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2.
Am J Transplant ; 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32347626

RESUMO

Severe aortic stenosis is a widespread valve disease, constituting a contraindication to organ transplantation due to cardiovascular morbidity and projected mortality. Mortality after conventional surgical aortic valve replacement in cirrhotic patients depends upon the Child Pugh's class. In the past few years, trans-catheter aortic valve replacement has progressively become the treatment of choice for high risk patients with severe aortic stenosis. Here, we report the cases of three cirrhotic patients who became eligible for liver transplantation after successful trans-catheter aortic valve replacement as bridge therapy.

3.
Lancet Gastroenterol Hepatol ; 5(5): 507-514, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32277903

RESUMO

The survival of patients with alcohol-related liver disease who receive a liver transplant has steadily improved to reach 80-85% at 1 year post-transplantation. The standard requirement for liver transplant-abstinence from alcohol for 6 months before transplantation-has been applied widely, but few data support the use of this rule as the sole criterion for selecting candidates for liver transplantation. When determining the suitability of a patient for transplantation, many liver transplant programmes now try to balance the period of abstinence against the risk of death associated with the severity of liver damage. Data accumulated since 2011 suggest that early liver transplantation (ie, transplantation without a specific period of abstinence) in patients with severe alcoholic hepatitis who do not respond to medical therapy is an effective therapeutic strategy. Further studies are needed to help refine the selection of patients with alcohol-related liver disease who have been abstinent for less than 6 months as suitable liver transplant candidates, and to improve the treatment of alcohol use disorder in those patients who have received a liver transplant.

4.
J Hepatol ; 72(6): 1052-1061, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31953139

RESUMO

BACKGROUND & AIMS: Severe alcoholic hepatitis (SAH) is associated with a high risk of infection. The IL-33/ST2 pathway is involved in sepsis control but data regarding its role in alcohol-related liver disease (ALD) are lacking. We aimed to characterize the role of IL-33/ST2 in the polymorphonuclear neutrophils (PMNs) of patients with ALD and SAH. METHODS: Serum and circulating neutrophils were collected from patients with SAH, alcoholic cirrhosis and healthy controls. We quantified IL-33/ST2 pathway activity and CXCR2 at baseline and after exposure to IL-33. We also determined the migration capacity of PMNs. RESULTS: The decoy receptor of IL-33 (soluble ST2 [sST2]) was increased in SAH vs. cirrhosis and controls, demonstrating the defect in this pathway during ALD. The sST2 level was associated with response to treatment, 2-month survival, infection-free survival and probability of infection in SAH. Endotoxemia was weakly correlated with sST2. GRK2, a negative regulator of CXCR2, was overexpressed in PMNs of patients with SAH and cirrhosis and was decreased by IL-33. CXCR2 levels on PMNs were lower in SAH vs. cirrhosis and controls. Treatment with IL-33 partially restored CXCR2 expression in SAH and cirrhosis. PMN migration upon IL-8 was lower in patients with SAH and cirrhosis vs. controls. Treatment with IL-33 partially restored migration in those with SAH and cirrhosis. Interestingly, the migration capacity of PMNs and the response to IL-33 were enhanced in responders to corticosteroids (Lille <0.45) compared to non-responders. CONCLUSION: The IL33/ST2 pathway is defective in SAH and predicts outcome. This defect is associated with decreased CXCR2 expression on the surface of PMNs and lower migration capacity, which can be corrected by IL-33, especially in patients responding to steroids. These results suggest that IL-33 has therapeutic potential for SAH and its infectious complications. LAY SUMMARY: The neutrophils of patients with severe alcoholic hepatitis are associated with a defect in the IL-33/ST2 pathway. This defect is associated with lower migration capacities in neutrophils and a higher probability of getting infected. Administration of IL-33 to the neutrophils at least partly restores this defect and may be effective at reducing the risk of infection in patients with severe alcoholic hepatitis.

5.
Am J Gastroenterol ; 115(3): 398-405, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31985531

RESUMO

OBJECTIVES: Severe alcoholic hepatitis (sAH) confers substantial mortality, but the disease course is difficult to predict. As iron parameters are attractive outcome predictors in other liver diseases, we tested their prognostic ability in sAH. METHODS: Serum ferritin, transferrin, iron, transferrin saturation, nontransferrin-bound iron, soluble transferrin receptor, and hepcidin were measured in 828 patients with sAH recruited prospectively through the STOPAH trial. The cohort was randomly divided into exploratory (n = 200) and validation sets (n = 628). RESULTS: Patients with sAH had diminished serum transferrin but increased transferrin saturation. Among iron parameters, baseline transferrin was the best predictor of 28-day (area under the receiver operated characteristic 0.72 [95% confidence interval 0.67-0.78]) and 90-day survival (area under the receiver operated characteristic 0.65 [0.61-0.70]). Transferrin's predictive ability was comparable with the composite scores, namely model of end-stage liver disease, Glasgow alcoholic hepatitis score, and discriminant function, and was independently associated with survival in multivariable analysis. These results were confirmed in a validation cohort. Transferrin did not correlate with markers of liver synthesis nor with non-transferrin-bound iron or soluble transferrin receptor (as markers of excess unbound iron and functional iron deficiency, respectively). DISCUSSION: In patients with sAH, serum transferrin predicts mortality with a performance comparable with commonly used composite scoring systems. Hence, this routinely available parameter might be a useful marker alone or as a component of prognostic models.


Assuntos
Hepatite Alcoólica/mortalidade , Índice de Gravidade de Doença , Transferrina/metabolismo , Adulto , Biomarcadores/sangue , Feminino , Seguimentos , Hepatite Alcoólica/sangue , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes
6.
Artigo em Inglês | MEDLINE | ID: mdl-31931181

RESUMO

BACKGROUND & AIMS: Alcohol-related liver disease (ALD) causes chronic liver disease. We investigated how information on patients' drinking history and amount, stage of liver disease, and demographic feature can be used to determine risk of disease progression. METHODS: We collected data from 2334 heavy drinkers (50 g/day or more) with persistently abnormal results from liver tests who had been admitted to a hepato-gastroenterology unit in France from January 1982 through December 1997; patients with a recorded duration of alcohol abuse were assigned to the development cohort (n=1599; 75% men) or the validation cohort (n=735; 75% men), based on presence of a liver biopsy. We collected data from both cohorts on patient history and disease stage at the time of hospitalization. For the development cohort, severity of the disease was scored by the METAVIR (due to the availability of liver histology reports); in the validation cohort only the presence of liver complications was assessed. We developed a model of ALD progression and occurrence of liver complications (hepatocellular carcinoma and/or liver decompensation) in association with exposure to alcohol, age at the onset of heavy drinking, amount of alcohol intake, sex and body mass index. The model was fitted to the development cohort and then evaluated in the validation cohort. We then tested the ability of the model to predict disease progression for any patient profile (baseline evaluation). Patients with a 5-y weighted risk of liver complications greater than 5% were considered at high risk for disease progression. RESULTS: Model results are given for the following patient profiles: men and women, 40 y old, who started drinking at an age of 25 y, drank 150 g/day, and had a body mass index of 22 kg/m2 according to the disease severity at baseline evaluation. For men with baseline F0-F2 fibrosis, the model estimated the probabilities of normal liver, steatosis, or steatohepatitis at baseline to be 31.8%, 61.5% and 6.7%, respectively. The 5-y weighted risk of liver complications was 1.9%, ranging from 0.2% for men with normal liver at baseline evaluation to 10.3% for patients with steatohepatitis at baseline. For women with baseline F0-F2 fibrosis, probabilities of normal liver, steatosis, or steatohepatitis at baseline were 25.1%, 66.5% and 8.4%, respectively; the 5-y weighted risk of liver complications was 3.2%, ranging from 0.5% for women with normal liver at baseline to 14.7% for patients with steatohepatitis at baseline. Based on the model, men with F3-F4 fibrosis at baseline have a 24.5% 5-y weighted risk of complications (ranging from 20.2% to 34.5%) and women have a 30.1% 5-y weighted risk of complications (ranging from 24.7% to 41.0%). CONCLUSIONS: We developed a Markov model that integrates data on level and duration of alcohol use to identify patients at high risk of liver disease progression. This model might be used to adapt patient care pathways.

7.
Addiction ; 115(3): 573-582, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31595554

RESUMO

BACKGROUND AND AIMS: Although people who inject drugs (PWID) are the core at-risk population in the hepatitis C virus (HCV) epidemic in industrialized countries, few initiate treatment. Alcohol use disorder (AUD), common within this population, has been identified as a barrier to HCV treatment uptake in the general population. We investigated whether the arrival of new and well-tolerated HCV treatments (direct-acting antivirals: DAA) has improved HCV treatment uptake in French PWID compared with former treatments (pegylated interferon-based treatments: Peg-IFN). DESIGN: Using discrete-time Cox proportional hazards models based on exhaustive care delivery data, we tested for associations between AUD (defined by AUD-related long-term illness status, diagnosis coding during hospitalization and/or AUD pharmacological treatment) and first HCV treatment delivery, after adjusting for gender, age, complementary universal health cover, liver disease severity and type of opioid agonist therapy (OAT) received. Separate analyses were performed for 2012-13 (Peg-IFN era) and 2014-16 (DAA era). SETTING: France. PARTICIPANTS: All French people chronically HCV-infected who received OAT at least once during 2012-16 and were covered by the national health insurance (n = 24 831). MEASUREMENTS: Incidence rate of HCV treatment uptake, hazard ratios associated with AUD and other covariates. FINDINGS: Incidence rate (IR) of HCV treatment uptake per 100 person-years was 6.56, confidence interval (CI) = 6.30-6.84; and IR = 5.70, 95% CI = 5.51-5.89 for Peg-IFN-based treatment (2012-13) and DAA (2014-16), respectively. After multiple adjustment, people with AUD not receiving related medication had 30 and 14% lower Peg-IFN-based treatment and DAA uptake, respectively, than those without AUD [hazard ratio (HR) = 0.70, 95% CI = 0.62-0.80 and HR = 0.86, 95% CI = 0.78-0.94]. No difference was observed between those treated for AUD and those without AUD. CONCLUSIONS: Despite the benefits of direct-acting antiviral treatment, untreated alcohol use disorder appears to remain a major barrier to hepatitis C virus treatment access for people who inject drugs in France.

8.
Hepatology ; 71(2): 522-538, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31228214

RESUMO

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

9.
Liver Transpl ; 26(1): 127-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31743578

RESUMO

Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

10.
Gut ; 69(4): 764-780, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31879281

RESUMO

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.

11.
Lancet ; 394(10215): 2184-2196, 2019 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-31813633

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. METHODS: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. FINDINGS: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). INTERPRETATION: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. FUNDING: Intercept Pharmaceuticals.


Assuntos
Ácido Quenodesoxicólico/análogos & derivados , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Administração Oral , Biomarcadores/análise , Biópsia , Ácido Quenodesoxicólico/administração & dosagem , Ácido Quenodesoxicólico/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade
12.
Nature ; 575(7783): 505-511, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723265

RESUMO

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

13.
Nat Commun ; 10(1): 3126, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311938

RESUMO

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFß1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFß1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH.


Assuntos
Hepatite Alcoólica/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Hepatócitos/patologia , Fígado/patologia , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Idoso , Animais , Biópsia , Montagem e Desmontagem da Cromatina , Metilação de DNA , Progressão da Doença , Epigênese Genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hepatite Alcoólica/patologia , Fator 4 Nuclear de Hepatócito/genética , Humanos , Fígado/citologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Análise de Sequência de RNA , Fator de Crescimento Transformador beta1/genética
15.
J Viral Hepat ; 26(10): 1229-1232, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31216086

RESUMO

Sofosbuvir-velpatasvir is approved for the treatment of chronic hepatitis C virus (HCV) infection. In this single-arm, open-label, phase 3, deferred treatment study, we investigated the efficacy and safety of sofosbuvir-velpatasvir among patients randomized to the placebo group in the ASTRAL-1 study. Patients received sofosbuvir-velpatasvir (400/100 mg) once daily for 12 weeks. The primary efficacy endpoint was the proportion of patients with sustained virologic response 12 weeks after the end of therapy (SVR12). The primary safety endpoint was any adverse events (AEs) leading to the permanent discontinuation of study drug. Overall, 108/111 (97%, 95% confidence interval [CI], 92%-99%) achieved SVR12, and only one patient had virological failure. SVR12 was achieved by 61/63 (97%, 95%CI, 89%-100%) genotype 1 patients, 20/20 (100%; 95%CI, 83%-100%) with genotype 2, 19/19 (100%; 95%CI, 82%-100%) with genotype 4 and 8/9 (89%; 95% CI, 52%-100%) with genotype 6. All (19/19; 95%CI, 82-100) patients with cirrhosis and all (31/31, 95%CI, 89-100) with prior treatment experience achieved SVR12. The safety profile during treatment was similar to that observed in patients receiving placebo treatment. The most common AEs were headache, fatigue and nausea. One patient (1%) discontinued treatment due to an AE of gallbladder carcinoma, which was not considered related to treatment. Of five reported serious AEs, none were considered related to study drug. Sofosbuvir-velpatasvir for 12 weeks was effective and well tolerated among untreated and previously treated patients with HCV genotype 1, 2, 4 or 6 infection, including those with compensated cirrhosis (ClinicalTrials.gov NCT02346721).

16.
Aliment Pharmacol Ther ; 50(1): 75-83, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31087566

RESUMO

BACKGROUND: Further study is needed on the prognostic impact of cirrhosis on haemodialysis patients. AIM: To evaluate cirrhosis' impact according to severity on survival and to provide therapeutic guidelines for haemodialysis cirrhotic patients. METHODS: Patients with end-stage renal failure treated with haemodialysis were included retrospectively from 01/01/2000 to 31/12/2004 and prospectively from 01/01/2005 to 31/12/2014 in our French Region. Clinical data, presence of cirrhosis and its severity were recorded at the beginning of haemodialysis. The primary endpoint was 2-year survival. RESULTS: Seven thousand three hundred and fifty-four patients (96%) without cirrhosis and 304 patients (4%) with cirrhosis were included. Two-year survival in noncirrhotic patients was higher than in cirrhotic patients (71.7% vs 54.4%, P < 0.0001). Patients with decompensated cirrhosis had a worse 2-year outcome (44.1%) as compared to compensated cirrhotic (62.8%, P = 0.002) and noncirrhotic patients (71.7%, P < 0.0001). Compensated and decompensated cirrhosis were independent predictive factors of 2-year mortality. In sensitivity analysis restricted to cirrhotic patients, 2-year survival of Child-Pugh A patients was higher than in Child-Pugh B and C patients (65.5% vs 27.7% vs 0%, P < 0.0001). Development of predictive models based either on severity scores (MELD and Child-Pugh) and extrahepatic comorbidities allowed correct classification of around 70% of patients in terms of mortality and may help to better stratify mortality risk in this population. CONCLUSIONS: Cirrhosis is independently associated with mortality in haemodialysis patients. Patients with severe cirrhosis have a poor 2-year outcome. Severity of cirrhosis and presence of extrahepatic comorbidities should be considered when deciding to initiate renal replacement therapy.

17.
Dig Dis Sci ; 64(7): 1878-1892, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31076986

RESUMO

BACKGROUND: Alcohol-related liver disease is one of the most prevalent chronic liver diseases worldwide. Mechanisms involved in the pathogenesis of alcohol-related liver disease are not well understood. Oxylipins play a crucial role in numerous biological processes and pathological conditions. Nevertheless, oxylipins are not well studied in alcohol-related liver disease. AIMS: (1) To characterize the patterns of bioactive ω-3 and ω-6 polyunsaturated fatty acid metabolites in alcohol use disorder and alcoholic hepatitis patients and (2) to identify associations of serum oxylipins with clinical parameters in patients with alcohol-related liver disease. METHODS: We performed a comprehensive liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis of serum and fecal oxylipins derived from ω-6 arachidonic acid, ω-3 eicosapentaenoic acid, and docosahexaenoic acid in a patient cohort with alcohol-related liver disease. RESULTS: Our results show profound alterations in the serum oxylipin profile of patients with alcohol use disorder and alcoholic hepatitis compared to nonalcoholic controls. Spearman correlation of the oxylipins with clinical parameters shows a link between different serum oxylipins and intestinal permeability, aspartate aminotransferase, bilirubin, albumin, international normalized ratio, platelet count, steatosis, fibrosis and model for end-stage liver disease score. Especially, higher level of serum 20-HETE was significantly associated with decreased albumin, increased hepatic steatosis, polymorphonuclear infiltration, and 90-day mortality. CONCLUSIONS: Patients with alcohol-related liver disease have different oxylipin profiles. Future studies are required to confirm oxylipins as disease biomarker or to connect oxylipins to disease pathogenesis.


Assuntos
Alcoolismo/sangue , Ácidos Graxos Ômega-3/sangue , Ácidos Graxos Ômega-6/sangue , Fezes/química , Hepatite Alcoólica/sangue , Oxilipinas/sangue , Adulto , Idoso , Alcoolismo/diagnóstico , Biomarcadores/sangue , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Feminino , Hepatite Alcoólica/diagnóstico , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
18.
Int J Drug Policy ; 72: 61-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31129024

RESUMO

BACKGROUND: In the era of direct-acting antivirals (DAA) for the treatment of hepatitis C virus (HCV) infection, HCV treatment uptake remains insufficiently documented in key populations such as people with opioid dependence. Access to opioid agonist therapy (OAT) is facilitated in France through delivery in primary care, and individuals with opioid dependence can be identified as those receiving OAT. Women with opioid dependence are especially vulnerable because of associated sex-related stigma, discrimination, and marginalization, all of which negatively interfere with access to HCV prevention and care. This study, based on data collected between 2012 and 2016 in France, aimed to assess whether (i) chronically HCV-infected women with opioid dependence had lower rates of HCV treatment uptake than their male counterparts during the same period (i.e., study period), and (ii) the advent of DAA resulted in increased treatment uptake rates in these women. METHODS: Individuals with opioid dependence were identified as those receiving OAT at least once during the study period. Analyses were based on exhaustive anonymous care delivery data from the French national healthcare reimbursement database. We used multinomial logistic regression to estimate sex-based disparities in HCV treatment uptake (DAA or pegylated-interferon (Peg-IFN)-based treatment versus no treatment) while accounting for potential confounders. RESULTS: The study sample comprised 27,127 individuals, including 5640 (20.8%) women. Median [interquartile range] age was 45 [40-49] years. Between 2012 and 2016, 70.9 (women: 77.2; men: 69.3), 17.3 (14.2; 18.2) and 11.7% (8.6%; 12.5%) of the study sample received, respectively, no HCV treatment, DAA and Peg-IFN-based treatment only. After multiple adjustment for potential confounders, women were 41% (adjusted odds-ratio (AOR) [95% confidence interval (CI]): 0.59[0.53-0.65]) and 28% (0.72[0.66-0.78]) less likely than men to have had Peg-IFN-based and DAA treatment, respectively. CONCLUSION: Despite increased HCV treatment uptake in women with opioid dependence in the DAA era, rates remain lower than for men. In the coming years, access to DAA treatment will continue to increase in France thanks to a forthcoming simplified model of HCV care which includes primary care as an entry point. Nevertheless, a greater understanding of sex-specific barriers to HCV care and the implementation of appropriate sex-specific measures remain a priority.

19.
PLoS One ; 14(5): e0215596, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31050687

RESUMO

BACKGROUND AND AIMS: This study evaluated the clinical and non-clinical determinants of health-related quality of life (HRQoL) associated with untreated chronic hepatitis C (CHC) in France. METHODS: From 01/2014 to 01/2015, untreated CHC patients were invited to complete a questionnaire including EQ-5D utility instrument and two visual analogue scales (VAS) measuring overall health and fatigue in three French centers (Paris, Lille and Montpellier). Answers were analyzed in mixed models (taking into account the clustering effects of centers and physicians). RESULTS: Five hundreds and five patients were enrolled: 52% males; the mean age was 54; 41% had BMI>25; 64% had genotype 1; 36% were at the stage of severe fibrosis (F3-F4); 38% had severe comorbidities other than liver-related. In the univariate analysis, EQ-5D utility was associated with socio-demographic variables as age, place of birth, education, and employment; CHC-related variables as conditions of HCV screening and severity of fibrosis; CHC-unrelated variables as comorbidities other than CHC, being overweight, and psychiatric disorders; feelings about CHC disease as perception of progression, lack of information on CHC and its treatments, and entourage's feeling. In multivariate analysis, EQ-5D utility was affected by not being in employment (0.72 vs. 0.80), having severe comorbidities other than CHC (0.72 vs. 0.79), being overweight (0.73 vs. 0.78), and feeling worried about CHC progression (0.66 vs. 0.72-0.84). Similar results were found for the VAS. CONCLUSIONS: The presence of severe comorbidities and worrying about CHC progression, but not stage of fibrosis, seem to alter significantly EQ-5D health utility in CHC French patients.


Assuntos
Hepatite C Crônica/psicologia , Qualidade de Vida/psicologia , Adulto , Idoso , Comorbidade , Estudos Transversais , Progressão da Doença , Feminino , França , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
20.
BMC Infect Dis ; 19(1): 300, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940090

RESUMO

BACKGROUND: Although real-life results of sofosbuvir/simeprevir have been extensively reported from the United States, data from other geographical areas are limited. In the French observational cohort, ANRS CO22 HEPATHER, 9432 patients were given the new oral antivirals from December 2013 to June 30, 2018. We report the results of sofosbuvir/simeprevir in genotypes 1- and 4-infected patients. METHODS: Demographics and history of liver disease were collected at entry in the cohort. Clinical, adverse events, and virological data were collected throughout treatment and post-treatment follow-up. The choice of treatment duration or addition of ribavirin was left up to the physician. RESULTS: Five hundred ninety-nine HCV (467 genotype 1 and 132 genotype 4) mono-infected, naïve for all oral-DAAs regimen patients were given sofosbuvir/simeprevir with (n = 63) or without ribavirin (n = 536) for 12 or 24 weeks; 56% had cirrhosis (4% decompensated) and 71% had prior treatment failure to interferon-based regimen. 7 patients (1.16%) were lost to follow-up. The overall SVR12 rate was 92.6%. The SVR12 was 90% in GT1a, 94.2% in GT1b and 91.6% in GT4 with no significant difference for genotype, treatment duration or ribavirin addition. Severity of liver disease was not associated with a lower SVR12 rate on multivariate analysis but was associated with a higher rate of severe side effects. Early treatment discontinuations were rare; no new safety signals were reported. CONCLUSION: In this real life, observational, prospective cohort study, the 12-week sofosbuvir/simeprevir+/-ribavirin combination appears to be efficient and safe. TRIAL REGISTRATION: Trial registration with ClinicalTrials.gov NCT01953458 .


Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Simeprevir/uso terapêutico , Sofosbuvir/uso terapêutico , Adulto , Idoso , Antivirais/efeitos adversos , Estudos de Coortes , Esquema de Medicação , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Simeprevir/efeitos adversos , Sofosbuvir/efeitos adversos , Resultado do Tratamento
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