Circulating MicroRNAs as a Tool for Diagnosis of Liver Disease Progression in People Living with HIV-1

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding specific cell mRNA targets, preventing their translation. miRNAs are implicated in the regulation of important physiological and pathological pathways. Liver disease, including injury, fibrosis, metabolism dysregulation, and tumor development disrupts liver-associated miRNAs. In addition to their effect in the originating tissue, miRNAs can also circulate in body fluids. miRNA release is an important form of intercellular communication that plays a role in the physiological and pathological processes underlying multiple diseases. Circulating plasma levels of miRNAs have been identified as potential disease biomarkers. One of the main challenges clinics face is the lack of available noninvasive biomarkers for diagnosing and predicting the different stages of liver disease (e.g., nonalcoholic fatty liver disease and nonalcoholic steatohepatitis), particularly among individuals infected with human immunodeficiency virus type 1 (HIV-1). Liver disease is a leading cause of death unrelated to acquired immunodeficiency syndrome (AIDS) among people living with HIV-1 (PLWH). Here, we review and discuss the utility of circulating miRNAs as biomarkers for early diagnosis, prognosis, and assessment of liver disease in PLWH. Remarkably, the identification of dysregulated miRNA expression may also identify targets for new therapeutics

Normalization of circulating plasma levels of miRNAs in HIV-1/HCV co-infected patients following direct-acting antiviral-induced sustained virologic response

In a previous recent work, we recognized three plasma circulating microRNAs (miRNAs)-miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p-that correlate largely with liver fibrosis evolution in human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus (HCV) co-infected patients. Here, we investigated whether levels of these three circulating miRNAs can be associated to liver disease evolution in HIV-1/HCV co-infected patients which have achieved HCV sustained virologic response (SVR) 12 weeks after finishing treatment. Eighty-one chronic HIV-1/HCV co-infected patients were longitudinally recruited at baseline (T0) of DAA therapy and 12 weeks (T12) after finishing therapy. At T0 most of the study patients displayed transient elastography values linked to an advanced stage of liver fibrosis (F0-1 9%, F2 11%, F3 32%, F4 48%). Significant reductions in the levels of circulating miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p were detected at T12 in SVR patients, in the overall cohort (P < 0.0001, P < 0.0001, and P = 0.0008, respectively) and in patients with advanced (F3-4) liver fibrosis (p < 0.0001, p < 0.0001, and P = 0.0011, respectively). Of note, no significant reduction in the study miRNA levels was found at T12 in patients who did not achieve SVR (P = 0.8750, P = 0.1250, and P = 0.1260, respectively). HCV-cured patients, in contrast to non-responders, significantly reduced their liver stiffness after two years of achieving SVR (p < 0.0001). DAA-induced SVR is linked with a significant reduction in circulating levels of miR-100-5p_iso3p:-2, miR-122-5p, and miR-192-5p. Our results indicate that miRNA plasma levels may be a useful biomarker of liver damage progression in HIV-1/HCV co-infected individuals that reach DAA-induced SVR

Hemorragia con la administración de insulina en paciente sin antecedentes de hemorragias previas

We report the case of a 69-years-old man who spontaneously presented a hemorrhagic diathesis, hematomas, and small hemorrhages at insulin puncture sites, during his stay in the Internal Medicine department. A prolonged activated partial thromboplastin time was observed with the following diagnosis of an acquired type A hemophilia, with a severe inhibition of factor VIII as a paraneoplastic effect of a primary bladder tumor.  Acquired hemophilia is a rare disease with a predisposition for males. Usually, it is diagnosed with a certain delay since the main trigger is a hemorrhage in patients without previous history and with a prolonged TTPa.Presentamos el caso de un varón de 69 años que, durante su estancia en Medicina Interna, presentó de forma espontánea una diátesis hemorrágica con pequeñas hemorragias en los sitios de punción de insulina. Se observó un TTPa prolongado con el posterior diagnóstico de hemofilia tipo A adquirida, con una inhibición severa del factor VIII como efecto paraneoplásico de un tumor primario de vejiga.La hemofilia adquirida es una enfermedad rara con mayor predisposición en los hombres. Suele diagnosticarse con retraso, ya que habitualmente el principal desencadenante es una hemorragia en pacientes sin antecedentes de hemorragias y con un TTPa prolongado

Influence of Hepatitis C Virus Infection on HIV-1 Disease Progression and Response to Highly Active Antiretroviral Therapy

ObjectiveTo assess hepatitis C virus (HCV) antibody prevalence in the EuroSIDA cohort, along with survival, human immunodeficiency virus (HIV)-1 disease progression, virologic response (plasma HIV-1 RNA load of <500 copies/mL), and CD4 cell count recovery by HCV serostatus in patients initiating highly active antiretroviral therapy (HAART) ResultsHCV serostatus at or before enrollment was available for 5957 patients; 1960 (33%) and 3997 (67%) were HCV seropositive and seronegative, respectively. No association between an increased incidence of acquired immunodeficiency syndrome-defining illnesses or death and HCV serostatus was seen after adjustment for other prognostic risk factors known at baseline (adjusted incidence rate ratio [IRR], 0.97 [95% confidence interval {CI}, 0.81-1.16]). However, there was a large increase in the incidence of liver disease-related deaths in HCV-seropositive patients in adjusted models (IRR, 11.71 [95% CI, 6.42-21.34]). Among 2260 patients of known HCV serostatus initiating HAART, after adjustment, there was no significant difference between HCV-seropositive and -seronegative patients with respect to virologic response (relative hazard [RH], 1.13 [95% CI, 0.84-1.51]) and immunologic response, whether measured as a ⩾50% increase (RH, 0.94 [95% CI, 0.77-1.16]) or a ⩾50 cells/μL increase (RH, 0.92 [95% CI, 0.77-1.11]) in CD4 cell count after HAART initiation ConclusionsHCV serostatus did not affect the risk of HIV-1 disease progression, but the risk of liver disease-related deaths was markedly increased in HCV-seropositive patients. The overall virologic and immunologic responses to HAART were not affected by HCV serostatu

Use of simple noninvasive biomarkers to predict liver fibrosis in HIV/HCV coinfection in routine clinical practice

This study was supported by a grant from Abbott Laboratories. The authors wish to thank the Spanish Health Ministry (ISCIII-RETIC RD06/006) for financial support.Background Simple noninvasive tests to predict fibrosis, as an alternative to liver biopsy (LB), are needed. Of these, the aspartate aminotransferase (AST) to platelet ratio index (APRI) and the Forns index (FI) have been validated in HIV/hepatitis C virus (HCV) coinfection. However, these indexes may have lower diagnostic value in situations other than the circumscribed conditions of validation studies. We therefore examined the value of the APRI and FI in HIV/HCV-coinfected patients for the detection of significant fibrosis in real-life conditions. Patients and methods HIV/HCV-coinfected patients who had participated in a multicentre cross-sectional retrospective study were selected if they had undergone an LB within 24 months before the last visit. The predictive accuracy of the APRI and FI was measured using the areas under receiver-operating-characteristic curves (AUROCs). Diagnostic accuracy was determined using the positive (PPV) and negative (NPV) predictive values. Results A total of 519 coinfected individuals were included in the study. The AUROC [95% confidence interval (95% CI)] of the APRI was 0.67 (0.66–0.71) and that of the FI was 0.67 (0.62–0.71). The PPV of the APRI was 79% and its NPV was 66%. The PPV of the FI was 74% and its NPV was 64%. LB length was available and was ≥15 mm in 120 individuals. In this group, the PPV of the APRI was 85%, and that of the FI was 81%. Using these indexes, 22% of patients could be spared LB. Applying both models sequentially, 30% of patients could be spared LB. Conclusions In HIV/HCV-coinfected patients, the diagnostic accuracy of the APRI in real-life conditions was similar to that in the validation studies. The FI performed less well. However, combining the two indexes to make decisions on anti-HCV therapy may prevent a significant proportion of patients from having to undergo LB.Abbott LaboratoriesSpanish Health Ministry (ISCIII-RETIC RD06/006

Evolution of cervical cytologic changes among HIV-infected women with normal cytology in the HAART era.

The influence of HAART on the evolution to cervical squamous intraepithelial lesions (SIL) among HIV(+) women with a normal cytological test in the HAART era was studied. A retrospective cohort study (1997-2005) of HIV-infected women treated with HAART was conducted. Those with a normal cervical cytology (Papanicolaou test) and at least one subsequent test were included. Survival (time until diagnosis of SIL), univariate, and multivariate analyses were performed. A total of 133 HIV-infected patients treated with HAART were included. The incidence of SIL was 35% (47 patients). SIL was diagnosed in 36 of 110 (33%) patients with a baseline and final immunological status of >200 CD4 cells/microl and in 6 of 9 (67%) patients with a baseline and final immunological status of 200 CD4) through the follow-up was associated with a reduction of SIL

Low levels of few micronutrients may impact COVID-19 disease progression : an observational study on the first wave

We report an observational study performed between March and May 2020 in a Spanish university hospital during the SARS-CoV-2 pandemic. The main objective was to analyse the association between the levels of micronutrients in severe Covid-19 patients and their outcome. Adult patients with a positive polymerase-chain-reaction (PCR) for SARS-CoV-2 in the nasopharyngeal swab or in tracheal aspirate culture in the case of intubation were included. Micronutrient data were obtained from plasma analysis of a standard nutritional assessment performed within the first 24 h of hospital admission. Vitamins A, B6, C and E were analysed with HPLC methods; 25-OH-vitamin D by immunoassay and zinc by colorimetric measurements. One hundred and twenty patients were included. We found that 74.2% patients had low levels of zinc (normal levels >84 µg/dL) with a mean value of 63.5 (SD 13.5); 71.7% patients had low levels of vitamin A (normal levels >0.3 mg/L) with a mean value of 0.17 (SD 0.06); 42.5% patients had low levels of vitamin B6 (normal levels >3.6 ng/mL) with a mean value of 2.2 (SD 0.9); 100% patients had low levels of vitamin C (normal levels >0.4 mg/dL) with a mean value of 0.14 (SD 0.05); 74.3% patients had low values of vitamin D (normal levels >20 ng/mL) with mean value of 11.4 (SD 4.3); but only 5.8% of patients had low levels of vitamin E (normal levels >5 mg/L) with a mean value of 3.95 (SD 0.87). The variables associated with the need for ICU admission were low levels of zinc (standard error 0.566, 95% CI 0.086 to 0.790, p = 0.017), low levels of vitamin A (standard error 0.582, 95% CI 0.061 to 0.594, p = 0.004), age over 65 (standard error 0.018, 95% CI 0.917 to 0.985, p = 0.005) and male gender (standard error 0.458, 95% CI 1.004 to 6.040, p = 0.049). The only variable that was independently associated with the need for orotracheal intubation was low levels of vitamin A (standard error 0.58, 95% CI 0.042 to 0.405, p = 0.000). Conclusions: Low levels of vitamin A and zinc are associated with a greater need for admission to the ICU and orotracheal intubation. Patients older than 65 years had higher mortality. Randomized clinical trials are needed to examine whether micronutrient supplementation could be beneficial as an adjunctive treatment in COVID-19

Loss of claudin-3 impairs hepatic metabolism, biliary barrier function and cell proliferation in the murine liver.

BACKGROUND & AIMS Tight junctions in the liver are essential to maintain the blood-biliary-barrier, however the functional contribution of individual tight junction proteins to barrier- and metabolic homeostasis remains largely unexplored. Here, we describe the cell type specific expression of tight junction genes in the murine liver, and explore the regulation and functional importance of the transmembrane protein claudin-3 in liver metabolism, barrier function and cell proliferation. METHODS The cell type specific expression of hepatic tight junction genes is described using our mouse liver single cell sequencing dataset. Differential gene expression in Cldn3-/- and Cldn3+/+ livers was assessed in young and aged mice by RNA-seq and hepatic tissue was analysed for lipid content and bile acid composition. A surgical model of partial hepatectomy (PHx) was used to induce liver cell proliferation. RESULTS Claudin-3 is a highly expressed tight junction protein found in the liver and is expressed predominantly in hepatocytes and cholangiocytes. The histology of Cldn3-/- livers showed no overt phenotype, and the canalicular tight junctions appeared intact. Nevertheless, by RNAseq we detected a downregulation of metabolic pathways in the livers of Cldn3-/- young and aged mice as well as a decrease in lipid content and a weakened biliary-barrier for primary bile acids, such as TCA, TCDCA and TMCA. Coinciding with defects in the biliary barrier and lower lipid metabolism, there was a diminished hepatocyte proliferative response in Cldn3-/- mice following PHx. CONCLUSION Our data shows that in the liver, claudin-3 is necessary to maintain metabolic homeostasis, retention of bile acids, and optimal hepatocyte proliferation during liver regeneration

Anàlisi dels casos dʼhepatitis C crònica tractats a Catalunya durant el període 2009-2010

Genotip; Hepatitis víriques; InfeccionsGenotype; Viral hepatitis; InfectionsGenotipo; Hepatitis víricas; InfeccionesEn aquest article es presenten els resultats de lʼanàlisi de les dades referents als casos d'hepatitis C crònica de la població catalana recollides durant el període comprès entre els anys 2009 i 2010 així com lʼevolució dʼaquestes dades durant la primera dècada del segle XXI.This article presents the results of the data analysis linked to chronic hepatitis C of Catalan population collected during the period between 2009 and 2010 as well as the evolution of this data during the first decade of the XXIth century.En este artículo se presentan los resultados del análisis de datos relacionados con la hepatitis C crónica de la población catalana recogidos durante el periodo comprendido entre los años 2009 y 2010, así como la evolución de estos datos durante la primera década del siglo XXI

Estimating the HIV undiagnosed population in Catalonia, Spain: descriptive and comparative data analysis to identify differences in MSM stratified by migrant and Spanish-born population

OBJECTIVE: Undiagnosed HIV continues to be a hindrance to efforts aimed at reducing incidence of HIV. The objective of this study was to provide an estimate of the HIV undiagnosed population in Catalonia and compare the HIV care cascade with this step included between high-risk populations. METHODS: To estimate HIV incidence, time between infection and diagnosis and the undiagnosed population stratified by CD4 count, we used the ECDC HIV Modelling Tool V.1.2.2. This model uses data on new HIV and AIDS diagnoses from the Catalan HIV/AIDS surveillance system from 2001 to 2013. Data used to estimate the proportion of people enrolled, on ART and virally suppressed in the HIV care cascade were derived from the PISCIS cohort. RESULTS: The total number of people living with HIV (PLHIV) in Catalonia in 2013 was 34 729 (32 740 to 36 827), with 12.3% (11.8 to 18.1) of whom were undiagnosed. By 2013, there were 8458 (8101 to 9079) Spanish-born men who have sex with men (MSM) and 2538 (2334 to 2918) migrant MSM living with HIV in Catalonia. A greater proportion of migrant MSM than local MSM was undiagnosed (32% vs 22%). In the subsequent steps of the HIV care cascade, migrants MSM experience greater losses than the Spanish-born MSM: in retention in care (74% vs 55%), in the proportion on combination antiretroviral treatment (70% vs 50%) and virally suppressed (65% vs 46%). CONCLUSIONS: By the end of 2013, there were an estimated 34 729 PLHIV in Catalonia, of whom 4271 were still undiagnosed. This study shows that the Catalan epidemic of HIV has continued to expand with the key group sustaining HIV transmission being MSM living with undiagnosed HIV