ORCID Profile
0000-0001-9314-2283
Current Organisation
UNSW Sydney
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Biological Mathematics | Applied Mathematics | Infectious Diseases | Dynamical Systems in Applications | Operations Research | Numerical and Computational Mathematics not elsewhere classified
Infectious Diseases | Preventive Medicine | Infectious diseases | Expanding Knowledge in the Mathematical Sciences | Expanding Knowledge in the Medical and Health Sciences | Mathematical sciences |
Publisher: Proceedings of the National Academy of Sciences
Date: 23-11-2005
Abstract: Mathematical modeling was performed to test the extent to which cytopathic and noncytopathic T cell effector functions contribute to resolution of hepatitis B virus (HBV) infection in three acutely infected chimpanzees. Simulations based exclusively on cytopathic functions show a poor fit to the data and would require the destruction and regeneration of ≈11 livers for clearance to occur. In contrast, a simulation based on a combination of cytopathic and noncytopathic functions provided a significantly better fit to the data ( P 0.001) and required as much as 5-fold less destruction to clear the virus from the liver. The best fit simulation supports the notion that during the early phase of HBV clearance, noncytopathic T cell effector mechanisms inhibit viral replication and greatly shorten the half-life of the long lived covalently closed circular viral DNA transcriptional template, thereby limiting the extent to which cytopathic T cell effector functions and tissue destruction are required to terminate acute HBV infection.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-08-2008
DOI: 10.1002/HEP.22469
Abstract: Analysis of hepatitis B virus (HBV) kinetics with mathematical models may disclose new aspects of HBV infection and host response mechanisms. To determine the kinetics of virion decay from the blood of patients in different phases of chronic infection, we applied mathematical modeling to real-time polymerase chain reaction assays, which enable quantification of viremia and intrahepatic HBV productivity by measuring both copy number and activity of covalently closed circular DNA (relaxed circular DNA/covalently closed circular DNA) in the liver of 80 untreated chronically active HBV carriers (38 hepatitis B e antigen [HBeAg]-positive and 42 HBeAg-negative in iduals). We found that the half-life of circulating virions is very fast (median 46 and 2.5 minutes in HBeAg-positive and HBeAg-negative in iduals, respectively) and strongly related to viremia, with clearance rates significantly accelerating as viral loads decrease. To investigate whether immune components can influence the kinetics of virion decay, we analyzed viral dynamics in immunodeficient urokinase-type plasminogen activator chimera mice. Virion half-life in mice (range, 44 minutes to >4 hours) was comparable to estimates determined in high viremic carriers, implying that clearance rates in these patients are mostly determined by common nonspecific mechanisms. Notably, the lack of correlation between virion half-life and viremia in mice indicated that immune components significantly accelerate virion clearance rates in in iduals with low titers. Our analyses suggest that both host defense mechanisms and levels of circulating virions affect the kinetics of HBV decay assessed in the serum of chronic carriers. Identification of the factors affecting clearance rates will be important for future antiviral drug developments and it may give insights into the mechanisms involved in clearance of other chronic infections, such as human immunodeficiency virus and hepatitis C virus.
Publisher: Mary Ann Liebert Inc
Date: 10-2013
Publisher: Oxford University Press (OUP)
Date: 17-01-2019
DOI: 10.1093/CVR/CVZ010
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.JTBI.2016.03.018
Abstract: Hepatitis-D virus (HDV) is a satellite virus of hepatitis-B virus (HBV) whose intracellular products are required for the completion of the HDV life cycle. HDV can replicate in a cell without the presence of HBV but needs hepatitis B surface antigen (HBsAg) to complete virus assembly and packaging. In order to better understand HDV dynamics, we developed a mathematical model and successfully simulated HBV and HDV data under a range of scenarios. Compared to HBV mono-infection, dual HDV infection resulted in lower chronic HBV DNA levels, with more marked suppression for coinfection (1 logs HBV DNA copies/ml lower) compared to superinfection (0.6 logs HBV DNA copies/ml). Although they have no effect on HBV, prenylation inhibitors may provide the best therapy for reducing HDV viremia irrespective of the stage in which they are commenced. We found that highly effective long term pegylated interferon (IFN) therapy (99.99%) eliminates HBV and HDV viremia while less effective long term IFN therapy (99%) will only produce approximately 2.03 logs and no decrease in HBV and HDV viremia respectively in both coinfection and superinfection settings. Our study also suggests that there is a substantial difference in the outcome of therapies depending upon the time of commencement. Mathematical modeling of HDV infection can describe the complex interplay between this virus and HBV. Simulations suggest that HDV impacts on the feedback mechanisms that maintain cccDNA levels and that targeting these mechanisms may result in new therapeutic agents for both viruses.
Publisher: Wiley
Date: 02-2018
DOI: 10.1002/JGM.3006
Abstract: The gene therapeutic Cal-1 comprises the anti-HIV agents: (i) sh5, a short hairpin RNA to CCR5 that down-regulates CCR5 expression and (ii) maC46 (C46), a peptide that inhibits viral fusion with the cell membrane. These constructs were assessed for inhibition of viral replication and selective cell expansion in a number of settings. HIV replication, selective outgrowth and cell surface viral binding were analysed with a single cycle infection assay of six pseudotyped HIV strains and a static and longitudinal passaging of MOLT4/CCR5 cells with HIV. Pronase digestion of surface virus and fluorescence microscopy assessed interactions between HIV virions and transduced cells. Cal-1 reduced CCR5 expression in peripheral blood mononuclear cells to CCR5Δ32 heterozygote levels. Even low level transduction resulted in significant preferential expansion in MOLT4/CCR5 gene-containing cells over a 3-week HIV challenge regardless of viral suppression [12.5% to 47.0% (C46), 46.7% (sh5), 62.2% (Dual), respectively]. The sh5 and Dual constructs at > 95% transduction also significantly suppressed virus to day 12 in the passage assay and all constructs, at varying percentage transduction inhibited virus in static culture. No escape mutations were present through 9 weeks of challenge. The Dual construct significantly suppressed infection by a panel of CCR5-using viruses, with its efficacy being independently determined from the single constructs. Dual and sh5 inhibited virion internalisation, as determined via pronase digestion of surface bound virus, by 70% compared to 13% for C46. The use of two anti-HIV genes allows optimal preferential survival and inhibition of HIV replication, with the impact on viral load being dependent on the percentage of gene marked cells.
Publisher: Wiley
Date: 12-2003
DOI: 10.1046/J.1440-1711.2003.01191.X
Abstract: Analysing T-cell receptor excision circle numbers in healthy in iduals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for in iduals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older in iduals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for in iduals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.
Publisher: Elsevier BV
Date: 2016
Publisher: Elsevier BV
Date: 09-2007
DOI: 10.1053/J.GASTRO.2007.06.057
Abstract: Knowledge of factors regulating transcriptional activity of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) may help in understanding mechanisms of viral decay and how these processes are thwarted in chronically HBV-infected patients. Liver biopsies from 119 treatment-naive chronically infected patients (42 HBeAg-positive and 77 HBeAg-negative) were determined for HBV transcriptional and replicative activity. Significantly lower median serum HBV DNA (-4 log), intrahepatic HBV DNA (-2 log), and cccDNA (-1 log) amounts were measured in HBeAg-negative versus HBeAg-positive patients. Despite a good correlation found between intrahepatic amounts of progeny virions and serum HBV DNA in all patients, cccDNA levels did not correlate with serum titers in HBeAg-negative in iduals. Analysis of HBV RNA transcripts showed that impaired virion productivity in HBeAg-negative in iduals was due to lower steady-state levels of pregenomic RNA produced per cccDNA. Interestingly, preS/S RNA levels and serum HBsAg concentrations did not differ between HBeAg-positive and HBeAg-negative patients when normalized for cccDNA contents, showing that subviral particle production was not impaired in HBeAg-negative patients and correlated with cccDNA levels. Although the majority of HBeAg-negative in iduals harbored cccDNA with common precore and/or basal core promoter mutations, occurrence of these variants was not responsible for reduced viral replication. Instead, replacement of wild-type cccDNA with core promoter mutants reestablished high virion productivity. Lower viremia in HBeAg-negative in iduals is not only due to lower cccDNA content but also to impaired virion productivity, which can arise without emergence of HBeAg variants and without affecting HBsAg production.
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/SH13197
Abstract: Background Papua New Guinea (PNG) has one of the highest prevalences of HIV and sexually transmissible infections (STIs) in the Asia-Pacific region, and one of the highest burdens of maternal syphilis and cervical cancer globally. Despite this disease burden, only limited clinical research in sexual and reproductive health has been conducted in PNG. Methods: A longitudinal clinical cohort study was conducted at two sexual health clinics. Participants completed a behavioural interview, clinical assessment and genital examination at baseline, and at 12, 24 and 50 weeks, including specimen collection for STI diagnostics. Results: In total, 154 people attended a screening visit. Reattendance at 12, 24 and 50-weeks was 87%, 78% and 80% respectively. At baseline, HIV prevalence was 3.3% chlamydia (Chlamydia trachomatis), 29.2% gonorrhoea (Neisseria gonorrhoeae), 22.1% Trichomonas vaginalis 15.6% herpes simplex type-2 (HSV-2), 46.1% active syphilis, 11.7%. Multiple infections were common particularly among women. The incidence of chlamydia was 27 per 100 person-years (PY) gonorrhoea, 15 out of 100 PY T. vaginalis, 29 out of 100 PY HSV-2, 12 out of 100 PY syphilis, 8 out of 100 PY. No incident HIV cases were recorded. At baseline, 39% of men in Mt Hagen and 65% in Port Moresby had a penile foreskin cut, with a dorsal slit being the most common. Two men underwent penile cutting during the follow-up period. Conclusions: The prevalence and incidence of STIs, HIV and penile cutting were high among sexual health clinic attendees. High retention figures suggest that this population may be suitable for future interventions research and clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 30-10-2009
Publisher: Mary Ann Liebert Inc
Date: 06-2010
Abstract: HIV treatment with CCR5 receptor blockers may impact CCR5(+) cell distribution. T cell subsets, plasmacytoid dendritic cells (PDC), and antigen-specific [Mycobacteria tuberculosis/avium (M.TB/MAI), cytomegalovirus (CMV), Herpes simplex (HSV), HIV-Gag] CD4(+) T cells were measured in untreated R5-tropic-HIV-infected adults receiving 10 days of SCH532706 (Phase 1), 15 days no therapy, then 10 days of cART (without SCH532706) (Phase 2). Ten males were enrolled with median cells/microl (range) of CD4(+) 310 (92-848), CCR5(+)CD4(+) 57 (17-118), CD8(+) 895 (459-1666), and CCR5(+)CD8(+) 392 (250-983), and median plasma HIV RNA of 4.6 log(10) copies/ml. At baseline, proportions of M.TB, MAI, CMV, HSV, and HIV-Gag-specific CD4(+) T cells were 0.3%, 3.0%, 6.0%, 2.0%, and 1.6%, respectively. Median log(10) HIV RNA copies/ml declines were 1.5 (Phase 1) and 1.75 (Phase 2) (p = 0.7). Median CD4(+) and CD8(+) changes, respectively, during Phases 1 (+16 +91) and 2 (+28 -71) were similar (p = 0.7 both). However, CCR5(+)CD8(+) T cell fluctuations were significantly different (p = 0.02) during Phase 1 (+147 cells) vs. Phase 2 (-35 cells). PDC increased significantly more during Phase 1 (p = 0.04). Declines in antigen-specific cells were similar except for M. avium, which declined significantly during Phase 2 (p = 0.04). Similar declines in activation and proliferation of T cell subsets were observed during both treatment phases. For equivalent HIV RNA declines, CCR5-receptor blockade differentially increased CD8(+) T cell and PDC numbers in the circulation. These results confirm that cell surface CCR5 expression on these cells constantly directs trafficking during HIV infection. The persistence and clinical meaning of these immunological changes during long-term exposure to this class of anti-HIV drugs are unknown, but may have implications for immunosurveillance of inflammation.
Publisher: CSIRO Publishing
Date: 2010
DOI: 10.1071/SH09080
Abstract: Background: Men who have sex with men (MSM) are disproportionately affected by HIV. The proven efficacy of circumcision in reducing the risk of HIV acquisition among African heterosexual males has raised the question of whether this protective effect may extend to MSM populations. We examined the potential impact of circumcision on an HIV epidemic within a population of MSM. Methods: A mathematical model was developed to simulate HIV transmission in an MSM population. The model incorporated both circumcision and seropositioning, and was used to predict the reduction in HIV prevalence and incidence as a result of the two interventions. Estimates for the time required to achieve these gains were also calculated. Results: We derive simple formulae for the decrease in HIV prevalence with increased circumcision. Our model predicts that if an initially uncircumcised MSM population in a developed country with a baseline HIV prevalence of 10% underwent universal circumcision, HIV incidence would only be reduced to 95% of pre-intervention levels and HIV prevalence to 9.6% after 20 years. In the longer term, our model predicts that prevalence would only decrease from 10% to 6%, but this would take several generations to achieve. The effectiveness of circumcision increases marginally with higher degrees of seropositioning. Conclusions: The results of these calculations suggest that circumcision as a public health intervention will not produce a substantial decrease in HIV prevalence or incidence among MSM in the near future, and only modest reductions are achievable in the long-term.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.DRUGALCDEP.2010.03.006
Abstract: This work used mathematical modelling to explore effective policy for Hepatitis C virus (HCV) treatment in Australia in the context of methadone maintenance treatment (MMT). We consider two models to depict HCV in the population of injecting drug users (IDU) within Australia. The first model considers the IDU population as a whole. The second model includes separate components for those that are or are not enrolled in MMT. The impact of different levels of HCV treatment and its allocation dependent on MMT status were then determined in terms of the steady state levels of each of these models. Although increasing levels of HCV treatment decrease chronic infection prevalence, initially numbers of acutely infected can rise. This is caused by the high rate of reinfection. We find that no matter the extent of HCV treatment, HCV prevalence cannot be eliminated without limiting risk behaviour. Assuming equal adherence to HCV therapy between MMT and non-MMT, over 84% of HCV treatment should be allocated to those not in MMT. Only if adherence to HCV therapy in non-MMT patients falls below 44% of that in MMT then treatment should be preferentially directed to those in MMT. Contrary to generally held beliefs regarding HCV treatment the majority of therapy should be allocated to those that are still actively injecting. This is due to rates of reinfection and to the high turnover of in iduals in MMT. Higher adherence to HCV therapy in MMT would need to be achieved before this changed.
Publisher: Public Library of Science (PLoS)
Date: 28-03-2013
Publisher: Elsevier BV
Date: 07-2015
Publisher: Public Library of Science (PLoS)
Date: 06-05-2020
Publisher: Public Library of Science (PLoS)
Date: 25-08-2016
Publisher: Oxford University Press (OUP)
Date: 09-2002
DOI: 10.1086/342559
Abstract: Sixteen subjects were treated with highly active antiretroviral therapy within 120 days of the onset of symptoms of newly acquired human immunodeficiency virus type 1 (HIV-1) infection. Eleven of the 16 participated in an adjunctive therapeutic vaccine trial. After a mean of 3.2 years of treatment, they elected to discontinue therapy. Virus rebound occurred in all subjects and was followed by a spontaneous, transient although significant reduction in log plasma HIV-1 RNA level, ranging from 0.3 to 3.1 log(10) copies/mL. Despite evidence of the induction of HIV-1-specific cell-mediated immune responses, plasma viremia was not persistently suppressed to <500 copies/mL in any subject. The magnitude and dynamics of virus rebound were similar in both vaccinated and unvaccinated subjects. Nevertheless, given the transient suppression of viremia observed in nearly all subjects after treatment has been discontinued, further investigations of adjunctive vaccination with optimized antiretroviral therapy in treating HIV-1 infection are warranted.
Publisher: MDPI AG
Date: 04-06-2018
DOI: 10.3390/V10060303
Publisher: American Society for Microbiology
Date: 15-10-2011
DOI: 10.1128/JVI.05095-11
Abstract: We estimate the time required for HIV to complete separate stages of its infection cycle in productively infected CD4 + T cells in vivo by comparing initial delays after administration of single antiretroviral drugs until HIV RNA reduction in peripheral blood. Data were obtained from monotherapy studies of eight antiretroviral drugs from all currently licensed HIV drug classes: CCR5 blockers (maraviroc), fusion inhibitors (enfuvirtide), nucleoside and nonnucleoside reverse transcriptase inhibitors (abacavir, tenofovir, and rilpivirine), integrase inhibitors (raltegravir), and protease inhibitors (ritonavir and nelfinavir). We find that HIV requires an average of 52 h between export of virions in one generation to export in the next, with most of this (33 h) taken up by reverse transcription. Reverse transcription in vivo was three times longer than in vitro and began soon after virion fusion, as we determined no difference in mean times for commencement of reverse transcription and virion fusion as calculated by timing of the effects for tenofovir and maraviroc. Approximately 7 h is required between HIV integration and virion production. First-phase HIV RNA decay (half-life of 17 h over all drugs) seemed to slow as the stage being inhibited by the drug was further from viral production. The mean estimated half-life of plasma virions was 5 min, significantly shorter than previous estimates.
Publisher: Public Library of Science (PLoS)
Date: 21-05-2021
DOI: 10.1371/JOURNAL.PONE.0250824
Abstract: The aim of our study was to quantify sex-specific patterns of smoking prevalence and initiation in 10-year birth cohorts from 1910 to 1989 in Australia. We combined in idual data of 385,810 participants from 33 cross-sectional surveys conducted between 1962 and 2018. We found that age-specific smoking prevalence varied considerably between men and women within birth cohorts born before 1960. The largest difference was observed in the earliest cohort (1910–1919), with up to 37.7% point greater proportion of current smokers in men than in women. In subsequent cohorts, the proportion decreased among men, but increased among women, until there was no more than 7.4% point difference in the 1960–69 birth cohort. In the 1970–79 and 1980–89 cohorts, smoking among men marginally increased, but the proportion was at most ~11.0% points higher than women. Our analysis of initiation indicated that many women born before the 1930s who smoked commenced smoking after age 25 years (e.g., ~27% born in 1910–19) compared to at most 8% of men in any birth cohort. The earliest birth cohort (1910–1919) had the greatest difference in age at initiation between sexes 26.6 years in women versus 19.0 in men. In later cohorts, male and female smokers initiated increasingly earlier, converging in the 1960–69 cohort (17.6 and 17.8 years, respectively). While 22.9% of men and 8.4% of women initiated smoking aged = 15 in the 1910–1919 cohort, in the latest cohort (1980–89) the reverse was true (21.4% and 28.8% for men and women, respectively). Marked differences in smoking prevalence and age at initiation existed between birth cohorts of Australian men and women born before 1960 after this, sex-specific trends in prevalence and initiation were similar. Understanding these patterns may inform the evaluation of tobacco control policies and the targeting of potential interventions for exposed populations such as lung cancer screening.
Publisher: Elsevier BV
Date: 2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2006
DOI: 10.1002/HEP.21364
Abstract: The virion half-life of hepatitis B virus (HBV) is currently estimated at approximately 1 day. This estimate has been obtained from drug perturbation experiments with reverse transcriptase inhibitors. However, the analyses of those experiments have not considered the export of virions produced from preformed mature DNA-containing HBV capsids in infected cells. Data from 3 acutely infected chimpanzees indicates that there is approximately 10-fold more total intracellular HBV DNA than HBV DNA in blood, and therefore the half-life of virions for chimpanzees during acute infection is 10-fold shorter at 3.8 hours than the half-life associated with export of total intracellular HBV DNA. Mathematical model simulations duplicating the viral dynamics observed in drug perturbation experiments suggest a half-life of at most 4.4 hours for HBV virions in chronically infected humans, significantly shorter than current estimates, but consistent with the half-lives of virions for hepatitis C virus and HIV. This faster turnover of HBV in blood indicates a correspondingly higher replication rate and risk of mutation against hepatitis B antiviral therapy. In conclusion, we find the half-life of HBV virions is approximately 4 hours, significantly shorter than current estimates of 1 day. This new value is consistent with virion half-life estimates for HIV and hepatitis C virus.
Publisher: Wiley
Date: 28-04-2010
DOI: 10.1111/J.1468-1293.2010.00834.X
Abstract: HIV physicians have limited time for cognitive screening. Here we developed an extra-brief, clinically based tool for predicting HIV-associated neurocognitive impairment (HAND) in order to determine which HIV-positive in iduals require a more comprehensive neurological/neuropsychological (NP) assessment. Ninety-seven HIV-positive in iduals with advanced disease recruited in an HIV out-patient clinic received standard NP testing. A screening algorithm was developed using support vector machines, an optimized prediction procedure for classifying in iduals into two groups (here NP-impaired and NP-normal) based on a set of predictors. The final algorithm utilized age, current CD4 cell count, past central nervous system HIV-related diseases and current treatment duration and required approximately 3 min to complete, with a good overall prediction accuracy of 78% (against the gold standard NP-impairment status derived from standard NP testing) and a good specificity of 70%. This noncognitive-based algorithm should prove useful to identify HIV-infected patients with advanced disease at high risk of HAND who require more formal assessment. We propose staged guidelines, using the algorithm, for improved HAND therapeutic management. Future larger, international studies are planned to test the predictive effect of nadir CD4 cell count, hepatitis C virus infection, gender, ethnicity and HIV viral clade. We recommend the use of this first version for HIV-infected Caucasian men with advanced disease.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JTBI.2015.12.005
Abstract: Hepatitis B virus (HBV) dynamics in treated patients can be complex and differ considerably from other viral infections. We analyse dynamics of liver and serum levels of HBV DNA in 24 chronically HBV-infected in iduals undergoing 1 year of combination therapy with pegylated interferon alpha and adefovir dipivoxil (ADV), followed by 2 years of ADV monotherapy. Serum viral dynamics differentiated the patients into four response groups dependent on how quickly viremia became undetectable: quickly suppressed (HBV DNA <100 copies/ml within 8 weeks and staying suppressed, GRP1) quickly suppressed but some rebound ( 10,000 copies/ml, GRP4). These groups did not differ before start of therapy by serum HBV DNA (p=0.2), HBsAg (p=0.1), ALT (p=0.4), total HBV DNA within the liver (p=0.08), or cccDNA (p=0.3). Despite very different serum HBV DNA levels after 3 years, there was no statistical difference in total HBV DNA within the liver (p=0.08), nor in cccDNA levels (p=0.1), but HBsAg levels in serum were significantly lower for GRP1 compared to GRP4 (p=0.02). Efficacy in terms of reduction over the 3 years of serum HBV DNA, liver HBV DNA, cccDNA, and ratios of liver HBV DNA to cccDNA were 99.98%, 99.5%, 98.4%, and 83.2% respectively, exhibiting larger antiviral effects in serum than in liver. Over the course of therapy, HBV DNA viremia exhibited large oscillations for some in iduals. Mathematical modelling reproduced the dynamics of these erse groups by assuming a number of viral clones arose that experienced delayed recognition by the antibody response. Large viremia oscillations under therapy suggest sequential outgrowth of viral clones with delayed recognition by the humoral response.
Publisher: Springer Science and Business Media LLC
Date: 30-01-2020
DOI: 10.1186/S12876-020-1168-9
Abstract: Chronic hepatitis delta virus (HDV) infection causes severe liver disease which often leads to cirrhosis and hepatocellular carcinoma (HCC). Aim of this study was to establish the disease severity and prognostic factors for disease outcome by analysing frequencies of clinical events and their correlation with baseline virological and biochemical parameters as well as interferon and nucleos(t)ide analogue treatment choice. We studied a single-centre cohort of 49 anti-HDAg-positive patients with HBsAg persistence for at least 6 months. Virological and biochemical parameters, interferon and nucleos(t)ide analogue treatment choice as well as clinical events during follow-up were analysed by retrospective chart review (mean follow-up time 3 years, range 0.25–7.67 years). Severe clinical events occurred in 11/49 hepatitis D patients, including HCC (8/49), death (8/49) or liver transplantation (2/49). HCCs only occurred secondary to liver cirrhosis and their event rates in this cohort of hepatitis D patients did not differ from a matched HBV mono-infected cohort with comparable frequency of liver cirrhosis. A stepwise multivariate logistic regression revealed low platelet count ( p = 0. 0290) and older age ( p = 0.0337) correlating most strongly with overall clinical events, while serum HDV RNA positivity at baseline did not correlate with any clinical outcome. Interferon-free but not nucleos(t)ide analogue-free patient care correlated with the occurrence of HCC at logistic regression, although only 3/18 interferon-treated patients demonstrated repeatedly negative HDV PCR results post therapy. Our data indicate that progressive liver disease at baseline plays a major role as predictive factor for overall clinical outcome of hepatitis D patients. In particular, HCC risk may not be underestimated in hepatitis D virus RNA negative hepatitis D patients with advanced liver fibrosis.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0025-5564(03)00093-2
Abstract: Optimal drug regimens for cancer chemotherapy are determined when knowledge is only available on the behaviour of the tumour and the drugs used, over a population of patients. The case of two drugs is investigated where they are equivalent on average. Our calculations indicate that the optimal regimen has both drugs given initially but then sequences the two drugs. Our calculations also indicate that as tumour heterogeneity increases, the benefit to be gained from the optimal regimen can decrease in comparison to reasonable regimens. This has the effect of complicating the calculation of optimal regimens in a clinical setting, and may explain why results in experimental oncology fail to carry over to clinical oncology.
Publisher: Oxford University Press (OUP)
Date: 03-03-2008
DOI: 10.1093/IJE/DYN038
Abstract: Observations that reduced adult HIV prevalence in sub-Saharan Africa correlated with levels of male circumcision (MC), have suggested that MC could be used as a preventative measure against HIV infection. The exact benefits of this intervention are uncertain. Moreover if MC is not feasible for the whole male population, which groups should be targeted? A mathematical model simulated observed levels of HIV prevalence under the complete range of current levels of circumcision. Increased MC from 2007 was incorporated in this model and used to simulate HIV prevalence in 2020. Complete coverage by MC could reduce HIV prevalence from 12 to 6% for an average population country in sub-Saharan Africa in 2020. This reduction is scaled proportionally when lower circumcision levels are achieved. These benefits are achieved mostly by circumcising men between 20 and 30 years of age (adult prevalence reduced from 12 to 10%), and those with riskier behaviour (8 to 6.9%). Complete negation of these benefits requires at least 40% of circumcised males to significantly increase risky behaviour. MC provides an effective intervention in sub-Saharan Africa to reduce HIV prevalence. It is most effective when applied to 20-30 year old risky males with diminishing returns with application to the wider male population.
Publisher: CSIRO Publishing
Date: 2009
DOI: 10.1071/SH08063
Abstract: Background: Antiretroviral therapy has increased survival for in iduals living with HIV and has led to an ageing of this population in developed countries. To date the rate of ageing has been unquantified, giving rise to uncertainty in the treatment emphasis and burden in this population. Methods: A mathematical model was used in conjunction with HIV/AIDS data from the Australian National HIV/AIDS Registry to estimate numbers and ages of Australian men who have sex with men (MSM) living with HIV infection from 1980 to 2005. Results: The average age of HIV-infected Australian MSM is estimated to exceed 44 years of age by the year 2010 and has increased by 1 year of age for each two calendar years since the mid-1980s. HIV-infected MSM over 60 years of age have been increasing in number by 12% per year since 1995. A consequence of successful therapy with subsequent ageing of those infected has meant that from 2001 estimated deaths from other causes exceed AIDS deaths in Australia. Conclusions: In summary, our analyses indicate an increasing and rapidly ageing population living with HIV in Australia. This will inevitably lead to more serious non-AIDS conditions in ageing patients living with HIV, and to increased treatment complexity.
Publisher: MDPI AG
Date: 25-08-2022
DOI: 10.3390/BIOMEDICINES10092080
Abstract: The continuous emergence of SARS-CoV-2 variants favors potential co-infections and/or viral mutation events, leading to possible new biological properties. The aim of this work was to characterize SARS-CoV-2 genetic variability during the Delta–Omicron shift in patients and in a neighboring wastewater treatment plant (WWTP) in the same urban area. The surveillance of SARS-CoV-2 was performed by routine screening of positive s les by single nucleotide polymorphism analysis within the S gene. Moreover, additionally to national systematic whole genome sequencing (WGS) once a week in SARS-CoV-2-positive patients, WGS was also applied when mutational profiles were difficult to interpret by routine screening. Thus, WGS was performed on 414 respiratory s les and on four wastewater s les, northeastern France. This allowed us to report (i) the temporally concordant Delta to Omicron viral shift in patients and wastewaters (ii) the characterization of 21J (Delta) and 21K (Omicron)/BA.1-21L (Omicron)/BA.2-BA.4 mixtures from humans or environmental s les (iii) the mapping of composite mutations and the predicted impact on immune properties in the viral Spike protein.
Publisher: Society for Industrial & Applied Mathematics (SIAM)
Date: 2021
DOI: 10.1137/21M1398549
Publisher: Elsevier BV
Date: 12-1998
DOI: 10.1016/S0025-5564(98)10046-9
Abstract: We construct a model based on biological principles of the interaction of HIV-1 with the CD4+ T cells at primary infection. Most of the parameters are obtained from the literature, the remainder from fitting the output of the model to data from seven patients. On the basis of the model we find that initial viral containment is due to an effective immune response. The viral level after the initial peak, a surrogate marker of disease progression, was determined by the rate of reactivation of memory cells. Differences in this rate may occur because of inter- or intra-in idual differences in the capability of memory cells to recognise and dispose of variants of HIV, either due to immune escape mutations within the virus or because the virus directly inhibits reactivation. With no choice of parameters could direct and indirect killing produce the gradual loss in CD4+ T cells with the observed viral behaviour. The loss of CD4+ T cells is perhaps due to defective expansion of activated cells of both HIV specific and nonspecific cells. As less memory cells are produced as a result then this compartment decreases and hence so do naive numbers through less reversion of memory cells to the naive phenotype.
Publisher: BMJ
Date: 06-2010
Publisher: Baishideng Publishing Group Inc.
Date: 2013
Publisher: Public Library of Science (PLoS)
Date: 07-12-2020
DOI: 10.1371/JOURNAL.PONE.0243391
Abstract: Human immunodeficiency virus (HIV) is subject to immune selective pressure soon after it establishes infection at the founder stage. As an in idual progresses from the founder to chronic stage of infection, immune pressure forces a history of mutations that are embedded in envelope sequences. Determining this pathway of coevolving mutations can assist in understanding what is different with the founder virus and the essential pathways it takes to maintain infection. We have combined operations research and bioinformatics methods to extract key networks of mutations that differentiate founder and chronic stages for 156 subtype B and 107 subtype C envelope (gp160) sequences. The chronic networks for both subtypes revealed strikingly different hub-and-spoke topologies compared to the less structured transmission networks. This suggests that the hub nodes are impacted by the immune response and the resulting loss of fitness is compensated by mutations at the spoke positions. The major hubs in the chronic C network occur at positions 12, 137 (within the N136 glycan), and 822, and at position 306 for subtype B. While both founder networks had a more heterogeneous connected network structure, interestingly founder B subnetworks around positions 640 and 837 preferentially contained CD4 and coreceptor binding domains. Finally, we observed a differential effect of glycosylation between founder and chronic subtype B where the latter had mutational pathways significantly driven by N-glycosylation. Our study provides insights into the mutational pathways HIV takes to evade the immune response, and presents features more likely to establish founder infection, valuable for effective vaccine design.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.JTBI.2014.11.020
Abstract: The progression of acute hepatitis B virus (HBV) to chronic infection or clearance is highly dependent on the host immune response composed of cytolytic (CTL) and non-cytolytic (non-CTL) effects. Cytolytic processes induce hepatocyte killing while non-CTL processes inhibit intracellular replication. Both effects are widely recognized and accepted. However, there are uncertainties about the assistance provided by either the loss of covalently circular closed DNA (cccDNA) during cell proliferation or the emergence of refractory cells to immune mediated clearance. We developed an agent-based mathematical model and tested the relative roles of different mechanisms of the immune system in the clearance of acute HBV infection. HBV viremia clearance time and hepatocyte turnover (HT) were used as the two major criteria in determining reasonable outcomes. Modelling results in 90% of cells containing between 1 and 17 cccDNA copies and normally distributed at the peak of infection. Variations in p36 levels, responsible for determining export of virions or recirculation to lify cccDNA numbers, have a much greater impact on mean cccDNA level/cell at peak viremia than virus infectivity and cccDNA half-life. A strong CTL effect alone failed to clear infection with HT ≈ 10. Acute infection clearance was possible with combined CTL and non-CTL effects along with complete loss of intracellular viral components during cell proliferation resulting in the desired range of HT (0.7-1). The emergence of cells refractory to infection can reduce HT by up to 90%. However their impact was less effective than complete loss of intracellular viral components during cell proliferation. the existence of refractory cells is not necessary when there is complete loss of intracellular quantities during cell proliferation but is essential with only partial clearance.
Publisher: American Society for Microbiology
Date: 15-03-2014
DOI: 10.1128/JVI.03331-13
Abstract: The latent HIV reservoir is a major impediment to curing HIV infection. The contribution of CD4 + T cell activation status to the establishment and maintenance of the latent reservoir was investigated by enumerating viral DNA components in a cohort of 12 in iduals commencing antiretroviral therapy (ART) containing raltegravir, an integrase inhibitor. Prior to ART, the levels of total HIV DNA were similar across HLA-DR + and HLA-DR − (HLA-DR ± ) CD38 ± memory CD4 + T cell phenotypes episomal two-long terminal repeat (2-LTR) HIV DNA levels were higher in resting (HLA-DR − CD38 − ) cells, and this phenotype exhibited a significantly higher ratio of 2-LTR to integrated HIV DNA ( P = 0.002). After 1 year of ART, there were no significant differences across each of the memory phenotypes of any HIV DNA component. The decay dynamics of integrated HIV DNA were slow within each subset, and integrated HIV DNA in the resting HLA-DR − CD38 − subset per mm 3 of peripheral blood exhibited no significant decay (half-life of 25 years). Episomal 2-LTR HIV DNA decayed relative to integrated HIV DNA in resting cells with a half-life of 134 days. Surprisingly, from week 12 on, the decay rates of both total and episomal HIV DNA were lower in activated CD38 + cells. By weeks 24 and 52, HIV RNA levels in plasma were most significantly correlated with the numbers of resting cells containing integrated HIV DNA. On the other hand, total HIV DNA levels in all subsets were significantly correlated with the numbers of HLA-DR + CD38 − cells containing integrated HIV DNA. These results provide insights into the interrelatedness of cell activation and reservoir maintenance, with implications for the design of therapeutic strategies targeting HIV persistence. IMPORTANCE It is generally believed that HIV is not cleared by extensive antiretroviral therapy (ART) due to the difficulty in eradicating the latent reservoir in resting CD4 + T cells. New therapies that attempt to activate this reservoir so that immune or viral cytopathic mechanisms can remove those infected cells are currently being investigated. However, results obtained in this research indicate that activation, at least on some level, already occurs within this reservoir. Furthermore, we are the first to describe the dynamics of different HIV DNA species in resting and activated memory CD4+ T cell subsets that point to the role different levels of activation play in maintaining the HIV reservoir.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JCV.2019.08.010
Abstract: "Treatment as Prevention" (TasP) aims to reduce new HIV infections through higher enrolment on suppressive antiretroviral therapy (ART). We studied the current epidemic and possible impact of TasP in a French HIV cohort including MSM and migrant subjects. Socio-demographic, clinical and laboratory variables were collected during the follow-up of 6995 HIV-infected patients. The numbers of in iduals living with HIV in each year were estimated from diagnoses up to that year minus recorded deaths. Patients were classified according to gender, transmission mode, country of birth and treatment status. The cohort includes 6995 in iduals diagnosed from 1985 to 2015, of whom 72% were men. Unprotected sexual intercourse was the main mode of transmission. Women were more likely to be migrants (45% versus 13%), whereas men were more likely to have been born in France (52% versus 27%). Diagnoses were more correlated with untreated than treated prevalence in each group. MSM diagnoses was strongly correlated to untreated prevalence whatever the country of birth (p < 0.0001). However, heterosexual diagnoses were better correlated with prevalence within in idual country groups (b = 0.29 female diagnoses/year per untreated male born in France, compared to b = 0.73 for foreigners). Using these transmission rates, mathematical modelling estimated that enrolling 75% of untreated in iduals per year would decrease diagnoses ten-fold by 2021. Enrolling at least 75% of in iduals on ART is necessary to substantially impact numbers of new HIV infections in this cohort. Treatment as prevention will actually be effective to reduce HIV prevalence.
Publisher: Springer Science and Business Media LLC
Date: 25-06-2012
Abstract: The characterization of HIV-1 transmission strains may inform the design of an effective vaccine. Shorter variable loops with fewer predicted glycosites have been suggested as signatures enriched in envelope sequences derived during acute HIV-1 infection. Specifically, a transmission-linked lack of glycosites within the V1 and V2 loops of gp120 provides greater access to an α4β7 binding motif, which promotes the establishment of infection. Also, a histidine at position 12 in the leader sequence of Env has been described as a transmission signature that is selected against during chronic infection. The purpose of this study is to measure the association of the presence of an α4β7 binding motif, the number of N-linked glycosites, the length of the variable loops, and the prevalence of histidine at position 12 with HIV-1 transmission. A case–control study design was used to measure the prevalence of these variables between subtype B and C transmission sequences and frequency-matched randomly-selected sequences derived from chronically infected controls. Subtype B transmission strains had shorter V3 regions than chronic strains ( p = 0.031) subtype C transmission strains had shorter V1 loops than chronic strains ( p = 0.047) subtype B transmission strains had more V3 loop glycosites ( p = 0.024) than chronic strains. Further investigation showed that these statistically significant results were unlikely to be biologically meaningful. Also, there was no difference observed in the prevalence of a histidine at position 12 among transmission strains and controls of either subtype. Although a genetic bottleneck is observed after HIV-1 transmission, our results indicate that summary characteristics of Env hypothesised to be important in transmission are not ergent between transmission and chronic strains of either subtype. The success of a transmission strain to initiate infection may be a random event from the ergent pool of donor viral sequences. The characteristics explored through this study are important, but may not function as genotypic signatures of transmission as previously described.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-02-2010
DOI: 10.1002/HEP.23611
Abstract: Chronic hepatitis B virus (HBV) infection is maintained by the presence of covalently closed circular DNA (cccDNA), the template of viral transcription and replication. In quiescent hepatocytes, cccDNA is a stable molecule that can persist throughout the hepatocyte lifespan. However, in chronic HBV infection, immunomediated cell injury and compensatory hepatocyte proliferation may favor cccDNA decline and selection of cccDNA-free cells. To investigate the impact of liver regeneration on cccDNA stability and activity in vivo, we used the urokinase-type plasminogen activator (uPA)/severe combined immunodeficiency (SCID) mouse model. Primary tupaia hepatocytes (PTHs) chronically infected with woolly monkey HBV (WM-HBV) were isolated from one highly viremic uPA/SCID chimeric mouse and transplanted into 20 uPA recipients. Expansion of transplanted PTHs and viral load changes were determined by real-time polymerase chain reaction and immunohistochemistry. Transplantation of WM-HBV infected hepatocytes led to an average of 3.8 PTH doublings within 80 days, 75% reduction of virion productivity (relaxed circular DNA/cccDNA), and lower expression levels of pregenomic RNA and hepatitis B core antigen. Remarkably, a median 2-log decline of cccDNA per cell determined during PTH proliferation was due to both dilution of the cccDNA pool among daughter cells and a 0.5-log loss of intrahepatic cccDNA loads (P = 0.02). Intrahepatic viral DNA sequences persisting at the end of the study were mostly present as replicative intermediates and not as integrated virus. Cell ision in the setting of liver regeneration and without administration of antiviral drugs induced strong destabilization of the cccDNA reservoir, resulting in cccDNA clearance in the great majority of chronically infected hepatocytes.
Publisher: Elsevier BV
Date: 07-2012
DOI: 10.1016/J.JTBI.2012.03.030
Abstract: While mathematical models exist describing the dynamics of hepatitis C virus (HCV), most of them focus on the short term dynamics after the commencement of antiviral therapy. This work is the first attempt at mathematically modelling the full course of HCV infection and the impact that these viral and immune processes have on the progression to hepatocellular carcinoma (HCC). This model is based on the premise that these long term conditions are ultimately random and likely driven by the cell-mediated immune response. The risk of cancer arising is modelled through a stochastic model that incorporates the dynamics of HCV over the course of infection. Our model simulations produce approximately 9% prevalence of HCC in in iduals after 40 years, consistent with the literature estimates. We find that higher viral infectivity leads to a greater likelihood of developing HCC (p<0.0001), but it does not determine the speed with which it arises. This infectivity drives the level of immune response, the amount of hepatocyte proliferation, and the risk of a mutational event. In our simulations the probability of developing HCC increases approximately linearly with duration of infection at the rate of 2.4 incident cases per thousand HCV-infected person years. This indicates that the sooner viral replication can be suppressed through antiviral therapy, the greater the chance of forestalling HCC.
Publisher: Rockefeller University Press
Date: 02-04-2001
Abstract: Using patient data from a unique single source outbreak of hepatitis B virus (HBV) infection, we have characterized the kinetics of acute HBV infection by monitoring viral turnover in the serum during the late incubation and clinical phases of the disease in humans. HBV replicates rapidly with minimally estimated doubling times ranging between 2.2 and 5.8 d (mean 3.7 ± 1.5 d). After a peak viral load in serum of nearly 1010 HBV DNA copies/ml is attained, clearance of HBV DNA follows a two or three phase decay pattern with an initial rapid decline characterized by mean half-life (t1/2) of 3.7 ± 1.2 d, similar to the t1/2 observed in the noncytolytic clearance of covalently closed circular DNA for other hepadnaviruses. The final phase of virion clearance occurs at a variable rate (t1/2 of 4.8 to 284 d) and may relate to the rate of loss of infected hepatocytes. Free virus has a mean t1/2 of at most 1.2 ± 0.6 d. We estimate a peak HBV production rate of at least 1013 virions/day and a maximum production rate of an infected hepatocyte of 200–1,000 virions/day, on average. At this peak rate of virion production we estimate that every possible single and most double mutations would be created each day.
Publisher: Public Library of Science (PLoS)
Date: 19-10-2017
Publisher: Wiley
Date: 06-01-2016
DOI: 10.1111/JVH.12498
Abstract: For hepatitis B virus (HBV)-related chronic infection under treatment by nucleos(t)ide analogues (NUCs), HBsAg clearance is the ultimate therapeutic goal but very infrequent. We investigated how HBV envelope protein variability could lead to differential HBsAg clearance on NUCs. For 12 HBV genotype D patients receiving NUCs, six resolvers (HBsAg clearance) were compared to six matched nonresolvers (HBsAg persistence). PreS/S amino acid (aa) sequences were analysed with bioinformatics to predict HBV envelope antigenicity and aa covariance. To enrich our analyses on very rare resolvers, these were compared with other HBV genotype D strains in three characterized clinical cohorts including common chronically infected patients. The sT125M+sP127T combination was observed in four nonresolvers of six, corroborated by aa covariance analysis, associated with a lower predicted antigenicity than sT125T+sP127P. Concordant features within this HBV key functional domain, at positions 125 and 127, were reported from two of the three comparative cohorts. In our hands, a lower ELISA reactivity of HBV-vaccinated mice sera was observed against the sT125M mutant. In the S gene, 56 aa changes in minor variants were detected in non-resolvers, mainly in the major hydrophilic region, vs 28 aa changes in resolvers. Molecular features in patients showing HBsAg persistence on NUCs argue in favour of a different aa pattern in the HBV S gene compared to those showing HBsAg clearance. In nonresolvers, a decrease in HBs 'a' determinant antigenicity and more frequent mutations in the S gene suggest a role for the HBV envelope characteristics in HBsAg persistence.
Publisher: Oxford University Press (OUP)
Date: 17-10-2011
Abstract: Most patients with human immunodeficiency virus (HIV) who remain CD4(+) T-cell deficient on antiretroviral therapy (ART) exhibit marked immune activation. As CD4(+) T-cell activation may be mediated by microbial translocation or interferon-alpha (IFN-α), we examined these factors in HIV patients with good or poor CD4(+) T-cell recovery on long-term ART. Messenger RNA levels for 3 interferon-stimulated genes were increased in CD4(+) T cells of patients with poor CD4(+) T-cell recovery, whereas levels in patients with good recovery did not differ from those in healthy controls. Poor CD4(+) T-cell recovery was also associated with CD4(+) T-cell expression of markers of activation, senescence, and apoptosis, and with increased serum levels of the lipopolysaccharide receptor and soluble CD14, but these were not significantly correlated with expression of the interferon-stimulated genes. Therefore, CD4(+) T-cell recovery may be adversely affected by the effects of IFN-α, which may be amenable to therapeutic intervention.
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1007/S40261-016-0409-8
Abstract: The cost-effectiveness of highly effective, but costly, peg-interferon (peg-IFN) treatment for chronic hepatitis B (CHB) infections in China is unknown. Endemic hepatitis D virus (HDV) may also modify the effectiveness of any HBV treatment option. The objective of this study is to determine the best antiviral treatment from a societal perspective in the Chinese population, which contains a mix of HBV and HDV infections. A Markov model is developed to simulate the clinical course of CHB and chronic hepatitis D (CHD) in iduals. For a hypothetical Chinese cohort of 10,000 in iduals aged 30-60 years, cost-utility analysis is performed for therapies with: lamivudine, adefovir, telbivudine, entecavir, IFN and Peg-IFN. Costs and quality-adjusted life-years (QALYs) are discounted at 3 % annually. A one-way sensitivity analysis is also conducted. Lamivudine, adefovir, telbivudine, and entecavir are all cost-effective treatments compared to palliative care at an incremental cost-effectiveness ratio (ICER) of -$418, -$197, -$443 and -$317 per QALY, respectively (2015 US dollars). Peg-IFN yields a maximum 156,000 QALYs with an ICER of $1149 per QALY while IFN results in the highest cumulative mortality of 48 % along with the lowest QALY gained. Probabilistic sensitivity analyses confirm that only Peg-IFN and ETV are the only two cost-effective options at the current willingness-to-pay (WTP) of $12,000 in China. However, entecavir has a higher probability of being cost-effective than Peg-IFN at current WTP for all age groups. Peg-IFN generates maximum QALYs compared to lamivudine, adefovir, telbivudine and interferon, and presents itself as a cost-effective option at current WTP. Alternatively entecavir can be used in China, generating 10 % lower QALYs than Peg-IFN but costing less than palliative care.
Publisher: Oxford University Press (OUP)
Date: 10-2003
DOI: 10.1093/IJE/DYG102
Abstract: Prevalence of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in the injecting drug user (IDU) community can differ considerably. In Australia in 1997, HIV prevalence among attendees at Needle Exchange Programs was 1% while HCV prevalence was 50%. The impact that different needle-sharing behaviour and drug injecting use may have on the future levels of these viruses is uncertain. We develop a mathematical model of the number of people who inject drugs with each of these infections to determine their changes under different scenarios. The impact of transmission probabilities and needle sharing on the incidence and prevalence of HIV and HCV infections are assessed. Critical levels of needle sharing, below which total infections would fall to minimal levels, were estimated to be 17 IDU partners per year for HIV compared with 3 IDU partners per year for HCV. Current average levels of needle sharing in Australia are estimated to be six IDU partners per year. This analysis suggests that under current drug injecting behaviour, HIV prevalence in IDU in Australia should remain below 1% but that HCV prevalence will stay elevated.
Publisher: Wiley
Date: 23-09-2009
DOI: 10.1002/JGM.1401
Abstract: Gene therapy represents a new treatment paradigm for HIV that is potentially delivered by a safe, once-only therapeutic intervention. Using mathematical modelling, we assessed the possible impact of autologous haematopoietic stem cell (HSC) delivered, anti-HIV gene therapy. The therapy comprises a ribozyme construct (OZ1) directed to a conserved region of HIV-1 delivered by transduced HSC (OZ1+HSC). OZ1+HSC contributes to the CD4+ T lymphocyte and monocyte/macrophage cell pools that preferentially expand under the selective pressure of HIV infection. The model was used to predict the efficacy of OZ1 in a highly active antiretroviral therapy (HAART) naïve in idual and a HAART-experienced in idual undergoing two structured treatment operations. In the standard scenario, OZ1+HSC was taken as 20% of total body HSC. For a HAART-naïve in idual, modelling predicts a reduction of HIV RNA at 1 and 2 years post-OZ1 therapy of 0.5 log(10) and 1 log(10), respectively. Eight years after OZ1 therapy, the CD4+ T-lymphocyte count was 271 cells/mm(3) compared to 96 cells/mm(3) for an untreated in idual. In a HAART-experienced in idual HIV RNA was reduced by 0.34 log(10) and 0.86 log(10) at 1 and 2 years. The OZ1 effect was maximal when both CD4+ T lymphocytes and monocytes/macrophages were protected from successful, productive infection by OZ1. The modelling indicates a single infusion of HSC cell-delivered gene therapy can impact on HIV viral load and CD4 T-lymphocyte count. Given that gene therapy avoids the complications associated with HAART, there is significant potential for this approach in the treatment of HIV.
Publisher: Public Library of Science (PLoS)
Date: 19-06-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2007
Publisher: Mary Ann Liebert Inc
Date: 20-01-2001
DOI: 10.1089/08892220150217238
Abstract: A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in in iduals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.
Publisher: Public Library of Science (PLoS)
Date: 10-02-2017
Publisher: Elsevier BV
Date: 10-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-04-2015
DOI: 10.1002/HEP.27423
Publisher: Public Library of Science (PLoS)
Date: 23-12-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-04-2009
DOI: 10.1002/HEP.22918
Publisher: Public Library of Science (PLoS)
Date: 11-08-2014
Publisher: Society for Industrial & Applied Mathematics (SIAM)
Date: 2005
DOI: 10.1137/040603024
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.JTBI.2017.04.007
Abstract: Hepatitis B virus (HBV) is endemic in China. Almost 10% of HBV infected in iduals are also infected with hepatitis D virus (HDV) which has a 5-10 times higher mortality rate than HBV mono-infection. The aim of this manuscript is to devise strategies that can not only control HBV infections but also HDV infections in China under the current health care budget in an optimal manner. Using a mathematical model, an annual budget of $10billion was optimally allocated among five interventions namely, testing and HBV adult vaccination, treatment for mono-infected and dually-infected in iduals, second line treatment for HBV mono-infections, and awareness programs. We determine that the optimal strategy is to test and treat both infections as early as possible while applying awareness programs at full intensity. Under this strategy, an additional 19.8million HBV, 1.9million HDV infections and 0.25million lives will be saved over the next 10years at a cost-savings of $79billion than performing no intervention. Introduction of second line treatment does not add a significant economic burden yet prevents 1.4million new HBV infections and 15,000 new HDV infections. Test and treatment programs are highly efficient in reducing HBV and HDV prevalence in the population. Under the current health budget in China, not only test and treat programs but awareness programs and second line treatment can also be implemented that minimizes prevalence and mortality, and maximizes economic benefits.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2015
Publisher: Springer Science and Business Media LLC
Date: 09-10-2010
Publisher: Society for Industrial & Applied Mathematics (SIAM)
Date: 2017
DOI: 10.1137/16M1069249
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2008
Publisher: Elsevier BV
Date: 2008
Publisher: Springer Science and Business Media LLC
Date: 02-04-2013
DOI: 10.1007/S11538-013-9834-5
Abstract: We have developed a mathematical model for in-host virus dynamics that includes spatial chemotaxis and diffusion across a two-dimensional surface representing the vaginal or rectal epithelium at primary HIV infection. A linear stability analysis of the steady state solutions identified conditions for Turing instability pattern formation. We have solved the model equations numerically using parameter values obtained from previous experimental results for HIV infections. Simulations of the model for this surface show hot spots of infection. Understanding this localization is an important step in the ability to correctly model early HIV infection. These spatial variations also have implications for the development and effectiveness of microbicides against HIV.
Publisher: Public Library of Science (PLoS)
Date: 14-10-2014
Publisher: Springer Science and Business Media LLC
Date: 15-02-2009
DOI: 10.1038/NM.1932
Publisher: Public Library of Science (PLoS)
Date: 20-12-2021
DOI: 10.1371/JOURNAL.PPAT.1010165
Abstract: The HIV latent reservoir exhibits slow decay on antiretroviral therapy (ART), impacted by homeostatic proliferation and activation. How these processes contribute to the total dynamic while also producing the observed profile of s led latent clone sizes is unclear. An agent-based model was developed that tracks in idual latent clones, incorporating homeostatic proliferation of cells and activation of clones. The model was calibrated to produce observed latent reservoir dynamics as well as observed clonal size profiles. Simulations were compared to previously published latent HIV integration data from 5 adults and 3 children. The model simulations reproduced reservoir dynamics as well as generating residual plasma viremia levels (pVL) consistent with observations on ART. Over 382 Latin Hypercube S le simulations, the median latent reservoir grew by only 0.3 log 10 over the 10 years prior to ART initiation, after which time it decreased with a half-life of 15 years, despite number of clones decreasing at a faster rate. Activation produced a maximum size of genetically intact clones of around one million cells. The in idual simulation that best reproduced the s led clone profile, produced a reservoir that decayed with a 13.9 year half-life and where pVL, produced mainly from proliferation, decayed with a half-life of 10.8 years. These slow decay rates were achieved with mean cell life-spans of only 14.2 months, due to expansion of the reservoir through proliferation and activation. Although the reservoir decayed on ART, a number of clones increased in size more than 4,000-fold. While small s led clones may have expanded through proliferation, the large sizes exclusively arose from activation. Simulations where homeostatic proliferation contributed more to pVL than activation, produced pVL that was less variable over time and exhibited fewer viral blips. While homeostatic proliferation adds to the latent reservoir, activation can both add and remove latent cells. Latent activation can produce large clones, where these may have been seeded much earlier than when first s led. Elimination of the reservoir is complicated by expanding clones whose dynamic differ considerably to that of the entire reservoir.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.TPB.2016.08.004
Abstract: Hepatitis delta virus (HDV) in conjunction with hepatitis B virus (HBV) increases adult morbidity and mortality. A number of studies have performed cost-benefit analyses for HBV interventions, but they have ignored the impact of HDV on these outcomes. Using a mathematical model of HBV-HDV epidemiology, we compare health benefits and cost outcomes of four interventions: testing with HBV adult vaccination (diagnosis), diagnosis with antiviral treatment for HBV infections (mono-infections), diagnosis with antiviral treatment for HBV-HDV infections (dual-infections), and awareness programs. The relationship between optimal levels and outcomes of each of these interventions and HDV prevalence in HBV infected in iduals ranging from 0 to 50% is determined. Over a 50 year period under no intervention, HBV prevalence, per capita total cost and death toll increase by 2.25%, -$11 and 2.6-fold respectively in moderate HDV endemic regions compared to mono-infected regions the corresponding values for high HDV endemic regions are 4.2%, -$21 and 3.9-fold. Optimal interventions can be strategized similarly in mono and dually endemic regions. Only implementation of all four interventions achieves a very low HBV prevalence of around 1.5% in a moderate HDV endemic region such as China, with 2.8 million fewer deaths compared to no intervention. Although the policy of implementation of all four interventions costs additional $382 billion compared to no intervention, it still remains cost-effective with an incremental cost-effectiveness ratio of $1400/QALY. Very high efficacy awareness programs achieve less prevalence with fewer deaths at a lower cost compared to treatment and/or vaccination programs. HDV substantially affects the performance of any HBV-related intervention. Its exclusion results in over-estimation of the effectiveness of HBV interventions.
Publisher: Elsevier BV
Date: 10-2017
Publisher: Wiley
Date: 28-04-2021
DOI: 10.1111/JVH.13513
Abstract: Hepatitis E virus (HEV) usually causes self‐limited liver diseases but can also result in severe cases. Genotypes 1 (G1) and 2 circulate in developing countries are human‐restricted and waterborne, while zoonotic G3 and G4 circulating in industrialized countries preferentially infect human through consumption of contaminated meat. Our aims were to identify amino acid patterns in HEV variants that could be involved in pathogenicity or in transmission modes, related to their impact on antigenicity and viral surface hydrophobicity. HEV sequences from human ( n = 37) and environmental origins (wild boar [ n = 3], pig slaughterhouse effluent [ n = 6] and urban wastewater [ n = 2]) were collected for the characterization of quasispecies using ultra‐deep sequencing (ORF2/ORF3 overlap). Predictive and functional assays were carried out to investigate viral particle antigenicity and hydrophobicity. Most quasispecies showed a major variant while a mixture was observed in urban wastewater and in one chronically infected patient. Amino acid signatures were identified, as a rabbit‐linked HEV pattern in two infected patients, or the S68L (ORF2) / H81C (ORF3) residue mostly identified in wild boars. By comparison with environmental strains, molecular patterns less likely represented in humans were identified. Patterns impacting viral hydrophobicity and/or antigenicity were also observed, and the higher hydrophobicity of HEV naked particles compared with the enveloped forms was demonstrated. HEV variants isolated from human and environment present molecular patterns that could impact their surface properties as well as their transmission. These molecular patterns may concern only one minor variant of a quasispecies and could emerge under selective pressure.
Publisher: MDPI AG
Date: 30-04-2021
DOI: 10.3390/MICROORGANISMS9050968
Abstract: Background: The prevalence of metabolic and cardiovascular diseases is rising worldwide. However, little is known about the impact of such disorders on hepatic disease progression in chronic hepatitis B (CHB) during the era of potent nucleo(s)tide analogues (NAs). Methods: We retrospectively analyzed a single-center cohort of 602 CHB patients, comparing the frequency of liver cirrhosis at baseline and incidences of liver-related events during follow-up (hepatocellular carcinoma, liver transplantation and liver-related death) between CHB patients with a history of diabetes, obesity, hypertension or coronary heart disease (CHD). Results: Rates of cirrhosis at baseline and liver-related events during follow-up (median follow-up time: 2.51 years NA-treated: 37%) were substantially higher in CHB patients with diabetes (11/23 3/23), obesity (6/13 2/13), CHD (7/11 2/11) or hypertension (15/43 4/43) compared to CHB patients without the indicated comorbidities (26/509 6/509). Multivariate analysis identified diabetes as the most significant predictor for cirrhosis (p = 0.0105), while comorbidities did not correlate with liver-related events in pre-existing cirrhosis. Conclusion: The combination of metabolic diseases and CHB is associated with substantially increased rates of liver cirrhosis and secondary liver-related events compared to CHB alone, indicating that hepatitis B patients with metabolic comorbidities warrant particular attention in disease surveillance and evaluation of treatment indication.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 08-02-2021
DOI: 10.1186/S12859-020-03901-Y
Abstract: The high variability in envelope regions of some viruses such as HIV allow the virus to establish infection and to escape subsequent immune surveillance. This variability, as well as increasing incorporation of N-linked glycosylation sites, is fundamental to this evasion. It also creates difficulties for multiple sequence alignment methods (MSA) that provide the first step in their analysis. Existing MSA tools often fail to properly align highly variable HIV envelope sequences requiring extensive manual editing that is impractical with even a moderate number of these variable sequences. We developed an automated library building tool NGlyAlign, that organizes similar N-linked glycosylation sites as block constraints and statistically conserved global sites as single site constraints to automatically enforce partial columns in consistency-based MSA methods such as Dialign. This combined method accurately aligns variable HIV-1 envelope sequences. We tested the method on two datasets: a set of 156 founder and chronic gp160 HIV-1 subtype B sequences as well as a set of reference sequences of gp120 in the highly variable region 1. On measures such as entropy scores, sum of pair scores, column score, and similarity heat maps, NGlyAlign+Dialign proved superior against methods such as T-Coffee, ClustalOmega, ClustalW, Praline, HIValign and Muscle. The method is scalable to large sequence sets producing accurate alignments without requiring manual editing. As well as this application to HIV, our method can be used for other highly variable glycoproteins such as hepatitis C virus envelope. NGlyAlign is an automated tool for mapping and building glycosylation motif libraries to accurately align highly variable regions in HIV sequences. It can provide the basis for many studies reliant on single robust alignments. NGlyAlign has been developed as an open-source tool and is freely available at github.com/UNSW-Mathematical-Biology/NGlyAlign_v1.0 .
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/SH11003
Abstract: Background The growing number of older in iduals with HIV in Australia implies that the prevalence of dementia and additional HIV-associated neurocognitive disorders will increase. There are currently no estimates of the future burden of neurocognitive disease in this population. Methods: We estimated the number and age profile of people living with HIV to the end of 2009 using HIV/AIDS Registry data, and extrapolated these estimates to 2030. Prevalence of HIV-associated dementia (HAD) from 2005 to 2010 from a large Sydney hospital and cost estimates from the AIDS Dementia and HIV Psychiatry Service were used to estimate future HAD burden and costs. Results: Based on our calculations, the number of HIV-positive in iduals in Australia will increase from 16 228 men and 1797 women in 2009 to 26 963 men and 5224 women in 2030, while the number of in iduals aged 60+ years will increase from 1140 men and 78 women to 5442 men and 721 women, i.e. a 377% increase of older men and an 825% increase in older women. Based on a 7.8% (157/2004) HAD prevalence obtained from hospital data, in iduals with HAD will increase in number from 1314 men and 143 women in 2009 to 2204 men and 421 women in 2030. An estimated 22 men and 2 women with non-HIV dementia in 2009 will increase to 104 men and 12 women by 2030. The annual cost of care will increase from ~$29 million in 2009 to $53 million in 2030, mostly for full-time residential care. Conclusions: Neurocognitive disorders will place an increasing burden on resources, especially as those living with HIV age. Because it is unclear if HAD is an increased risk factor for non-HIV dementia, our calculations may be conservative.
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1016/S0025-5564(00)00045-6
Abstract: Chemotherapy is useful in a number of cancers to reduce or eliminate residual disease. When used in this way the objective is to maximise the likelihood that the cancer will be eliminated. In this article, we extend a stochastic model of chemotherapy for cancer to incorporate its concomitant effect on the normal system and derive overall measures of outcome. The model includes the development of drug resistance and is sufficiently flexible to include a variety of tumour and normal system growth functions. The model is then applied to situations previously examined in the literature and it is shown that early intensification is a common feature of successful regimens in situations where drug resistance is likely. The model is also applied to data collected from clinical trials analysing the effect of adriamycin, and cyclophosphamide, methotrexate and 5-flourouracil (CMF) therapy in the treatment of operable breast cancer. The model is able to mimic the data and provides a description of the optimal regimen.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-11-2011
Publisher: Mary Ann Liebert Inc
Date: 12-2013
Publisher: Public Library of Science (PLoS)
Date: 17-07-2012
Publisher: Oxford University Press (OUP)
Date: 18-01-2013
Abstract: A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape. We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1. Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C). Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.
Publisher: Wiley
Date: 17-01-2005
DOI: 10.1002/JGM.705
Abstract: An anti-HIV-1 tat ribozyme, termed Rz2, has been shown to inhibit HIV-1 infection/replication and to decrease HIV-1-induced pathogenicity in T-lymphocyte cell lines and normal peripheral blood T-lymphocytes. We report here the results of a phase I gene transfer clinical trial using Rz2. Apheresis was used to obtain a peripheral blood cell population from each of four HIV-negative donors. After enrichment for CD4+ T-lymphocytes, ex vivo expansion and genetic manipulation (approximately equal aliquots of the cells were transduced with the ribozyme-containing (RRz2) and the control (LNL6) retroviral vector), these cells were infused into the corresponding HIV-1-positive twin recipient. Marking was assessed over an initial 24-week period and in total over an approximate 4-year period. The gene transfer procedure was shown to be safe, and technically feasible. Both RRz2- and LNL6-gene-containing peripheral blood mononuclear cells (PBMC) were detected at all time points examined to 4 years. There was concomitant gene construct expression in the absence of the need for ex vivo peripheral blood cell stimulation and there was no evidence of immune elimination of the neoR T-lymphocytes nor of silencing of the Moloney murine leukemia virus long terminal repeat. The proof of principle results reported here demonstrate safety and feasibility of this type of gene transfer approach. While not specifically tested, T-lymphocytes containing an anti-HIV gene construct may impact on HIV-1 viral load and CD4+ T-lymphocyte count, potentially representing a new therapeutic modality for HIV-1 infection.
Publisher: Elsevier BV
Date: 08-2012
DOI: 10.1016/J.CLIM.2012.06.004
Abstract: Analysis and mathematical modeling of T-lymphocyte perturbation following administration of granulocyte colony stimulating factor (G-CSF) and two large-scale aphereses are reported. 74 HIV-1 positive antiretroviral-treated in iduals were infused with gene- or sham-transduced CD34+ hematopoietic stem cells (HSC) in a Phase II clinical trial. T cell numbers were examined in four phases: 1) during steady state 2) increases in peripheral blood (PB) following G-CSF administration 3) depletion post-aphereses and 4) reconstitution post HSC infusion. The present analysis provides the first direct estimate of CD4+ T cell distribution and trafficking in HIV-infected in iduals on stable HAART, indicating that CD4+ T lymphocytes in PB represent 5.5% of the pool of CD4+ T lymphocytes that traffic to PB.
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/SH10114
Abstract: Background Australia has experienced rising notifications of HIV diagnoses despite widely available combination antiretroviral therapy (CART). New HIV diagnoses have also been younger than the average age of those living with HIV. We investigated the degree to which several risk factors could explain this rise in notifications and the younger age profile. Methods: Numbers and ages of men who have sex with men (MSM) living with HIV in Australia from 1983 to 2007 were calculated from notifications of HIV diagnoses and deaths. We compared the trend over time as well as the average ages of MSM newly diagnosed with HIV infection from 1998 to 2007 with those for: notifications of gonorrhoea and syphilis, total MSM living with HIV infection, and the component not on CART. Results: The percentage of younger MSM not taking CART has increased since 1998 (aged years P 0.001 30–39 years P = 0.004). The trend of new HIV diagnoses was most significantly correlated with the total number of MSM living with HIV infection and the sector not taking CART (P 0.0001). Based on similarity of average ages, MSM living with HIV infection and not taking CART was the best predictor of the increasing trend in new HIV diagnoses (99.9999% probability, Akaike information criterion). Conclusions: Our analyses suggest MSM living with HIV infection and not taking CART could be the source of the increase in HIV infections. Consequently, greater CART enrolment should decrease HIV incidence, especially in younger MSM.
Publisher: Public Library of Science (PLoS)
Date: 20-06-2013
Start Date: 2018
End Date: 2020
Funder: Australian Research Council
View Funded ActivityStart Date: 2010
End Date: 2012
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 2016
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: Australian Research Council
View Funded ActivityStart Date: 2018
End Date: 08-2024
Amount: $297,478.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2013
End Date: 04-2017
Amount: $285,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 08-2013
End Date: 08-2016
Amount: $340,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 02-2010
End Date: 02-2013
Amount: $360,000.00
Funder: Australian Research Council
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