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1.
EClinicalMedicine ; 40: 101116, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34522873

RESUMO

Background: De novo steatosis is the main criteria for non-alcoholic fatty liver disease (NAFLD), which is becoming a clinically relevant comorbidity in HIV-infected patients. This may be due to the HIV virus itself, as well as long-term toxicities deriving from antiretroviral therapy. Therefore, HIV infected patients require prevention and monitoring regarding NAFLD. Methods: This study investigated the differential role of body mass index (BMI) and combination antiretroviral treatment (cART) drugs on NAFLD progression. This single center prospective longitudinal observational study enrolled HIV monoinfected individuals between August 2013 to December 2018 with yearly visits. Each visit included liver stiffness and steatosis [defined as controlled attenuation parameter (CAP)>237 dB/m] assessment by annually transient elastography using an M- or XL-probe of FibroScan, and calculation of the novel FibroScan-AST (FAST) score. Risk factors for denovo/progressed steatosis and tripling of FAST-score increase were investigated using Cox regression model with time-dependent covariates. Findings: 319 monoinfected HIV positive patients with at least two visits were included into the study, of which 301 patients had at least two valid CAP measurements. 51·5%(155) patients did not have steatosis at first assessment, of which 45%(69) developed steatosis during follow-up. A BMI>23 kg/m2 (OR: 4·238, 95% CI: 2·078-8·938; p < 0·0001), tenofovir-alafenamid (TAF) (OR: 5·073, 95% CI: 2·362-10·899); p < 0·0001) and integrase strand transfer inhibitors (INSTI) (OR: 2·354, 95% CI: 1·370-4·048; p = 0·002), as well as type 2 diabetes mellitus (OR: 7·605, 95% CI: 2·315-24·981; p < 0·0001) were independent predictors of de novo steatosis in multivariable analysis. Tenofovir disoproxilfumarate (TDF) was associated with a lower risk for weight gain and steatosis progression/onset using CAP value (HR: 0·28, 95% CI: 0·12-0·64; p = 0·003) and FAST scores (HR: 0·31, 95% CI: 0·101-0·945; p = 0·04). Interpretation: Steatosis can develop despite non-obese BMI in patients with HIV monoinfection under cART, especially in male patients with BMI over 23 kg/m2. While TAF and INSTI increase the risk of progression of steatosis, TDF was found to be independently associated with a lower risk of a clinically significant weight gain and thereby, might slow down development and progression of steatosis. Funding: There was no additional funding received for this project. All funders mentioned in the 'declaration of interests' section had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript.

2.
Immunity ; 54(11): 2650-2669.e14, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34592166

RESUMO

Longitudinal analyses of the innate immune system, including the earliest time points, are essential to understand the immunopathogenesis and clinical course of coronavirus disease (COVID-19). Here, we performed a detailed characterization of natural killer (NK) cells in 205 patients (403 samples; days 2 to 41 after symptom onset) from four independent cohorts using single-cell transcriptomics and proteomics together with functional studies. We found elevated interferon (IFN)-α plasma levels in early severe COVD-19 alongside increased NK cell expression of IFN-stimulated genes (ISGs) and genes involved in IFN-α signaling, while upregulation of tumor necrosis factor (TNF)-induced genes was observed in moderate diseases. NK cells exert anti-SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) activity but are functionally impaired in severe COVID-19. Further, NK cell dysfunction may be relevant for the development of fibrotic lung disease in severe COVID-19, as NK cells exhibited impaired anti-fibrotic activity. Our study indicates preferential IFN-α and TNF responses in severe and moderate COVID-19, respectively, and associates a prolonged IFN-α-induced NK cell response with poorer disease outcome.


Assuntos
COVID-19/imunologia , Interferon-alfa/imunologia , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Sequência de Bases , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interferon-alfa/sangue , Fibrose Pulmonar/patologia , RNA-Seq , Índice de Gravidade de Doença , Transcriptoma/genética , Reino Unido , Estados Unidos
4.
J Clin Gastroenterol ; 54(2): 192-199, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30789853

RESUMO

GOALS AND BACKGROUND: International guidelines recommend prioritized treatment initiation in hepatitis C virus (HCV)-infected patients with advanced liver disease. We aimed to evaluate whether the widespread usage of direct acting antivirals (DAAs) has led to a decrease in late presentation for care. STUDY: Data derived from the multicenter German Hepatitis C Cohort (GECCO) was analyzed. Treatment naive HCV-infected patients initiating DAA-based treatment between January 2014 and September 2017 were included. Advanced liver disease was defined by aspartate aminotransferase to platelet ratio index score ≥1.5, METAVIR≥F3, or FibroScan ≥9.5 kPa. Period prevalence and risk factors for late presentation were evaluated. RESULTS: Six hundred fifty-three HCV-monoinfected and 210 HIV/HCV-coinfected patients (mean age, 48.6±12.7 y; 65.5% male) were included. Overall 32.5% of patients had advanced liver disease. In 2014 39.4% of patients presented with advanced liver disease, decreasing to 30.1%, 34.4%, and 26.4% in the years 2015, 2016, and 2017 (P=0.057), respectively. Patients with and without advanced liver disease differed in age (P<0.0001), CD4 ≤350/µL (P=0.027), genotype (P=0.005), transmission route (P=0.047), body mass index (P<0.001), and time since diagnosis (P=0.007). In the multivariable binary logistic regression analysis GT3, age above 45 years and being diagnosed >2 years ago were positively and HCV transmission through men who have sex with men was negatively associated with advanced liver disease. CONCLUSIONS: Overall 32.5% of patients presented with advanced liver disease. We observed a trend toward a lower proportion of patients starting treatment late.GT3, age, years since HCV diagnosis and HCV transmission route were identified as risk factors for presentation with advanced liver disease.


Assuntos
Coinfecção , Infecções por HIV , Hepatite C Crônica , Hepatite C , Minorias Sexuais e de Gênero , Adulto , Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Feminino , Alemanha/epidemiologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Hepacivirus , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Homossexualidade Masculina , Humanos , Masculino , Pessoa de Meia-Idade
5.
Int J Antimicrob Agents ; 56(1): 105527, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30145247

RESUMO

Direct-acting antivirals (DAAs) have tremendously improved the treatment of hepatitis C virus (HCV) infections also in human immunodeficiency virus (HIV)-positive individuals. Curing HCV infection is of particular importance in HIV-positive individuals as liver disease progression is accelerated in the course of concomitant HIV infection. Former challenges, such as safety and tolerability as well as reduced treatment uptake of pegylated interferon and ribavirin-based treatments, have been overcome with the approval of DAAs. Indeed, rates of discontinuation under modern all-oral DAA therapy in HIV/HCV coinfection have been reported to be <1%. Rates of sustained virological response (SVR) following treatment have aligned with those seen in HCV monoinfected patients, resulting in an equalisation of treatment recommendations for HCV monoinfected and HIV/HCV coinfected patients. Nevertheless, coinfection with HIV has been associated with slightly higher relapse rates in some real-world cohorts, arousing discussion regarding more individualised treatment once again. Moreover, an ongoing epidemic of acute HCV infections in HIV-positive men who have sex with men with high re-infection rates challenges physicians and researchers. The present review gives a concise summary of the remaining challenges in HCV treatment of HIV-positive individuals.


Assuntos
Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Infecções por HIV/patologia , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade/métodos , Benzimidazóis/uso terapêutico , Carbamatos/uso terapêutico , Coinfecção/virologia , Interações Medicamentosas , Quimioterapia Combinada , Fluorenos/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Cirrose Hepática/prevenção & controle , Cirrose Hepática/virologia , Polietilenoglicóis/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Ribavirina/uso terapêutico , Minorias Sexuais e de Gênero/estatística & dados numéricos , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Resultado do Tratamento
6.
PLoS One ; 14(7): e0219526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31295293

RESUMO

BACKGROUND AND AIMS: Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies showed that circulating levels of extracellular matrix (ECM) fragments might reflect degree of portal hypertension and fibrosis stage in liver disease. In this study, we analyzed the correlation between liver fibrosis assessed by Fibroscan and levels of the formation and degradation markers of type III and IV collagen in HIV positive patients receiving cART. METHODS: 116 HIV positive patients (82.7% male, median age 47 years) were enrolled into the study. Liver stiffness and liver fat content were determined using a Fibroscan with integrated CAP function. We quantified ECM formation and degradation fragments of collagen III and IV: PRO-C3, PRO-C4, C3M and C4M. These fragments were measured in peripheral serum by using specific ELISAs. RESULTS: Fifteen (12.9%) out of the 116 HIV positive patients had relevant fibrosis with a liver stiffness ≥ 7.1 kPa, and 79 patients had relevant steatosis with a CAP value > 248 dB/m. Circulating PRO-C3 levels significantly correlated with increasing degree of liver fibrosis assessed by Fibroscan (p = 0.0005), as well as with APRI score (p = 0.015). Interestingly, circulating PRO-C3 levels were significantly correlated with bilirubin (p = 0.022), reduced platelet count (p = 0.0008) and low albumin levels (p = 0.001), suggesting the association of type III collagen deposition with impaired liver function. None of the other measured ECM components significantly correlated with fibrosis or steatosis. CONCLUSION: The formation marker of type III collagen, PRO-C3 not only reflects liver fibrosis, but might also mirror liver dysfunction in HIV positive patients receiving cART. Therefore, the circulating levels of PRO-C3 might be suitable to monitor progression of liver fibrosis and deterioration of liver function in HIV positive patients receiving cART.


Assuntos
Complemento C3/metabolismo , Complemento C4/metabolismo , Fígado Gorduroso/sangue , Infecções por HIV/sangue , Cirrose Hepática/sangue , Adulto , Antirretrovirais/administração & dosagem , Terapia Antirretroviral de Alta Atividade , Biomarcadores/sangue , Colágeno Tipo III/sangue , Colágeno Tipo IV/sangue , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Matriz Extracelular/genética , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , HIV/genética , HIV/patogenicidade , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade
7.
Liver Int ; 39(8): 1514-1520, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30916873

RESUMO

BACKGROUND: Severe hepatic steatosis shows a high prevalence and contributes to morbidity and mortality in human immunodeficiency virus (HIV) infected patients. Known risk factors include obesity, dyslipidaemia and features of metabolic syndrome. Fibroblast growth factor 21 (FGF-21) is involved with hepatic glucose and lipid metabolism. This study aimed to evaluate FGF-21 as a biomarker for severe hepatic steatosis in non-obese HIV-infected patients. METHODS: This is a prospective, cross-sectional, monocentric study including HIV-infected out-patients. Hepatic steatosis was measured via controlled attenuation parameter (CAP) using FibroScan 502 touch (ECHOSENS, France). Severe hepatic steatosis was defined at CAP ≥ 253 dB/m. Peripheral blood samples were collected and plasma was analysed for FGF-21. Demographic and clinical characteristics were collected from patient's health records. RESULTS: In total, 73 non-obese HIV-monoinfected patients were included in this study. Prevalence of severe hepatic steatosis was 41%. Patients with severe hepatic steatosis showed significantly higher levels of FGF-21. Univariate analysis revealed FGF-21, BMI, hyperlipidaemia, ALT levels and arterial hypertension as significant, while multivariate analysis showed only FGF-21, arterial hypertension and ALT levels as significant independent risk factors for severe hepatic steatosis. CONCLUSION: This study presents FGF-21 as an independent and stronger predictor of severe hepatic steatosis than blood lipids in HIV-infected patients. Moreover, arterial hypertension and ALT levels predict severe steatosis even in non-obese HIV-monoinfected patients. Furthermore, this study supports existing metabolic risk factors and expands them to non-obese HIV-infected patients.


Assuntos
Fígado Gorduroso/sangue , Fatores de Crescimento de Fibroblastos/sangue , Infecções por HIV/complicações , Adulto , Idoso , Estudos Transversais , Fígado Gorduroso/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
HIV Clin Trials ; 19(6): 225-234, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30890063

RESUMO

BACKGROUND: Direct-acting antivirals (DAAs) lead to high cure rates of Hepatitis C Virus (HCV) infections in HIV/HCV coinfected patients. Recent data suggest that treatment failures occur more often in HIV/HCV coinfected persons. OBJECTIVE: We aimed to identify risk factors for treatment failure in coinfected patients. METHODS: We analyzed data collected from the German Hepatitis C-Registry (DHC-R, Trials Registration number DRKS00009717). 437 HIV/HCV coinfected patients were included. Sustained virological response (SVR) rates and the impact of CD4+ count, HIV viral load, liver cirrhosis and splenomegaly were evaluated. RESULTS: 83.5% (365/437) of the patients were male (average age: 46.6 ± 9.2 y). Most patients received antiretroviral therapy (ART) (88.1%; 385/437), had a HIV RNA ≤40 copies/ml (88.5%; 285/322) and were infected with HCV genotype (GT) 1 (77.6%; 339/437). Overall SVR12 rate was 92% (402/437). In patients with HIV RNA ≤40 copies/ml and >40 copies/ml SVR12 rates were 93.2% (272/292) and 85.3%, respectively (29/34; p = .11). SVR12 rates were 91.8% (45/49) and 92.7% (253/273; p = .84) in patients with a CD4+ <350/µl and ≥350/µl. We observed no difference in either of the subgroups in patients with cirrhosis or splenomegaly. In the univariate logistic regression analysis none of the analyzed HIV or HCV specific parameters, liver cirrhosis or splenomegaly were associated with treatment outcome. CONCLUSION: We found high SVR12 rates in HIV/HCV coinfected patients and no significant difference was observed due to the patients CD4+ cell count, HIV viral load, portal hypertension or liver cirrhosis.


Assuntos
Antirretrovirais/uso terapêutico , Coinfecção , Infecções por HIV/tratamento farmacológico , HIV/fisiologia , Hepacivirus/fisiologia , Hepatite C/tratamento farmacológico , Adulto , Contagem de Linfócito CD4 , Estudos de Coortes , Feminino , Alemanha , Infecções por HIV/complicações , Infecções por HIV/virologia , Hepatite C/complicações , Hepatite C/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Resposta Viral Sustentada , Carga Viral
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