School of Mathematics and Statistics - Research Publications
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ItemAssessing the utility of an anti-malarial pharmacokinetic-pharmacodynamic model for aiding drug clinical development(BIOMED CENTRAL LTD, 2012-08-30)BACKGROUND: Mechanistic within-host models relating blood anti-malarial drug concentrations with the parasite-time profile help in assessing dosing schedules and partner drugs for new anti-malarial treatments. A comprehensive simulation study to assess the utility of a stage-specific pharmacokinetic-pharmacodynamic (PK-PD) model for predicting within-host parasite response was performed. METHODS: Three anti-malarial combination therapies were selected: artesunate-mefloquine, dihydroartemisinin-piperaquine, and artemether-lumefantrine. The PK-PD model included parameters to represent the concentration-time profiles of both drugs, the initial parasite burden and distribution across the parasite life cycle, and the parasite multiplication factor due to asexual reproduction. The model also included the maximal killing rate of each drug, and the blood drug concentration associated with half of that killing effect (in vivo EC50), derived from the in vitro IC50, the extent of binding to 0.5% Albumax present in the in vitro testing media, and the drugs plasma protein binding and whole blood to plasma partitioning ratio. All stochastic simulations were performed using a Latin-Hypercube-Sampling approach. RESULTS: The simulations demonstrated that the proportion of patients cured was highly sensitive to the in vivo EC50 and the maximal killing rate of the partner drug co-administered with the artemisinin derivative. The in vivo EC50 values that corresponded to on average 95% of patients cured were much higher than the adjusted values derived from the in vitro IC50. The proportion clinically cured was not strongly influenced by changes in the parameters defining the age distribution of the initial parasite burden (mean age of 4 to 16 hours) and the parasite multiplication factor every life cycle (ranging from 8 to 12 fold/cycle). The median parasite clearance times, however, lengthened as the standard deviation of the initial parasite burden increased (i.e. the infection became more asynchronous). CONCLUSIONS: This simulation study demonstrates that the PD effect predicted from in vitro growth inhibition assays does not accord well with the PD effect of the anti-malarials observed within the patient. This simulation-based PK-PD modelling approach should not be considered as a replacement to conducting clinical trials but instead as a decision tool to improve the design of a clinical trial during drug development.
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ItemApplication of a case-control study design to investigate genotypic signatures of HIV-1 transmission(BMC, 2012-06-25)BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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 divergent between transmission and chronic strains of either subtype. The success of a transmission strain to initiate infection may be a random event from the divergent 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.
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ItemHousehold transmission of respiratory viruses - assessment of viral, individual and household characteristics in a population study of healthy Australian adults(BMC, 2012-12-11)BACKGROUND: Household transmission of influenza-like illness (ILI) may vary with viral and demographic characteristics. We examined the effect of these factors in a population-based sample of adults with ILI. METHODS: We conducted a prospective cohort study in community-dwelling Australian adults nested within an influenza vaccine effectiveness trial. On presentation with ILI, participants were swabbed for a range of respiratory viruses and asked to return a questionnaire collecting details of household members with or without similar symptoms. We used logistic and Poisson regression to assess the key characteristics of household transmission. RESULTS: 258 participants from multi-occupancy households experienced 279 ILI episodes and returned a questionnaire. Of these, 183 were the primary case in the household allowing assessment of factors associated with transmission. Transmission was significantly associated in univariate analyses with female sex (27% vs. 13%, risk ratio (RR) = 2.13 (1.08, 4.21)) and the presence of a child in the house (33% vs. 17%, RR = 1.90 (1.11, 3.26)). The secondary household attack proportion (SHAP) was 0.14, higher if influenza was isolated (RR = 2.1 (1.0, 4.5)). Vaccinated participants who nonetheless became infected with influenza had a higher SHAP (Incidence RR = 5.24 (2.17, 12.6)). CONCLUSIONS: The increased SHAP in households of vaccinated participants who nonetheless had confirmed influenza infection supports the hypothesis that in years of vaccine mismatch, not only is influenza vaccine less protective for the vaccine recipient, but that the population's immunity is also lower.
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ItemLikely effectiveness of pharmaceutical and non-pharmaceutical interventions for mitigating influenza virus transmission in Mongolia(WORLD HEALTH ORGANIZATION, 2012-04)OBJECTIVE: To assess the likely benefit of the interventions under consideration for use in Mongolia during future influenza pandemics. METHODS: A stochastic, compartmental patch model of susceptibility, exposure, infection and recovery was constructed to capture the key effects of several interventions--travel restrictions, school closure, generalized social distancing, quarantining of close contacts, treatment of cases with antivirals and prophylaxis of contacts--on the dynamics of influenza epidemics. The likely benefit and optimal timing and duration of each of these interventions were assessed using Latin-hypercube sampling techniques, averaging across many possible transmission and social mixing parameters. FINDINGS: Timely interventions could substantially alter the time-course and reduce the severity of pandemic influenza in Mongolia. In a moderate pandemic scenario, early social distancing measures decreased the mean attack rate from around 10% to 7-8%. Similarly, in a severe pandemic scenario such measures cut the mean attack rate from approximately 23% to 21%. In both moderate and severe pandemic scenarios, a suite of non-pharmaceutical interventions proved as effective as the targeted use of antivirals. Targeted antiviral campaigns generally appeared more effective in severe pandemic scenarios than in moderate pandemic scenarios. CONCLUSION: A mathematical model of pandemic influenza transmission in Mongolia indicated that, to be successful, interventions to prevent transmission must be triggered when the first cases are detected in border regions. If social distancing measures are introduced at this stage and implemented over several weeks, they may have a notable mitigating impact. In low-income regions such as Mongolia, social distancing may be more effective than the large-scale use of antivirals.
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ItemInfluence of Contact Definitions in Assessment of the Relative Importance of Social Settings in Disease Transmission Risk(PUBLIC LIBRARY SCIENCE, 2012-02-16)BACKGROUND: Realistic models of disease transmission incorporating complex population heterogeneities require input from quantitative population mixing studies. We use contact diaries to assess the relative importance of social settings in respiratory pathogen spread using three measures of person contact hours (PCH) as proxies for transmission risk with an aim to inform bipartite network models of respiratory pathogen transmission. METHODS AND FINDINGS: Our survey examines the contact behaviour for a convenience sample of 65 adults, with each encounter classified as occurring in a work, retail, home, social, travel or "other" setting. The diary design allows for extraction of PCH-interaction (cumulative time in face-face conversational or touch interaction with contacts)--analogous to the contact measure used in several existing surveys--as well as PCH-setting (product of time spent in setting and number of people present) and PCH-reach (product of time spent in setting and number of people in close proximity). Heterogeneities in day-dependent distribution of risk across settings are analysed using partitioning and cluster analyses and compared between days and contact measures. Although home is typically the highest-risk setting when PCH measures isolate two-way interactions, its relative importance compared to social and work settings may reduce when adopting a more inclusive contact measure that considers the number and duration of potential exposure events. CONCLUSIONS: Heterogeneities in location-dependent contact behaviour as measured by contact diary studies depend on the adopted contact definition. We find that contact measures isolating face-face conversational or touch interactions suggest that contact in the home dominates, whereas more inclusive contact measures indicate that home and work settings may be of higher importance. In the absence of definitive knowledge of the contact required to facilitate transmission of various respiratory pathogens, it is important for surveys to consider alternative contact measures.
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ItemNo Preview AvailableDrivers and consequences of influenza antiviral resistant-strain emergence in a capacity-constrained pandemic response(ELSEVIER SCIENCE BV, 2012-12)Antiviral agents remain a key component of most pandemic influenza preparedness plans, but there is considerable uncertainty regarding their optimal use. In particular, concerns exist regarding the likelihood of wide-scale distribution to select for drug-resistant variants. We used a model that considers the influence of logistical constraints on diagnosis and drug delivery to consider achievable 'reach' of alternative antiviral intervention strategies targeted at cases of varying severity, with or without pre-exposure prophylaxis of contacts. To identify key drivers of epidemic mitigation and resistance emergence, we used Latin hypercube sampling to explore plausible ranges of parameters describing characteristics of wild type and resistant viruses, along with intervention efficacy, target coverage and distribution capacity. Within our model framework, 'real world' constraints substantially reduced achievable drug coverage below stated targets as the epidemic progressed. In consequence, predictions of both intervention impact and selection for resistance were more modest than earlier work that did not consider such limitations. Definitive containment of transmission was unlikely but, where observed, achieved through early liberal post-exposure prophylaxis of known contacts of treated cases. Predictors of resistant strain dominance were high intrinsic fitness relative to the wild type virus, and early emergence in the course of the epidemic into a largely susceptible population, even when drug use was restricted to severe case treatment. Our work demonstrates the importance of consideration of 'real world' constraints in scenario analysis modeling, and highlights the utility of models to guide surveillance activities in preparedness and response.