How severe would prioritization-induced bottlenecks need to be offset the benefits from prioritizing COVID-19 vaccination to those most at risk in New York City?

BACKGROUND: Prioritization of higher-risk people for COVID-19 vaccination could prevent more deaths, but could slow vaccination speed. We used mathematical modeling to examine the trade-off between vaccination speed and prioritization for individuals age 65+ and essential workers. METHODS: We used a stochastic, discrete-time susceptible-exposed-infected-recovered (SEIR) model with age- and comorbidity-adjusted COVID-19 outcomes (infections, hospitalizations, and deaths). The model was calibrated to COVID-19 hospitalizations, ICU census, and deaths in NYC. We assumed 10,000 vaccinations per day, initially restricted to healthcare workers and nursing home populations, and subsequently expanded to other populations at alternative times (4, 5, or 6 weeks after vaccine launch) and speeds (20,000, 50,000, 100,000, or 150,000 vaccinations per day), as well as prioritization options (+/- prioritization of people age 65+ and essential workers). In sensitivity analyses, we examined the effect of a SARS-COV-2 variant with greater transmissibility. RESULTS: To be beneficial, prioritization must not create a bottleneck that decreases vaccination speed by > 50% without a more transmissible variant, or by > 33% with the emergence of the more transmissible variant. More specifically, prioritizing people age 65+ and essential workers increased the number of lives saved per vaccine dose delivered: 3000 deaths could be averted by delivering 83,000 vaccinations per day without prioritization or 50,000 vaccinations per day with prioritization. Other tradeoffs involve vaccination speed and timing. Compared to the slowest-examined vaccination speed of 20,000 vaccinations per day, achieving the fastest-examined vaccination speed of 150,000 vaccinations per day would avert additional 313,700 (28.6%) infections and 1693 (24.1%) deaths. Emergence of a more transmissible variant would double COVID-19 infections, hospitalizations, and deaths over the first 6 months of vaccination. The fastest-examined vaccination speed could only offset the harm of the more transmissible variant if achieved within 5 weeks of vaccine launch. CONCLUSIONS: Faster vaccination speed with sooner vaccination expansion would save more lives. Prioritization of COVID-19 vaccines to higher-risk populations would be more beneficial only if it does not create an excessive vaccine delivery bottleneck.

Policy Review and Modeling Analysis of Mitigation Measures for Coronavirus Disease Epidemic Control, Health System, and Disease Burden, South Korea.

We reviewed the timeline of key policies for control of the coronavirus disease epidemic and determined their impact on the epidemic and hospital burden in South Korea. Using a discrete stochastic transmission model, we estimated that multilevel policies, including extensive testing, contact tracing, and quarantine, reduced contact rates by 90% and rapidly decreased the epidemic in Daegu and nationwide during February‒March 2020. Absence of these prompt responses could have resulted in a >10-fold increase in infections, hospitalizations, and deaths by May 15, 2020, relative to the status quo. The model suggests that reallocation of persons who have mild or asymptomatic cases to community treatment centers helped avoid overwhelming hospital capacity and enabled healthcare workers to provide care for more severely and critically ill patients in hospital beds and negative-pressure intensive care units. As small outbreaks continue to occur, contact tracing and maintenance of hospital capacity are needed.

Glucose-lactate metabolic cooperation in cancer: insights from a spatial mathematical model and implications for targeted therapy.

A recent study has hypothesised a glucose-lactate metabolic symbiosis between adjacent hypoxic and oxygenated regions of a developing tumour, and proposed a treatment strategy to target this symbiosis. However, in vivo experimental support remains inconclusive. Here we develop a minimal spatial mathematical model of glucose-lactate metabolism to examine, in principle, whether metabolic symbiosis is plausible in human tumours, and to assess the potential impact of inhibiting it. We find that symbiosis is a robust feature of our model system-although on the length scale at which oxygen supply is diffusion-limited, its occurrence requires very high cellular metabolic activity-and that necrosis in the tumour core is reduced in the presence of symbiosis. Upon simulating therapeutic inhibition of lactate uptake, we predict that targeted treatment increases the extent of tissue oxygenation without increasing core necrosis. The oxygenation effect is correlated strongly with the extent of wild-type hypoxia and only weakly with wild-type symbiotic behaviour, and therefore may be promising for radiosensitisation of hypoxic, lactate-consuming tumours even if they do not exhibit a spatially well-defined symbiosis. Finally, we conduct in vitro experiments on the U87 glioblastoma cell line to facilitate preliminary speculation as to where highly malignant tumours might fall in our parameter space, and find that these experiments suggest a weakly symbiotic regime for U87 cells, thus raising the new question of what relationship might exist between symbiosis and tumour malignancy.

A general reaction-diffusion model of acidity in cancer invasion.

We model the metabolism and behaviour of a developing cancer tumour in the context of its microenvironment, with the aim of elucidating the consequences of altered energy metabolism. Of particular interest is the Warburg Effect, a widespread preference in tumours for cytosolic glycolysis rather than oxidative phosphorylation for glucose breakdown, as yet incompletely understood. We examine a candidate explanation for the prevalence of the Warburg Effect in tumours, the acid-mediated invasion hypothesis, by generalising a canonical non-linear reaction-diffusion model of acid-mediated tumour invasion to consider additional biological features of potential importance. We apply both numerical methods and a non-standard asymptotic analysis in a travelling wave framework to obtain an explicit understanding of the range of tumour behaviours produced by the model and how fundamental parameters govern the speed and shape of invading tumour waves. Comparison with conclusions drawn under the original system--a special case of our generalised system--allows us to comment on the structural stability and predictive power of the modelling framework.

Social distancing and mask-wearing could avoid recurrent stay-at-home restrictions during COVID-19 respiratory pandemic in New York City.

Stay-at-home restrictions such as closure of non-essential businesses were effective at reducing SARS-CoV-2 transmission in New York City (NYC) in the spring of 2020. Relaxation of these restrictions was desirable for resuming economic and social activities, but could only occur in conjunction with measures to mitigate the expected resurgence of new infections, in particular social distancing and mask-wearing. We projected the impact of individuals' adherence to social distancing and mask-wearing on the duration, frequency, and recurrence of stay-at-home restrictions in NYC. We applied a stochastic discrete time-series model to simulate community transmission and household secondary transmission in NYC. The model was calibrated to hospitalizations, ICU admissions, and COVID-attributable deaths over March-July 2020 after accounting for the distribution of age and chronic health conditions in NYC. We projected daily new infections and hospitalizations up to May 31, 2021 under the different levels of adherence to social distancing and mask-wearing after relaxation of stay-at-home restrictions. We assumed that the relaxation of stay-at-home policies would occur in the context of adaptive reopening, where a new hospitalization rate of ≥ 2 per 100,000 residents would trigger reinstatement of stay-at-home restrictions while a new hospitalization rate of ≤ 0.8 per 100,000 residents would trigger relaxation of stay-at-home restrictions. Without social distancing and mask-wearing, simulated relaxation of stay-at-home restrictions led to epidemic resurgence and necessary reinstatement of stay-at-home restrictions within 42 days. NYC would have stayed fully open for 26% of the time until May 31, 2021, alternating reinstatement and relaxation of stay-at-home restrictions in four cycles. At a low (50%) level of adherence to mask-wearing, NYC would have needed to implement stay-at-home restrictions between 8% and 32% of the time depending on individual adherence to social distancing. At moderate to high levels of adherence to mask-wearing without social distancing, NYC would have needed to implement stay-at-home restrictions. In threshold analyses, avoiding reinstatement of stay-at-home restrictions required a minimum of 60% adherence to mask-wearing at 50% adherence to social distancing. With low adherence to mask-wearing and social distancing, reinstatement of stay-at-home restrictions in NYC was inevitable. High levels of adherence to social distancing and mask-wearing could have attributed to avoiding recurrent surges without reinstatement of stay-at-home restrictions.

The influence of constraints on the efficient allocation of resources for HIV prevention.

OBJECTIVE: To investigate how 'real-world' constraints on the allocative and technical efficiency of HIV prevention programmes affect resource allocation and the number of infections averted. DESIGN: Epidemiological modelling and economic analyses in Benin, South Africa and Tanzania. METHODS: We simulated different HIV prevention programmes, and first determined the most efficient allocation of resources, in which the HIV prevention budget is shared among specific interventions, risk-groups and provinces to maximize the number of infections averted. We then identified the efficient allocation of resources and achievable impact given the following constraints to allocative efficiency: earmarking [provinces with budgets fund pre-exposure prophylaxis (PrEP) for low-risk women first], meeting targets [provinces with budgets fund universal test-and-treat (UTT) first] and minimizing changes in the geographical distribution of funds. We modelled technical inefficiencies as a reduction in the coverage of PrEP or UTT, which were factored into the resource allocation process or took effect following the allocation. Each scenario was investigated over a range of budgets, such that the impact reaches its maximum. RESULTS: The 'earmarking', 'meeting targets' and 'minimizing change' constraints reduce the potential impact of HIV prevention programmes, but at the higher budgets these constraints have little to no effect (approximately 35 billion US$ in Tanzania). Over-estimating technical efficiency can result in a loss of impact compared to what would be possible if technical efficiencies were known accurately. CONCLUSION: Failing to account for constraints on allocative and technical efficiency can result in the overestimation of the health gains possible, and for technical inefficiencies the allocation of an inefficient strategy.

The emerging health impact of voluntary medical male circumcision in Zimbabwe: An evaluation using three epidemiological models.

BACKGROUND: Zimbabwe adopted voluntary medical male circumcision (VMMC) as a priority HIV prevention strategy in 2007 and began implementation in 2009. We evaluated the costs and impact of this VMMC program to date and in future. METHODS: Three mathematical models describing Zimbabwe's HIV epidemic and program evolution were calibrated to household survey data on prevalence and risk behaviors, with circumcision coverage calibrated to program-reported VMMCs. We compared trends in new infections and costs to a counterfactual without VMMC. Input assumptions were agreed in workshops with national stakeholders in 2015 and 2017. RESULTS: The VMMC program averted 2,600-12,200 infections (among men and women combined) by the end of 2016. This impact will grow as circumcised men are protected lifelong, and onward dynamic transmission effects, which protect women via reduced incidence and prevalence in their male partners, increase over time. If other prevention interventions remain at 2016 coverages, the VMMCs already performed will avert 24,400-69,800 infections (2.3-5% of all new infections) through 2030. If coverage targets are achieved by 2021 and maintained, the program will avert 108,000-171,000 infections (10-13% of all new infections) by 2030, costing $2,100-3,250 per infection averted relative to no VMMC. Annual savings from averted treatment needs will outweigh VMMC maintenance costs once coverage targets are reached. If Zimbabwe also achieves ambitious UNAIDS targets for scaling up treatment and prevention efforts, VMMC will reduce the HIV incidence remaining at 2030 by one-third, critically contributing to the UNAIDS goal of 90% incidence reduction. CONCLUSIONS: VMMC can substantially impact Zimbabwe's HIV epidemic in the coming years; this investment will save costs in the longer term.

Consequences of a changing US strategy in the global HIV investment landscape.

OBJECTIVE: The global fight against HIV/AIDS in Africa has long been a focus of US foreign policy, but this could change if the federal budget for 2018 proposed by the US Office of Management and Budget is adopted. We aim to inform public and Congressional debate around this issue by evaluating the historical and potential future impact of US investment in the African HIV response. DESIGN/METHODS: We use a previously published mathematical model of HIV transmission to characterize the possible impact of a series of financial scenarios for the historical and future AIDS response across Sub-Saharan Africa. RESULTS: We find that US funding has saved nearly five million adults in Sub-Saharan Africa from AIDS-related deaths. In the coming 15 years, if current numbers on antiretroviral treatment are maintained without further expansion of programs (the proposed US strategy), nearly 26 million new HIV infections and 4.4 million AIDS deaths may occur. A 10% increase in US funding, together with ambitious domestic spending and focused attention on optimizing resources, can avert up to 22 million HIV infections and save 2.3 million lives in Sub-Saharan Africa compared with the proposed strategy. CONCLUSION: Our synthesis of available evidence shows that the United States has played, and could continue to play, a vital role in the global HIV response. Reduced investment could allow more than two million avoidable AIDS deaths by 2032, whereas continued leadership by the United States and other countries could bring UNAIDS targets for ending the epidemic into reach.

PrEP as a feature in the optimal landscape of combination HIV prevention in sub-Saharan Africa.

INTRODUCTION: The new WHO guidelines recommend offering pre-exposure prophylaxis (PrEP) to people who are at substantial risk of HIV infection. However, where PrEP should be prioritised, and for which population groups, remains an open question. The HIV landscape in sub-Saharan Africa features limited prevention resources, multiple options for achieving cost saving, and epidemic heterogeneity. This paper examines what role PrEP should play in optimal prevention in this complex and dynamic landscape. METHODS: We use a model that was previously developed to capture subnational HIV transmission in sub-Saharan Africa. With this model, we can consider how prevention funds could be distributed across and within countries throughout sub-Saharan Africa to enable optimal HIV prevention (that is, avert the greatest number of infections for the lowest cost). Here, we focus on PrEP to elucidate where, and to whom, it would optimally be offered in portfolios of interventions (alongside voluntary medical male circumcision, treatment as prevention, and behaviour change communication). Over a range of continental expenditure levels, we use our model to explore prevention patterns that incorporate PrEP, exclude PrEP, or implement PrEP according to a fixed incidence threshold. RESULTS: At low-to-moderate levels of total prevention expenditure, we find that the optimal intervention portfolios would include PrEP in only a few regions and primarily for female sex workers (FSW). Prioritisation of PrEP would expand with increasing total expenditure, such that the optimal prevention portfolios would offer PrEP in more subnational regions and increasingly for men who have sex with men (MSM) and the lower incidence general population. The marginal benefit of including PrEP among the available interventions increases with overall expenditure by up to 14% (relative to excluding PrEP). The minimum baseline incidence for the optimal offer of PrEP declines for all population groups as expenditure increases. We find that using a fixed incidence benchmark to guide PrEP decisions would incur considerable losses in impact (up to 7%) compared with an approach that uses PrEP more flexibly in light of prevailing budget conditions. CONCLUSIONS: Our findings suggest that, for an optimal distribution of prevention resources, choices of whether to implement PrEP in subnational regions should depend on the scope for impact of other possible interventions, local incidence in population groups, and total resources available. If prevention funding were to become restricted in the future, it may be suboptimal to use PrEP according to a fixed incidence benchmark, and other prevention modalities may be more cost-effective. In contrast, expansions in funding could permit PrEP to be used to its full potential in epidemiologically driven prevention portfolios and thereby enable a more cost-effective HIV response across Africa.

Optimum resource allocation to reduce HIV incidence across sub-Saharan Africa: a mathematical modelling study.

BACKGROUND: Advances in HIV prevention methods offer promise to accelerate declines in incidence, but how these methods can be deployed to have the best effect on the heterogeneous landscape and drivers of the pandemic remains unclear. We postulated that use of epidemic heterogeneity to inform the allocation of resources for combination HIV prevention could enhance the impact of HIV funding across sub-Saharan Africa. METHODS: We developed a compartmental mathematical model of HIV transmission and disease progression by risk group to subnational resolution in 18 countries, capturing 80% of the adult HIV burden in sub-Saharan Africa. Adults aged 15-49 years were grouped by risk of HIV acquisition and transmission, and those older than 50 years were assumed to have negligible risk. For each top-level administrative division, we calibrated the model to historical data for HIV prevalence, sexual behaviours, treatment scale-up, and demographics. We then evaluated four strategies for allocation of prevention funding over a 15 year period from 2016 to 2030, which exploited epidemic differences between subnational regions to varying degrees. FINDINGS: For a $US20 billion representative expenditure over the 15 year period, scale-up of prevention along present funding channels could avert 5·3 million infections relative to no scale-up. Prioritisation of key populations could avert 3·7 million more infections than present funding channels, and additional prioritisation by within-country geography could avert 400 000 more infections. Removal of national constraints could avert a further 600 000 infections. Risk prioritisation has greater marginal impact than geographical prioritisation across multiple expenditure levels. However, targeting by both risk and geography is best for total impact and could achieve gains of up to three times more than present channels. A shift from the present pattern to the optimum pattern would rebalance resources towards more cost-effective interventions and emerging epidemics. INTERPRETATION: If domestic and international funders were to align strategically to build an aggregate funding pattern that is guided by the epidemiology of HIV, and particularly by the emerging understanding of local dynamics and epidemic drivers, more cost-effective and impactful HIV prevention investments could be achieved across sub-Saharan Africa. FUNDING: The Bill & Melinda Gates Foundation.

Maximising HIV prevention by balancing the opportunities of today with the promises of tomorrow: a modelling study.

BACKGROUND: Many ways of preventing HIV infection have been proposed and more are being developed. We sought to construct a strategic approach to HIV prevention that would use limited resources to achieve the greatest possible prevention impact through the use of interventions available today and in the coming years. METHODS: We developed a deterministic compartmental model of heterosexual HIV transmission in South Africa and formed assumptions about the costs and effects of a range of interventions, encompassing the further scale-up of existing interventions (promoting condom use, male circumcision, early antiretroviral therapy [ART] initiation for all [including increased HIV testing and counselling activities], and oral pre-exposure prophylaxis [PrEP]), the introduction of new interventions in the medium term (offering intravaginal rings, long-acting injectable antiretroviral drugs) and long term (vaccine, broadly neutralising antibodies [bNAbs]). We examined how available resources could be allocated across these interventions to achieve maximum impact, and assessed how this would be affected by the failure of the interventions to be developed or scaled up. FINDINGS: If all interventions are available, the optimum mix would place great emphasis on the following: scale-up of male circumcision and early ART initiation with outreach testing, as these are available immediately and assumed to be low cost and highly efficacious; intravaginal rings targeted to sex workers; and vaccines, as these can achieve a large effect if scaled up even if imperfectly efficacious. The optimum mix would rely less on longer term developments, such as long-acting antiretroviral drugs and bNAbs, unless the costs of these reduced. However, if impossible to scale up existing interventions to the extent assumed, emphasis on oral PrEP, intravaginal rings, and long-acting antiretroviral drugs would increase. The long-term effect on the epidemic is most affected by scale-up of existing interventions and the successful development of a vaccine. INTERPRETATION: With current information, a strategic approach in which limited resources are used to maximise prevention impact would focus on strengthening the scale-up of existing interventions, while pursuing a workable vaccine and developing other approaches that can be used if further scale-up of existing interventions is limited. FUNDING: Bill & Melinda Gates Foundation.