RESUMO
BACKGROUND & AIMS: Although off-label use of sofosbuvir-containing regimens occurs regularly in patients with hepatitis C virus (HCV) infection undergoing dialysis for severe renal impairment or end-stage renal disease (ESRD), these regimens are not licensed for this indication, and there is an absence of dosing recommendations in this population. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir in patients with HCV infection with ESRD undergoing dialysis. METHODS: In this phase II, single-arm study, 59 patients with genotype 1-6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis received open-label sofosbuvir/velpatasvir (400â¯mg/100â¯mg) once daily for 12â¯weeks. Patients were HCV treatment naive or treatment experienced without cirrhosis or with compensated cirrhosis. Patients previously treated with any HCV NS5A inhibitor were not eligible. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response (SVR) 12â¯weeks after discontinuation of treatment (SVR12). The primary safety endpoint was the proportion of patients who discontinued study drug due to adverse events. RESULTS: Overall, 56 of 59 patients achieved SVR12 (95%; 95% CI 86-99%). Of the 3 patients who did not achieve SVR12, 2 patients had virologic relapse determined at post-treatment Week 4 (including 1 who prematurely discontinued study treatment), and 1 patient died from suicide after achieving SVR through post-treatment Week 4. The most common adverse events were headache (17%), fatigue (14%), nausea (14%), and vomiting (14%). Serious adverse events were reported for 11 patients (19%), and all were deemed to be unrelated to sofosbuvir/velpatasvir. CONCLUSIONS: Treatment with sofosbuvir/velpatasvir for 12â¯weeks was safe and effective in patients with ESRD undergoing dialysis. LAY SUMMARY: Sofosbuvir/velpatasvir is a combination direct-acting antiviral that is approved for treatment of patients with hepatitis C virus (HCV) infection. Despite the lack of dosing recommendations, sofosbuvir-containing regimens (including sofosbuvir/velpatasvir) are frequently used for HCV-infected patients undergoing dialysis. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir for 12â¯weeks in patients with HCV infection who were undergoing dialysis. Treatment with sofosbuvir/velpatasvir was safe and well tolerated, resulting in a cure rate of 95% in patients with HCV infection and end-stage renal disease. Clinical Trial Number: NCT03036852.
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Carbamatos , Hepatite C Crônica , Compostos Heterocíclicos de 4 ou mais Anéis , Falência Renal Crônica , Diálise Renal/métodos , Sofosbuvir , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Combinação de Medicamentos , Monitoramento de Medicamentos/métodos , Feminino , Hepacivirus/genética , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
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).
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Antivirais/administração & dosagem , Carbamatos/administração & dosagem , Combinação de Medicamentos , Genótipo , Hepacivirus/classificação , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Sofosbuvir/administração & dosagem , Antivirais/efeitos adversos , Carbamatos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Masculino , Placebos/administração & dosagem , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). METHODS: In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. RESULTS: In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). CONCLUSIONS: In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.
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Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Macrocíclicos/uso terapêutico , Sofosbuvir/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Aminoisobutíricos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Carbamatos/administração & dosagem , Carbamatos/efeitos adversos , Ciclopropanos , Quimioterapia Combinada , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compostos Macrocíclicos/administração & dosagem , Compostos Macrocíclicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prolina/análogos & derivados , Quinoxalinas , Sofosbuvir/administração & dosagem , Sofosbuvir/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resposta Viral Sustentada , Adulto JovemRESUMO
BACKGROUND: Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. METHODS: We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. RESULTS: Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%-94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). CONCLUSIONS: In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. CLINICAL TRIALS REGISTRATION: NCT02413593.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus , Hepatite C Crônica/tratamento farmacológico , Ribavirina/uso terapêutico , Uridina Monofosfato/análogos & derivados , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Farmacorresistência Viral/genética , Feminino , Fluorenos/efeitos adversos , Fluorenos/farmacologia , Genótipo , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Ribavirina/farmacologia , Sofosbuvir , Resposta Viral Sustentada , Uridina Monofosfato/efeitos adversos , Uridina Monofosfato/farmacologia , Uridina Monofosfato/uso terapêuticoRESUMO
INTRODUCTION: Recurrence of HCV infection in patients with chronic hepatitis C virus (HCV) at the time of liver transplantation is nearly universal and reduces the likelihood of graft and patient survival. MATERIALS AND METHODS: We evaluated outcomes of 17 patients (16 with HCV genotype 1 and 1 with genotype 4) who received up to 12 or 24 weeks of ledipasvir/sofosbuvir plus ribavirin prior to or up to the time of liver transplant in the SOLAR-1 and SOLAR-2 trials. In all patients, HCV RNA was < 15 IU/mL prior to transplant. At screening, 6 patients were Child-Pugh-Turcotte (CPT) class B and 11 were CPT class C. Seven patients underwent transplant prior to completing assigned treatment, with 4 treated for < 12 weeks. The primary endpoint was posttransplant virologic response 12 weeks after transplant (pTVR12) in patients with HCV RNA < 15 IU/mL at their last measurement prior to transplant. RESULTS: Overall, 94% (16/17) achieved pTVR12. All who achieved pTVR12 received at least 11 weeks of treatment. The single patient who did not achieve pTVR12 discontinued study drug on day 21 and underwent liver transplant the following day. The patient had HCV RNA < 15 IU/mL at post-transplant week 2 but died 15 days post-transplant because of multi-organ failure and septic shock. CONCLUSION: Among a small population of HCV patients with decompensated cirrhosis, virologic response to ledipasvir / sofosbuvir plus ribavirin prior to liver transplantation was maintained after transplantation, even if treatment was stopped early. Administration of ledipasvir / sofosbuvir plus ribavirin before liver transplant can prevent post-transplant HCV recurrence.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Cirrose Hepática/cirurgia , Transplante de Fígado , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Resposta Viral Sustentada , Idoso , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Quimioterapia Combinada , Feminino , Fluorenos/efeitos adversos , Genótipo , Hepacivirus/genética , Hepatite C/diagnóstico , Hepatite C/mortalidade , Hepatite C/virologia , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/virologia , Transplante de Fígado/efeitos adversos , Transplante de Fígado/mortalidade , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Ribavirina/efeitos adversos , Sofosbuvir/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Carga ViralRESUMO
This study aims to analyse the potential availability of essential metals including as Co, Fe, Ni, Zn, Mn, and Cu and non-essential metals such as Pb, Cr, and Cd within anaerobic mono- and co-digestion of pig manure and maize. The metals partitioning was determined using the Modified BCR (European Community Bureau of Reference) sequential extraction at defined intervals over a 45-days period, correlating changes in metals speciation with key digestion variables. The findings revealed that Cr, Cu, Fe, and Pb were predominantly associated with the oxidisable fraction, while Zn, Mn, and Cd were potentially available in both processes. Notably, NH4+-N and the VFAs, except propionic acid, correlated significantly with the available fractions of Co, Mn, Ni, Zn, Cr, and Pb during mono-digestion of pig manure. The wider pH range and the chemical properties of the feedstock in co-digestion resulted in varied correlations between the metals availability and the digestion variables.
Assuntos
Esterco , Metais , Zea mays , Animais , Zea mays/química , Anaerobiose , Suínos , Concentração de Íons de Hidrogênio , Sus scrofaRESUMO
Roadside grass clippings hold potential as a sustainable source of bioenergy as they do not compete with crops for land use, and are only partially utilized for low-value applications. In this study, we proposed using roadside grass as a sole feedstock for anaerobic digestion (AD) in three different settings, and assessed the potential of producing biomaterials and fertilizers from grass-based digestate. Wet continuous digestion at pilot scale and dry batch digestion at pilot and large scales resulted in biogas yields up to 700 Nm3.t-1 DOM with a methane content of 49-55 %. Despite promising results, wet AD had operational problems such as clogging and poor mixing; once upscaled, the dry digestion initially also presented an operational problem with acidification, which was overcome by the second trial. Digested grass fibers from the pilot dry AD were processed into biomaterials and performed similarly or better than the undigested fibers, while around 20 % performance reduction was observed when compared to reference wood fibers. A mass balance indicated reduced fiber recovery when higher biogas production was obtained. The liquid fraction from the pilot dry AD was characterized for its nutrient content and used as a biofertilizer in another study. In contrast, the leachate collected from the large-scale dry AD had a low nitrogen content and high chloride content that could hinder its further use. Finally, a regional market analysis was conducted showing that the biocomposites produced with the available grass fibers could substitute at least half of the current European market based on our results.
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Biocombustíveis , Metano , Poaceae , Anaerobiose , Biocombustíveis/análise , Metano/metabolismo , Fertilizantes/análise , Projetos Piloto , Reatores Biológicos , Eliminação de Resíduos/métodosRESUMO
Single nucleotide polymorphisms (SNPs) in the proximity of the interleukin-28B (IL28B) gene can predict spontaneous resolution of hepatitis C virus (HCV) infection and response to interferon therapy. Screening for this polymorphism has become part of the standard criteria for the management of HCV-infected patients, hence the need for a rapid, cost-effective screening method. Here, we describe a rapid PCR-based test to screen for two IL28B SNPs (rs12979860 and rs8099917). We used this test to investigate IL28B polymorphism and prevalence in a cohort of French Canadian injection drug users who are part of a unique population known to have a strong genetic founder effect. This population had lower linkage disequilibrium between the two tested SNPs as compared to other cohorts (|d'| = 0.68, r = 0.59). The special genetic makeup should be considered in the management of HCV-infected patients within that population.
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Hepacivirus/isolamento & purificação , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/genética , Interleucinas/genética , Reação em Cadeia da Polimerase/métodos , Adulto , Canadá/epidemiologia , Estudos de Coortes , Feminino , Genótipo , Hepatite C Crônica/epidemiologia , Humanos , Interferons , Desequilíbrio de Ligação , Masculino , Polimorfismo de Nucleotídeo Único , PrevalênciaRESUMO
Although chronic viral infections have evolved mechanisms to interfere with aspects of pathogen recognition by dendritic cells (DCs), the role that these APCs play in virus-specific T cell exhaustion is unclear. Herein we report that NS3-dependent suppression of Toll/IL-1 domain-containing adapter-inducing IFN-beta- and IFN-beta promoter stimulator-1- but not MyD88-coupled pathogen-recognition receptor-induced synthesis of proinflammatory cytokines (IL-12 and TNF-alpha) from DCs by hepatitis C virus (HCV) is a distinctive feature of a subgroup of chronically infected patients. The result is decreased CD8(+) T cell polyfunctional capacities (production of IFN-gamma, IL-2, TNF-alpha, and CD107a mobilization) that is confined to HCV specificities and that relates to the extent to which HCV inhibits DC responses in infected subjects, despite comparable plasma viral load, helper T cell environments, and inhibitory programmed death 1 receptor/ligand signals. Thus, subjects in whom pathogen-recognition receptor signaling in DCs was intact exhibited enhanced polyfunctionality (i.e., IL-2-secretion and CD107a). In addition, differences between HCV-infected patients in the ability of CD8(+) T cells to activate multiple functions in response to HCV did not apply to CD8(+) T cells specific for other immune-controlled viruses (CMV, EBV, and influenza). Our findings identify reversible virus evasion of DC-mediated innate immunity as an additional important factor that impacts the severity of polyfunctional CD8(+) T cell exhaustion during a chronic viral infection.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Células Dendríticas/imunologia , Células Dendríticas/virologia , Hepacivirus/imunologia , Hepatite C Crônica/imunologia , Hepatite C Crônica/virologia , Terapia de Imunossupressão , Antígenos de Superfície/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Linfócitos T CD8-Positivos/patologia , Degranulação Celular/imunologia , Células Dendríticas/patologia , Feminino , Hepatite C Crônica/patologia , Humanos , Interleucina-2/biossíntese , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Células Mieloides/imunologia , Células Mieloides/patologia , Células Mieloides/virologia , Receptor de Morte Celular Programada 1 , Receptores de Reconhecimento de Padrão/antagonistas & inibidores , Receptores de Reconhecimento de Padrão/fisiologia , Carga Viral/imunologia , Ativação Viral/imunologiaRESUMO
The integration of phototrophic microalgal production and anaerobic digestion can recycle excess nutrients across European surplus hotspots to produce protein-rich biomass for nutritional applications. However, the challenging physico-chemical properties of raw digestate constrain microalgal growth and limit digestate valorization potential. This study focused on the pre-treatment of food waste-based digestate using paper-filtration to improve its properties for cultivating Desmodesmus sp. and Chlorella vulgaris. The microalgal growth performance in paper-filtered digestate (PFD, 10 µm-pore size) was then compared to growth in membrane-filtered digestate (MFD, 0.2 µm-pore size). A microplate-based screening coupled with Cytation device assessment of PFD and MFD samples after dilution and with/without phosphorus supplementation showed that PFD was the best substrate. Moreover, phosphorus supplementation resulted in improved growth at higher digestate concentrations (5-10% v/v PFD), indicating the importance of using a balanced growth medium to increase the volumetric usage of digestate. Results were validated in a 3-L bioreactor at 10% PFD with phosphorus supplementation, reaching a biomass concentration of 2.4 g L-1 with a protein and carbohydrate content of 67% and 13% w/w respectively. This trial indicates that paper-filtration is a promising pre-treatment technique to maximize digestate recycling and deliver a sustainable animal feed-grade protein alternative.
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Chlorella vulgaris , Microalgas , Eliminação de Resíduos , Ração Animal , Animais , Biomassa , Nutrientes , Águas ResiduáriasRESUMO
Early alpha interferon (IFN-alpha) therapy against hepatitis C virus (HCV) rescues polyfunctional, virus-specific memory CD8(+) T cells, but whether immune restoration is possible during late therapy remains controversial. We compared immune restoration of HCV-specific memory T cells in patients who cleared HCV infection spontaneously and following early or late IFN therapy. Multifunctional CD4(+) and CD8(+) memory T cells were detected in spontaneous resolvers and in individuals treated early following an acute infection. In contrast, limited responses were detected in patients treated during chronic infection, and the phenotype of HCV-specific cells was influenced by autologous viral sequences. Our data suggest that irreversible damage to the HCV-specific memory T-cell response is associated with chronic HCV infection.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/imunologia , Hepatite C Crônica/terapia , Hepatite C/imunologia , Hepatite C/terapia , Interferon Tipo I/uso terapêutico , Doença Aguda , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Degranulação Celular/imunologia , Estudos de Coortes , Hepacivirus/imunologia , Hepatite C/virologia , Hepatite C Crônica/virologia , Humanos , Memória Imunológica , Interferon gama/biossíntese , Interleucina-2/biossíntese , Dados de Sequência Molecular , RNA Viral/sangue , Proteínas Recombinantes , Fatores de TempoRESUMO
BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with chronic liver disease (CLD) and liver transplant (LT) recipients remains a concern. The aim of this study was to report the impact of coronavirus disease 2019 (COVID-19) infection among patients at the tertiary health care centre Centre hospitalier de l'Université de Montréal (CHUM) during the first wave of the SARS-CoV-2 pandemic. METHODS: This real-world, retrospective cohort included all patients admitted to our liver unit and/or seen as an outpatient with CLD with or without cirrhosis and/or LT recipients who tested positive to SARS-CoV-2 infection. Cases were considered positive as defined by the detection of SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. RESULTS: Between April 1 and July 31, 2020, 5,637 were admitted to our liver unit and/or seen as outpatient. Among them, 42 were positive for SARS-CoV-2. Twenty-two patients had CLD without cirrhosis while 16 patients had cirrhosis at the time of the infection (13, 2, and 1 with Child-Pugh A, B, and C scores, respectively). Four were LT recipients. Overall, 15 of 42 patients (35.7%) were hospitalized; among them, 7 of 42 (16.7%) required respiratory support and 4 of 42 (9.5%) were transferred to the intensive care unit. Only 4 of 42 (9.5%) patients died: 2 with CLD without cirrhosis and 2 with CLD with cirrhosis. Overall survival was 90.5%. CONCLUSION: This real-world study demonstrates an unexpectedly low prevalence and low mortality in the context of SARS-CoV-2 infection among patients with CLD with or without cirrhosis and LT recipients.
RESUMO
The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-alpha) antiviral therapy achieves the highest rate of success when IFN-alpha is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-gamma- and IL-2-producing and CD107a(+)) virus-specific CD8(+) T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8(+) T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-alpha rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Hepacivirus/imunologia , Hepatite C , Interferon-alfa , Subpopulações de Linfócitos T/imunologia , Adulto , Sequência de Aminoácidos , Linfócitos T CD8-Positivos/citologia , Epitopos , Feminino , Hepacivirus/genética , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Humanos , Memória Imunológica/imunologia , Interferon-alfa/imunologia , Interferon-alfa/uso terapêutico , Subunidade alfa de Receptor de Interleucina-7/imunologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Subpopulações de Linfócitos T/citologiaRESUMO
BACKGROUND/AIM: Since the discovery of hepatitis C virus (HCV), researchers have encountered difficulties with in vitro models. The aim of this study was to determine whether HCV-infected human primary hepatocytes, isolated from cirrhotic livers at liver transplantation, can be used as a model to study HCV infection. METHODS: Hepatocytes were isolated with collagenase and cultured over a 20-day period on different matrices. Viral kinetics was monitored with/without treatment by real-time polymerase chain reaction. RESULTS: Cell yield and viability were higher with uninfected/non-cirrhotic livers (77.2+/-1.8%) in comparison with HCV-infected cirrhotic livers (68.8+/-12%). HCV-infected hepatocytes behaved similar to non-infected cells and expressed albumin and cytochrome P4502E1. HCV-positive strand was identified in supernatants and cell lysates. HCV-negative strand was only found inside cells and correlated with viral RNA recovery in the medium. Improvement in the degree of hepatocyte differentiation was associated with better HCV recovery. Antiviral treatment with interferon-alpha, EX4 and cyclosporine A induced significant reductions in HCV RNA. CONCLUSION: Primary cultures of HCV-infected human hepatocytes from end-stage cirrhotic livers is feasible, represents an excellent model to study specific virus-host interactions and can be used to assess viral replication.
Assuntos
Hepacivirus/genética , Hepatite C/virologia , Hepatócitos/virologia , Interações Hospedeiro-Patógeno , Fígado/citologia , Fígado/virologia , Análise de Variância , Western Blotting , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Ciclosporina/farmacologia , Primers do DNA/genética , Hepacivirus/fisiologia , Hepatócitos/efeitos dos fármacos , Humanos , Interferon-alfa/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Replicação Viral/efeitos dos fármacosRESUMO
Modelling is increasingly used for optimizing environmental treatment processes such as anaerobic digestion. It allows problems such as instability of the process to be solved by predicting various scenarios. The anaerobic digestion model No. 1 (ADM1) is accepted worldwide as the standard model for the description of anaerobic digestion. However, it is sophisticated and complex, so it is not user friendly. Therefore, a mathematical method was developed that allows the calculation of the reactor pH, as well as the biogas flow rate (Q) and composition (expressed as the CO2 partial pressure, pCO2), based on a small number of widely available analyses such as chemical oxygen demand and total organic carbon. Furthermore, the ADM1 model was originally designed for anaerobic digestion of wastewater. In this work, the ADM1 model is evaluated for the first time for application in the modelling of solid waste digestion. This evaluation was performed in two steps. First, a list of experimentally available lab-scale data (pH and Q) was grouped according to the composition and origin of the treated solid waste (e.g. manure or vegetable waste). For each group the developed model for the calculation of pH, Q and pCO2 was calibrated with this lab-scale data. After calibration, the model was validated with additional experimental results. It could be demonstrated statistically that the model was able to predict the experimental results, although the confidence region was rather large.
Assuntos
Bactérias Anaeróbias/fisiologia , Reatores Biológicos/microbiologia , Resíduos Industriais/prevenção & controle , Modelos Biológicos , Modelos Estatísticos , Eliminação de Resíduos/métodos , Esgotos/microbiologia , Calibragem , Simulação por Computador , Interpretação Estatística de Dados , Eliminação de Resíduos/normasRESUMO
Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (Tregs), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17+CD4+/FOXP3hiCD4+ ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor-ß signaling in HSCs in a p38 mitogen-activated protein kinase-dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.
Assuntos
Interleucina-17/imunologia , Interleucinas/imunologia , Cirrose Hepática/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Compostos Azo/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo , Interleucinas/antagonistas & inibidores , Interleucinas/metabolismo , Cirrose Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pirazóis/farmacologia , Fator de Crescimento Transformador beta/metabolismo , Interleucina 22RESUMO
RATIONALE: Acute kidney injury (AKI) is a frequent complication after liver transplantation. In some patients, prompt intervention targeted at a specific etiology is of paramount importance. PRESENTING CONCERNS OF THE PATIENTS: A 25 years old man with advanced liver cirrhosis caused by sclerosing cholangitis and autoimmune hepatitis underwent orthotopic liver transplantation. One month after surgery, severe AKI developed in conjunction with recurrent ascites and lower extremity edema. Notable clinical findings included a persistently low urinary sodium excretion, a bland urinary sediment, and an abnormally monophasic hepatic vein waveform on Doppler ultrasound. DIAGNOSES: Inferior vena cava stenosis. INTERVENTIONS: Angioplasty with stent installation. OUTCOMES: Rapid improvement of renal function after stent installation. LESSONS LEARNED: The following case illustrates the importance of integrating clinical cues, ultrasound features, and laboratory findings. The combination of AKI associated with lower extremity edema, abnormal monophasic hepatic vein flow on Doppler ultrasound, and a low urinary sodium excretion after liver transplantation should evoke the possibility of inferior vena cava stenosis as the etiologic factor.
FONDEMENT: L'insuffisance rénale aiguë (IRA) est une complication survenant fréquemment à la suite d'une greffe hépatique. Pour certains patients, une intervention rapide et ciblée sur l'étiologie spécifique s'avère d'une importance capitale. PRÉSENTATION DU CAS: Un homme âgé de 25 ans atteint d'une cirrhose hépatique avancée causée par une cholangite sclérosante et une hépatite auto-immune a subi une greffe hépatique orthotopique. Un mois après l'intervention, le patient a développé une sévère IRA conjointement à des ascites récurrentes et un Ådème des membres inférieurs. Parmi les principales manifestations cliniques figuraient la persistance d'une faible excrétion urinaire du sodium, la présence de sédiments urinaires neutres et une forme d'onde anormalement monophasique pour la veine hépatique à l'échographie Doppler. DIAGNOSTIC: Sténose de la veine cave inférieure. INTERVENTION: Angioplastie avec implantation d'une endoprothèse vasculaire. RÉSULTATS: Amélioration rapide de la fonction rénale à la suite de l'implantation de l'endoprothèse vasculaire. ENSEIGNEMENTS TIRÉS: Ce cas illustre l'importance d'intégrer les indicateurs cliniques, les informations obtenues à l'échographie et les résultats de laboratoire. L'IRA survenant à la suite d'une greffe hépatique, lorsqu'elle est associée à de l'Ådème des membres inférieurs, à des ondes anormalement monophasiques de la veine hépatique à l'échographie Doppler, de même qu'à une faible excrétion urinaire de sodium, devrait évoquer la possibilité d'une sténose de la veine cave inférieure comme facteur étiologique.
RESUMO
Concomitant HIV and hepatitis C virus (HCV) is a common yet complex coinfection. The present document is a practical guide for treating HCV infection in people coinfected with HIV. Effective antiretroviral therapies have prolonged survival rates for HIV-infected people over the past decade, which have made latent complications of HCV major causes of morbidity and mortality in these patients. Advances in the treatment of HCV (eg, combined pegylated interferon and ribavirin) offer the possibility of eradicating HCV infection in coinfected persons. The treatment of HCV must be considered in all cases. Intensive management of the adverse effects of HCV treatment is one of the factors for the success of these therapies. HCV eradication is predicted to decrease the mortality associated with coinfection and reduce the toxicity of HIV treatment.