Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
PLoS One ; 14(8): e0221231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31469856

RESUMO

Treatment guidelines differ in their recommendation to determine baseline resistance associated substitutions (RAS) before starting a first-line treatment with direct-acting antivirals (DAAs). Here we analyze the efficacy of DAA treatment with baseline RAS information. We conducted a prospective study involving 23 centers collaborating in the GEHEP-004 DAA resistance cohort. Baseline NS5A and NS3 RASs were studied by Sanger sequencing. After issuing a comprehensive resistance report, the treating physician decided the therapy, duration and ribavirin use. Sustained virological response (SVR12) data are available in 275 patients. Baseline NS5A RAS prevalence was between 4.3% and 26.8% according to genotype, and NS3 RASs prevalence (GT1a) was 6.3%. Overall, SVR12 was 97.8%. Amongst HCV-GT1a patients, 75.0% had >800,000 IU/ml and most of those that started grazoprevir/elbasvir were treated for 12 weeks. In genotype 3, NS5A Y93H was detected in 9 patients. 42.8% of the HCV-GT3 patients that started sofosbuvir/velpatasvir included ribavirin, although only 14.7% carried Y93H. The efficacy of baseline resistance-guided treatment in our cohort has been high across the most prevalent HCV genotypes in Spain. The duration of the grazoprevir/elbasvir treatment adhered mostly to AASLD/IDSA recommendations. In cirrhotic patients infected with GT-3 there has been a high use of ribavirin.

2.
J Hepatol ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31279901

RESUMO

BACKGROUND: Most hepatitis C virus (HCV) infected patients failing NS5A inhibitors develop resistance-associated substitutions (RASs). Here we report the use of resistance-guided retreatment of patients who failed prior NS5A inhibitor-containing regimens in the GEHEP-004 cohort. This is the largest direct-acting antiviral (DAA)-resistance cohort study conducted in Spain. We aim to provide indications on how to use resistance information in settings where Vosevi® may not be available. PATIENTS & METHODS: GEHEP-004 is a prospective multicenter cohort enrolling HCV-infected patients treated with interferon (IFN)-free DAA regimens. Prior to retreatment, population-based sequencing of HCV NS3, NS5A and NS5B genes was performed. After receiving a comprehensive resistance interpretation report, the retreatment regimen was chosen and the sustained virological response at 12 weeks after treatment completion (SVR12) was recorded. RESULTS: A total of 342 patients experiencing virological failure after treatment with sofosbuvir/ledipasvir±ribavirin (54%), sofosbuvir/daclatasvir±ribavirin (23%), or paritaprevir-ritonavir/ombitasvir±dasabuvir±ribavirin (20%) have been studied. After a resistance report, 186 patients were retreated. A SVR12 was achieved for 88.1% of the patients who failed after sofosbuvir/ledipasvir±ribavirin, 83.3% of the patients who failed after sofosbuvir/daclatasvir±ribavirin, 93.7% of the patients who failed after Paritaprevirritonavir+Ombitasvir±Dasabuvir ±ribavirin. CONCLUSIONS: In our study we show how the resistance-guided retreatment in conjunction with an interpreted report allows achieving SVR rates close to 90%. We hypothesize that SVR rates may even be improved if resistance data are discussed between experienced virologists and treating clinicians. We believe that our data may be relevant for countries where the access to new DAA combination regimens is limited. LAY SUMMARY: Currently, hepatitis C infection can be cured with the available antiviral agents. Despite a low proportion of patients fail to be cured; in absolute numbers, a high number of patients may need retreatment worldwide. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. The results of emerging resistance to the antiviral drugs used in the first treatment, in conjunction with an interpreted comprehensive report about these resistances allow us to show how retreatment efficacy with old drugs may be very close to the efficacy of the new drug combinations.

3.
Aliment Pharmacol Ther ; 48(11-12): 1260-1270, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30353552

RESUMO

BACKGROUND: Metabolically healthy obesity (MHO) shows a reduced risk compared with obese patients with adverse metabolic conditions. Lean people suffering some metabolic derangements also have non-alcoholic fatty liver disease (NAFLD)-related outcomes compared with non-obese subjects with a few metabolic risks. AIM: To define the impact of the metabolic status on the NAFLD-related outcomes, beyond the presence of obesity. METHODS: We designed a multicentre cross-sectional study, including 1058 biopsy-proven NAFLD patients. Metabolically healthy status was strictly defined by the lack of metabolic risk factors (diabetes mellitus, low HDL, hypertriglyceridemia, arterial hypertension). Non-alcoholic steatohepatitis (NASH) and significant fibrosis (F2-F4) were identified by liver biopsy. Chronic kidney disease epidemiology collaboration equation was calculated for kidney function and the atherogenic index of plasma (AIP) for cardiovascular risk. RESULTS: Metabolically healthy (OR 1.88; P = 0.050) and unhealthy obesity (OR 3.47: P < 0.0001), and unhealthy non-obesity (OR 3.70; P < 0.0001) were independently associated with NASH together with homeostatic model assessment (HOMA), ALT, and platelets. Significant fibrosis was more frequently observed in the presence of adverse metabolic conditions in obese (OR 3.89; P = 0.003) and non-obese patients (OR 3.92; P = 0.002), and independently associated with platelets, albumin, ALT, HOMA, and age. The number of metabolic factors determined the risk of NASH and significant fibrosis. Glomerular filtration rate was lower in unhealthy (91.7 ± 18) than healthy metabolism (95.6 ± 17) (P = 0.007). AIP was higher in adverse metabolic conditions (P = 0.0001). Metabolically unhealthy non-obesity showed higher liver damage (NASH 55.8% vs 42.4%; P < 0.05; significant fibrosis 31.7% vs 11.4%; P < 0.0001) and cardiovascular risk (P < 0.0001) than healthy obesity. CONCLUSIONS: Metabolic unhealthy status showed a greater impact on NASH, significant fibrosis, kidney dysfunction, and atherogenic profile than obesity. However, metabolically healthy obesity was not a full healthy condition. We should focus our messages especially on patients with adverse metabolic conditions.

4.
Sci Rep ; 8(1): 15203, 2018 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-30315279

RESUMO

Obesity-related comorbidities are, in large part, originated from the dysfunction of adipose tissue. Most of them revert after the normalization of body mass. Adipose tissue is essentially occupied by adipocytes. However, different populations of immunological cells and adipocyte precursor cells (AdPCs) are the main cellular components of tissue. During obesity, body fat depots acquire a low-level chronic inflammation and adipocytes increase in number and volume. Conversely, weight loss improves the inflammatory phenotype of adipose tissue immune cells and reduces the volume of adipocytes. Nevertheless, very little is known about the evolution of the human AdPCs reservoir. We have developed a flow cytometry-based methodology to simultaneously quantify the main cell populations of adipose tissue. Starting from this technical approach, we have studied human adipose tissue samples (visceral and subcutaneous) obtained at two different physiological situations: at morbid obesity and after bariatric surgery-induced weight loss. We report a considerable increase of the AdPCs reservoir after losing weight and several changes in the immune cells populations of adipose tissue (mast cells increase, neutrophils decrease and macrophages switch phenotype). No changes were observed for T-lymphocytes, which are discussed in the context of recent findings.

5.
Liver Int ; 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30160363

RESUMO

BACKGROUND & AIMS: The interferon-free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8-week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8-week administration of PTV/r/OBV/DSV in a real-world cohort. METHODS: We performed a multicentre observational study from Spanish Hepa-C database including patients receiving 8 weeks of PTV/r/OBV/DSV (October 2016-November 2017). Those with advanced fibrosis, with non-genotype 1b or who were treatment-experienced were excluded. RESULTS: A total of 211 patients were registered from 23 Spanish centres; eleven were excluded. At baseline, 42.5% (n = 85) were male, median (range) age was 57 (23-86), ALT was 45 (11-494) IU/mL, viral load was 6.1 (3.3-8.2) log10 IU/mL, and 74.5% had mild liver fibrosis (F0-F1) and 25.5% moderate fibrosis (F2). At the end of treatment (EOT), HCV viral load was undetectable in 100% (200/200). Seven patients relapsed after treatment discontinuation. Sustained virological response (SVR12) rates by intention-to-treat analysis were 96% (192/200). Regarding treatment safety, 2 patients developed ALT elevation >5x ULN, but there were no treatment discontinuations. One patient died 7 weeks after EOT. CONCLUSION: Treatment with PTV/r/OBV/DSV in genotype 1b-infected treatment-naive patients with mild-moderate fibrosis shows excellent efficacy and safety in real life, similarly to clinical trials. Clinicaltrials.gov, number: NCT03122132.

6.
PLoS One ; 13(7): e0201268, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30044871

RESUMO

Despite high response rates associated to hepatitis C virus (HCV) treatment, no protective immunity is acquired, allowing for reinfection and continued infectiousness. Distinguishing between relapse and reinfection is crucial for patient counselling and to choose the most appropriate retreatment. Here, refined phylogenetic analysis using multiple genes served to assess genotype and reinfection for 53 patients for whom the virus was sampled before start of therapy and at time of sustained virological response evaluation at week 12. At baseline, genotypes were determined as HCV1a (41.5%), HCV1b (24.5%), HCV4 (18.9%) and HCV3a (15.1%), while six cases revealed to be discordantly assigned by phylogeny and commercial assays. Overall, 60.4% was co-infected with HIV. The large majority was classified as people who inject drugs (78.6%), often co-infected with HIV. Transmission was sexual in seven cases, of which five in HIV-positive men-who-have-sex-with-men. Overall, relapse was defined for 44 patients, while no conclusion was drawn for four patients. Five patients were reinfected with a different HCV strain, of which three with a different genotype, showing that phylogeny is needed not only to determine the genotype, but also to distinguish between relapse and intra-subtype reinfection. Of note, phylogenies are more reliable when longer fragments of the viral genome are being sequenced.

8.
Gastroenterol. hepatol. (Ed. impr.) ; 41(5): 328-349, mayo 2018. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-180611

RESUMO

La enfermedad hepática grasa no alcohólica (EHGNA) es la causa más frecuente de hepatopatía crónica en nuestro medio y se prevé un incremento de su incidencia en los próximos años asociada al incremento de la obesidad y el síndrome metabólico. Esta guía de práctica clínica propone recomendaciones sobre el diagnóstico y en especial marcadores no invasivos, así como en el manejo y seguimiento de esta enfermedad. La intervención dietética basada en la dieta mediterránea y el cambio del estilo de vida constituyen el pilar del tratamiento de la EHGNA, pero aún falta por elucidar si la composición de la dieta puede influir en la mejoría de la enfermedad más allá de la pérdida de peso. El tratamiento con fármacos debe restringirse a los pacientes con esteatohepatitis y fibrosis significativa que no consiguen resolución de la esteatohepatitis después de una intervención con dieta y ejercicio físico durante un año. Nuevos fármacos aún en fases iniciales de desarrollo han demostrado ser superiores a placebo. Por último, el impacto de la EHGNA en la indicación de trasplante hepático, la viabilidad del injerto y la recidiva de EHGNA de novo tras el trasplante, así como el incrementado riesgo cardiovascular determinan todo el proceso peritrasplante hepático. Esta guía de práctica clínica se ha elaborado tras la I Reunión de Consenso sobre EHGNA con un panel de experto nacionales e internaciones en Sevilla y tienen como objetivo proponer recomendaciones basadas en la evidencia científica disponible para el manejo de estos pacientes


Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville


Assuntos
Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/terapia , Guias de Prática Clínica como Assunto
9.
Gastroenterol Hepatol ; 41(5): 328-349, 2018 May.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-29631866

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.

10.
J Hepatol ; 68(5): 940-948, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29288753

RESUMO

BACKGROUND & AIMS: Patients with advanced liver fibrosis remain at risk of cirrhosis-related outcomes and those with severe comorbidities may not benefit from hepatitis C (HCV) eradication. We aimed to collect data on all-cause mortality and relevant clinical events within the first two years of direct-acting antiviral therapy, whilst determining the prognostic capability of a comorbidity-based model. METHODS: This was a prospective non-interventional study, from the beginning of direct-acting antiviral therapy to the event of interest (mortality) or up to two years of follow-up, including 14 Spanish University Hospitals. Patients with HCV infection, irrespective of liver fibrosis stage, who received direct-acting antiviral therapy were used to build an estimation and a validation cohort. Comorbidity was assessed according to Charlson comorbidity and CirCom indexes. RESULTS: A total of 3.4% (65/1,891) of individuals died within the first year, while 5.4% (102/1,891) died during the study. After adjusting for cirrhosis, platelet count, alanine aminotransferase and sex, the following factors were independently associated with one-year mortality: Charlson index (hazard ratio [HR] 1.55; 95% CI 1.29-1.86; p = 0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; p = 0.004), age (HR 1.06 95% CI 1.02-1.11; p = 0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; p = 0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; p = 0.0001). HepCom score showed a good calibration and discrimination (C-statistics 0.90), and was superior to the other prognostic scores (model for end-stage liver disease 0.81, Child-Pugh 0.72, CirCom 0.68) regarding one- and two-year mortality. HepCom score identified low- (≤5.7 points: 2%-3%) and high-risk (≥25 points: 56%-59%) mortality groups, both in the estimation and validation cohorts. The distribution of clinical events was similar between groups. CONCLUSIONS: The HepCom score, a combination of Charlson comorbidity index, age, and liver function (international normalized ratio, albumin, and bilirubin) enables detection of a group at high risk of one- and two-year mortality, and relevant clinical events, after starting direct-acting antiviral therapy. LAY SUMMARY: The prognosis of patients with severe comorbidities may not benefit from HCV viral clearance. An algorithm to decide who will benefit from the treatment is needed to manage the chronic HCV infection better.

11.
World J Gastroenterol ; 23(41): 7459-7469, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29151700

RESUMO

AIM: To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM. METHODS: This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed. RESULTS: Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 ± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001). CONCLUSION: TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.


Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Organofosfonatos/uso terapêutico , Tenofovir/uso terapêutico , Adenina/economia , Adenina/farmacologia , Adenina/uso terapêutico , Adulto , Idoso , Alanina Transaminase/sangue , Antivirais/economia , Antivirais/farmacologia , DNA Viral/isolamento & purificação , Farmacorresistência Viral , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/economia , Quimioterapia Combinada/métodos , Feminino , Antígenos de Superfície da Hepatite B/imunologia , Antígenos E da Hepatite B/imunologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Hepatite B Crônica/sangue , Hepatite B Crônica/imunologia , Custos Hospitalares/estatística & dados numéricos , Humanos , Lamivudina/economia , Lamivudina/farmacologia , Masculino , Pessoa de Meia-Idade , Organofosfonatos/economia , Organofosfonatos/farmacologia , Estudos Prospectivos , Tenofovir/economia , Tenofovir/farmacologia , Falha de Tratamento , Carga Viral/efeitos dos fármacos
12.
PLoS One ; 12(10): e0187130, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29073231

RESUMO

Poly(ADP-ribose)polymerases (PARPs) are a family of NAD+ consuming enzymes that play a crucial role in many cellular processes, most clearly in maintaining genome integrity. Here, we present an extensive analysis of the alteration of mitochondrial morphology and the relationship to PARPs activity after oxidative stress using an in vitro model of human hepatic cells. The following outcomes were observed: reactive oxygen species (ROS) induced by oxidative treatment quickly stimulated PARPs activation, promoted changes in mitochondrial morphology associated with early mitochondrial fragmentation and energy dysfunction and finally triggered apoptotic cell death. Pharmacological treatment with specific PARP-1 (the major NAD+ consuming poly(ADP-ribose)polymerases) and PARP-1/PARP-2 inhibitors after the oxidant insult recovered normal mitochondrial morphology and, hence, increased the viability of human hepatic cells. As the PARP-1 and PARP-1/PARP-2 inhibitors achieved similar outcomes, we conclude that most of the PARPs effects were due to PARP-1 activation. NAD+ supplementation had similar effects to those of the PARPs inhibitors. Therefore, PARPs activation and the subsequent NAD+ depletion are crucial events in decreased cell survival (and increased apoptosis) in hepatic cells subjected to oxidative stress. These results suggest that the alterations in mitochondrial morphology and function seem to be related to NAD+ depletion, and show for the first time that PARPs inhibition abrogates mitochondrial fragmentation. In conclusion, the inhibition of PARPs may be a valuable therapeutic approach for treating liver diseases, by reducing the cell death associated with oxidative stress.


Assuntos
Hepatócitos/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Mitocôndrias/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular , Hepatócitos/citologia , Humanos , Espécies Reativas de Oxigênio/metabolismo
13.
World J Gastroenterol ; 23(25): 4538-4547, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28740342

RESUMO

AIM: To determine the number of mutations in the NS5A region of the hepatitis C virus (HCV) and its relationship to the response to antiviral therapy in patients with chronic hepatitis C genotype 1 who are non-responders to two or more treatments. METHODS: Sequences within HCV NS5A [PKR binding domain (PKRBD) and the interferon-sensitivity-determining region (ISDR)] were analysed via direct sequencing in a selected cohort of 72 patients, with a total of 201 treatments [interferon-alpha (IFN-α), n = 49; IFN-α + ribavirin (RBV), n = 75; pegylated (peg) IFN-α + RBV, n = 47; first-generation direct-acting antivirals (DAAs), n = 13; and second-generation DAAs, n = 17]. Of these, 48/201 achieved a sustained virological response (SVR) and 153/201 achieved no virological response (NVR). RESULTS: For both regions, treatments resulting in SVR were associated with more baseline mutations than were treatments resulting in NVR (SVR vs NVR; PKRBD: 5.82 ± 3 vs 4.86 ± 2 mutations, P = 0.045; ISDR: 2.65 ± 2 vs 1.51 ± 1.7 mutations, P = 0.005). A decrease or no change in the number of mutations over time between treatments in the PKRBD or ISDR, as shown by sequencing, was associated with patients who usually failed to respond to treatment (PKRBD, P = 0.02; ISDR, P = 0.001). Moreover, patients showing a post-treatment baseline viral load > 600000 IU/mL and increased ISDR mutations with respect to the previous treatment were 9.21 times more likely to achieve SVR (P = 0.001). CONCLUSION: The obtained results show that among patients who have shown no response to two or more antiviral treatments, the likelihood of achieving SVR increases with the genetic variability in the ISDR region (≥ 2 mutations or number of substitutions from the HCV-J and HCV-1 prototype), especially when the viral load is greater than 600000 IU/mL.


Assuntos
Antivirais/farmacologia , Farmacorresistência Viral Múltipla/genética , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Proteínas não Estruturais Virais/genética , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Masculino , Mutação , Polietilenoglicóis/farmacologia , Polietilenoglicóis/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Análise de Sequência de RNA , Resposta Viral Sustentada , Carga Viral/efeitos dos fármacos
14.
PLoS One ; 12(7): e0180927, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704535

RESUMO

INTRODUCTION: Chronic hepatitis C (CHC) is a major cause of liver disease worldwide which often leads to progressive liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). CHC displays heterogeneous progression depending on a broad set of factors, some of them intrinsic to each individual such as the patient's genetic profile. This study aims to evaluate the contribution of certain genetic variants of crucial interferon alpha and lambda signaling pathways to the hepatic necroinflammatory activity (NIA) grade of CHC patients. METHODS: NIA was evaluated in 119 CHC patients by METAVIR scale and classified as low (NIA = 0-2, n = 80) or high grade (NIA = 3, n = 39). In a candidate gene approach, 64 SNPs located in 30 different genes related to interferon pathways (IL-28B, IFNAR1-2, JAK-STAT and OAS1-3, among others) were genotyped using the Illumina GoldenGate® Genotyping Assay. Statistical association was determined by logistic regression and expressed as OR and 95% CI. Those SNPs significantly associated were further adjusted by other covariates. RESULTS: Seven SNPs located in IL-28B (rs12979860), JAK1 (rs11576173 and rs1497056), TYK2 (rs280519), OAS1 (rs2057778), SOCS1 (rs33932899) and RNASEL (rs3738579) genes were significantly related to severe NIA grade (p<0.05). Regarding to clinical variables, elevated NIA was notably associated with aspartate aminotransferase (AST) serum levels >40 IU/L (p<0.05) but not with other clinical factors. Multivariate logistic regression analysis of these factors reflected that AST (>40 IU/L), TYK2 rs280519 (G allele) and RNASEL rs3738579 (G allele) were factors independently associated with elevated NIA (p<0.05). AST concentration showed a moderate AUC value (AUC = 0.63), similar to TYK2 (rs280519) and RNASEL (rs3738579) SNPs (AUC = 0.61, both) in the ROC_AUC analysis. Interestingly, the model including all significant variables reached a considerable predictive value (AUC = 0.74). CONCLUSION: The identified genetic variants in interferon signaling pathways may constitute useful prognostic markers of CHC progression. Further validation in larger cohorts of patients is needed.


Assuntos
Hepatite C Crônica/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , 2',5'-Oligoadenilato Sintetase/genética , Adulto , Idoso , Aspartato Aminotransferases/sangue , Endorribonucleases/genética , Feminino , Hepatite C Crônica/sangue , Hepatite C Crônica/patologia , Humanos , Janus Quinase 1/genética , Masculino , Pessoa de Meia-Idade , Proteína 1 Supressora da Sinalização de Citocina/genética , TYK2 Quinase/genética
15.
Int J Mol Sci ; 18(6)2017 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-28604612

RESUMO

The characterization of colon cancer stem cells (CSCs) may help to develop novel diagnostic and therapeutic procedures. p53 loss increases the pool of CSCs in colorectal cancer (CRC). Recent reports suggest that the oncostatic effects of melatonin could be related to its ability to kill CSCs. Although there are no data linking the loss of p53 function and melatonin synthesis or signaling in cancer, melatonin does activate the p53 tumor-suppressor pathway in this disease. In this work, we analyze whether the expression of melatonin synthesis and signaling genes are related to the expression of CSC markers and the implication of p53 status in samples from patients with CRC. Arylalkylamine N-acetyltransferase (AA-NAT), MT1, and MT2 expression decreased in tumor samples versus normal mucosa samples in mutated p53 (mtp53) tumors versus those with wild-type p53 (wtp53). Further, AA-NAT and MT2 expression were lower in advanced stages of the disease in wtp53 tumors. On the contrary, CD44 and CD66c expression was higher in tumor versus normal mucosa in wtp53 tumors. Additionally, CD44 expression was higher in advanced stages of the disease regardless of the p53 status. Patients with CD44highCD66chigh and wtp53 tumors in advanced stages showed low expression of AA-NAT and MT2 in wtp53 tumors. These results could indicate a possible interaction of these pathways in CRC.


Assuntos
Arilalquilamina N-Acetiltransferase/genética , Neoplasias Colorretais/metabolismo , Melatonina/genética , Células-Tronco Neoplásicas/metabolismo , Proteína Supressora de Tumor p53/genética , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
16.
Curr Med Chem ; 24(20): 2156-2173, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28302009

RESUMO

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays a critical role in diverse cellular functions, such as DNA damage detection and repair, transcriptional regulation and cell death. Furthermore, PARP-1 has emerged as a key player in the pathogenesis of multiple inflammatory diseases and has become a promising target for the treatment of cardiovascular disorders, neurodegenerative diseases and cancer. An increasing body of evidence has linked alterations in the expression levels of PARP-1, enzymatic activity and presence of polymorphism to gastrointestinal malignancies, including oesophageal, gastric, pancreas, liver and colorectal cancers. PARP inhibition has been proposed as a valuable strategy for treating these gastrointestinal disorders. This paper summarises the most significant current literature on the involvement of PARP-1 in gastrointestinal cancer, focusing in particular on its role in the development and occurrence of tumours, providing information about clinical trials and exploring therapeutic possibilities.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/patologia , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Polimorfismo de Nucleotídeo Único , Animais , Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Gastrointestinais/patologia , Trato Gastrointestinal/metabolismo , Humanos , Terapia de Alvo Molecular , Poli(ADP-Ribose) Polimerase-1/análise , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
17.
Hepatology ; 65(6): 1810-1822, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28170112

RESUMO

Direct-acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa-C registry investigated the effectiveness and safety of interferon-free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child-Turcotte-Pugh [CTP] class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End-Stage Liver Disease (MELD) score alone (cut-off 18) was the best predictor of survival. CONCLUSION: Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810-1822).


Assuntos
Antivirais/administração & dosagem , Doença Hepática Terminal/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Sistema de Registros , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Estudos de Coortes , Progressão da Doença , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Doença Hepática Terminal/virologia , Feminino , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/mortalidade , Hepatite C Crônica/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/mortalidade , Cirrose Hepática/fisiopatologia , Cirrose Hepática/virologia , Testes de Função Hepática , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Ribavirina/administração & dosagem , Medição de Risco , Índice de Gravidade de Doença , Sofosbuvir/administração & dosagem , Espanha , Análise de Sobrevida , Resultado do Tratamento
18.
Med. clín (Ed. impr.) ; 147(11): 499-505, dic. 2016. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-158471

RESUMO

La infección crónica por el virus de la hepatitis C (VHC) ha sido reconocida como un problema de salud mundial. Constituye la principal causa de cirrosis, carcinoma hepatocelular y trasplante hepático. Su prevalencia en gestantes es similar a la de la población general y no se asocia con complicaciones obstétricas. La transmisión vertical del VHC (TV-VHC) constituye la vía principal de infección en niños en países desarrollados (> 90%), si bien, el porcentaje de TV-VHC y cronificación es relativamente bajo (3-8%). Sin embargo, la TV-VHC aumenta hasta el 15-20% en madres coinfectadas con el virus de la inmunodeficiencia humana. En esta revisión se analizará la historia natural de la infección en la gestación y en el niño, los factores de riesgo de TV-VHC, los métodos de diagnóstico/seguimiento recomendados y las nuevas posibilidades de tratamiento con antivirales de acción directa, factores claves para la creación de futuras guías clínicas (AU)


Hepatitis C virus (HCV) infection has been recognised as a worldwide health problem. HCV is the most common cause of cirrhosis, hepatocellular carcinoma and liver transplantation. The HCV prevalence reported in pregnant women is similar to that found among the general population and does not appear to have an adverse effect on the course of pregnancy. The vertical transmission of HCV (HCV-VT) is a major route of HCV infection in children in the developed countries (> 90%). The overall rate of mother-to- child transmission and chronification is about 3%-8%; however, this rate is higher for mothers who are co-infected with the human immunodeficiency virus (15-20%). In this review, we analyse the course of HCV infection during gestation, the risk factors associated with HCV-VT, the diagnostic methods/clinical monitoring recommended and the new possibilities of treatment in the era of directacting antiviral agents, which are essential to guide future public health efforts appropriately (AU)


Assuntos
Humanos , Feminino , Gravidez , Hepatite C Crônica/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Antivirais/uso terapêutico , Hepacivirus/patogenicidade , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Fatores de Risco
20.
Med Clin (Barc) ; 147(11): 499-505, 2016 Dec 02.
Artigo em Espanhol | MEDLINE | ID: mdl-27209226

RESUMO

Hepatitis C virus (HCV) infection has been recognised as a worldwide health problem. HCV is the most common cause of cirrhosis, hepatocellular carcinoma and liver transplantation. The HCV prevalence reported in pregnant women is similar to that found among the general population and does not appear to have an adverse effect on the course of pregnancy. The vertical transmission of HCV (HCV-VT) is a major route of HCV infection in children in the developed countries (>90%). The overall rate of mother-to-child transmission and chronification is about 3%-8%; however, this rate is higher for mothers who are co-infected with the human immunodeficiency virus (15-20%). In this review, we analyse the course of HCV infection during gestation, the risk factors associated with HCV-VT, the diagnostic methods/clinical monitoring recommended and the new possibilities of treatment in the era of direct-acting antiviral agents, which are essential to guide future public health efforts appropriately.


Assuntos
Hepatite C Crônica , Transmissão Vertical de Doença Infecciosa , Complicações Infecciosas na Gravidez , Antivirais/uso terapêutico , Europa (Continente)/epidemiologia , Feminino , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/transmissão , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Transmissão Vertical de Doença Infecciosa/estatística & dados numéricos , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Complicações Infecciosas na Gravidez/epidemiologia , Cuidado Pré-Natal/métodos , Prevalência , Fatores de Risco , Estados Unidos/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA