The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim (COVID-19 Agent-based Simulator), an open-source model developed to help address these questions. Covasim includes country-specific demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, long-term care facilities, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing and protective equipment; pharmaceutical interventions, including vaccination; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. Implemented in pure Python, Covasim has been designed with equal emphasis on performance, ease of use, and flexibility: realistic and highly customized scenarios can be run on a standard laptop in under a minute. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine epidemic dynamics and inform policy decisions in more than a dozen countries in Africa, Asia-Pacific, Europe, and North America.

The COVID-19 pandemic has created an urgent need for models that can project epidemic trends, explore intervention scenarios, and estimate resource needs. Here we describe the methodology of Covasim , an open-source model developed to help address these questions. Covasim includes demographic information on age structure and population size; realistic transmission networks in different social layers, including households, schools, workplaces, and communities; age-specific disease outcomes; and intrahost viral dynamics, including viral-load-based transmissibility. Covasim also supports an extensive set of interventions, including non-pharmaceutical interventions, such as physical distancing, hygiene measures, and protective equipment; and testing interventions, such as symptomatic and asymptomatic testing, isolation, contact tracing, and quarantine. These interventions can incorporate the effects of delays, loss-to-follow-up, micro-targeting, and other factors. In collaboration with local health agencies and policymakers, Covasim has already been applied to examine disease dynamics and policy options in Africa, Europe, Oceania, and North America.

Background New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly. Methods We used multiple independent mathematical models in four settings—South Africa, Zambia, India, and Vietnam—to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered ‘very cost-effective’ if the $/DALY was less than the country’s per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and ‘cost-effective’ if $/DALY was less than three times per capita GDP. Findings In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective. Interpretation Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets. Funding The Bill and Melinda Gates Foundation and World Health Organization

Bill and Melinda Gates Foundation.

Next-generation sequencing (NGS) enables the highly sensitive measurement of whole transcriptomes. We report the first application to our knowledge of this technology to the analysis of RNA from a CD4+ T cell line infected with intact HIV. We sequenced the total mRNA from infected cells and detected differences in the expression of both host and viral mRNA. Viral reads represented a large portion of the total mapped sequencing reads: approximately 20% at 12 h postinfection (hpi) and 40% at 24 hpi. We also detected a small but significant suppression of T cell activation-related genes at 12 hpi. This suppression persisted and expanded by 24 hpi, providing new possible markers of virus-induced T cell cytopathology. By 24 hpi, the expression of over 50% of detectable host loci was also altered, indicating widespread alteration of host processes, including RNA processing, splicing, and transport to an extent not previously reported. In addition, next-generation sequencing provided insights into alternative viral RNA splice events and the expression of noncoding RNAs, including microRNA host genes.

BACKGROUND The End TB Strategy sets global goals of reducing TB incidence and mortality by 50% and 75% respectively by 2025. We assessed resource requirements and cost-effectiveness of strategies to achieve these targets in China, India, and South Africa. METHODS We examined intervention scenarios developed in consultation with country stakeholders, which scaled-up existing interventions to high but feasible coverage by 2025. Nine independent TB modelling groups collaborated to estimate policy outcomes, and we costed each scenario by synthesizing service utilization estimates, empirical cost data, and expert opinion on implementation strategies. We estimated health impact and resource implications for 2016–2035, including patient-incurred costs. To assess resource requirements and cost-effectiveness, we compared scenarios to a base case representing continued current practice. FINDINGS Incremental TB service costs differed by scenario and country, and in some cases more than doubled current funding needs. In general, expanding TB services substantially reduced patient-incurred costs; and in India and China this produced net cost-savings for most interventions under a societal perspective. In all countries, expanding TB care access produced substantial health gains. Compared to current practice, most intervention approaches appeared highly cost-effective when compared to conventional cost-effectiveness thresholds. INTERPRETATION Expanding TB services appears cost-effective for high-burden countries and could generate substantial health and economic benefits for patients, though funding needs challenge affordability. Further work is required to determine the optimal intervention mix for each country.

Previous experimental studies suggest that Mycobacterium tuberculosis inhibits a number of macrophage intracellular processes associated with antigen presentation, including antigen processing, MHC class II expression, trafficking of MHC class II molecules, and peptide-MHC class II binding. In this study, we investigate why multiple mechanisms have been observed. Specifically, we consider what purpose multiple mechanisms may serve, whether experimental protocols favor the detection of some mechanisms over others, and whether alternative mechanisms exist. By using a mathematical model of antigen presentation in macrophages that tracks levels of various molecules, including peptide-MHC class II complexes on the cell surface, we show that mechanisms targeting MHC class II expression are effective at inhibiting antigen presentation, but only after a delay of at least 10 h. By comparison, the effectiveness of mechanisms targeting other cellular processes is immediate, but may be attenuated under certain conditions. Therefore, targeting multiple cellular processes may represent an optimal strategy for M. tuberculosis (and other pathogens with relatively long doubling times) to maintain continuous inhibition of antigen presentation. In addition, based on a sensitivity analysis of the model, we identify other cellular processes that may be targeted by such pathogens to accomplish the same effect, representing potentially novel mechanisms.antigen processing ͉ mathematical model ͉ HLA ͉ cell-mediated immunity

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