A changing landscape: Tracking and analysis of the international HDV epidemiology 1999-2020.

The international epidemiology of Hepatitis Delta Virus (HDV) is challenging to accurately estimate due to limited active surveillance for this rare infectious disease. Prior HDV epidemiological studies have relied on meta-analysis of aggregated and static datasets. These limitations restrict the capacity to actively detect low-level and/or geographically dispersed changes in the incidence of HDV diagnoses. This study was designed to provide a resource to track and analyze the international HDV epidemiology. Datasets analyzed collectively consisted of >700,000 HBV and >9,000 HDV reported cases ranging between 1999-2020. Datasets mined from government publications were identified for Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Finland, Germany, Macao, Netherlands, New Zealand, Norway, Sweden, Taiwan, Thailand, United Kingdom, and United States. Time series analyses, including Mann-Kendall (MK) trend test, Bayesian Information Criterion (BIC), and hierarchal clustering, were performed to characterize trends in the HDV timelines. An aggregated prevalence of 2,560 HDV/HBV100,000 cases (95% CI 180-4940) or 2.56% HDV/HBV cases was identified, ranging from 0.26% in Canada to 20% in the United States. Structural breaks in the timeline of HDV incidence were identified in 2002, 2012, and 2017, with a significant increase occurring between 2013-2017. Significant increasing trends in reported HDV and HBV cases were observed in 47% and 24% of datasets, respectively. Analyses of the HDV incidence timeline identified four distinct temporal clusters, including Cluster I (Macao, Taiwan), Cluster II (Argentina, Brazil, Germany, Thailand), Cluster III (Bulgaria, Netherlands, New Zealand, United Kingdom, United States) and Cluster IV (Australia, Austria, Canada, Finland, Norway, Sweden). Tracking of HDV and HBV cases on an international scale is essential in defining the global impact of viral hepatitis. Significant disruptions of HDV and HBV epidemiology have been identified. Increased surveillance of HDV is warranted to further define the etiology of the recent breakpoints in the international HDV incidence

Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein

AbstractIn a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and α-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl

Significant divergence in HDV and HBV time series trends between 1999–2020.

A) 47% of HBV datasets have a significant negative Mann-Kendall (MK) trend suggesting a decrease in HBV incidence over time series analyzed. 24% of HBV datasets have a significant positive MK trend suggesting an increase in HBV incidence over time series analyzed. B) 47% of HDV datasets have a significant positive and 12% a significant negative MK trend. The MK represents a significantly different profile from HBV (fisher exact, pC) HDV MK trends were increased relative to the HBV MK trends for all but 3 (18%) including United States, Brazil and Thailand. Data are detailed in S2 Table. *p<0.05, **p<0.005.</p

Prevalence of Hepatitis Delta Virus (HDV) for infectious disease datasets utilized in study.

Publicly accessible epidemiological datasets from 17 countries or region were identified that contained the yearly incidence of newly reported HDV and HBV cases.</p

Mann-Kendall Trends in time series for newly reported HDV and HBV cases.

Mann-Kendall analyses were performed to identify trends in the incidence of HDV and HBV over the time series analyzed. Kental Tau, Mann-Kendall (MK) analysis, p-value and Sen Slope reported for each country or region HDV and HBV dataset. Graphical view of MK analyses are depicted in Fig 2 and S2 Fig. (PDF)</p

Structural break analysis identified three structural breaks at 2002, 2012 and 2017 in the aggregated yearly incidence of HDV/HBV_100,000 cases.

A) The presence of three structural breaks in average HDV/HBV100,000 cases occur in 2002, 2012 and 2017. Fitting the null hypothesis model (no structural break) and alternative hypothesis model (3 structural breaks) to the data indicate clear structural shifts at those times. B) BIC analysis identified 3 structural breaks in the aggregated HDV/HBV100,000 cases time series. C) HDV/HBV100,000 cases compared for 1999–2002, 2003–2012, 2013–2017 and 2018–2020. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.</p

Yearly incidence of HDV/HBV_100,000 newly reported cases.

Publicly accessible infectious disease datasets containing yearly incidence of HDV and HBV for 17 countries or region spanning 5 continents were utilized in analyses. Data ranges in full or in part between 1999–2020. Order of countries is based on year of maximal HDV/HBV100,000 within each dataset. Total International (Int’l) is the average HDV/HBV100,000 across all datasets analyzed. Data sources are available in S1 Table.</p

HDV cases/100,000 HBV cases for each country based on structural breaks identified for aggregated dataset.

Structural breaks were identified in 2002, 2013, and 2017. Comparison of the identified timeframes 1999–2002, 2003–2012, 2013–2017 and 2018–2020 for each country or region are depicted. Grouping of countries or region are based of continent location and/or scale of HDV cases/100,000 HBV cases. Comparison of HDV/HBV incidence for identified breakpoints in the aggregated data, Country level analyses for A) Asia and Australia, B) Europe, C) Americas, and D) United States. *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. (PDF)</p

Yearly reported cases for HDV and HBV.

Publicly accessible infectious disease datasets containing yearly incidence of HDV and HBV for 17 countries or region spanning 5 continents were utilized in analyses. Data ranges between 1999–2020. Details of years reported by each country or region is detailed in Table 1. (PDF)</p