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1.
N Engl J Med ; 390(6): 497-509, 2024 02 08.
Artículo en Inglés | MEDLINE | ID: mdl-38324483

RESUMEN

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta-selective agonist in development for the treatment of NASH with liver fibrosis. METHODS: We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score. RESULTS: Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was -13.6% in the 80-mg resmetirom group and -16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group. CONCLUSIONS: Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage. (Funded by Madrigal Pharmaceuticals; MAESTRO-NASH ClinicalTrials.gov number, NCT03900429.).


Asunto(s)
Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico , Piridazinas , Uracilo , Adulto , Humanos , Método Doble Ciego , Hígado/diagnóstico por imagen , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/patología , Piridazinas/uso terapéutico , Resultado del Tratamiento , Uracilo/análogos & derivados , Receptores beta de Hormona Tiroidea/agonistas , Biopsia , Relación Dosis-Respuesta a Droga
2.
Am J Hum Genet ; 109(2): 299-310, 2022 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-35090584

RESUMEN

Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQß1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQß1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQß1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQß1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQß1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.


Asunto(s)
Cadenas beta de HLA-DQ/genética , Hepacivirus/patogenicidad , Hepatitis C/genética , Interacciones Huésped-Patógeno/genética , Polimorfismo de Nucleótido Simple , Enfermedad Aguda , Alelos , Sustitución de Aminoácidos , Población Negra , Femenino , Expresión Génica , Estudio de Asociación del Genoma Completo , Genotipo , Cadenas beta de HLA-DQ/inmunología , Hepacivirus/crecimiento & desarrollo , Hepacivirus/inmunología , Hepatitis C/etnología , Hepatitis C/inmunología , Hepatitis C/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Leucina/inmunología , Leucina/metabolismo , Masculino , Prolina/inmunología , Prolina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Remisión Espontánea , Población Blanca
3.
Semin Liver Dis ; 44(2): 258-271, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38657680

RESUMEN

Although therapy with direct-acting antiviral (DAA) agents achieves high hepatitis C virus (HCV) cure rates and is forgiving of missed doses, certain patient populations, such as people who inject drugs (PWID), are often denied therapy because of a perceived high risk of nonadherence. However, a relationship between adherence to DAAs for various patient populations and efficacy has not been well defined. The lack of a standardized method for evaluating adherence complicates making comparisons between studies, making it difficult to develop and implement novel measures that may improve adherent behavior. Traditional methods for assessing adherence may overestimate medication adherence, while newer, technology-based methods may assist with accurately assessing and maintaining patient adherence to therapy. Data demonstrate that special populations of patients with HCV, such as PWID, can be successfully treated, with relatively high rates of sustained virologic response (SVR) despite less-than-optimal adherence. While rates of adherence, and subsequently SVR, can be improved, antiviral therapy should not be withheld because of fear of nonadherence. This article addresses medication adherence and forgiveness of DAA regimens, such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir, in different patient populations with HCV. Considerations in evaluating adherence in HCV therapy and available methods for assessing adherence are detailed.


Asunto(s)
Antivirales , Cumplimiento de la Medicación , Respuesta Virológica Sostenida , Humanos , Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Hepacivirus/efectos de los fármacos , Resultado del Tratamiento , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/psicología , Quimioterapia Combinada , Abuso de Sustancias por Vía Intravenosa/complicaciones
4.
J Pediatr Gastroenterol Nutr ; 78(6): 1342-1354, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38644678

RESUMEN

BACKGROUND: The safety and efficacy of sofosbuvir-velpatasvir in children aged 3-17 years with chronic hepatitis C virus (HCV) infection of any genotype were evaluated. METHODS: In this Phase 2, multicenter, open-label study, patients received once daily for 12 weeks either sofosbuvir-velpatasvir 400/100 mg tablet (12-17 years), 200/50 mg low dose tablet or oral granules (3-11 years and ≥17 kg), or 150/37.5 mg oral granules (3-5 years and <17 kg). The efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Dose appropriateness was confirmed by intensive pharmacokinetics in each age group. FINDINGS: Among 216 patients treated, 76% had HCV genotype 1% and 12% had genotype 3. Rates of SVR12 were 83% (34/41) among 3-5-year-olds, 93% (68/73) among 6-11-year-olds, and 95% (97/102) among 12-17-year-olds. Only two patients experienced virologic failure. The most common adverse events were headache, fatigue, and nausea in 12-17-year-olds; vomiting, cough, and headache in 6-11-year-olds; and vomiting in 3-5-year-olds. Three patients discontinued treatment because of adverse events. Four patients had serious adverse events; all except auditory hallucination (n = 1) were considered unrelated to study drug. Exposures of sofosbuvir, its metabolite GS-331007, and velpatasvir were comparable to those in adults in prior Phase 2/3 studies. Population pharmacokinetic simulations supported weight-based dosing for children in this age range. INTERPRETATION: The pangenotypic regimen of sofosbuvir-velpatasvir is highly effective and safe in treating children 3-17 years with chronic HCV infection.


Asunto(s)
Antivirales , Carbamatos , Combinación de Medicamentos , Hepatitis C Crónica , Compuestos Heterocíclicos de 4 o más Anillos , Sofosbuvir , Humanos , Sofosbuvir/uso terapéutico , Sofosbuvir/farmacocinética , Sofosbuvir/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Niño , Carbamatos/uso terapéutico , Carbamatos/farmacocinética , Carbamatos/efectos adversos , Carbamatos/administración & dosificación , Masculino , Preescolar , Femenino , Antivirales/uso terapéutico , Antivirales/farmacocinética , Antivirales/administración & dosificación , Antivirales/efectos adversos , Adolescente , Hepatitis C Crónica/tratamiento farmacológico , Resultado del Tratamiento , Hepacivirus/genética , Hepacivirus/efectos de los fármacos , Respuesta Virológica Sostenida , Genotipo , Bencimidazoles , Benzopiranos
5.
Hepatology ; 76(2): 445-455, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35112372

RESUMEN

BACKGROUND AND AIMS: Sofosbuvir-velpatasvir-voxilaprevir is a pangenotypic regimen for chronic HCV infection. In the USA and Europe, sofosbuvir-velpatasvir-voxilaprevir once daily for 12 weeks is indicated for adults who previously received an HCV NS5A inhibitor. In Europe, sofosbuvir-velpatasvir-voxilaprevir is also indicated in the absence of prior HCV direct-acting antiviral (DAA) therapy as an 8-week or 12-week regimen. In an open-label study, we evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir-voxilaprevir in adolescents 12 to 17 years with chronic HCV of any genotype. METHODS: In this Phase 2, multicenter study, sofosbuvir-velpatasvir-voxilaprevir 400/100/100 mg daily was administered to adolescents for 8 weeks if DAA-naïve or for 12 weeks for cirrhosis or prior DAA failure. The key efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Intensive pharmacokinetic sampling was done in 14 patients at week 2 or 4, and samples for population pharmacokinetics were collected in all patients. RESULTS: All patients (n = 21) were naïve to HCV DAAs, and none had cirrhosis. HCV genotype 3a infection was most common, occurring in 43% of patients. Overall, 100% of patients (21 of 21) reached SVR12. The most common adverse events were abdominal pain and headache (24% each) and nausea (19%); no adverse events led to discontinuation. The only serious adverse event, hypotension, was considered related to study drug and resolved the same day without interruption of treatment. Sofosbuvir-velpatasvir-voxilaprevir exposures were similar to those observed in adults. CONCLUSIONS: The pangenotypic regimen of sofosbuvir-velpatasvir-voxilaprevir is highly efficacious and well-tolerated in treating chronic HCV infection in adolescents.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Adolescente , Adulto , Ácidos Aminoisobutíricos , Antivirales/efectos adversos , Carbamatos , Niño , Ciclopropanos , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/efectos adversos , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Cirrosis Hepática/tratamiento farmacológico , Prolina/análogos & derivados , Quinoxalinas , Sofosbuvir/efectos adversos , Sulfonamidas , Respuesta Virológica Sostenida , Resultado del Tratamiento
6.
Clin Gastroenterol Hepatol ; 20(2): 438-446, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-33493697

RESUMEN

BACKGROUND & AIMS: Achieving sustained virologic response (SVR) among patients with hepatitis C virus (HCV) leads to patient reported outcome (PRO) improvement. We aimed to assess the long-term post-SVR PRO trends in HCV patients with cirrhosis. METHODS: Patients with HCV and cirrhosis treated in clinical trials with direct acting antiviral agents (DAAs) who achieved SVR-12 were prospectively enrolled in a long-term registry (clinicaltrials.gov #NCT02292706). PROs were collected every 24 weeks using the Short Form-36v2 (SF-36), CLDQ-HCV, and WPAI-HCV. RESULTS: Pre-treatment baseline data were available for 854 cirrhotic patients who achieved SVR after DAAs. Of these, 730 had compensated (CC) and 124 had decompensated cirrhosis (DCC) before treatment- patients with DCC reported severe impairment in their PROs in comparison to CC patients (by mean -5% to -16% of a PRO range size; p < .05 for 16 out of 20 studied PROs]. After achieving SVR and registry enrollment, significant PRO improvements were noted from pre-treatment levels in 11/20 domains for those with DCC (+4% to +21%) and 19/20 PRO domains in patients with CC (+3% to +17%). Patients with baseline DCC had higher rates of hepatocellular carcinoma and mortality (P < .05). In patients with CC, the PRO gains persisted up to 168 weeks (3.5 years) of registry follow-up. In patients with DCC, the improvements lasted for at least 96 weeks but a declining trend after year 2. CONCLUSIONS: Patients with HCV cirrhosis experience severe PRO impairment at baseline with sustainable improvement after SVR. Though those with DCC experience improvement, there is a decline after 2 years.


Asunto(s)
Hepatitis C Crónica , Antivirales/uso terapéutico , Quimioterapia Combinada , Hepacivirus , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Atención Dirigida al Paciente , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Respuesta Virológica Sostenida
7.
J Pathol ; 254(1): 80-91, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33586163

RESUMEN

Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Antígenos de Superficie de la Hepatitis B/metabolismo , Hepatopatías/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína Sequestosoma-1/metabolismo , alfa 1-Antitripsina/metabolismo , Animales , Antígenos de Superficie de la Hepatitis B/toxicidad , Humanos , Hepatopatías/patología , Ratones , Estrés Fisiológico/fisiología , alfa 1-Antitripsina/toxicidad
8.
BMC Infect Dis ; 22(1): 3, 2022 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-34983405

RESUMEN

BACKGROUND: It has been estimated that the incidence of chronic hepatitis C virus (HCV) will not decline over the next 10 years despite the improved efficacy of antiviral therapy because most patients remain undiagnosed and/or untreated. This study aimed to investigate the opinion of relevant target populations on the practicability, effectiveness and best modalities of the test-and-treat approach in the fight against HCV in Italy. METHODS: A survey was delivered to patients with HCV from the general population, patients from drug addiction services, hospital physicians and healthcare providers for drug addiction services. RESULTS: For both hospital clinicians and SerD HCPs, tolerability is shown as the most important feature of a suitable treatment. Time to treatment (the time from first contact to initiation of treatment) is deemed important to the success of the strategy by all actors. While a tolerable treatment was the main characteristic in a preferred care pathway for general patients, subjects from drug addiction services indicated that a complete Meet-Test-Treat pathway is delivered within the habitual care center as a main preference. This is also important for SerD HCPs who are a strong reference for their patients; hospital clinicians were less aware of the importance of the patient-HCP relationship in this process. CONCLUSION: The health system is bound to implement suitable pathways to facilitate HCV eradication. A Meet-Test-Treat program within the drug addiction services may provide good compliance from subjects mainly concerned with virus transmission.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Trastornos Relacionados con Sustancias , Antivirales/uso terapéutico , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/diagnóstico , Hepatitis C Crónica/tratamiento farmacológico , Hospitales , Humanos , Incidencia , Trastornos Relacionados con Sustancias/tratamiento farmacológico
9.
J Infect Dis ; 223(12): 2090-2098, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-33119750

RESUMEN

BACKGROUND: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors. METHODS: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group. RESULTS: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor. CONCLUSIONS: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.


Asunto(s)
Hepatitis C , Factores Sexuales , Femenino , Estudio de Asociación del Genoma Completo , Hepacivirus/genética , Hepatitis C/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Proteínas Ribosómicas/genética , Septinas/genética , Carga Viral
10.
Am J Gastroenterol ; 116(9): 1924-1928, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34465694

RESUMEN

INTRODUCTION: We evaluated 8, 12, or 24 weeks of ledipasvir/sofosbuvir in patients with hepatitis C virus and end-stage renal disease undergoing dialysis. METHODS: Primary efficacy end point was sustained virologic response 12 weeks after treatment. Primary safety end point was treatment discontinuation because of adverse events (AEs). RESULTS: Ninety-four percent (89/95) achieved sustained virologic response 12 weeks after treatment. Six patients died during treatment (n = 4) or before study completion (n = 2); no deaths were related to treatment. No patients discontinued treatment because of AEs. Thirteen percent had serious AEs; none were related to treatment. DISCUSSION: Treatment with ledipasvir/sofosbuvir was safe and effective in patients with end-stage renal disease undergoing dialysis.


Asunto(s)
Antivirales/uso terapéutico , Bencimidazoles/uso terapéutico , Fluorenos/uso terapéutico , Hepatitis C/tratamiento farmacológico , Fallo Renal Crónico/terapia , Sofosbuvir/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/administración & dosificación , Bencimidazoles/administración & dosificación , Esquema de Medicación , Femenino , Fluorenos/administración & dosificación , Hepatitis C/complicaciones , Humanos , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Sofosbuvir/administración & dosificación , Respuesta Virológica Sostenida , Resultado del Tratamiento
11.
Clin Chem Lab Med ; 59(12): 2019-2026, 2021 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-34614550

RESUMEN

OBJECTIVES: After exceptional research efforts, several vaccines were developed against SARS-CoV-2 which sustains the pandemic COVID-19. The Comirnaty vaccine showed high efficacy in clinical trials and was the first to be approved for its distribution to the general population. We evaluated the immune response induced by the first vaccine dose in different sex/age groups and subjects with or without naturally present anti-SARS-CoV-2 antibodies. METHODS: As part of an Italian multicenter project (Covidiagnostix), serum samples from 4,290 health-professionals were serologically tested the day of the first vaccination dose, and 21 days later, using two different instrumentations (Siemens-Healthineers and Roche). RESULTS: In total, 97% of samples showed the presence of specific antibodies 21 days after the vaccination dose; the percentage of non-responders increased with age in both genders. Remarkably, naturally seropositive individuals showed antibody persistence up to 11 months and an exceptionally higher vaccination response compared to subjects never infected by SARS-CoV-2. CONCLUSIONS: This study highlighted the importance of the serological test i) to identify naturally SARS-CoV-2 seropositive individuals and ii) to evaluate the antibody level elicited by the first vaccination dose. Both tests, highlighted differences in the immune response, when subjects were stratified by sex and age, and between naturally seropositive and seronegative subjects. The data obtained show how serological tests could play a crucial role in the triage of the population subjected to the vaccination campaign for COVID-19. The definition of suitable instrumentation-specific thresholds is needed to correctly follow eventually acquired post-vaccination immunity in the general population.


Asunto(s)
Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , Programas de Inmunización , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/inmunología , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Femenino , Personal de Salud , Humanos , Inmunidad Humoral , Inmunoensayo , Masculino , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Adulto Joven
12.
Pathologica ; 113(3): 194-202, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34294937

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of different conditions which are characterized by hepatic steatosis in the absence of secondary causes. It is currently the most common chronic liver disease worldwide, and its estimated prevalence is about 1.5-6.5%. The only histological finding of steatosis ("simple" steatosis) represents the uncomplicated form of NAFLD, while non-alcoholic steatohepatitis (NASH) is its inflammatory subtype associated with disease progression to cirrhosis and hepatocellular carcinoma (HCC), and represents the major indication for liver transplantation. NASH is still a diagnostic and therapeutic challenge for clinicians and liver biopsy is currently the only accepted method to reliably distinguish NASH from "simple" steatosis. From the histological perspectives, NAFLD and NASH continue to be an area of active interest for pathologists, with a specific focus on better methods of evaluation, morphologic clues to pathogenesis, and predictors of fibrosis progression. This review focuses on histopathology of NAFLD in adults, with the aim to provide a practical diagnostic approach useful in the clinical routine.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Adulto , Biopsia , Progresión de la Enfermedad , Humanos , Cirrosis Hepática , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología
13.
Pathologica ; 113(3): 170-184, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34294935

RESUMEN

Autoimmune cholestatic liver diseases are rare hepato-biliary disorders characterized by a progressive, inflammatory destruction of bile ducts. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the main autoimmune cholestatic liver diseases. Both may evolve into secondary biliary cirrhosis and its complications. Therapeutic options are limited and liver transplantation remains the only definitive treatment for PBC and PSC.Most PBC and PSC patients have a typical presentation, which does not require liver biopsy. However, in routine clinical practice, important variants or specific subgroups that benefit from liver biopsy for proper management may be observed. Herein, we provide a general overview of clinical and pathological characteristic of PBC and PSC, highlighting the most important features for routine diagnostic practice.


Asunto(s)
Enfermedades Autoinmunes , Colangitis Esclerosante , Cirrosis Hepática Biliar , Enfermedades Autoinmunes/complicaciones , Colangitis Esclerosante/complicaciones , Colangitis Esclerosante/diagnóstico , Colangitis Esclerosante/epidemiología , Humanos , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/diagnóstico
14.
Genes Immun ; 21(5): 348-359, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33116245

RESUMEN

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10-04) and rs8099917 (P value = 5.5 × 10-04). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10-05). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10-04). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.


Asunto(s)
Hepatitis C/genética , Interferones/genética , Polimorfismo de Nucleótido Simple , Población Negra/genética , Haplotipos , Hepatitis C/etnología , Hepatitis C/patología , Humanos , Fenotipo , Población Blanca/genética
15.
Gastroenterology ; 156(5): 1496-1507.e7, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30593799

RESUMEN

BACKGROUND & AIMS: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. METHODS: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed. RESULTS: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants. CONCLUSIONS: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.


Asunto(s)
Población Negra/genética , Hepacivirus/fisiología , Hepatitis C/genética , Hispánicos o Latinos/genética , Población Blanca/genética , Femenino , Estudio de Asociación del Genoma Completo , Hepatitis C/diagnóstico , Hepatitis C/etnología , Hepatitis C/virología , Interacciones Huésped-Patógeno , Humanos , Interferones , Interleucinas/genética , Complejo Mayor de Histocompatibilidad/genética , Masculino , Receptores Acoplados a Proteínas G/genética , Remisión Espontánea , Estados Unidos/epidemiología , Carga Viral
16.
Gastroenterology ; 157(1): 227-241.e7, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30930022

RESUMEN

BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients. RESULTS: GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells. CONCLUSIONS: In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.


Asunto(s)
Antivirales/uso terapéutico , Vacunas contra Hepatitis B/uso terapéutico , Hepatitis B Crónica/tratamiento farmacológico , Tenofovir/uso terapéutico , Adolescente , Adulto , Anciano , Linfocitos T CD8-positivos/inmunología , ADN Viral , Quimioterapia Combinada , Femenino , Antígenos del Núcleo de la Hepatitis B/inmunología , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/inmunología , Humanos , Tolerancia Inmunológica/inmunología , Interferón gamma/inmunología , Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , Transactivadores/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Carga Viral , Proteínas Reguladoras y Accesorias Virales , Adulto Joven
17.
Liver Int ; 40(8): 1841-1852, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32449966

RESUMEN

BACKGROUND AND AIMS: Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real-world analysis to date, the effectiveness of pangenotypic, panfibrotic, single-tablet, sofosbuvir/velpatasvir (SOF/VEL) once-daily for 12 weeks was assessed in 12 clinical real-world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. METHODS: Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post-treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. RESULTS: Overall, 5552 patients were included: 13.3% treatment-experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P = .002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non-virological reasons (67% lost to follow-up; 26.5% early treatment discontinuation). CONCLUSIONS: In this large cohort, representative of clinical practice, a simple 12-week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Adulto , Antivirales/uso terapéutico , Carbamatos , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos , Humanos , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Respuesta Virológica Sostenida , Resultado del Tratamiento
18.
BMC Gastroenterol ; 20(1): 251, 2020 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-32746786

RESUMEN

Beta-thalassemia represents a heterogeneous group of haemoglobin inherited disorders, among the most common genetic diseases in the world, frequent in the Mediterranean basin. As beta-thalassemia patients' survival has increased over time, previously unknown complications are observed with increasing frequency. Among them, an increased risk of hepatocellular carcinoma (HCC) has been registered. Our aim is to reduce inequalities in diagnosis and treatment and to offer patients univocal recommendations in any institution.The members of the panel - gastroenterologists, radiologists, surgeons and oncologists -were selected on the basis of their publication records and expertise. Thirteen clinical questions, derived from clinical needs, and an integration of all the committee members' suggestions, were formulated. Modified Delphi approach involving a detailed literature review and the collective judgement of experts, was applied to this work.Thirteen statements were derived from expert opinions' based on the current literature, on recently developed reviews and on technological advancements. Each statement is discussed in a short paragraph reporting the current key evidence. As this is an emerging issue, the number of papers on HCC in beta-thalassemia patients is limited and based on anecdotal cases rather than on randomized controlled studies. Therefore, the panel has discussed, step by step, the possible differences between beta-thalassemia and non beta-thalassemia patients. Despite the paucity of the literature, practical and concise statements were generated.This paper offers a practical guide organized by statements describing how to manage HCC in patients with beta-thalassemia.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Talasemia , Adulto , Carcinoma Hepatocelular/etiología , Testimonio de Experto , Humanos , Neoplasias Hepáticas/etiología , Factores de Riesgo
19.
Clin Infect Dis ; 69(11): 1969-1979, 2019 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-30715261

RESUMEN

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.


Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Virus de la Hepatitis B/patogenicidad , Hepatitis B Crónica/tratamiento farmacológico , Interferón-alfa/metabolismo , Interferones/metabolismo , Adulto , Antivirales/uso terapéutico , Femenino , Técnicas de Genotipaje , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Prospectivos
20.
Gastroenterology ; 154(6): 1764-1777.e7, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29378197

RESUMEN

BACKGROUND & AIMS: The oral Toll-like receptor (TLR) 7 agonist GS-9620 has antiviral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection. We investigated, in a clinical trial, the capacity of this agent to reconstitute protective immunity in patients with chronic HBV infection. METHODS: We performed a prospective study of 28 patients with suppression of HBV infection by nucleos(t)ide analogue therapy and who tested negative for hepatitis B e antigen at 4 medical centers in Italy. Patients were randomly assigned (1:3:3:3) to groups given placebo or different doses of GS-9620 (1, 2, and 4 mg, weekly for 12 weeks). We added data from 8 patients receiving nucleos(t)ide analogue therapy to the placebo group (controls); 13 treatment-naïve patients with chronic HBV infection and 15 subjects who spontaneously recovered from an acute HBV infection served as additional controls. Peripheral blood mononuclear cells were collected at baseline, during administration of GS-9620 or placebo, and 12 weeks afterward. Phenotype and function of natural killer (NK) and HBV-specific T cells were analyzed by flow cytometry. T cells were expanded by incubation with peptides from the entire HBV proteome and studied after overnight or 10 days culture. NK-cell inhibition of T-cell responses was measured by assessing cytokine production by T cells stimulated with peptides in the presence or absence of NK cells. RESULTS: T cells collected at baseline before addition of GS-9620, when patients were receiving only nucleos(t)ide therapy, had greater responses to HBV than T cells from treatment-naïve patients, based on cytokine production in response to HBV peptides. However, during or after administration of GS-9620, T cells produced higher levels of cytokines compared to baseline. NK-cell activation and function increased after patients were given GS-9620, but the ability of NK cells to suppress T-cell responses was lower during GS-9620 therapy than before. Changes in T-cell or NK-cell function did not correlate with levels of hepatitis B surface antigen. Serum levels of hepatitis B surface antigen did not decrease significantly compared to baseline in patients given any dose of GS-9620. CONCLUSIONS: Twelve weeks administration of GS-9620 had no significant effect on serum hepatitis B surface antigen levels, but did appear to increase T-cell and NK-cell responses and reduce the ability of NK to suppress T cells. GS-9620 might therefore be included in therapies to increase the immune response to HBV.


Asunto(s)
Antivirales/administración & dosificación , Virus de la Hepatitis B/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Células Asesinas Naturales/efectos de los fármacos , Pteridinas/administración & dosificación , Linfocitos T/efectos de los fármacos , Adulto , Femenino , Antígenos de Superficie de la Hepatitis B/sangre , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/virología , Humanos , Masculino , Persona de Mediana Edad , Nucleósidos/uso terapéutico , Estudios Prospectivos , Receptor Toll-Like 7/agonistas
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