Mapping natural polymorphism of Hepatitis C Virus NS3/4A protease and antiviral resistance to inhibitors in worlwide isolates

Background: Several inhibitors for the hepatitis C virus (HCV) NS3/4A protease are under development. Although previous studies identified viral resistance mutations, there is little information on the natural variability of proteases from the different viral subtypes. Here, we aimed to determine both the natural variability and presence of resistance or compensatory mutations to new protease inhibitors (PI) in NS3/4A proteases from worldwide HCV isolates. Methods: A comprehensive analysis was performed in 380 HCV NS3 sequences (275 genotype 1; 105 other genotypes) from public HCV databases (EuHCVdb and Los Alamos). Amino acid polymorphism and signature patterns were deduced in the protease domain, including all sites associated with resistance to the PIs BILN-2061, Telaprevir (VX-950), Boceprevir (SCH-503034), SCH-6 and ITMN-191. Results: Few of the residues in the catalytic triad or in substrate/metal-binding sites were polymorphic, and were identified in only 4/380 isolates. However, a relevant polymorphism was found in sites associated either with resistance to PI (V36, 1170 and D168) or with compensatory mutations (171, T72, Q86 and 1153). Furthermore, some unique genotype-specific signature patterns associated with resistance to PI were also identified. Conclusions: We describe for the first time the relevant natural polymorphisms of the HCV NS3/4A protease in worldwide isolates. Although the prevalence of major resistance mutations is very low, many compensatory sites are naturally polymorphic among proteases from several HCV subtypes. These data will help to determine whether HCV resistance is likely to be selected with new PIs and will aid the design of genotypic resistance testing

Resumen de congreso: 20 años después del primer Simposium Internacional sobre el virus de la hepatitis C y otros virus relacionados

The hepatitis C virus (HCV) was discovered by the team of Michael Houghton at Chiron Corporation in 1989 and the first symposium on HCV and related viruses was held in Venice, Italy, shortly after, in 1992. This conference was organized to advance knowledge on what then was a mysterious virus responsible for most cases of «non-A, non-B» hepatitis. During the 20 years since the first conference, the scientific quality of presentations has steadily increased, together with the tremendous advances in basic and clinical research and epidemiology. What started as a small conference on a new virus, about which there were very few data, has today become a first-in-class congress: a meeting place for basic researchers, clinicians, epidemiologists, public health experts, and industry members to present the most important advances and their application to HCV treatment and control. The nineteenth HCV symposium was held in September 2012, once again in Venice

Relating the outcome of HCV infection with different host SNP polymorphisms in a Majorcan coinfected HCV-HIV population treated with pegIFN-RBV

Hepatitis C virus (HCV) is one of the major causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and the development of HCV-related disease is accelerated in individuals coinfected with human immunodeficiency-1 virus (HIV). In the present study, we correlated different host single-nucleotide polymorphisms (SNPs) in the IL28B, CTLA4, LDLr, and HFE genes and mitochondrial DNA (mtDNA) haplogroups with the outcome of HCV infection and the response to pegylated-interferon plus ribavirin (pegIFN-RBV) treatment. Our study population consisted of 63 Majorcan patients coinfected with HCV and HIV and 59 anonymous unrelated controls. Whereas the population frequency of IL28B alleles was similar to that found in a North-American cohort of European descent, the frequency of the rs12979860 C allele was lower than that determined in other cohorts from Spain. The frequencies of CTLA4 and LDLr polymorphisms were comparable to those reported in other populations. Significant differences between cases and control cohorts occurred only for the H63D mutation of the HFE gene. There were no other differences in the frequencies of other polymorphisms or mtDNA haplogroups. The IL28B rs12979860 CC genotype was shown to be associated with a rapid virological response, and the spontaneous viral clearance rate for HCV was higher in patients with the CTLA4+49 G allele. There was no relationship between SNPs in the LDLr and HFE genes and mtDNA haplogroups and the response to treatment. Our results suggest that the host genetic background plays a significant role in the pegIFN-RBV response of patients coinfected with HCV and HIV

Influenza vaccine effectiveness against laboratory-confirmed influenza in hospitalised adults aged 60 years or older, Valencia Region, Spain, 2017/18 influenza season.

IntroductionInfluenza immunisation is recommended for elderly people each season. The influenza vaccine effectiveness (IVE) varies annually due to influenza viruses evolving and the vaccine composition.AimTo estimate, in inpatients ≥ 60 years old, the 2017/18 trivalent IVE, overall, by vaccine type and by strain. The impact of vaccination in any of the two previous seasons (2016/17 and 2015/16) on current (2017/18) IVE was also explored.MethodsThis was a multicentre prospective observational study within the Valencia Hospital Surveillance Network for the Study of Influenza and Respiratory Viruses Disease (VAHNSI, Spain). The test-negative design was applied taking laboratory-confirmed influenza as outcome and vaccination status as main exposure. Information about potential confounders was obtained from clinical registries and/or by interviewing patients; vaccine information was only ascertained by registries.ResultsOverall, 2017/18 IVE was 9.9% (95% CI: -15.5 to 29.6%), and specifically, 48.3% (95% CI: 13.5% to 69.1%), -29.9% (95% CI: -79.1% to 5.8%) and 25.7% (95% CI: -8.8% to 49.3%) against A(H1N1)pdm09, A(H3N2) and B/Yamagata lineage, respectively. For the adjuvanted and non-adjuvanted vaccines, overall IVE was 10.0% (95% CI: -24.4% to 34.9%) and 7.8% (95% CI: -23.1% to 31.0%) respectively. Prior vaccination significantly protected against influenza B/Yamagata lineage (IVE: 50.2%; 95% CI: 2.3% to 74.6%) in patients not vaccinated in the current season. For those repeatedly vaccinated against influenza A(H1N1)pdm09, IVE was 46.4% (95% CI: 6.8% to 69.2%).ConclusionOur data revealed low vaccine effectiveness against influenza in hospitalised patients ≥60 years old in 2017/18. Prior vaccination protected against influenza A(H1N1)pdm09 and B/Yamagata-lineage

Genetic characterization of influenza viruses from influenza-related hospital admissions in the St. Petersburg and Valencia sites of the Global Influenza Hospital Surveillance Network during the 2013/14 influenza season.

Background: Continuous surveillance for genetic changes in circulating influenza viruses is needed to guide influenza prevention and control. Objectives: To compare intra-seasonal influenza genetic diversity of hemagglutinin in influenza A strains isolated from influenza hospital admissions collected at two distinct sites during the same season. Study design: Comparative phylogenetic analysis of full-length hemagglutinin genes from 77 isolated influenza A viruses from the St. Petersburg, Russian Federation and Valencia, Spain sites of the Global Influenza Hospital Surveillance Network (GIHSN) during the 2013/14 season. Results: We found significant variability in A(H3N2) and A(H1N1)pdm09 viruses between the two sites, with nucleotide variation at antigenic positions much lower for A(H1N1)pdm09 than for A(H3N2) viruses. For A(H1N1)pdm09, antigenic sites differed by three to four amino acids from the vaccine strain, two of them common to all tested isolates. For A(H3N2) viruses, antigenic sites differed by six to nine amino acids from the vaccine strain, four of them common to all tested isolates. A fifth amino acid substitution in the antigenic sites of A(H3N2) defined a new Glade, 3C.2. For both influenza A subtypes, pairwise amino acid distances between circulating viruses and vaccine strains were significantly higher at antigenic than at non-antigenic sites. Whereas A(H1N1)pdm09 viruses clustered with Glade 6B and 94% of A(H3N2) with Glade 3C.3, at both study sites A(H3N2) Glade 3C.2 viruses emerged towards the end of the season, showing greater pairwise amino acid distances from the vaccine strain compared to the predominant Glade 3C.3. Conclusions: Influenza A antigenic variants differed between St. Petersburg and Valencia, and A(H3N2) Glade 3C.2 viruses were characterized by more amino acid differences from the vaccine strain, especially at the antigenic sites

Epidemiology of Hospital Admissions with Influenza during the 2013/2014 Northern Hemisphere Influenza Season: Results from the Global Influenza Hospital Surveillance Network

Background: The Global Influenza Hospital Surveillance Network was established in 2012 to obtain valid epidemiologic data on hospital admissions with influenza-like illness. Here we describe the epidemiology of admissions with influenza within the Northern Hemisphere sites during the 2013/2014 influenza season, identify risk factors for severe outcomes and complications, and assess the impact of different influenza viruses on clinically relevant outcomes in at-risk populations. Methods: Eligible consecutive admissions were screened for inclusion at 19 hospitals in Russia, Turkey, China, and Spain using a prospective, active surveillance approach. Patients that fulfilled a common case definition were enrolled and epidemiological data were collected. Risk factors for hospitalization with laboratory-confirmed influenza were identified by multivariable logistic regression. Findings: 5303 of 9507 consecutive admissions were included in the analysis. Of these, 1086 were influenza positive (534 A(H3N2), 362 A(H1N1), 130 B/Yamagata lineage, 3 B/Victoria lineage, 40 untyped A, and 18 untyped B). The risk of hospitalization with influenza (adjusted odds ratio [95% confidence interval]) was elevated for patients with cardiovascular disease (1.63 [1.33-2.02]), asthma (2.25 [1.67-3.03]), immunosuppression (2.25 [1.23-4.11]), renal disease (2.11 [1.48-3.01]), liver disease (1.94 [1.18-3.19], autoimmune disease (2.97 [1.58-5.59]), and pregnancy (3.84 [2.48-5.94]). Patients without comorbidities accounted for 60% of admissions with influenza. The need for intensive care or in-hospital death was not significantly different between patients with or without influenza. Influenza vaccination was associated with a lower risk of confirmed influenza (adjusted odds ratio = 0.61 [0.48-0.77]). Conclusions: Influenza infection was detected among hospital admissions with and without known risk factors. Pregnancy and underlying comorbidity increased the risk of detecting influenza virus in patients hospitalized with influenza-like illness. Our results support influenza vaccination as a measure for reducing the risk of influenza-associated hospital admission

Estudios de epidemiología molecular en población inmigrante en España

Background: Molecular epidemiology is a new scientific discipline which allows to integrate information on the genetic variation of infectious pathogens with their diffusion in a population and its subgroups including, for instance, resistance mutations to antibiotics and antiretrovirals. We present the results of an analysis of scientific publications that analyze the health status of the immigrant population in Spain from a molecular epidemiology perspective. Methods: We reviewed original articles published in 1998-2014 with the keywords "molecular epidemiology", "molecular typing", "sequencing", "immigrant", and "Spain". Results: From a total of 267 articles identified initially, only 50 passed through the established filters. Most of them (36) analyzed infections by Mycobacterium tuberculosis (3) and HIV (3), followed at a large distance by Staphylococcus aureus and hepatitis B virus. The main goal of these works was the typing of the pathogen and to determine the frequency of resistance mutations. Conclusion: Is difficult to generalize the conclusions from the analyzed articles because most of them have a purely descriptive and quite restricted scope, considering the type and size of the samples studied. Several studies are focused on the most likely origin for the strains or variants of the pathogen but others also reveal transmissions from the local to the immigrant populations.Fundamentos: La epidemiología molecular es una nueva disciplina que permite la integración de la información sobre la variabilidad genética de patógenos infecciosos con su difusión en la población y subgrupos de la misma incluyendo, por ejemplo, las mutaciones de resistencia a antibióticos y antivirales. El objetivo es conocer qué posibles diferencias existe en las características genéticas de los agentes infecciosos que afectan a las poblaciones inmigrante y autóctoctona en España. Métodos: Se revisaron artículos originales publicados entre 1998-2013, con las palabras clave "epidemiología molecular", "tipado molecular", "secuenciación", "inmigrante", "España". Resultados: De un total de 267 artículos identificados inicialmente, 50 pasaron los diferentes filtros establecidos. De ellos, 36 analizan las infecciones por Mycobacterium tuberculosis y VIH, seguidos de los que analizan infecciones por Staphylococcus aureus (3) y el Virus de la Hepatitis B (3). Conclusiones: Los objetivos principales de estos trabajos fueron el tipado del patógeno y la determinación de la frecuencia de mutaciones de resistencia. Los estudios más frecuentes correspondieron a cohortes retrospectivas, seguidos por los estudios ecológicos y los ensayos clínicos. En general los estudios son descriptivos y su ámbito por el tipo y tamaño de muestra es bastante restringido. En varios se determina que las cepas o variantes del patógeno encontradas en inmigrantes tienen su origen más probable en sus países de origen, si bien otros también ponen de manifiesto la transmisión desde la población autóctona a la inmigrante

Trends in Targeted Therapy Usage in Inflammatory Bowel Disease : TRENDY Study of ENEIDA

Markers that allow for the selection of tailored treatments for individual patients with inflammatory bowel diseases (IBD) are yet to be identified. Our aim was to describe trends in real-life treatment usage. For this purpose, patients from the ENEIDA registry who received their first targeted IBD treatment (biologics or tofacitinib) between 2015 and 2021 were included. A subsequent analysis with Machine Learning models was performed. The study included 10,009 patients [71% with Crohn's disease (CD) and 29% with ulcerative colitis (UC)]. In CD, anti-TNF (predominantly adalimumab) were the main agents in the 1st line of treatment (LoT), although their use declined over time. In UC, anti-TNF (mainly infliximab) use was predominant in 1st LoT, remaining stable over time. Ustekinumab and vedolizumab were the most prescribed drugs in 2nd and 3rd LoT in CD and UC, respectively. Overall, the use of biosimilars increased over time. Machine Learning failed to identify a model capable of predicting treatment patterns. In conclusion, drug positioning is different in CD and UC. Anti-TNF were the most used drugs in IBD 1st LoT, being adalimumab predominant in CD and infliximab in UC. Ustekinumab and vedolizumab have gained importance in CD and UC, respectively. The approval of biosimilars had a significant impact on treatment

A European multicentre evaluation of detection and typing methods for human enteroviruses and parechoviruses using RNA transcripts

Polymerase chain reaction (PCR) detection has become the gold standard for diagnosis and typing of enterovirus (EV) and human parechovirus (HPeV) infections. Its effectiveness depends critically on using the appropriate sample types and high assay sensitivity as viral loads in cerebrospinal fluid samples from meningitis and sepsis clinical presentation can be extremely low. This study evaluated the sensitivity and specificity of currently used commercial and in-house diagnostic and typing assays. Accurately quantified RNA transcript controls were distributed to 27 diagnostic and 12 reference laboratories in 17 European countries for blinded testing. Transcripts represented the four human EV species (EV-A71, echovirus 30, coxsackie A virus 21, and EV-D68), HPeV3, and specificity controls. Reported results from 48 in-house and 15 commercial assays showed 98% detection frequencies of high copy (1000 RNA copies/5 µL) transcripts. In-house assays showed significantly greater detection frequencies of the low copy (10 copies/5 µL) EV and HPeV transcripts (81% and 86%, respectively) compared with commercial assays (56%, 50%; P = 7 × 10-5 ). EV-specific PCRs showed low cross-reactivity with human rhinovirus C (3 of 42 tests) and infrequent positivity in the negative control (2 of 63 tests). Most or all high copy EV and HPeV controls were successfully typed (88%, 100%) by reference laboratories, but showed reduced effectiveness for low copy controls (41%, 67%). Stabilized RNA transcripts provide an effective, logistically simple and inexpensive reagent for evaluation of diagnostic assay performance. The study provides reassurance of the performance of the many in-house assay formats used across Europe. However, it identified often substantially reduced sensitivities of commercial assays often used as point-of-care tests