RESUMO
Human and viral microRNAs (miRNAs) are involved in the regulation of gene transcription, and the establishment of their profiles in acute (AHI) and chronic (CHI) HIV infections may shed light on the pathogenetic events related to different phases of HIV disease. Next-generation sequencing (NGS) of miRNA libraries was performed, and the reads were used to analyze miRNA differential expression in the plasma with AHI and CHI. Functional analysis was then undertaken to investigate the biological processes characterizing the two phases of HIV infection. Except for hsa-miR-122-5p, which was found in 3.39% AHI vs. 0.18% CHI, the most represented human miRNAs were similarly represented in AHI and CHI. However, when considering the overall detected miRNAs in AHI and CHI, 15 displayed differential expression (FDR p < 0.05). Functional analysis identified 163 target mRNAs involved in promoting angiogenesis activation in AHI versus CHI through the action of hsa-miR10b-5p, hsa-miR1290, hsa-miR1-3p, and hsa-miR296-5p. The viral miRNAs detected, all belonging to herpesviruses, accounted for only 0.014% of total reads. The present data suggest that AHI patients exhibit strong innate immune activation through the upregulation of hsa-miR-122-5p and early activation of angiogenesis. More specific investigations are needed to study the role of viral miRNAs in HIV pathogenesis.
Assuntos
Infecções por HIV , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNAs , RNA Viral , Humanos , MicroRNAs/genética , Infecções por HIV/virologia , Infecções por HIV/genética , RNA Viral/genética , Perfilação da Expressão Gênica , Masculino , Adulto , Feminino , Doença Aguda , Doença Crônica , Pessoa de Meia-Idade , HIV-1/genética , Imunidade Inata , Regulação da Expressão GênicaRESUMO
Torquetenovirus (TTV) is the most abundant component of the human blood virome and its replication is controlled by a functioning immune system. In this study, TTV replication was evaluated in 21 people with acute HIV infection (AHI) and immune reconstitution following antiretroviral therapy (ART). PBMC-associated TTV and HIV-1 DNA, as well as plasma HIV-1 RNA, were measured by real-time PCR. CD4 and CD8 differentiation, activation, exhaustion, and senescence phenotypes were analyzed by flow cytometry. Thirteen healthy donors (HD) and twenty-eight chronically infected HIV individuals (CHI), late presenters at diagnosis, were included as control groups. TTV replication in AHI seems to be controlled by the immune system being higher than in HD and lower than in CHI. During ART, a transient increase in TTV DNA levels was associated with a significant perturbation of activation and senescence markers on CD8 T cells. TTV loads were positively correlated with the expansion of CD8 effector memory and CD57+ cells. Our results shed light on the kinetics of TTV replication in the context of HIV acute infection and confirm that the virus replication is strongly regulated by the modulation of the immune system.
Assuntos
Infecções por HIV , HIV-1 , Torque teno virus , Humanos , Leucócitos Mononucleares , Torque teno virus/genética , HIV-1/genética , DNARESUMO
The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression [VS] (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA [LL-HIVDNA] (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan−Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery.
RESUMO
BACKGROUND: Direct-acting antivirals (DAAs) treatment, although highly efficacious for the treatment of hepatitis C virus (HCV) infection, may not completely reconstitute the HCV-mediated dysregulated immune system, especially in patients co-infected with human immunodeficiency virus (HIV) and HCV. OBJECTIVES: We aimed to evaluate the impact of HCV eradication following DAA therapy on the immune system and liver disease improvement through comparative monitoring of 10 HCV mono-infected and 10 HCV/HIV co-infected patients under combined antiretroviral therapy (cART). Early and late longitudinal phenotypic changes in peripheral blood mononuclear cell (PBMC) subsets, T-cell activation, differentiation and exhaustion, as well as inflammatory biomarkers, indoleamine 2-3 dioxygenase (IDO) activity, and liver stiffness, APRI and FIB-4 scores were assessed. MATERIALS AND METHODS: Samples were obtained at baseline (T0), week 1 (T1), week 2 (T2), week 12 (T3, end of treatment, EOT), and month 9 (T4, end of follow-up, 36 weeks post EOT). RESULTS: All patients achieved a sustained virological response (SVR 12) after DAA treatment. Overall, changes of the T-cell immune phenotypes were greater in HCV/HIV co-infected than in HCV mono-infected, due to an increase in CD4+ and CD8+ T-cell percentages and of CD8+ T-cell activation and memory markers, in particular at the end of follow-up. On the other end, HCV mono-infected showed changes in the activation profile and in the memory CD4+ T-cell compartment. In HCV/HIV co-infected, a decrease in the IDO activity by DAA treatment was observed; conversely, in HCV mono-infected, it resulted unmodified. Regarding inflammatory mediators, viral suppression was associated with a reduction in IP-10 levels, while interferon regulatory factor (IRF)-7, interferon (IFN)-ß, and interferon (IFN)-γ levels were downregulated during therapy and increased post therapy. A decrease in liver stiffness, APRI, and FIB-4 scores was also observed. CONCLUSIONS: Our study suggests that, although patients achieved HCV eradication, the immune activation state in both HCV mono-infected and HCV/HIV co-infected patients remains elevated for a long time after the end of DAA therapy, despite an improvement of liver-specific outcomes, meanwhile highlighting the distinct immunophenotypic and inflammatory biomarker profile between the groups of patients.
RESUMO
Hepatitis C virus (HCV) infection induces a long-term inflammatory response and oxidative-stress in the liver microenvironment, leading to hepatic fibrosis and metabolic alterations. Direct-acting-antiviral-agents (DAAs) induce HCV-clearance, even though liver damage is only partially restored. In this context, understanding the impact of viral-eradication on liver metabolic activities could allow optimizing the metabolic care of the patient. The present prospective longitudinal study aims at characterizing the urinary metabolic profile of HCV-induced severe liver fibrosis and the metabolic changes induced by DAAs and HCV-clearance by nuclear magnetic resonance-based metabolomics. The urinary metabolic profile of 23 HCV males with severe liver fibrosis and 20 age-matched healthy-controls was analyzed by NMR-based-metabolomics before starting DAAs, at the end-of-therapy, after one and three months of follow-up. The urinary metabolic profile of patients with severe liver fibrosis was associated to pseudouridine, hypoxanthine, methylguanidine and dimethylamine, highlighting a profile related to oxidative damage, and to tyrosine and glutamine, related to a decreased breakdown of aromatic aminoacids and ammonia detoxification, respectively. 1-methylnicotinamide, a catabolic intermediate of nicotinamide-adenine-dinucleotide, was significantly increased in HCV-patients and restored after HCV-clearance, probably due to the reduced hepatic inflammation. 3-hydroxy-3-methylbutyrate, an intermediate of leucine-catabolism which was permanently restored after HCV-clearance, suggested an improvement of skeletal muscle protein synthesis. Finally, 3-hydroxyisobutyrate and 2,3-dihydroxy-2-methylbutyrate, intermediates of valine-catabolism, glycine and choline increased temporarily during therapy, resulting as potential biomarkers of DAAs systemic effects.
Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Metaboloma , Metabolômica , Idoso , Biomarcadores/urina , Hepatite C/diagnóstico , Hepatite C/urina , Hepatite C/virologia , Humanos , Hidroxibutiratos/urina , Cirrose Hepática/diagnóstico , Cirrose Hepática/urina , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/urina , Valor Preditivo dos Testes , Espectroscopia de Prótons por Ressonância Magnética , Índice de Gravidade de Doença , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , UrináliseRESUMO
BACKGROUND/AIMS: Hepatitis C virus (HCV) has been identified in tubular epithelial cells of infected patients; however, the presence of tubular dysfunction, which is a risk factor for chronic kidney disease (CKD), has never been examined in vivo. The present prospective longitudinal study aimed to estimate the prevalence of tubular dysfunction alone or with glomerular damage and its evolution after HCV clearance in cirrhotic patients. METHODS: One hundred and thirty-five consecutive Child-Pugh A cirrhotic patients were evaluated before antiviral treatment and 6 months after the end of therapy. Tubular dysfunction was evaluated by urinary alpha1-microglobulin to creatinine ratio (α1-MCR), and glomerular damage was assessed by urinary albumin to creatinine ratio (ACR). RESULTS: Almost all the patients (93.3%) showed a normal or mildly decreased e-GFR (KDIGO-G1/G2-categories). Tubular dysfunction was found in 23.7% (32/135) of patients, co-occurring with glomerular damage in 37.5% (12/32) of cases, while glomerular damage was found in 16.3% (22/135) of patients. In multiple logistic regression, glomerular damage and the concomitant presence of diabetes and hypertension were the only predictors significantly associated with tubular dysfunction. After HCV clearance, patients experienced a significant reduction of α1-MCR levels (21.0 vs 10.5 µg/mg, P = .009) and tubular dysfunction resolved in 57.1% of subjects. CONCLUSIONS: Tubular dysfunction is an unrecognized feature of HCV-related kidney disease in cirrhotic patients and its presence should be primarily investigated in subjects with glomerular damage, diabetes and hypertension, despite normal e-GFR. Tubular dysfunction resolves in the majority of cases after HCV clearance; however, it may persist after antiviral treatment and further studies should evaluate its long-term impact on kidney function.
Assuntos
Hepatite C Crônica , Hepatite C , Antivirais/uso terapêutico , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/epidemiologia , Estudos Longitudinais , Estudos Prospectivos , Resposta Viral SustentadaRESUMO
Here we describe a case of a methicillin-resistant coagulase-negative staphylococci prosthetic valve endocarditis in a patient considered not eligible for valve replacement due to high perioperative mortality risk and who did not tolerate oral antibiotic treatment. Under these circumstances, intravenous long-term chronic suppressive antibiotic therapy with dalbavancin, scheduling the doses using the serum bactericidal activity titers, proved to be safe and effective.
RESUMO
BACKGROUND: In recent years Europe has experienced a dramatic increase in migration flows. Nevertheless, limited data is available about the occurrence of neglected parasitic diseases among migrant population. The purpose of the present study was to evaluate the prevalence of intestinal and urinary parasites in newly arrived asylum seekers. METHODS: A total of 364 newly arrived migrants hosted at the Asylum Seekers Centre of Castelnuovo di Porto (Italy) were screened during 8 months period for intestinal and urinary parasites. Each enrolled subject was interviewed using a standardized questionnaire, with focus on socio-demographical data and risk factors of parasitic infections. RESULTS: Stool analysis showed a prevalence of intestinal parasites of 20.6%. The travel route did not affect the prevalence of intestinal parasites (pâ¯=â¯0.096), while a significant negative correlation was found between the length of travel and the prevalence of parasite infection (pâ¯=â¯0.019). No statistically significant correlation between gastrointestinal symptoms and the presence of intestinal parasites was detected. CONCLUSION: The prevalence of intestinal parasitosis reported in asylum seekers does not necessarily reflect the prevalence of the parasitosis in the motherland. An anamnestic and syndromic approach may not be sufficient to highlight the problem of intestinal parasitic infestations in a screening setting.
Assuntos
Fezes/parasitologia , Enteropatias Parasitárias/diagnóstico , Intestinos/parasitologia , Refugiados , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Enteropatias Parasitárias/epidemiologia , Itália/epidemiologia , Masculino , Programas de Rastreamento/estatística & dados numéricos , Pessoa de Meia-Idade , Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/epidemiologia , Doenças Negligenciadas/parasitologia , Parasitos/isolamento & purificação , Prevalência , Fatores de Risco , Fatores Socioeconômicos , Inquéritos e Questionários , Viagem , Adulto JovemRESUMO
INTRODUCTION: Hepatitis E virus (HEV) is an emerging cause of autochthonous-acute-hepatitis and acute-on-chronic-liver-failure in western countries. Treatment is not routinely used, despite ribavirin has a good antiviral effect. In vitro sofosbuvir inhibits HEV replication, but clinical data are lacking. CASE REPORT: We report a case of acute-on-chronic-liver-failure due to HEV treated with sofosbuvir and ribavirin. The treatment was capable of rapidly inducing both HCV and HEV viral suppression. CONCLUSION: In conclusion, although more data are required before firm conclusions could be drawn, the combination of sofosbuvir and ribavirin in not immunosuppressed patients with acute hepatitis E may be able to clear HEV infection.
Assuntos
Hepatite E/tratamento farmacológico , Hepatite E/transmissão , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/tratamento farmacológico , Insuficiência Hepática Crônica Agudizada/virologia , Biomarcadores , Coinfecção , Quimioterapia Combinada , Evolução Fatal , Hepatite E/diagnóstico , Hepatite E/virologia , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Ribavirina/administração & dosagem , Choque Séptico , Sofosbuvir/administração & dosagem , Resultado do Tratamento , Carga ViralAssuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Talassemia beta/complicações , Adulto , Benzoatos/uso terapêutico , Crioglobulinemia/etiologia , Deferasirox , Desferroxamina/uso terapêutico , Técnicas de Imagem por Elasticidade , Feminino , Ferritinas/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/psicologia , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Cirrose Hepática/etiologia , Cirrose Hepática/patologia , Masculino , Qualidade de Vida , Triazóis/uso terapêutico , Carga Viral , Talassemia beta/psicologiaRESUMO
BACKGROUND: Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role. METHODS: Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied. RESULTS: At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1±0.3 vs 4.0±0.3%, p<0.001), serum endotoxins (157.8±7.6 vs 33.1±4.8pg/ml), serum isoprostanes (341±14 vs 286±10 pM, p=0.009) and NOx (24.3±1.1 vs 29.7±2.2µM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs=0.386, p=0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1±0.3 to 4.6±0.4%, p<0.001 and from 24.3±1.1 to 31.1±1.5µM, p<0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8±7.6 to 55.5±2.3pg/ml, p<0.001, and from 341±14 to 312±14 pM, p<0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs=-0.315; p=0.001). CONCLUSIONS: The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress.
Assuntos
Infecções Comunitárias Adquiridas/fisiopatologia , Endotélio Vascular/fisiopatologia , Isoprostanos/sangue , Lipopolissacarídeos/sangue , Nitratos/sangue , Nitritos/sangue , Pneumonia/fisiopatologia , Vasodilatação , Idoso , Idoso de 80 Anos ou mais , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiopatologia , Infecções Comunitárias Adquiridas/sangue , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Pneumonia/sangue , Estudos Prospectivos , UltrassonografiaRESUMO
It has been shown that sexual hormones have an opposite effect on hepatic fibrosis progression and hepatocellular carcinoma development. Sex differences among 2,762 chronic HBsAg carriers consecutively referring Italian hospitals in 2001 and in 2007 have been evaluated, particularly focusing on the role of gender on severity of liver disease. The overall sex ratio (males/females) was 2.6. Females were more likely born abroad and new diagnosis cases; but less likely HIV coinfected. No sex difference was observed regarding coinfection with other hepatitis viruses. The sex ratio linearly increased with increasing severity of liver disease, being 1.3 in normal ALT, 2.8 in chronic hepatitis, 3.6 in liver cirrhosis, and 6.8 in hepatocellular carcinoma. Adjustment by multiple logistic regression analysis for the confounding effect of age, alcohol intake, HDV infection, HCV infection, and BMI shows that male gender is an independent predictor of the likelihood of more severe liver disease (O.R. 1.7; C.I. 95% = 1.3-2.1). HBV-DNA levels resulted not associated with the outcome of chronic HBV infection. Despite some potential risk factors associated with liver disease, such as HBV genotype or mutations, not having been controlled for due to lack of availability, the observed sex disparity in the outcome of chronic HBV infection may support biological observation that HBV infection could be considered a sex hormone-responsive virus.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/complicações , Hepatite B Crônica/epidemiologia , Cirrose Hepática/complicações , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Adulto , Idoso , Feminino , Humanos , Itália/epidemiologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Fatores SexuaisRESUMO
BACKGROUND: Autochthonous (locally acquired) cases of acute hepatitis E virus have been recently reported in several developed countries. AIM: To evidence cases, if any, and characteristics of acute hepatitis E virus infections in North-East of Italy several years ago. METHODS: In 2014, stored sera of 165 nonA-nonB acute hepatitis referred to the hospital of Padua during the period 1978-1991 were tested for hepatitis C virus antibodies by EIA III and for anti-hepatitis E virus IgM by Wantai HEV IgM ELISA. Anti-hepatitis E virus IgM positive sera were tested by Real Star HEV RT-PCR kit (Altona Diagnostics, Hamburg, Germany). RESULTS: Ninety-six (58.1%) sera resulted anti-HCV positive, and thus classified as acute C hepatitis. None of these subjects was anti-HEV IgM positive. Out of the 69 anti-HCV negative cases, 4 (5.8%) resulted anti-HEV IgM positive (one case hepatitis E virus-RNA positive), with an increasing trend from 2.8% during the years 1978-1984 to 9.1% during the years 1985-1991. All cases occurred in Italian patients with no travel abroad history. CONCLUSIONS: There is evidence for the presence of autochthonous cases of acute hepatitis E virus infections in Italy since 80s.
Assuntos
Vírus da Hepatite E/isolamento & purificação , Hepatite E/diagnóstico , Hepatite E/virologia , Doença Aguda , Adolescente , Adulto , Algoritmos , Estudos de Coortes , Feminino , Hepatite E/epidemiologia , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Fatores de Tempo , Adulto JovemRESUMO
Hepatitis B (HBV) virus infection is one of the most important causes of liver disease in patients with end-stage renal failure on hemodialysis. The natural history of chronic HBV infection acquired in childhood starts with an immune tolerant phase, followed by an immune clearance phase that may lead to the inactive carrier state or the development of chronic liver disease. Information on antiviral therapy administered very early during the immune clearance phase are lacking and no data exist on the treatment of early immune activation in the hemodialysis setting. This report describes the case of a patient affected by end-stage renal failure and HBeAg-positive chronic HBV virus infection treated very early during the immune clearance phase of HBV infection with an adjusted-dose of nucleoside analogue entecavir. The patient achieved a very rapid HBV-DNA undetectability, anti-HBe, and anti-HBs seroconversion. This is the first report of antiviral therapy with entecavir started during the immune reactive phase of HBV infection in a patient on hemodialysis and it suggests that antiviral treatment can enhance the effects of host immune activation resulting in biochemical, serological, and viral response, even in end-stage renal failure patients with partial immunodeficiency. Antiviral therapy with entecavir in the setting of hemodialysis was safe and well tolerated.