Model design for non-parametric phylodynamic inference and applications to pathogen surveillance.

Inference of effective population size from genomic data can provide unique information about demographic history, and when applied to pathogen genetic data can also provide insights into epidemiological dynamics. The combination of non-parametric models for population dynamics with molecular clock models which relate genetic data to time has enabled phylodynamic inference based on large sets of time-stamped genetic sequence data. The methodology for non-parametric inference of effective population size is well-developed in the Bayesian setting, but here we develop a frequentist approach based on non-parametric latent process models of population size dynamics. We appeal to statistical principles based on out-of-sample prediction accuracy in order to optimize parameters that control shape and smoothness of the population size over time. We demonstrate the flexibility and speed of this approach in a series of simulation experiments, and apply the methodology to reconstruct the previously described waves in the seventh pandemic of cholera. We also estimate the impact of non-pharmaceutical interventions for COVID-19 in England using thousands of SARS-CoV-2 sequences. By incorporating a measure of the strength of these interventions over time within the phylodynamic model, we estimate the impact of the first national lockdown in the UK on the epidemic reproduction number.

Genetic evidence for the association between COVID-19 epidemic severity and timing of non-pharmaceutical interventions.

Unprecedented public health interventions including travel restrictions and national lockdowns have been implemented to stem the COVID-19 epidemic, but the effectiveness of non-pharmaceutical interventions is still debated. We carried out a phylogenetic analysis of more than 29,000 publicly available whole genome SARS-CoV-2 sequences from 57 locations to estimate the time that the epidemic originated in different places. These estimates were examined in relation to the dates of the most stringent interventions in each location as well as to the number of cumulative COVID-19 deaths and phylodynamic estimates of epidemic size. Here we report that the time elapsed between epidemic origin and maximum intervention is associated with different measures of epidemic severity and explains 11% of the variance in reported deaths one month after the most stringent intervention. Locations where strong non-pharmaceutical interventions were implemented earlier experienced much less severe COVID-19 morbidity and mortality during the period of study.

Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England.

The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England1, was first identified in the UK in late summer to early autumn 20202. Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number.

Assessing the Potential Impact of Disruptions Due to COVID-19 on HIV Among Key and Lower-Risk Populations in the Largest Cities of Cameroon and Benin.

BACKGROUND: The COVID-19 pandemic indirectly impacts HIV epidemiology in Central/West Africa. We estimated the potential impact of COVID-19-related disruptions to HIV prevention/treatment services and sexual partnerships on HIV incidence and HIV-related deaths among key populations including female sex workers (FSW), their clients, men who have sex with men, and overall. SETTING: Yaoundé (Cameroon) and Cotonou (Benin). METHODS: We used mathematical models of HIV calibrated to city population-specific and risk population-specific demographic/behavioral/epidemic data. We estimated the relative change in 1-year HIV incidence and HIV-related deaths for various disruption scenarios of HIV prevention/treatment services and decreased casual/commercial partnerships, compared with a scenario without COVID-19. RESULTS: A 50% reduction in condom use in all partnerships over 6 months would increase 1-year HIV incidence by 39%, 42%, 31%, and 23% among men who have sex with men, FSW, clients, and overall in Yaoundé, respectively, and 69%, 49%, and 23% among FSW, clients, and overall, respectively, in Cotonou. Combining a 6-month interruption of ART initiation and 50% reduction in HIV prevention/treatment use would increase HIV incidence by 50% and HIV-related deaths by 20%. This increase in HIV infections would be halved by a simultaneous 50% reduction in casual and commercial partnerships. CONCLUSIONS: Reductions in condom use after COVID-19 would increase infections among key populations disproportionately, particularly FSW in Cotonou, who need uninterrupted condom provision. Disruptions in HIV prevention/treatment services have the biggest impacts on HIV infections and deaths overall, only partially mitigated by equal reductions in casual/commercial sexual partnerships. Maintaining ART provision must be prioritized to minimize short-term excess HIV-related deaths.

Genomic epidemiology of a densely sampled COVID-19 outbreak in China.

Analysis of genetic sequence data from the SARS-CoV-2 pandemic can provide insights into epidemic origins, worldwide dispersal, and epidemiological history. With few exceptions, genomic epidemiological analysis has focused on geographically distributed data sets with few isolates in any given location. Here, we report an analysis of 20 whole SARS- CoV-2 genomes from a single relatively small and geographically constrained outbreak in Weifang, People's Republic of China. Using Bayesian model-based phylodynamic methods, we estimate a mean basic reproduction number (R 0) of 3.4 (95% highest posterior density interval: 2.1-5.2) in Weifang, and a mean effective reproduction number (Rt) that falls below 1 on 4 February. We further estimate the number of infections through time and compare these estimates to confirmed diagnoses by the Weifang Centers for Disease Control. We find that these estimates are consistent with reported cases and there is unlikely to be a large undiagnosed burden of infection over the period we studied.

Reduction in mobility and COVID-19 transmission.

In response to the COVID-19 pandemic, countries have sought to control SARS-CoV-2 transmission by restricting population movement through social distancing interventions, thus reducing the number of contacts. Mobility data represent an important proxy measure of social distancing, and here, we characterise the relationship between transmission and mobility for 52 countries around the world. Transmission significantly decreased with the initial reduction in mobility in 73% of the countries analysed, but we found evidence of decoupling of transmission and mobility following the relaxation of strict control measures for 80% of countries. For the majority of countries, mobility explained a substantial proportion of the variation in transmissibility (median adjusted R-squared: 48%, interquartile range - IQR - across countries [27-77%]). Where a change in the relationship occurred, predictive ability decreased after the relaxation; from a median adjusted R-squared of 74% (IQR across countries [49-91%]) pre-relaxation, to a median adjusted R-squared of 30% (IQR across countries [12-48%]) post-relaxation. In countries with a clear relationship between mobility and transmission both before and after strict control measures were relaxed, mobility was associated with lower transmission rates after control measures were relaxed indicating that the beneficial effects of ongoing social distancing behaviours were substantial.

The potential effect of COVID-19-related disruptions on HIV incidence and HIV-related mortality among men who have sex with men in the USA: a modelling study.

BACKGROUND: During the COVID-19 pandemic, men who have sex with men (MSM) in the USA have reported similar or fewer sexual partners and reduced HIV testing and care access compared with before the pandemic. Pre-exposure prophylaxis (PrEP) use has also declined. We aimed to quantify the potential effect of COVID-19 on HIV incidence and HIV-related mortality among US MSM. METHODS: We used a calibrated, deterministic, compartmental HIV transmission model for MSM in Baltimore (MD, USA) and available data on COVID-19-related disruptions to HIV services to predict effects of reductions in sexual partners (0%, 25%, 50%), condom use (5%), HIV testing (20%), viral suppression (10%), PrEP initiations (72%), PrEP adherence (9%), and antiretroviral therapy (ART) initiations (50%). In our main analysis, we modelled disruptions due to COVID-19 starting Jan 1, 2020, and lasting 6 months. We estimated the median change in cumulative new HIV infections and HIV-related deaths among MSM over 1 and 5 years, compared with a base case scenario without COVID-19-related disruptions. FINDINGS: A 25% reduction in sexual partners for 6 months among MSM in Baltimore, without HIV service changes, could reduce new HIV infections by median 12·2% (95% credible interval 11·7 to 12·8) over 1 year and median 3·0% (2·6 to 3·4) over 5 years. In the absence of changes in sexual behaviour, the 6-month estimated reductions in condom use, HIV testing, viral suppression, PrEP initiations, PrEP adherence, and ART initiations combined are predicted to increase new HIV infections by median 10·5% (5·8 to 16·5) over 1 year, and by median 3·5% (2·1 to 5·4) over 5 years. Disruptions to ART initiations and viral suppression are estimated to substantially increase HIV-related deaths (ART initiations by median 1·7% [0·8 to 3·2], viral suppression by median 9·5% [5·2 to 15·9]) over 1 year, with smaller proportional increases over 5 years. The other individual disruptions (to HIV testing, PrEP and condom use, PrEP initiation, and partner numbers) were estimated to have little effect on HIV-related deaths (<1% change over 1 or 5 years). A 25% reduction in sexual partnerships is estimated to offset the effect of the combined service disruptions on new HIV infections (change over 1 year: median -3·9% [-7·4 to 1·0]; over 5 years: median 0·0% [-0·9 to 1·4]), but not on HIV deaths (change over 1 year: 11·0% [6·2 to 17·7]; over 5 years: 2·6% [1·5 to 4·3]). INTERPRETATION: Maintaining access to ART and adherence support is of the utmost importance to maintain viral suppression and minimise excess HIV-related mortality due to COVID-19 restrictions in the USA, even if disruptions to services are accompanied by reductions in sexual partnerships. FUNDING: National Institutes of Health.

Mathematical Model Impact Analysis of a Real-Life Pre-exposure Prophylaxis and Treatment-As-Prevention Study Among Female Sex Workers in Cotonou, Benin.

BACKGROUND: Daily pre-exposure prophylaxis (PrEP) and treatment-as-prevention (TasP) reduce HIV acquisition and transmission risk, respectively. A demonstration study (2015-2017) assessed TasP and PrEP feasibility among female sex workers (FSW) in Cotonou, Benin. SETTING: Cotonou, Benin. METHODS: We developed a compartmental HIV transmission model featuring PrEP and antiretroviral therapy (ART) among the high-risk (FSW and clients) and low-risk populations, calibrated to historical epidemiological and demonstration study data, reflecting observed lower PrEP uptake, adherence and retention compared with TasP. We estimated the population-level impact of the 2-year study and several 20-year intervention scenarios, varying coverage and adherence independently and together. We report the percentage [median, 2.5th-97.5th percentile uncertainty interval (95% UI)] of HIV infections prevented comparing the intervention and counterfactual (2017 coverages: 0% PrEP and 49% ART) scenarios. RESULTS: The 2-year study (2017 coverages: 9% PrEP and 83% ART) prevented an estimated 8% (95% UI 6-12) and 6% (3-10) infections among FSW over 2 and 20 years, respectively, compared with 7% (3-11) and 5% (2-9) overall. The PrEP and TasP arms prevented 0.4% (0.2-0.8) and 4.6% (2.2-8.7) infections overall over 20 years, respectively. Twenty-year PrEP and TasP scale-ups (2035 coverages: 47% PrEP and 88% ART) prevented 21% (17-26) and 17% (10-27) infections among FSW, respectively, and 5% (3-10) and 17% (10-27) overall. Compared with TasP scale-up alone, PrEP and TasP combined scale-up prevented 1.9× and 1.2× more infections among FSW and overall, respectively. CONCLUSIONS: The demonstration study impact was modest, and mostly from TasP. Increasing PrEP adherence and coverage improves impact substantially among FSW, but little overall. We recommend TasP in prevention packages.

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant.

Estimating the potential impact of COVID-19-related disruptions on HIV incidence and mortality among men who have sex with men in the United States: a modelling study.

BACKGROUND: During the COVID-19 pandemic, gay and other men who have sex with men (MSM) in the United States (US) report similar or fewer sexual partners and reduced HIV testing and care access. Pre-exposure prophylaxis (PrEP) use has declined. We estimated the potential impact of COVID-19 on HIV incidence and mortality among US MSM. METHODS: We used a calibrated HIV transmission model for MSM in Baltimore, Maryland, and available data on COVID-19-related disruptions to predict impacts of data-driven reductions in sexual partners(0%,25%,50%), condom use(5%), HIV testing(20%), viral suppression(10%), PrEP initiations(72%), PrEP use(9%) and ART initiations(50%), exploring different disruption durations and magnitudes. We estimated the median (95% credible interval) change in cumulative new HIV infections and deaths among MSM over one and five years, compared with a scenario without COVID-19-related disruptions. FINDINGS: A six-month 25% reduction in sexual partners among Baltimore MSM, without HIV service changes, could reduce new HIV infections by 12·2%(11·7,12·8%) and 3·0%(2·6,3·4%) over one and five years, respectively. In the absence of changes in sexual behaviour, the six-month data-driven disruptions to condom use, testing, viral suppression, PrEP initiations, PrEP use and ART initiations combined were predicted to increase new HIV infections by 10·5%(5·8,16·5%) over one year, and by 3·5%(2·1,5·4%) over five years. A 25% reduction in partnerships offsets the negative impact of these combined service disruptions on new HIV infections (overall reduction 3·9%(-1·0,7·4%), 0·0%(-1·4,0·9%) over one, five years, respectively), but not on HIV deaths (corresponding increases 11·0%(6·2,17·7%), 2·6%(1·5,4·3%)). The predicted impacts of reductions in partnerships or viral suppression doubled if they lasted 12 months or if disruptions were twice as large. INTERPRETATION: Maintaining access to ART and adherence support is of the utmost importance to minimise excess HIV-related mortality due to COVID-19 restrictions in the US, even if accompanied by reductions in sexual partnerships. FUNDING: NIH. RESEARCH IN CONTEXT: Evidence before this study: The COVID-19 pandemic and responses to it have disrupted HIV prevention and treatment services and led to changes in sexual risk behaviour in the United States, but the overall potential impact on HIV transmission and HIV-related mortality is not known. We searched PubMed for articles documenting COVID-related disruptions to HIV prevention and treatment and changes in sexual risk behaviour in the United States, published between 1 st January and 7 th October 2020, with no language restrictions, using the terms COVID* AND (HIV OR AIDS) AND ("United States" OR US). We identified three cross-sectional surveys assessing changes in sexual risk behaviour among men who have sex with men (MSM) in the United States, one finding a reduction, one a slight increase, and one no change in partner numbers during COVID-19 restrictions. Two of these studies also found reductions in reported HIV testing, HIV care and/or access to pre-exposure prophylaxis (PrEP) among MSM due to COVID-19. A separate study from a San Francisco clinic found declines in viral suppression among its clients during lockdown. We searched PubMed for articles estimating the impact of COVID-related disruptions on HIV transmission and mortality published between 1 st January 2020 and 12 th October 2020, with no language restrictions, using the following terms: COVID* AND model* AND (HIV OR AIDS). We identified two published studies which had used mathematical modelling to estimate the impact of hypothetical COVID-19-related disruptions to HIV programmes on HIV-related deaths and/or new HIV infections in Africa, another published study using modelling to estimate the impact of COVID-19-related disruptions and linked HIV and SARS-CoV-2 testing on new HIV infections in six cities in the United States, and a pre-print reporting modelling of the impact of COVID-19-related disruptions on HIV incidence among men who have sex with men in Atlanta, United States. None of these studies were informed by data on the size of these disruptions. The two African studies and the Atlanta study assessed the impact of disruptions to different healthcare disruptions separately, and all found that the greatest negative impacts on new HIV infections and/or deaths would arise from interruptions to antiretroviral therapy. They all found smaller effects on HIV-related mortality and/or incidence from other healthcare disruptions, including HIV testing, PrEP use and condom supplies. The United States study assessing the impact of linked HIV and SARS-CoV-2 testing estimated that this could substantially reduce HIV incidence. Added value of this study: We used mathematical modelling to derive estimates of the potential impact of the COVID-19 pandemic and associated restrictions on HIV incidence and mortality among MSM in the United States, directly informed by data from the United States on disruptions to HIV testing, antiretroviral therapy and pre-exposure prophylaxis services and reported changes in sexual risk behaviour during the COVID-19 pandemic. We also assessed the impact of an HIV testing campaign during COVID-19 lockdown.Implications of all the available evidence: In the United States, maintaining access to antiretroviral therapy and adherence support for both existing and new users will be crucial to minimize excess HIV-related deaths arising from the COVID-19 pandemic among men who have sex with men. While reductions in sexual risk behaviour may offset increases in new HIV infections arising from disruptions to HIV prevention and treatment services, this will not offset the additional HIV-related deaths which are also predicted to occur. There are mixed findings on the impact of an HIV testing campaign among US MSM during COVID-19 lockdown. Together, these studies highlight the importance of maintaining effective HIV treatment provision during the COVID-19 pandemic.

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City region.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.

Sequencing identifies multiple early introductions of SARS-CoV-2 to the New York City Region.

Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in Spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.

The impact of COVID-19 and strategies for mitigation and suppression in low- and middle-income countries.

The ongoing coronavirus disease 2019 (COVID-19) pandemic poses a severe threat to public health worldwide. We combine data on demography, contact patterns, disease severity, and health care capacity and quality to understand its impact and inform strategies for its control. Younger populations in lower-income countries may reduce overall risk, but limited health system capacity coupled with closer intergenerational contact largely negates this benefit. Mitigation strategies that slow but do not interrupt transmission will still lead to COVID-19 epidemics rapidly overwhelming health systems, with substantial excess deaths in lower-income countries resulting from the poorer health care available. Of countries that have undertaken suppression to date, lower-income countries have acted earlier. However, this will need to be maintained or triggered more frequently in these settings to keep below available health capacity, with associated detrimental consequences for the wider health, well-being, and economies of these countries.

Phylodynamic analysis of HIV-1 subtypes B, C and CRF 02_AG in Senegal.

Surveillance of HIV epidemics in key populations and in developing countries is often challenging due to sparse, incomplete, or low-quality data. Analysis of HIV sequence data can provide an alternative source of information about epidemic history, population structure, and transmission patterns. To understand HIV-1 dynamics and transmission patterns in Senegal, we carried out model-based phylodynamic analyses using the structured-coalescent approach using HIV-1 sequence data from three different subgroups: reproductive aged males and females from the adult Senegalese population and men who have sex with other men (MSM). We fitted these phylodynamic analyses to time-scaled phylogenetic trees individually for subtypes C and CRF 02_AG, and for the combined data for subtypes B, C and CRF 02_AG. In general, the combined analysis showed a decreasing proportion of effective number of infections among all reproductive aged adults relative to MSM. However, we observed a nearly time-invariant distribution for subtype CRF 02_AG and an increasing trend for subtype C on the proportion of effective number of infections. The population attributable fraction also differed between analyses: subtype CRF 02_AG showed little contribution from MSM, while for subtype C and combined analyses this contribution was much higher. Despite observed differences, results suggested that the combination of high assortativity among MSM and the unmet HIV prevention and treatment needs represent a significant component of the HIV epidemic in Senegal.

Early antiretroviral therapy and daily pre-exposure prophylaxis for HIV prevention among female sex workers in Cotonou, Benin: a prospective observational demonstration study.

INTRODUCTION: In sub-Saharan Africa, HIV prevalence remains high, especially among key populations. In such situations, combination prevention including clinical, behavioural, structural and biological components, as well as adequate treatment are important. We conducted a demonstration project at the Dispensaire IST, a clinic dedicated to female sex workers (FSWs) in Cotonou, on early antiretroviral therapy (E-ART, or immediate "test-and-treat") and pre-exposure prophylaxis (PrEP). We present key indicators such as uptake, retention and adherence. METHODS: In this prospective observational study, we recruited FSWs from October 4th 2014 to December 31st 2015 and followed them until December 31st 2016. FSWs were provided with daily tenofovir disoproxil fumarate/emtricitabine (Truvada® ) for PrEP or received a first-line antiretroviral regimen as per Benin guidelines. We used generalized estimating equations to assess trends in adherence and sexual behaviour. RESULTS: Among FSWs in the catchment area, HIV testing coverage within the study framework was 95.5% (422/442). At baseline, HIV prevalence was 26.3% (111/422). Among eligible FSWs, 95.5% (105/110) were recruited for E-ART and 88.3% (256/290) for PrEP. Overall retention at the end of the study was 59.0% (62/105) for E-ART and 47.3% (121/256) for PrEP. Mean (±SD) duration of follow-up was 13.4 (±7.9) months for E-ART and 11.8 (±7.9) months for PrEP. Self-reported adherence was over 90% among most E-ART participants. For PrEP, adherence was lower and the proportion with 100% adherence decreased over time from 78.4% to 56.7% (p-trend < 0.0001). During the 250.1 person-years of follow-up among PrEP initiators, two seroconversions occurred (incidence 0.8/100 person-years (95% confidence interval: 0.3 to 1.9/100 person-years)). The two seroconverters had stopped using PrEP for at least six months before being found HIV-infected. In both groups, there was no evidence of reduced condom use. CONCLUSIONS: This study provides data on key indicators for the integration of E-ART and PrEP into the HIV prevention combination package already offered to FSWs in Benin. PrEP may be more useful as an individual intervention for adherent FSWs rather than a specific public health intervention. E-ART was a more successful intervention in terms of retention and adherence and is now offered to all key populations in Benin. STUDY REGISTRATION: ClinicalTrials.gov NCT02237.