, the real virus infection system is actually not homogeneous and some spatial factors might play a nontrivial role in governing the development of HBV infection and its outcome. For instance, the localized populations of dead cells might adversely affect the spread of infection. To consider this kind of inhomogeneous feature, a simple 2D (dimensional) probability Cellular Automaton model was introduced to study the dynamic process of HBV infection. The model took into account the existence of different types of HBV infectious and non-infectious particles. The simulation results thus obtained showed that the Cellular Automaton model could successfully account for some important features of the disease, such as its wide variety in manifestation and its age dependency. Meanwhile, the effects of the model's parameters on the dynamical process of the infection were also investigated. It is anticipated that the Cellular Automaton model may be extended to serve as a useful vehicle for studying, among many other complicated dynamic biological systems, various persistent infections with replicating parasites.
Collapse
Affiliation(s)
- Xuan Xiao
- Institute of Information, Donghua University, Shanghai 200051, China.
| | | | | |
Collapse
|
|
45
|
Abstract
Coinfection of hepatitis C virus (HCV), hepatitis B virus (HBV), and HIV is common due to shared modes of transmission. These coinfections accelerate the course of chronic liver disease and facilitate progression to cirrhosis and hepatocellular carcinoma. The viral interactions between these viruses are complex, and their treatment may be challenging for clinicians.
Collapse
Affiliation(s)
- James S Park
- Division of Liver Diseases, Department of Medicine, Mount Sinai Medical Center, 5 East 98th Street, 11th Floor, New York, NY 10029, USA
| | | | | |
Collapse
|
|
46
|
Mihm U, Gärtner BC, Faust D, Hofmann WP, Sarrazin C, Zeuzem S, Herrmann E. Viral kinetics in patients with lamivudine-resistant hepatitis B during adefovir-lamivudine combination therapy. J Hepatol 2005; 43:217-24. [PMID: 15964093 DOI: 10.1016/j.jhep.2005.02.037] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2004] [Revised: 01/28/2005] [Accepted: 02/09/2005] [Indexed: 12/29/2022]
Abstract
BACKGROUND/AIMS Mathematical analysis of viral kinetics during lamivudine-adefovir combination therapy has not yet been performed in patients with lamivudine-resistant hepatitis B. METHODS In 8 patients with lamivudine-resistant hepatitis B, adefovir dipivoxil (10 mg/day) was added to ongoing lamivudine. Viral decay during the first 8 weeks of combination therapy was described by a biphasic model to determine the efficacy: epsilon, of blocking viral production, the clearance: c, of free virus, and the loss of infected cells: delta. RESULTS Median epsilon was 98%, median c was 0.7/day, and median delta was 0.07/day. No significant association was found between viral kinetic and baseline parameters and virologic and biochemical treatment response. When compared with viral kinetic constants reported for higher dose adefovir dipivoxil monotherapy, epsilon was lower (P=0.026) and delta was higher (P=0.008) in this study whereas c did not differ between both studies. CONCLUSIONS Although a recent study did not show any differences in the reduction of HBV DNA comparing monotherapy with adefovir dipivoxil to adefovir-lamivudine combination therapy in patients with lamivudine-resistant chronic hepatitis B, mathematical analysis of early viral kinetics suggests an additional effect of lamivudine on the infected cell loss during adefovir-lamivudine combination therapy.
Collapse
Affiliation(s)
- Ulrike Mihm
- Klinik für Innere Medizin II, Universitätsklinikum des Saarlandes, Kirrberger Str., 66421 Homburg/Saar, Germany
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Affiliation(s)
- Avidan U Neumann
- Faculty of Life Sciences, University of Bar-Ilan, Ramat-Gan 52900, Israel.
| |
Collapse
|
|
48
|
Sypsa VA, Mimidis K, Tassopoulos NC, Chrysagis D, Vassiliadis T, Moulakakis A, Raptopoulou M, Haida C, Hatzakis A. A viral kinetic study using pegylated interferon alfa-2b and/or lamivudine in patients with chronic hepatitis B/HBeAg negative. Hepatology 2005; 42:77-85. [PMID: 15962284 DOI: 10.1002/hep.20738] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
We studied viral dynamic parameters in 44 chronic hepatitis B/hepatitis B e antigen (HBeAg)(-) patients treated with pegylated interferon alfa-2b (PEG-IFN) 100 or 200 microg weekly or lamivudine 100 mg daily or the combination of PEG-IFN 100 or 200 microg with lamivudine. Patients receiving PEG-IFN monotherapy exhibited viral load oscillations between weekly injections, which were resolved by the addition of lamivudine. The median pharmacological delay was estimated at 4.1, 5.8, and 1.8 hours in PEG-IFN monotherapy, PEG-IFN 100/200 microg + lamivudine, and lamivudine monotherapy, respectively (P = .44). The median half-life of free virus was 12.7 hours (range, 2.4-69.2 hours). The mean antiviral effectiveness of PEG-IFN 100/200 microg monotherapy was lower than that of lamivudine (82.6% vs. 96.4%; P = .005). The mean effectiveness of PEG-IFN 100 microg + lamivudine and PEG-IFN 200 microg + lamivudine was 92.8% and 94.4%, respectively. The half-life of infected cells ranged from 2.7 to 75 days. The median half-life of infected cells in patients receiving the combination regimens of PEG-IFN and lamivudine was similar to that of lamivudine patients (5.0 days vs. 6.0 days, P = .77). In conclusion, the addition of pegylated interferon alfa-2b in lamivudine treatment was found to neither enhance the potency of blocking HBV production nor the decay rates of infected cells. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
Collapse
|
|
49
|
Konnick EQ, Erali M, Ashwood ER, Hillyard DR. Evaluation of the COBAS amplicor HBV monitor assay and comparison with the ultrasensitive HBV hybrid capture 2 assay for quantification of hepatitis B virus DNA. J Clin Microbiol 2005; 43:596-603. [PMID: 15695651 PMCID: PMC548123 DOI: 10.1128/jcm.43.2.596-603.2005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Performance characteristics of the COBAS Amplicor HBV Monitor test (Roche Diagnostics), which measures hepatitis B virus (HBV) DNA quantitatively, were evaluated and compared with the Ultrasensitive HBV Hybrid Capture 2 (HC2; Digene Corporation) assay. Linearity and within-run precision were assessed for both methods by using eight HBV DNA-positive samples serially diluted to obtain a range of <100 to 500,000 HBV DNA copies/ml and run in triplicate. Agreement between the methods was studied with 100 clinical samples. HC2 assay performance near the limit of detection was investigated through repeat testing of 149 samples with HC2 and testing of 37 samples with HC2 results of <4,700 HBV DNA copies/ml by Amplicor assay and a qualitative PCR assay. The linearity experiment for Amplicor had regression of observed values compared to expected values (y = 1.073x - 0.247; R(2) = 0.993, n = 32; for HC2, y = 0.855x + 0.759, R(2) = 0.729, n = 18). Within-run standard deviation of log HBV DNA copies/ml ranged from 0.003 to 0.348 (Amplicor) and 0.027 to 0.253 (HC2). Agreement assessed by Deming regression was poor [Amplicor = 1.197(HC2) - 0.961; R(2) = 0.799, standard error of the estimate (SEE) = 0.710, n = 94]. Near the lower limit of detection, 32 of 149 repeat HC2 results were <4,700 HBV DNA copies/ml. Of the 37 samples with HC2 results of <4,700 HBV DNA copies/ml, HBV DNA was not detected in 15 samples, while HBV DNA was detected by at least one PCR method in 12 samples. Amplicor is linear from 200 to 200,000 HBV DNA copies/ml with undiluted samples, and this range can be expanded through dilution. Inconsistent HC2 results near the limit of detection justify use of a grey zone.
Collapse
Affiliation(s)
- Eric Q Konnick
- ARUP Institute for Clinical and Experimental Pathology, 500 Chipeta Way, Salt Lake City, UT 84108, USA.
| | | | | | | |
Collapse
|
|
50
|
Lacombe K, Gozlan J, Boelle PY, Serfaty L, Zoulim F, Valleron AJ, Girard PM. Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate. AIDS 2005; 19:907-15. [PMID: 15905671 DOI: 10.1097/01.aids.0000171404.07995.5c] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND The long-term impact of tenofovir disoproxil fumarate (TDF) on hepatitis B virus (HBV) replication has not yet been studied in HIV-HBV-co-infected patients. METHODS We conducted a prospective study of HBV-DNA decay kinetics in 28 HIV-HBV-co-infected patients treated by TDF. HBV dynamics were studied using mixed linear models, and baseline factors affecting them were analysed using Cox models. RESULTS The HBV-DNA load declined by a mean of 4.6 log copies/ml during follow-up (mean 71 weeks), and fell below the detection limit (200 copies/ml) in 21 patients. Inhibition of viral replication by TDF was associated with a decrease in alanine aminotransferase levels (125 versus 68 IU, P < 0.05). HBV-DNA decay was biphasic, with an rapid fall followed by a gradual decline. Baseline factors associated with a steeper first slope in the HBV-DNA decrease were high HBV load, positive hepatitis B e antigen (HBeAg) and YMDD mutations. Baseline factors increasing the time to reach an HBV-DNA level less than 200 copies/ml were high HBV load (150 days when HBV-DNA < 10 log, 316 days when HBV-DNA > 10 log) and positive HBeAg. Previous exposure to lamivudine or TDF-lamivudine did not modify HBV-DNA decrease under therapy in this population with a high prevalence of YMDD mutations. CONCLUSION The long-term decline in HBV DNA under TDF is biphasic and is primarily influenced by the initial HBV load. However, the clinical significance of such an association remains moderate, and TDF can be efficiently included in the highly active antiretroviral therapy regimen of HIV-HBV-co-infected patients, regardless of HBV strains and their degree of replication.
Collapse
Affiliation(s)
- Karine Lacombe
- Inserm U707, Université Pierre et Marie Curie, 27 rue de Chaligny, 75571 Paris cedex 12, France.
| | | | | | | | | | | | | |
Collapse
|