Hepatitis C virus resistance to the new direct-acting antivirals

Introduction: The treatment of hepatitis C virus (HCV) infection has dramatically improved in recent years with the widespread use of interferon-free combination regimens. Despite the high sustained virological response (SVR) rates (over 90%) obtained with direct-acting antivirals (DAAs), drug resistance has emerged as a potential challenge. The high replication rate of HCV and the low fidelity of its RNA polymerase result in a high degree of genetic variability in the HCV population, which ultimately explains the rapid selection of drug resistance associated variants (RAVs). Areas covered: Results from clinical trials and real-world experience have both provided important information on the rate and clinical significance of RAVs. They can be present in treatment-naive patients as natural polymorphisms although more frequently they are selected upon treatment failure. In patients engaged in high-risk behaviors, RAVs can be transmitted. Expert opinion: Although DAA failures generally occur in less than 10% of treated chronic hepatitis C patients, selection of drug resistance is the rule in most cases. HCV re-treatment options are available, but first-line therapeutic strategies should be optimized to efficiently prevent DAA failure due to baseline HCV resistance. Considerable progress is being made and next-generation DAAs are coming with pangenotypic activity and higher resistance barrier.Fil: Esposito, Isabella. Hospital Universitario La Paz; EspañaFil: Trinks, Julieta. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Soriano, Vicente. Hospital Universitario La Paz; Españ

Hepatitis C virus pharmacogenomics in Latin American populations: implications in the era of direct-acting antivirals

In recent years, great progress has been made in the field of new therapeutic options for hepatitis C virus (HCV) infection. The new direct-acting antiviral agents (DAAs) represent a great hope for millions of chronically infected individuals because their use may lead to excellent cure rates with fewer side effects. In Latin America, the high prevalence of HCV genotype 1 infection and the significant association of Native American ancestry with risk predictive single-nucleotide polymorphisms (SNPs) in IFNL4 and ITPA genes highlight the need to implement new treatment regimens in these populations. However, the universal accessibility to DAAs is still not a reality in the region as their high cost is one of the major, although not the only, limiting factors for their broad implementation. Therefore, under these circumstances, could the assessment of host genetic markers be a useful tool to prioritize DAA treatment until global access to these new drugs can be achieved? This review will summarize the scientific evidences and the potential implications of HCV pharmacogenomics in this rapidly evolving era of anti-HCV drug development.Fil: Trinks, Julieta. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Caputo, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hulaniuk, María L.. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; ArgentinaFil: Corach, Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Flichman, Diego Martin. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Estudio epidemiológico de especies de Mollicutes y agentes virales de transmisión sexual en mujeres sexualmente activas de la Ciudad Autónoma de Buenos Aires (CABA) y Gran Buenos Aires (GBA)

La infección crónica por el virus de la Hepatitis C (HCV) es una de las principales causas de carcinoma hepatocelular al ser responsable de la mitad de las indicaciones de trasplante hepático en adultos del mundo occidental. La terapia actual, que comprende la administración combinada de interferón pegilado y ribavirina, presenta eficacia limitada y se encuentra asociada a efectos adversos potencialmente severos que requieren la reducción de la dosis y/o la discontinuación del tratamiento. Ante la necesidad de contar con opciones terapéuticas mejor toleradas y más efectivas, más de 50 nuevas drogas, llamadas antivirales de acción directa (AAD) y dirigidas contra las proteínasvirales NS3/4A, NS5A y NS5B, han sido desarrolladas para el tratamiento de la infección crónica por HCV. Ensayos farmacológicos demostraron la selección de mutantes resistentes. Más aún, estudios recientes reportaron la presencia de variantes de resistencia natural a inhibidores de la proteasa NS3/4A y la polimerasa NS5B.Determinar la prevalencia de variantes de resistencia natural a los inhibidores de la polimerasa NS5A en las secuencias genómicas completas del HCV disponibles en la base de datos del GenBank.Utilizando el programa BioEdit versión 7.1.3.0., 722 secuencias genómicas completas del HCV incluidas en el GenBank antes del desarrollo de los AAD fueron alineadas y la secuencia aminoacídica fue deducida.La región NS5A fue analizada en búsqueda de variantes de resistencia natural. El genotipo viral fue asignado mediante análisis filogenético con el paquete PHYLIP versión 3.5c.Los genotipos más prevalentes de las secuencias analizadas fueron: 1a (59%), 1b (25%) y 6 (6%).La variante Q30R —que confiere resistencia a daclatasvir— fue la más prevalente (29%), seguida por P58T —resistencia a DBPR110— (4%) y L31M —resistencia a daclatasvir— (4%).El 78% de las secuencias con Q30R pertenecieron al HCV-1b, 70% de las secuencias con P58T fueron clasificadas como pertenecientes al HCV-6 y 35% de las que presentaron L31M se agruparon con el HCV-1b.Estos resultados sugerirían la necesidad de realizar ensayos de resistencia genotípica previos al tratamiento con AAD para evitar la falla terapéutica, gastos excesivos de salud pública y la diseminaciónde variantes de resistencia natural

Development of a nested real time PCR/high resolution melting assay for human T-cell lymphotropic viruses types 1 and 2 (HTLV-1 and 2) identification

HTLV-1 and HTLV-2 are present in different high-risk populations, such as sexual workers and injecting drug users (IDUs). HTLV-1 is endemic in areas of Middle East, Southern Japan and Latin America, whereas HTLV-2 infection is endemic among some Native Americans and some Central African tribes. The pathogenic consequences and clinical manifestations of these two viruses differ significantly, demanding an adequate identification; therefore, proper diagnosis of HTLV-1 and 2 infection is crucial. To get a final diagnosis of HTLV-1 or 2 infection, it is recommended that positive serologic samples should be confirmed by PCR assays or western blot (WB) analysis. Thus, the aim of this study was to develop and implement a simple reaction for the rapid identification of HTLV-1 and 2. Nested real-time PCR technique followed by high resolution melting was performed based on the tax/rex sequences of HTLV-1 (M2) and HTLV-2 (MoT) cell lines perfectly discriminating between HTLV-1 from HTLV-2, by distinct melting curve profiles. The sensitivity assay of this method revealed that at least 1 viral copy of HTLV-1 or 1·5 viral copy of HTLV-2 could be amplified. Later, this method was validated using 200 blood samples from corpses. In agreement with previous epidemiological, the HTLV-1 and 2 prevalence was 1·5% (CI 95%: 0·31–4·3) and 0·5% (CI 95%: 0·013–2·75), respectively. The strategy proposed herein has some advantages over other PCR-based tests because it not only reduces considerably time and the costs of the total diagnosis but also allows detection and discrimination of HTLV-1 and 2 in the same reaction.Fil: Caputo, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Trinks, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Azcurra, Marcela. No especifíca;Fil: Corach, Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

A simple and rapid approach for human herpesvirus type 8 subtype characterization using single base extension

Sequence analysis of the ORFK1 of human herpesvirus type 8 (HHV-8) allows the identification of six major subtypes (A-F), which are related to human migrations and the clinical progression of Kaposi´s sarcoma. Sequencing and subsequent phylogenetic analysis of ORFK1 is considered to be the most reliable method for HHV-8 genotyping. However, it exhibits challenges and limitations. Herein, we designed and validated a single base extension (SBE) protocol for characterization of HHV-8 ORFK1 subtypes. A nested polymerase chain reaction (PCR) protocol was carried out to amplify a small 294-bp PCR product encompassing four single nucleotide polymorphisms at positions 360, 406, 465 and 527 of the HHV-8 genome. Finally, a multiplex SBE technique was developed and validated in 20 samples previously genotyped by phylogenetic analysis. The patterns obtained in this reaction could successfully discriminate between ORFK1 subtypes. The typing results obtained completely matched with those of the ´gold standard´ method in all analysed samples. This method can reliably identify HHV-8 subtypes A, B and C, which are the most prevalent ones worldwide, and the remaining subtypes (D, E and F). SBE can be useful as an efficient, rapid and low-cost screening method for viral genotyping in a single tube, particularly samples with low-quality DNA, and with easy data interpretation.Fil: Hulaniuk Wolaniuk, Maria Laura. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Corach, Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; ArgentinaFil: Trinks, Julieta. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Caputo, Maria Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentin

A Two-Time Point Analysis of Gut Microbiota in the General Population of Buenos Aires and Its Variation Due to Preventive and Compulsory Social Isolation During the COVID-19 Pandemic

The COVID-19 pandemic poses a great challenge to global public health. The extraordinary daily use of household disinfectants and cleaning products, social distancing and the loss of everyday situations that allow contact between individuals, have a direct impact on the transfer of microorganisms within the population. Together, these changes, in addition to those that occur in eating habits, can affect the composition and diversity of the gut microbiota. A two-time point analysis of the fecal microbiota of 23 Metropolitan Buenos Aires (BA) inhabitants was carried out, to compare pre-pandemic data and its variation during preventive and compulsory social isolation (PCSI) in 2020. To this end, 23 healthy subjects, who were previously studied by our group in 2016, were recruited for a second time during the COVID-19 pandemic, and stool samples were collected from each subject at each time point (n = 46). The hypervariable region V3-V4 of the 16S rRNA gene was high-throughput sequenced. We found significant differences in the estimated number of observed features (p < 0.001), Shannon entropy index (p = 0.026) and in Faith phylogenetic diversity (p < 0.001) between pre-pandemic group (PPG) vs. pandemic group (PG), being significantly lower in the PG. Although no strong change was observed in the core microbiota between the groups in this study, a significant decrease was observed during PCSI in the phylum Verrucomicrobia, which contributes to intestinal health and glucose homeostasis. Microbial community structure (beta diversity) was also compared between PPG and PG. The differences observed in the microbiota structure by unweighted UniFrac PCoA could be explained by six differential abundant genera that were absent during PCSI. Furthermore, putative functional genes prediction using PICRUSt infers a smaller predicted prevalence of genes in the intestinal tryptophan, glycine-betaine, taurine, benzoate degradation, as well as in the synthesis of vitamin B12 during PCSI. This data supports the hypothesis that the microbiome of the inhabitants of BA changed in the context of isolation during PCSI. Therefore, these results could increase the knowledge necessary to propose strategic nutraceutical, functional food, probiotics or similar interventions that contribute to improving public health in the post-pandemic era.Fil: Aguilera, Pablo Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Mascardi, María Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Belforte, Fiorella Sabrina. Universidad Nacional de Luján; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Universidad Nacional de Luján. Instituto de Ecología y Desarrollo Sustentable; ArgentinaFil: Rosso, Ayelen Daiana. Universidad Nacional de Luján; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Universidad Nacional de Luján. Instituto de Ecología y Desarrollo Sustentable; ArgentinaFil: Quesada, Sofía. Universidad Nacional de Luján; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Llovet, Ignacio Diego. Universidad Nacional de Luján; ArgentinaFil: Iraola, Gregorio. Instituto Pasteur de Montevideo; UruguayFil: Trinks, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaFil: Penas Steinhardt, Alberto. Universidad Nacional de Luján; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Influence of ethnicity on the distribution of genetic polymorphisms associated with risk of chronic liver disease in South American populations

BACKGROUND: The global burden of chronic liver disease is rising. Besides environmental, behavioral, viral and metabolic factors, genetic polymorphisms in patatin-like phospholipase-3 (PNPLA3) and vitamin D receptor (VDR) genes have been related to the development of chronic liver disease and progression towards liver cancer. Although their prevalence differs remarkably among ethnic groups, the frequency of these polymorphisms in South American populations -whose genetic background is highly admixed- has been poorly studied. Hence, the aim of this study was to characterize polymorphisms related to chronic liver disease and their association with the genetic ancestry of South American populations. RESULTS: DNA samples from 258 healthy unrelated male volunteers were analyzed. The frequencies of G and C alleles of rs738409 polymorphism (PNPLA3 gene) were 74 % and 26 %, respectively; whereas the bAt (CCA) haplotype (VDR gene) was observed in 32.5 % of the samples. The GG genotype of PNPLA3 rs738409 and the bAt (CCA) haplotype -associated with an increased risk of chronic liver disease and progression towards liver cancer- were significantly more frequent among samples exhibiting maternal and paternal Native American haplogroups (63.7 % and 64.6 %), intermediate among admixed samples (45.1 % and 44.9 %; p = 0.03) and the lowest for Non-native American ancestry (30.1 % and 29.6 %; p = 0.001 and p = 0.0008). CONCLUSIONS: These results suggest that individuals with Native American ancestry might have a high risk of chronic liver disorders and cancer. Furthermore, these data not only support the molecular evaluation of ancestry in multi-ethnic population studies, but also suggest that the characterization of these variants in South American populations may be useful for establishing public health policies aimed at high risk ethnic communities.Fil: Pontoriero, Ana Cecilia. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Trinks, Julieta. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hulaniuk, María Laura. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; ArgentinaFil: Caputo, Mariela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fortuny, Lisandro. Hospital Italiano; ArgentinaFil: Burgos Pratx, Leandro. Hospital Italiano; ArgentinaFil: Frías, Analía. Hospital Materno Infantil “Ramón Sardá”; ArgentinaFil: Torres, Oscar. Hospital Materno Infantil “Ramón Sardá”; ArgentinaFil: Nuñez, Félix. Hospital Italiano; ArgentinaFil: Gadano, Adrián. Hospital Italiano; ArgentinaFil: Argibay, Pab lo. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Corach, Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Flichman, Diego Martin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Virología; Argentin

Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3

AIM: To evaluate pre-treatment factors associated with sustained virological response (SVR) in patients with hepatitis C virus (HCV) genotype 3 treated with peginterferon and ribavirin (RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index, steatosis, INFL3 polymorphism, pre-treatment HCV-RNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1 (± 1.8) wk. Overall, 58% (62/107) of the patients achieved an SVR and 42% (45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/mL (OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis (OR = 0.278, 95%CI: 0.113-0.684, P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥ 600000 UI/mL and advanced fibrosis, the probability of achieving an SVR was 29% (95%CI: 13.1-45.2). In patients with pre-treatment HCV-RNA < 600000 UI/mL and mild to moderate fibrosis, the probability of achieving an SVR was 81% (95%CI: 68.8-93.4). CONCLUSION: In patients with HCV genotype 3 infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agents-based regimes.Fil: Marciano, Sebastián. Hospital Italiano; ArgentinaFil: Borzi, Silvia Mabel. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Dirchwolf, Melisa. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Ridruejo, Ezequiel. Universidad Austral. Hospital Universitario Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Bessone, Fernando. Sanatorio del Parque. Unidad de Hepatología; ArgentinaFil: Sirotinsky, María Ester. Hepatosur group; ArgentinaFil: Giunta, Diego Hernan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; ArgentinaFil: Trinks, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Hospital Italiano; ArgentinaFil: Olivera Sendra, Pablo Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Galdame, Omar Andres. Hospital Italiano; ArgentinaFil: Silva, Marcelo Oscar. Universidad Austral. Hospital Universitario Austral; Argentina. Hospital Italiano; ArgentinaFil: Fainboim, Hugo. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Gadano, Adrián Carlos. Hospital Italiano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Inesperada alta frecuencia de infección por el virus de la hepatitis E en pacientes cirróticos alcohólicos de Argentina

El virus de la Hepatitis E (HEV) es un virus ARN de simple cadena de trasmisión entérica y zoonótico, frecuentemente asociado a hepatitis agudas autolimitadas. Recientemente, se describió la progresión a cronicidad en pacientes inmunosuprimidos y la cirrosis ha sido postulada como un factor predisponente a la infección por HEV. En Argentina, se ha reportado la circulación de HEV genotipo 3 en cerdos y matrices acuosas y una seroprevalencia de anticuerpos anti-HEV entre 1,8 y 16% en población general y donantes de sangre. Además, se reportaron seroprevalencias mayores (6 – 35%) en pacientes hemodializados, trasplantados de órganos sólidos y en individuos HIV+, siendo escasas las evidencias de HEV en pacientes cirróticos. El objetivo del trabajo fue describir la frecuencia de infección de HEV y factores asociados en pacientes cirróticos de Argentina. El diagnóstico de HEV se realizó detectando IgM e IgG anti-HEV por ELISA y ARN por PCR en tiempo final, en muestras de suero obtenidas de 3 centros de salud de Córdoba y Buenos Aires (n=122). La prevalencia global de IgG anti-HEV en pacientes cirróticos fue de 22,1% (27/122). El 70,4% de los IgG anti-HEV positivos fueron individuos alcohólicos, existiendo asociación estadísticamente significativa entre cirrosis alcohólica e infección por HEV (p&lt;0,05). Se detectó IgM en el 51,8% (14/27) de los pacientes IgG anti-HEV (+) y ARN HEV en 2 de ellos. Los resultados muestran una inesperada alta prevalencia de HEV en este grupo de pacientes adultos cirróticos alcohólicos argentinos. Se necesitan más estudios para dilucidar si la cirrosis alcohólica sería un factor predisponente para la infección por HEV, o si la infección (crónica) por HEV induciría la progresión a cirrosisFil: Fantilli, Anabella. Universidad Nacional de CórdobaFil: Pisano, María Belén. Buenos Aires (Argentina). Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).Fil: Zárate, Fabián.Fil: Trinks, Julieta. Buenos Aires (Argentina). Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).Fil: Marciano, Sebastián.Fil: Balderramo, Domingo.Fil: Fernando, Diehl.Fil: Martínez Wassaf, Maribel.Fil: Haddad, Leila.Fil: Gadano, Adrián.Fil: Debes, José.Fil: Ré, Viviana

Plasma and stool metabolomic biomarkers of non-alcoholic fatty liver disease in Argentina

Background: Non-invasive biomarkers are urgently needed to identify patients with non-alcoholic fatty liver disease (NAFLD) at risk of disease progression, particularly in high prevalence areas such as Latin America. In this regard, targeted metabolomics is a powerful technology for discovering new gut microbiome-derived metabolites. Thus, we aimed to identify potential metabolomic biomarkers related to NAFLD stage in Argentina, and to assess their relationship with clinical and host genetic factors. Methods: Adult healthy volunteers (HV) and biopsy-proven simple steatosis (SS) or non-alcoholic steatohepatitis (NASH) patients were recruited. Demographic, clinical and food frequency consumption data, as well as plasma and stool samples were collected. SNP rs738409 (PNPLA3 gene) was determined in all volunteers. HPLC and flow injection analysis with MS/MS in tandem was applied for metabolomic studies using the MxP Quant 500 Kit (Biocrates Life Sciences AG, Austria). Significantly different metabolites among groups were identified with MetaboAnalyst v4.0. Bivariate and multivariate analyses were used to identify variables that were independently related to NAFLD stage. Forward stepwise logistic regression models were constructed to design the best feature combination that could distinguish between study groups. Receiver Operating Characteristic (ROC) curves were used to evaluate models? accuracy.Results: 19 HV, 12 SS and 22 NASH patients were recruited. Diet was similar between groups. The concentration of 33 out of 424 detected metabolites (25 in plasma and 8 in stool) was significantly different among study groups. Levels of triglycerides (TG) were higher among NAFLD patients, whereas levels of phosphatidylcholines (PC) and lysoPC were higher among HV. The PNPLA3 risk genotype for NAFLD and NASH (GG) was related to higher plasma levels of eicosenoic acid FA(20:1) (p<0.001). Plasma metabolites showed a higher accuracy for diagnosis of NAFLD and NASH when compared to stool metabolites (Table 1). Body mass index (BMI) and plasma levels of PC aa C24:0, FA(20:1) and TG(16:1_34:1) showed high accuracy for diagnosis of NAFLD; whereas the best AUROC for discriminating NASH from SS was that of plasma levels of PC aa C24:0 and PC ae C40:1 (Table 1).Conclusions: Gut microbiome-derived metabolomic biomarkers were identified in plasma and stool, but plasma metabolites were better diagnostic biomarkers of NAFLD and NASH in Argentina. Further validation studies are needed.Fil: Mazzini, Flavia Noelia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Cook, Frank. Novartis Institutes For Biomedical Research; Estados UnidosFil: Gounarides, John. Novartis Institutes For Biomedical Research; Estados UnidosFil: Marciano, Sebastian. Hospital Italiano; ArgentinaFil: Haddad, Leila. Hospital Italiano; ArgentinaFil: Tamaroff, Ana Jesica. Hospital Italiano; ArgentinaFil: Casciato, Paola. Hospital Italiano; ArgentinaFil: Narvaez, Adriana Haydée. Hospital Italiano; ArgentinaFil: Mascardi, María Florencia. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Anders, Margarita. Hospital Alemán; ArgentinaFil: Orozco, Federico. Hospital Alemán; ArgentinaFil: Quiroz, Nicolas. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Risk, Marcelo. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Hospital Italiano. Instituto de Medicina Traslacional E Ingenieria Biomedica. - Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional E Ingenieria Biomedica.; ArgentinaFil: Gutt, Susana. Hospital Italiano; ArgentinaFil: Gadano, Adrián Carlos. Hospital Italiano; ArgentinaFil: Mendez Garcia, Celia. Hospital Italiano; ArgentinaFil: Marro, Martin. Novartis Institutes For Biomedical Research; Estados UnidosFil: Penas Steinhardt, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A. Margni; ArgentinaFil: Trinks, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional e Ingeniería Biomédica - Hospital Italiano. Instituto de Medicina Traslacional e Ingeniería Biomédica.- Instituto Universitario Hospital Italiano de Buenos Aires. Instituto de Medicina Traslacional e Ingeniería Biomédica; ArgentinaThe Liver Meeting Digital ExperienceEstados UnidosAmerican Association for the Study of the Liver Diseas