Apolipoprotein E and Protection Against Hepatitis E Viral Infection in American Non-Hispanic Blacks

Hepatitis E viral (HEV) infection imposes a heavy health burden worldwide and is common in the United States. Previous investigations of risks addressed environmental and host behavioral/ lifestyle factors, but host genetic factors have not been examined. We assessed strength of associations between antibody to HEV (anti-HEV) immunoglobulin G seropositivity indicating past or recent HEV infection and human genetic variants among three major racial/ ethnic populations in the United States, involving 2434 non-Hispanic whites, 1919 non- Hispanic blacks, and 1919 Mexican Americans from the Third National Health and Nutrition Examination Survey, 1991-1994. We studied 497 single-nucleotide polymorphisms across 190 genes (particularly those associated with lipid metabolism). The genomic control method was used to adjust for potential population stratification. Non-Hispanic blacks had the lowest seroprevalence of anti-HEV immunoglobulin G (15.3%, 95% confidence interval [CI] 12.3%-19.0%) compared with non-Hispanic whites (22.3%, 95% CI 19.1%-25.7%) and Mexican Americans (21.8%, 95% CI 19.0%-25.3%; P \u3c 0.01). Non-Hispanic blacks were the only population that showed association between anti-HEV seropositivity and functional Ɛ3 and Ɛ4 alleles of the apolipoprotein E (APOE) gene, encoding the apolipoprotein E protein thatmediates lipoprotein metabolism. Seropositivity was significantly lower in participants carrying APOE Ɛ4 (odds ratio50.5, 95% CI 0.4-0.7; P50.00004) and Ɛ3 (odds ratio50.6, 95% CI 0.4-0.8; P50.001) compared to those carrying APOE Ɛ2. No significant associations were observed between other single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic blacks or between any single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic whites or Mexican Americans. Conclusion: Both APOE Ɛ3 and Ɛ4 are significantly associated with protection against HEV infection in non- Hispanic blacks; additional studies are needed to understand the basis of protection so that preventive services can be targeted to at-risk persons

Apolipoprotein E and Protection Against Hepatitis E Viral Infection in American Non-Hispanic Blacks

Hepatitis E viral (HEV) infection imposes a heavy health burden worldwide and is common in the United States. Previous investigations of risks addressed environmental and host behavioral/ lifestyle factors, but host genetic factors have not been examined. We assessed strength of associations between antibody to HEV (anti-HEV) immunoglobulin G seropositivity indicating past or recent HEV infection and human genetic variants among three major racial/ ethnic populations in the United States, involving 2434 non-Hispanic whites, 1919 non- Hispanic blacks, and 1919 Mexican Americans from the Third National Health and Nutrition Examination Survey, 1991-1994. We studied 497 single-nucleotide polymorphisms across 190 genes (particularly those associated with lipid metabolism). The genomic control method was used to adjust for potential population stratification. Non-Hispanic blacks had the lowest seroprevalence of anti-HEV immunoglobulin G (15.3%, 95% confidence interval [CI] 12.3%-19.0%) compared with non-Hispanic whites (22.3%, 95% CI 19.1%-25.7%) and Mexican Americans (21.8%, 95% CI 19.0%-25.3%; P \u3c 0.01). Non-Hispanic blacks were the only population that showed association between anti-HEV seropositivity and functional Ɛ3 and Ɛ4 alleles of the apolipoprotein E (APOE) gene, encoding the apolipoprotein E protein thatmediates lipoprotein metabolism. Seropositivity was significantly lower in participants carrying APOE Ɛ4 (odds ratio50.5, 95% CI 0.4-0.7; P50.00004) and Ɛ3 (odds ratio50.6, 95% CI 0.4-0.8; P50.001) compared to those carrying APOE Ɛ2. No significant associations were observed between other single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic blacks or between any single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic whites or Mexican Americans. Conclusion: Both APOE Ɛ3 and Ɛ4 are significantly associated with protection against HEV infection in non- Hispanic blacks; additional studies are needed to understand the basis of protection so that preventive services can be targeted to at-risk persons

Next-generation sequencing reveals large connected networks of intra-host HCV variants

Background: Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host. Results: Intra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient. The distance between any two variants calculated over the component correlated strongly with nucleotide distances (r = 0.9499; p = 0.0001), a better correlation than the one obtained with Neighbour-Joining trees (r = 0.7624; p = 0.0001). In each patient, components were well separated, with the average distance between (6.53%) being 10 times greater than within each component (0.68%). The ratio of nonsynonymous to synonymous changes was calculated and some patients (6.9%) showed a mixture of networks under strong negative and positive selection. All components were robust to in silico stochastic sampling; even after randomly removing 85% of all reads, the largest connected component in the new subsample still involved 82.4% of remaining nodes. In vitro sampling showed that 93.02% of components present in the original sample were also found in experimental replicas, with 81.6% of reads found in both. When syringe-sharing transmission events were simulated, 91.2% of all simulated transmission events seeded all components present in the source. Conclusions: Most intra-host variants are organized into distinct single-mutation components that are: well separated from each other, represent genetic distances between viral variants, robust to sampling, reproducible and likely seeded during transmission events. Facilitated by NGS, large components offer a novel evolutionary framework for genetic analysis of intra-host viral populations and understanding transmission, immune escape and drug resistance

Hepatitis E in England and Wales

In 2005, 329 cases of hepatitis E virus infection were confirmed in England and Wales; 33 were confirmed indigenous infections, and a further 67 were estimated to be indigenous infections. Hepatitis E should be considered in the investigation of patients with hepatitis even if they have no history of travel

Drug-resistance of a viral population and its individual intra-host variants during the first 48 hours of therapy

Using HCV and IFN-resistance as a proof of concept, we have devised a new methodology for calculating the effect of a drug over a viral population and the resistance of its individual intra-host variants. By means of next-generation sequencing, HCV variants were obtained from sera collected at 9 time-points from 16 patients during the first 48 hours after injection of IFN-α. IFN-resistance coefficients were calculated for individual variants using changes in their relative frequencies, and for the entire intra-host viral population using changes in viral titer during the initial 48 hours. Population-wide resistance and presence of IFN-resistant variants were highly associated with pegIFN-α2a/RBV treatment outcome at week 12 (p = 3.78×10-5 and 0.0114, respectively). This new method allows an accurate measurement of resistance based solely on changes in viral titer or the relative frequency of intra-host viral variants during a short observation time

Hepatitis E Epidemic, Uganda

In October 2007, an epidemic of hepatitis E was suspected in Kitgum District of northern Uganda where no previous epidemics had been documented. This outbreak has progressed to become one of the largest hepatitis E outbreaks in the world. By June 2009, the epidemic had caused illness in >10,196 persons and 160 deaths

Hepatitis B virus infection among HIV-infected pregnant women in Malawi and transmission to infants

The extent of HBV infection to infants of HBV/HIV-coinfected pregnant women in sub-Saharan Africa is unknown. The aim of this study was to assess prevalence of HBV infection among antiretroviral-naïve, HIV-infected pregnant women in Malawi and examine HBV transmission to their infants

Characteristics of Adults in the Hepatitis B Research Network in North America Reflect Their Country of Origin and Hepatitis B Virus Genotype

Chronic hepatitis B virus (HBV) infection is an important cause of cirrhosis and hepatocellular carcinoma worldwide; populations that migrate to the US and Canada might be disproportionately affected. The Hepatitis B Research Network (HBRN) is a cooperative network of investigators from the United States and Canada, created to facilitate clinical, therapeutic, and translational research in adults and children with hepatitis B. We describe the structure of the network and baseline characteristics of adults with hepatitis B enrolled in the network

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Analysis of the Epstein-Barr virus-host relationship by in situ hybridisation : a thesis submitted to the University of London for the degree of Doctor of Philosophy

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