TRPM5 rs886277 Polymorphism Predicts Hepatic Fibrosis Progression in Non-Cirrhotic HCV-Infected Patients.

BACKGROUND: TRPM5 (transient receptor potential cation channel subfamily M member 5) rs886277 polymorphism has been related to liver cirrhosis from different etiologies. The present study investigates the association of TRPM5 rs886277 polymorphism with liver fibrosis progression and cirrhosis development in chronic hepatitis C (CHC) patients. METHODS: We conducted a retrospective study of 208 non-cirrhotic patients with CHC, who had at least two liver stiffness measurements (LSM) with a separation of 12 months (baseline LSM (LSM1) and the last LSM (LSM2)). Two outcome variables were considered: (1) LSM2/LSM1 ratio; (2) cirrhosis progression (F4; LSM ≥ 12.5 kPa). DNA genotyping was done at the CeGen using a MassARRAY platform. RESULTS: The follow-up time was similar irrespective of the rs886277 genotype (46.4 months in TT genotype, 46.4 months in CT genotype, and 49.2 months in CC genotype; p = 0.649). The highest LSM increases were found in patients with CC genotype compared with TT and CT genotypes (p = 0.044 and p = 0.038, respectively). The cirrhosis progression was higher in patients with CC genotype than TT genotype (p = 0.033). Thus, the rs886277 C allele was associated with higher cirrhosis progression (adjusted odds ratio (aOR) = 2.64; p = 0.014). Moreover, rs886277 CC genotype was also related to higher values of LSM2/LSM1 ratio (adjusted arithmetic mean ratio a(AMR) = 1.31; p = 0.001) and cirrhosis progression (aOR = 4.33; p = 0.027). CONCLUSIONS: TRPM5 rs886277 polymorphism was associated with liver fibrosis progression and cirrhosis development among hepatitis C virus (HCV)-infected patients. Specifically, the rs886277 C allele and CC genotype were risk factors for advancing liver fibrosis and cirrhosis compared to the rs886277 T allele and CT/TT genotype, respectively.

MTHFR rs1801133 Polymorphism Is Associated With Liver Fibrosis Progression in Chronic Hepatitis C: A Retrospective Study.

Background: The MTHFR (methylenetetrahydrofolate reductase) rs1801133 polymorphism leads to higher circulating levels of homocysteine, which is related to several liver diseases. We aimed to evaluate the relationship between MTHFR rs1801133 polymorphism and liver fibrosis progression in HCV-infected patients. Methods: We conducted a preliminary retrospective cohort study in 208 non-cirrhotic HCV-infected patients. These subjects had at least two liver stiffness measurements (LSM), which were assessed using transient elastography, and no patient had cirrhosis at baseline. We analyzed the association between MTHFR rs1801133 and outcome variables using Generalized Linear Models. Results: HCV-infected patients were 47 years old, around 54% were males, a low frequency of high alcohol intake (13.5%) or prior use of intravenous drugs (10.1%). A total of 26 patients developed cirrhosis (LSM1 ≥ 12.5) during a median follow-up of 46.6 months. The presence of the rs1801133 C allele showed an inverse association with the LSM2/LSM1 ratio (adjusted AMR = 0.90; 95%CI = 0.83-0.98; p = 0.020) and the cirrhosis progression (adjusted OR = 0.43; 95%CI = 0.19-0.95; p = 0.038). Besides, rs1801133 CT/CC genotype had an inverse association with the LSM2/LSM1 ratio (adjusted AMR = 0.80; 95%CI = 0.68-0.95; p = 0.009) and the cirrhosis progression (adjusted OR= 0.21; 95%CI = 0.06-0.74; p = 0.015). Conclusions: MTHFR rs1801133 C allele carriers presented a diminished risk of liver fibrosis progression and development of cirrhosis than rs1801133 T allele carriers. This statement supports the hypothesis that MTHFR rs1801133 polymorphism appears to play a crucial role in chronic hepatitis C immunopathogenesis.

Características y supervivencia del carcinoma hepatocelular en hígado no cirrótico / Characteristics and survival of hepatocellular carcinoma in non-cirrhotic liver

Introducción: las características, cribado, y supervivencia del carcinoma hepatocelular (CHC) en pacientes sin cirrosis están menos definidas. Pacientes y métodos: se recogieron retrospectivamente (enero 2004-octubre 2018) los pacientes con CHC diagnosticados citohistológicamente sin cirrosis. Analizamos sus características, tratamiento y supervivencia. Resultados: de los 332 pacientes con CHC, 25 cumplían los criterios de inclusión (7,5%). Varones: 76%. Mediana de edad: 69,9 años. El virus de la hepatitis B (VHB) fue el principal agente etiológico de hepatopatía: 32%, seguido de la esteatohepatitis no alcohólica (EHNA): 20%. La fibrosis fue leve (0-1) en el 44%. El nódulo se descubrió por ecografía de seguimiento en el 32%, en el 60% fue casual, y 8% por síntomas. El estadio de Barcelona Clinic Liver Cancer (BCLC) fue 0 en 4%, A 88%, B 4%, y C 4%. El tratamiento inicial mayoritario fue la resección quirúrgica (76%), 8% rechazaron tratamiento, y se realizó etanolización, quimioembolización, sorafenib y tratamiento sintomático en el 4% para cada uno. El 21% de los pacientes operados presentó complicaciones, la mitad severas. La mediana de seguimiento fue 22,2 (2,9-150,6) meses, con remisión en el 56%. Mediana de supervivencia global: 57,4 +/- 29,8 meses. Supervivencia acumulada: 84% al año, 61,6% a los 3 años y 47,9% a los 5 años. Conclusión: el 7,5% de los CHC se desarrollaron sin cirrosis. El grado de fibrosis fue leve en casi la mitad. El VHB fue la causa principal, seguida de EHNA. El estadio de BCLC principal al diagnóstico fue el precoz. La cirugía fue el tratamiento más habitual. La supervivencia a los 5 años fue cercana al 50%

Introduction: the characteristics, screening, and survival of hepatocellular carcinoma (HCC) for patients without cirrhosis have not been fully studied. Methods: A retrospective cohort study was performed in non-cirrhotic patients with histological HCC, between January 2004 and October 2018. Their characteristics, treatment, follow-up and overall survival were described. Results: 25 of the 332 patients with HCC met the inclusion criteria (7.5%), 76% were males and the median age was 69.9 years. The main etiology of liver disease was the hepatitis B virus (HBV) (32%), followed by non-alcoholic steatohepatitis (NASH) (20%). Liver fibrosis was mild (0-1) in 44% of cases. The nodule was diagnosed by ultrasonography in 32% of cases, 60% were found incidentally and 8% due to clinical symptoms. The Barcelona Clinic Liver Cancer (BCLC) staging was 0 in 4% of cases, A in 88%, B in 4% and C in 4%. The main initial treatment was surgical resection (76%) and 8% refused to be treated. Percutaneous ethanol injection, chemoembolization, sorafenib and palliative care were each performed in 4% of cases. There were some complications in 21% of patients treated with surgery, half of them were severe. The median follow-up was 22.2 (2.9-150.6) months and 56% were in remission and the median overall survival was 57.4 +/- 29.8 months. The overall cumulative survival at 1, 3 and 5 years was 84%, 61.6% and 47.9%, respectively. Conclusion: 7.5% of HCC presented without cirrhosis and almost half of patients had mild fibrosis. HBV was the main cause of HCC, followed by NASH. The most frequent BCLC stage at diagnosis was early stage and surgery was the most common treatment. Overall cumulative survival at 5 years was almost 50%

Characteristics and survival of hepatocellular carcinoma in non-cirrhotic liver.

INTRODUCTION: the characteristics, screening, and survival of hepatocellular carcinoma (HCC) for patients without cirrhosis have not been fully studied. METHODS: A retrospective cohort study was performed in non-cirrhotic patients with histological HCC, between January 2004 and October 2018. Their characteristics, treatment, follow-up and overall survival were described. RESULTS: 25 of the 332 patients with HCC met the inclusion criteria (7.5%), 76% were males and the median age was 69.9 years. The main etiology of liver disease was the hepatitis B virus (HBV) (32%), followed by non-alcoholic steatohepatitis (NASH) (20%). Liver fibrosis was mild (0-1) in 44% of cases. The nodule was diagnosed by ultrasonography in 32% of cases, 60% were found incidentally and 8% due to clinical symptoms. The Barcelona Clinic Liver Cancer (BCLC) staging was 0 in 4% of cases, A in 88%, B in 4% and C in 4%. The main initial treatment was surgical resection (76%) and 8% refused to be treated. Percutaneous ethanol injection, chemoembolization, sorafenib and palliative care were each performed in 4% of cases. There were some complications in 21% of patients treated with surgery, half of them were severe. The median follow-up was 22.2 (2.9-150.6) months and 56% were in remission and the median overall survival was 57.4 ± 29.8 months. The overall cumulative survival at 1, 3 and 5 years was 84%, 61.6% and 47.9%, respectively. CONCLUSION: 7.5% of HCC presented without cirrhosis and almost half of patients had mild fibrosis. HBV was the main cause of HCC, followed by NASH. The most frequent BCLC stage at diagnosis was early stage and surgery was the most common treatment. Overall cumulative survival at 5 years was almost 50%.

Impact of DARC rs12075 Variants on Liver Fibrosis Progression in Patients with Chronic Hepatitis C: A Retrospective Study.

: The Duffy antigen receptor for chemokines (DARC) rs12075 polymorphism regulates leukocyte trafficking and proinflammatory chemokine homeostasis. Hepatitis C virus (HCV)-mediated liver fibrosis is associated with an uncontrolled inflammatory response. In this study, we evaluate the association between the DARC rs12075 polymorphism and liver stiffness progression in HCV-infected patients. We carried out a retrospective cohort study (repeated measures design) in 208 noncirrhotic patients with chronic hepatitis C (CHC) who had at least two liver stiffness measurements (LSM) with a separation of at least 12 months. We used generalized linear models to analyze the association between DARC rs12075 polymorphism and outcome variables. During a follow-up of 46.6 months, the percentage of patients with stages of fibrosis F0/F1 decreased (p < 0.001), while LSM values and the percentage of patients with cirrhosis increased (p < 0.001). This pattern of changes was maintained in each of the groups of patients analyzed according to their rs12075 genotypes (AA or AG/GG). However, the variations in liver stiffness characteristics were lower in patients with the rs12075 AG/GG genotype (AG/GG versus AA). Thereby, in the adjusted analysis, patients with the rs12075 AG/GG genotype had a lower risk of an increased value of LSM2/LSM1 arithmetic mean ratio (AMR = 0.83; p = 0.001) and of an increase in LSM ≥ 5 kPa (odds ratio (OR) = 0.28; p = 0.009). Besides, patients with rs12075 AG/GG had a lower risk of cirrhosis progression (OR = 0.24; p = 0.009). No significant associations were found for an increase in LSM ≥ 10 kPa. We found an association between the DARC rs12075 single nucleotide polymorphism (SNP) and CHC progression. Specifically, patients with the DARC rs12075 AG/GG genotype had a lower risk of liver fibrosis progression and development of cirrhosis.

The Myeloid-Epithelial-Reproductive Tyrosine Kinase (MERTK) rs4374383 Polymorphism Predicts Progression of Liver Fibrosis in Hepatitis C Virus-Infected Patients: A Longitudinal Study.

BACKGROUND: The myeloid-epithelial-reproductive tyrosine kinase (MERTK) is involved in hepatic steatosis, inflammation, and liver fibrosis. Here we evaluated the association between the MERTK rs4374383 single nucleotide polymorphism (SNP) and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. METHODS: We performed a retrospective study (repeated measures design) in 208 patients who had liver stiffness measurement (LSM), which was assessed using transient elastography. No patient had cirrhosis at baseline (LSM ≥ 12.5 kPa). RESULTS: At baseline, 53.8% were male, the median age was 47.1 years, 13.5% reported a high intake of alcohol, 10.1% were prior injection drug users, 85.3% were infected with HCV genotype 1, and 22.6% had previously failed antiviral therapy (pegylated-interferon-alpha/ribavirin). During a median follow-up of 46.6 months, 26 patients developed cirrhosis. The rs4374383 G carriers had a higher risk of increasing LSM (adjusted arithmetic mean ratio (aAMR) = 1.14; p = 0.006) and a higher likelihood of having an increase in LSM greater than 5 kPa (ΔLSM ≥ 5 kPa) (adjusted odds ratio (aOR) = 2.37; p = 0.029), and greater than 7 kPa (ΔLSM ≥ 7 kPa) (aOR = 3.24; p = 0.032), after controlling for confounding. The SNP's association with cirrhosis progression was close to statistical significance (aOR = 2.18; p = 0.070). CONCLUSIONS: MERTK rs4374383 A carriers had a lower risk of liver fibrosis progression than G carriers, supporting the hypothesis that this SNP seems to have a critical role in the pathogenesis of liver disease in HCV-infected patients.

The IL7RA rs6897932 polymorphism is associated with progression of liver fibrosis in patients with chronic hepatitis C: Repeated measurements design.

The polymorphisms at the α-chain of the IL-7 receptor (IL7RA) have been related to T-cell homeostasis and development and may contribute to immune system deregulation. In the present study, we analyzed the association between IL7RA polymorphisms and the progression of liver fibrosis in patients infected with HCV. We carried out a retrospective study with a design consisting of repeated measurements in 187 HCV-infected patients, to study the risk prediction of liver fibrosis progression using genetic factors. We genotyped the rs6897932, rs987106 and rs3194051 IL7RA polymorphisms using the Agena Bioscience's MassARRAY. Transient elastography was used to measure liver stiffness. The used cut-offs were: <7.1 kPa (F0-F1), 7.1-9.4 kPa (F2; significant fibrosis), 9.5-12.4 kPa (F3; advanced fibrosis), and ≥12.5 kPa (F4; cirrhosis). All HCV genotypes were analyzed. The median of follow-up time was 47.9 months. Baseline liver stiffness measurement (LSM) values did not show significant statistical differences for IL7RA genotypes (p>0.05). In univariate analysis, the rs6897932 T allele had a positive relationship with an increase in LSM (arithmetic mean ratio (AMR) = 1.21 (95%CI = 1.08; 1.36); p = 0.001), progression to advanced fibrosis (F≥3) (odds ratio (OR) = 2.51 (95%CI = 1.29; 4.88); p = 0.006) and progression to cirrhosis (F4) (OR = 2.71 (95%CI = 0.94; 5.03); p = 0.069). In multivariable analysis, the rs6897932 T allele was related to a higher increase of LSM values during follow-up (adjusted AMR = 1.27 (95%CI = 1.13; 1.42); p<0.001) and higher odds of progression to advanced fibrosis [adjusted OR = 4.46 (95%CI = 1.87; 10.62); p = 0.001], and progression to cirrhosis [adjusted OR = 3.92 (95%CI = 1.30; 11.77); p = 0.015]. Regarding IL7RA rs987106 and rs3194051 polymorphisms, we did not find significant results except for the relationship between IL7RA rs987106 and the increase in LSM values [adjusted OR = 1.12 (95%CI = 1.02; 1.23); p = 0.015]. The IL7RA rs6897932 polymorphism seems to be related to increased risk of liver fibrosis progression in HCV-infected patients. Thus, the rs6897932 polymorphism could be related to the physiopathology of CHC and might be used to successfully stratify the risk of CHC progression.

Influencia de la puntuación MELD basal en la eficacia del tratamiento de la hepatitis C con sofosbuvir y simeprevir / Influence of baseline MELD score in the efficacy of treatment of hepatitis C with simeprevir and sofosbuvir

INTRODUCCIÓN: Hay pocos estudios publicados acerca de los factores predictivos de respuesta al tratamiento de la hepatitis C con sofosbuvir y simeprevir. OBJETIVO: Conocer qué factores influyen en la respuesta a simeprevir (SIM) y sofosbuvir (SOF) en pacientes infectados por los genotipos 1 o 4 de la hepatitis C. PACIENTES Y MÉTODOS: Estudio prospectivo observacional de cohortes en 12 hospitales. La efectividad se evaluó con respuesta virológica sostenida (RVS12). RESULTADOS: Se incluyeron 204 pacientes (62,3% varones, edad media 55 años). Ciento ochenta y seis (91,2%) genotipo 1 (60,3% 1b, 25% 1a) y 18 (8,8%) genotipo 4. Ciento treinta y dos (64,7%) cirróticos (87,9% Child A), 33 (16,2%) F3, 31 (15,2%) F2, 8 (3,9%) F0-1. Un 80,8% MELD < 10. Noventa y tres (45,6%) naive. Se asoció ribavirina en 68 (33,3%). Carga viral basal media 2.151.549 UI/ML (DE: 2.391.840). Duración tratamiento 12 semanas en 93,1%. Cuatro suspendieron tratamiento: suicidio, brote psicótico, hiperbilirrubinemia y recurrencia hepatocarcinoma. Ciento noventa (93,1%) alcanzaron RVS12. No hubo diferencias RVS12 en función del genotipo, duración tratamiento, empleo de ribavirina, tratamiento previo, CV y plaquetas basales. En análisis univariante, negatividad carga viral a las 4 semanas (p = 0,042), ausencia de cirrosis (p = 0,021), albúmina basal ≥ 4g/dl (p:0,001) y MELD<10 (p < 0,0001) se asociaron con mayor RVS12. En estudio multivariante solo hubo relación significativa entre puntuación MELD basal < 10 y mayor RVS12 (p < 0,001). CONCLUSIONES: La combinación de simeprevir y sofosbuvir es muy eficaz en pacientes infectados por los genotipos 1 y 4 de la hepatitis C. Es un tratamiento seguro, especialmente en pacientes sin ribavirina. Esta combinación es más efectiva en pacientes con puntuación MELD inferior a 10

INTRODUCTION: There are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. OBJECTIVE: The objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. PATIENTS AND METHODS: Prospective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). RESULTS: 204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0-1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549 IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p = 0.042), absence of cirrhosis (p = 0.021), baseline albumin ≥ 4g/dl (p = 0.001) and MELD < 10 (p < 0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score < 10 patients had higher SVR12 (p < 0.001). CONCLUSIONS: The combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10

PNPLA3 rs738409 polymorphism is associated with liver fibrosis progression in patients with chronic hepatitis C: A repeated measures study.

BACKGROUND: Host genetic background has been associated with liver fibrosis progression. OBJECTIVE: To analyze the association between the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism and liver fibrosis progression in hepatitis C virus (HCV)-infected patients. STUDY DESIGN: In this retrospective cohort study, 187 patients with chronic HCV infection were included, who had at least two liver stiffness measurements (LSM) by transient elastography during the follow-up. Results were expressed in kilopascals (kPa). The analysis of genetic association was carried out according to additive model by using Generalized Linear Models. RESULTS: No patients had advanced fibrosis/cirrhosis at baseline. During a median follow-up time of 47.9 months, 15 patients developed advanced fibrosis and 17 cirrhosis. In multivariate analysis adjusted by the main clinical and epidemiological covariates, the rs738409 G allele was related to higher increase of LSM values during the follow-up (adjusted arithmetic mean ratio (aAMR) = 1.16 (95%CI = 1.04; 1.29); p = .006) and higher odds of having progression to advanced fibrosis [aOR = 2.03 (95%CI = 1.01; 4.06); p = .045], and progression to cirrhosis [aOR = 3.03 (95%CI = 1.26; 7.30); p = .014]. CONCLUSIONS: PNPLA3 rs738409 polymorphism appears to be related to the increased progression of liver fibrosis in HCV infected patients.

Influence of baseline MELD score in the efficacy of treatment of hepatitis C with simeprevir and sofosbuvir. / Influencia de la puntuación MELD basal en la eficacia del tratamiento de la hepatitis C con sofosbuvir y simeprevir.

INTRODUCTION: There are few published studies on predictors of response to treatment with sofosbuvir and simeprevir in HCV patients. OBJECTIVE: The objective of the study was to analyse possible predictors of response to simeprevir (SMV) and sofosbuvir (SOF) in patients infected with hepatitis C genotypes 1 or 4. PATIENTS AND METHODS: Prospective observational cohort study in 12 hospitals. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). RESULTS: 204 patients (62.3% male, mean age 55 years) were included: 186 (91.2%) genotype 1 (60.3% 1b 25% 1a) and 18 (8.8%) genotype 4. 132 (64.7%) cirrhotic (87.9% Child A), 33 (16.2%) F3, 31 (15.2%) F2, 8 (3.9%) F0-1. 80.8% MELD<10. 93 (45.6%) naive. Ribavirin was added in 68 (33.3%). Mean baseline viral load 2,151,549 IU/ml (SD: 2,391,840). Treatment duration 12 weeks in 93.1%. 4 discontinued therapy: suicide, psychotic attack, hyperbilirubinaemia and liver cancer recurrence. 190 (93.1%) achieved SVR12. There were no differences in SVR12 depending on the genotype, treatment duration, ribavirin use, prior therapy, viral load (VL) or baseline platelets. In univariate analysis, undetectable VL at 4 weeks (p=0.042), absence of cirrhosis (p=0.021), baseline albumin ≥ 4g/dl (p=0.001) and MELD<10 (p<0.0001) were associated with higher SVR12. In multivariate analysis, only baseline MELD score <10 patients had higher SVR12 (p<0.001). CONCLUSIONS: The combination of simeprevir and sofosbuvir in patients infected with genotype 1 and 4 hepatitis C is highly effective. It is a safe therapy, especially in patients without ribavirin. This combination was more effective in patients with a MELD score below 10.

Liver stiffness measurement predicts liver-related events in patients with chronic hepatitis C: A retrospective study.

The management of patients with chronic hepatitis C (CHC) depends on their clinical stage. Thus, noninvasive early recognition of patients with CHC at high risk for developing liver-related events (LREs) is important because it ensures optimal preventative management strategies may be employed that can affect the course of CHC disease. Our aim was to determine whether liver stiffness measurement (LSM) in hepatitis C virus (HCV)-infected patients is associated with a risk of LREs, particularly in cirrhotic patients. We carried out a retrospective study on 343 HCV-infected patients stratified according to cirrhosis (LSM<12.5 kPa vs. LSM≥12.5 kPa), and the cirrhotic patient group (LSM≥12.5 kPa) was divided according to risk of esophageal varices (LSM <25 kPa vs. LSM≥25 kPa). For all patients, each incremental unit in the natural logarithm (Ln) of LSM was associated with 14.76 times higher risk of developing LREs (p<0.001). Patients with cirrhosis (LSM≥12.5 kPa) had a higher risk of LREs than patients without cirrhosis (LSM<12.5 kPa) [adjusted hazard ratio (aHR) = 30.97; p<0.001]. When only cirrhotic patients were analyzed (n = 60), each incremental unit in the Ln of LSM was associated with 10.56 times higher risk of developing LREs (p = 0.010). Patients with LSM≥25 kPa had a greater risk for LRE development compared to those with LSM<25 kPa (aHR = 3.65; p = 0.045). The AUROC for predicting the onset of LREs was 0.876 in all patients and 0.729 in cirrhotic patients. In conclusion, LSM was associated with an increased risk of developing LREs in HCV-infected patients, even within the group of cirrhotic patients.

CXCL9-11 polymorphisms are associated with liver fibrosis in patients with chronic hepatitis C: a cross-sectional study.

BACKGROUND AND AIMS: CXCL9-11 polymorphisms are related to various infectious diseases, including hepatitis C virus (HCV) infection. In this study, we analyzed the association between CXCL9-11 polymorphisms and liver fibrosis in HCV-infected patients. METHODS: We performed a cross-sectional study in 389 patients who were genotyped for CXCL9-11 polymorphisms (CXCL9 rs10336, CXCL10 rs3921, and CXCL11 rs4619915) using the Sequenom's MassARRAY platform. The primary outcome variable was the liver stiffness measurement (LSM). We established three cut-offs of LSM: LSM ≥ 7.1 kPa (F ≥ 2-significant fibrosis), LSM ≥ 9.5 kPa (F ≥ 3-advanced fibrosis), and LSM ≥ 12.5 kPa (F4-cirrhosis). RESULTS: Recessive, overdominant and codominant models of inheritance showed significant values, but the overdominant model was the best fitting our data. In this case, CXCL9 rs10336 AG, CXCL10 rs3921 CG and CXCL11 rs4619915 AG were mainly associated with lower values of LSM [(adjusted GMR (aGMR) = 0.85 (p = 0.005), aGMR = 0.84 (p = 0.003), and aGMR = 0.84 (p = 0.003), respectively]. Patients with CXCL9 rs10336 AG genotype had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.59 (p = 0.016)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.54 (p = 0.010)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.56 (p = 0.043)]. Patients with CXCL10 rs3921 CG or CXCL11 rs4619915 AG genotypes had lower odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 0.56 (p = 0.008)], advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 0.55 (p = 0.013)], and cirrhosis (LSM ≥ 12.5 kPa) [aOR = 0.57 (p = 0.051)]. Additionally, CXCL9-11 polymorphisms were related to lower liver stiffness under a codominant model of inheritance, being the heterozygous genotypes also protective against hepatic fibrosis. In the recessive inheritance model, the CXCL9 rs10336 AA, CXCL10 rs3921 CC and CXCL11 rs4619915 AA were associated with higher LSM values [(adjusted GMR (aGMR) = 1.19 (p = 0.030), aGMR = 1.21 (p = 0.023), and aGMR = 1.21 (p = 0.023), respectively]. Moreover, patients with CXCL9 rs10336 AA genotype had higher odds of significant fibrosis (LSM ≥ 7.1 kPa) [adjusted OR (aOR) = 1.83 (p = 0.044)] and advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.85 (p = 0.045)]. Furthermore, patients with CXCL10 rs3921 CC or CXCL11 rs4619915 AA genotypes had higher odds of advanced fibrosis (LSM ≥ 9.5 kPa) [aOR = 1.89 (p = 0.038)]. CONCLUSIONS: CXCL9-11 polymorphisms were related to likelihood of having liver fibrosis in HCV-infected patients. Our data suggest that CXCL9-11 polymorphisms may play a significant role against the progression of CHC and could help prioritize antiviral therapy.

Interferon-Free Therapy in Elderly Patients With Advanced Liver Disease.

OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged ≥80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin ≤3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age ≥75 years (2.59 (1.16-5.83); P =0.02) and albumin ≤3.5 (17 (6.3-47); P <0.01). CONCLUSIONS: SVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (≤3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (≥75 years) or those with advanced liver disease (albumin ≤3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended.

Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection.

Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second-generation direct-acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4-infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin <3.5 g/dL (OMV/PTVr) and bilirubin >2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE-associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA-based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non-cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes.

Effectiveness and safety of first-generation protease inhibitors in clinical practice: Hepatitis C virus patients with advanced fibrosis.

AIM: To evaluates the effectiveness and safety of the first generation, NS3/4A protease inhibitors (PIs) in clinical practice against chronic C virus, especially in patients with advanced fibrosis. METHODS: Prospective study and non-experimental analysis of a multicentre cohort of 38 Spanish hospitals that includes patients with chronic hepatitis C genotype 1, treatment-naïve (TN) or treatment-experienced (TE), who underwent triple therapy with the first generation NS3/4A protease inhibitors, boceprevir (BOC) and telaprevir (TVR), in combination with pegylated interferon and ribavirin. The patients were treatment in routine practice settings. Data on the study population and on adverse clinical and virologic effects were compiled during the treatment period and during follow up. RESULTS: One thousand and fifty seven patients were included, 405 (38%) were treated with BOC and 652 (62%) with TVR. Of this total, 30% (n = 319) were TN and the remaining were TE: 28% (n = 298) relapsers, 12% (n = 123) partial responders (PR), 25% (n = 260) null-responders (NR) and for 5% (n = 57) with prior response unknown. The rate of sustained virologic response (SVR) by intention-to-treatment (ITT) was greater in those treated with TVR (65%) than in those treated with BOC (52%) (P < 0.0001), whereas by modified intention-to-treatment (mITT) no were found significant differences. By degree of fibrosis, 56% of patients were F4 and the highest SVR rates were recorded in the non-F4 patients, both TN and TE. In the analysis by groups, the TN patients treated with TVR by ITT showed a higher SVR (P = 0.005). However, by mITT there were no significant differences between BOC and TVR. In the multivariate analysis by mITT, the significant SVR factors were relapsers, IL28B CC and non-F4; the type of treatment (BOC or TVR) was not significant. The lowest SVR values were presented by the F4-NR patients, treated with BOC (46%) or with TVR (45%). 28% of the patients interrupted the treatment, mainly by non-viral response (51%): this outcome was more frequent in the TE than in the TN patients (57% vs 40%, P = 0.01). With respect to severe haematological disorders, neutropaenia was more likely to affect the patients treated with BOC (33% vs 20%, P ≤ 0.0001), and thrombocytopaenia and anaemia, the F4 patients (P = 0.000, P = 0.025, respectively). CONCLUSION: In a real clinical practice setting with a high proportion of patients with advanced fibrosis, effectiveness of first-generation PIs was high except for NR patients, with similar SVR rates being achieved by BOC and TVR.

Profiles and clinical management of hepatitis C patients in Spain: disHCovery study.

INTRODUCTION: To assess the clinical profile and management of patients with hepatitis C (HCV) infection in an observational study in Spanish hospitals. METHODS: The study included an initial cross-sectional phase (study phase I), in which investigators at 48 hospitals from 14 Spanish regions collected data from approximately 20 consecutive patients each (a total of 1,000 patients) to assess the general features of HCV-infected patients of any genotype. During the second phase (study phase II), data from 878 patients that were infected exclusively with genotype 1 HCV were assessed retrospectively. Eight pre-defined clinical profiles were established, in order to assess clinical and previous treatments characteristics. RESULTS: Among the HCV-infected individuals that were analysed during the first part, HCV genotype 1 was found to be predominant (with a prevalence of 76.6%), prevailing the subtype 1b (69.8%), with other significant groups infected by genotype 3 (12.3%) and 4 (7.4%). In the second part of the study, 44% of the HCV genotype 1-infected patients were at a F3/F4 fibrosis stage. 15.9% had never been treated, and previously unsuccessfully treated patients that were no longer receiving anti-HCV treatment accounted for 50.8% of cases. Individuals with a sustained virologic response (SVR) to previous dual therapies (based on Interferon and Ribavirin) were only 14.5% and patients under treatment during the study accounted for the remaining 18.8%. A total of 713 patients (81.2%) in the second phase were not receiving any type of therapy over the period analysed, mainly due to the anticipation of new anti-HCV drugs (41.8%), SVR achievement (17.8%) and unresponsiveness to therapies available at the time of the study (9.5%). CONCLUSIONS: HCV genotype 1, predominately 1b, is the most prevalent type in Spain. Advanced fibrosis or cirrhosis is frequent in this group, mainly patients not yet cured.

Profiles and clinical management of hepatitis C patients in Spain: disHCovery study / / Perfil clínico y seguimiento de los pacientes con hepatitis C crónica en hospitales españoles: Estudio disHCovery

Introduction. To assess the clinical profile and management of patients with hepatitis C (HCV) infection in an observational study in Spanish hospitals. Methods. The study included an initial cross-sectional phase (study phase I), in which investigators at 48 hospitals from 14 Spanish regions collected data from approximately 20 consecutive patients each (a total of 1,000 patients) to assess the general features of HCV-infected patients of any genotype. During the second phase (study phase II), data from 878 patients that were infected exclusively with genotype 1 HCV were assessed retrospectively. Eight pre-defined clinical profiles were established, in order to assess clinical and previous treatments characteristics. Results. Among the HCV-infected individuals that were analysed during the first part, HCV genotype 1 was found to be predominant (with a prevalence of 76.6%), prevailing the subtype 1b (69.8%), with other significant groups infected by genotype 3 (12.3%) and 4 (7.4%). In the second part of the study, 44% of the HCV genotype 1-infected patients were at a F3/F4 fibrosis stage. 15.9% had never been treated, and previously unsuccessfully treated patients that were no longer receiving anti-HCV treatment accounted for 50.8% of cases. Individuals with a sustained virologic response (SVR) to previous dual therapies (based on Interferon and Ribavirin) were only 14.5% and patients under treatment during the study accounted for the remaining 18.8%. A total of 713 patients (81.2%) in the second phase were not receiving any type of therapy over the period analysed, mainly due to the anticipation of new anti-HCV drugs (41.8%), SVR achievement (17.8%) and unresponsiveness to therapies available at the time of the study (9.5%). Conclusions. HCV genotype 1, predominately 1b, is the most prevalent type in Spain. Advanced fibrosis or cirrhosis is frequent in this group, mainly patients not yet cured (AU)

Introducción. Evaluar el perfil clínico y el manejo de los pacientes con infección por hepatitis C crónica (VHC) en un estudio observacional en hospitales españoles. Métodos. El estudio incluye una fase inicial de registro transversal de datos agregados (primera fase del estudio) en la cual investigadores de 48 hospitales en 14 regiones diferentes de España recopilaron datos de aproximadamente 20 pacientes atendidos consecutivamente en consulta (un total de 1.000 pacientes) en los que se analizó, en cada uno de ellos, las características generales de la infección por VHC de cualquier genotipo. Durante la segunda fase del estudio se realizó una evaluación retrospectiva de datos procedentes de 878 pacientes exclusivamente portadores del genotipo 1 del VHC. Se establecieron ocho perfiles clínicos predefinidos con el objetivo de evaluar las características tanto clínicas como de los tratamientos previos. Resultados. Entre los pacientes con infección por VHC que fueron analizados durante la primera parte del estudio, se observó que el genotipo 1 del VHC era el más frecuente (con una prevalencia del 76,6%), predominando el subtipo 1b (69,8%) seguido de los genotipo 3 (12,3%) y genotipo 4 (7,4%). En la segunda parte del estudio se observó que el 44% de los pacientes infectados por genotipo 1 del VHC presentaban un grado de fibrosis F3/F4. Un 15,9 % de los pacientes no habían sido previamente tratados y un 50,8% habían fracasado a un tratamiento previo y en ese momento no recibían ningún tratamiento. Un 14,5% de los pacientes habían presentado previamente respuesta viral sostenida (RVS) tras terapia con interferón y ribavirina y durante el punto de corte de estudio se encontraban bajo tratamiento el 18,8% de los pacientes en seguimiento. En la segunda fase, un total de 713 pacientes (81,2% de la población evaluada) no estaba recibiendo tratamiento, debido fundamentalmente a la previsión de llegada de nuevos fármacos (41,8%), a que ya estaban en RVS (17,8%) o a la ausencia de respuesta a las terapias disponibles en el momento del estudio (9,5%). Conclusiones. El genotipo más prevalente del VHC en España es el genotipo 1, predominantemente 1b. El perfil de paciente más frecuente fue el que presentaba fibrosis avanzadas o cirrosis, principalmente en pacientes aún no curados (AU)

Tratamiento percutáneo del carcinoma hepatocelular en pacientes con edad avanzada en la práctica clínica / Percutaneous ablation of hepatocellular carcinoma in older patients in clinical practice

INTRODUCCIÓN: Existe un alto porcentaje de pacientes con carcinoma hepatocelular (CHC) en estadio precoz con edad avanzada, que son potenciales candidatos a tratamiento percutáneo. MATERIAL Y MÉTODO: Evaluamos prospectivamente los datos de pacientes con CHC mayores de 70 años. Describimos sus características y el tratamiento pautado, así como la respuesta, las complicaciones y la supervivencia de los tratados con radiofrecuencia (RF) y/o inyección percutánea de alcohol (IPA). RESULTADOS: De los 194 pacientes con CHC, 84 eran mayores de 70 años (43,3%). La edad media era 76,8 ± 4,5 años. El 75% eran varones. El 91,7% eran cirróticos. El 61,9% se descubrió por cribado. Se diagnosticaron en estadio precoz (0-A) de Barcelona Clinic Liver Cancer el 60,7%, en B, el 19%, en C, el 12%, y en D, el 8,3%. El 38,2% recibió tratamiento potencialmente curativo (4,8% resección, 22,6% IPA, 4,8% RF, 6% IPA + RF), el 20,2%, quimioembolización, el 3,6%, sorafenib, el 25% no fue candidato a tratamiento, y el 13% rechazó el tratamiento recomendado. La mediana de seguimiento desde que recibieron el tratamiento percutáneo fue de 23 (IIC 14,2-40,6) meses. La media del número de sesiones de IPA fue de 3,5 ± 2,2 y de RF 1,8 ± 1,6. Hubo un 4% de complicaciones por sesión. Permanecieron en remisión el 35,7%. La mediana de supervivencia fue de 45,7 meses (IC 95% 20,8-70,6). CONCLUSIONES: El 43,3% de nuestros pacientes con CHC tenían una edad avanzada. Más de la mitad se diagnosticaron en estadio precoz. En un tercio se realizó tratamiento percutáneo, con un 35,7% de remisión y complicaciones poco frecuentes. Por lo tanto, este tipo de pacientes deben evaluarse para tratamiento percutáneo

INTRODUCTION: A high percentage of older patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for percutaneous ablation.Material and methods We prospectively assessed data from patients older than 70 years with HCC. We determined their demographic and clinical characteristics, the treatment provided and the response, complications and survival among those treated with radiofrequency ablation (RFA) and/or percutaneous ethanol injection (PEI). RESULTS: Of 194 patients with HCC, 84 were older than 70 years (43.3%). The mean age was 76.8 ± 4.5 years. Seventy-five percent were male and 91.7% had cirrhosis. Cancer was initially identified by a surveillance program in 61.9%. According to the Barcelona Clinic Liver Cancer staging system, 60.7% were classified as having early stage cancer (0-A), 19% as stage B, 12% as stage C, and 8.3% as stage D. Potentially curative initial treatment was provided in 38.2% (surgical resection in 4.8%, PEI in 22.6%, RFA in 4.8%, PEI + RFA in 6%), transarterial chemoembolization in 20.2%, and sorafenib in 3.6%. Twenty-five percent of patients were not treatment candidates and 13% refused the recommended treatment. The median follow-up after percutaneous ablation was 23 months (IQR 14.2-40.6). The mean number of sessions was 3.5 ± 2.2 for PEI and 1.8 ± 1.6 for RFA. The complications rate per session was 4%. Remission was achieved in 35.7%. The overall median survival was 45.7 months (95% CI 20.8-70.6). CONCLUSIONS: Almost half of the patients with HCC in our sample were elderly and more than half were diagnosed at an early stage. Percutaneous ablation was performed in one-third of the sample, achieving remission in 37.5%. There were few complications. Therefore, these patients should be assessed for percutaneous ablation

[Percutaneous ablation of hepatocellular carcinoma in older patients in clinical practice]. / Tratamiento percutáneo del carcinoma hepatocelular en pacientes con edad avanzada en la práctica clínica.

INTRODUCTION: A high percentage of older patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for percutaneous ablation. MATERIAL AND METHODS: We prospectively assessed data from patients older than 70 years with HCC. We determined their demographic and clinical characteristics, the treatment provided and the response, complications and survival among those treated with radiofrequency ablation (RFA) and/or percutaneous ethanol injection (PEI). RESULTS: Of 194 patients with HCC, 84 were older than 70 years (43.3%). The mean age was 76.8 ± 4.5 years. Seventy-five percent were male and 91.7% had cirrhosis. Cancer was initially identified by a surveillance program in 61.9%. According to the Barcelona Clinic Liver Cancer staging system, 60.7% were classified as having early stage cancer (0-A), 19% as stage B, 12% as stage C, and 8.3% as stage D. Potentially curative initial treatment was provided in 38.2% (surgical resection in 4.8%, PEI in 22.6%, RFA in 4.8%, PEI+RFA in 6%), transarterial chemoembolization in 20.2%, and sorafenib in 3.6%. Twenty-five percent of patients were not treatment candidates and 13% refused the recommended treatment. The median follow-up after percutaneous ablation was 23 months (IQR 14.2-40.6). The mean number of sessions was 3.5 ± 2.2 for PEI and 1.8 ± 1.6 for RFA. The complications rate per session was 4%. Remission was achieved in 35.7%. The overall median survival was 45.7 months (95% CI 20.8-70.6). CONCLUSIONS: Almost half of the patients with HCC in our sample were elderly and more than half were diagnosed at an early stage. Percutaneous ablation was performed in one-third of the sample, achieving remission in 37.5%. There were few complications. Therefore, these patients should be assessed for percutaneous ablation.

Does low-dose prolonged steroid therapy affect the natural history of chronic hepatitis C?

Chronic hepatitis C patients may require steroids due to other comorbidities. However, there is not enough information to consider steroids as beneficial or harmful drugs on natural history of chronic hepatitis C. The aim of the present study was to examine the effect of low-dose prolonged therapy with corticosteroids with or without azathioprine on these study patients. A retrospective-prospective observational study was established. Twenty-eight patients with chronic hepatitis C and treated with corticosteroids at low-dose (≤30 mg/day) with or without azathioprine for more than 6 months were included. AST, ALT, HCV RNA, and liver fibrosis were determined, and results were compared with a control group of non-treated chronic hepatitis C patients. The mean age was 47 ± 10 years. The male proportion was 43%. The mean dose of prednisone was 9 ± 5 mg/day (range: 2.5-30 mg/day). The mean treatment time was 76 ± 80 months (range: 7-349 months). Thirty six percent received concomitant azathioprine. Transaminases decreased significantly only within the first 3 months of treatment, with non-significant changes thereafter. Corticosteroids led to a non-significant increase in HCV RNA. Knodell Histology Activity Index decreased (from 8.5 ± 3.7 to 4.7 ± 1.7; P = 0.1). Fibrosis progression per year (final fibrosis stage-initial fibrosis stage/time between explorations, in years), was lower in treated cases than in control group (0.054 ± 0.25 units vs. 0.196 ± 0.6 units, P = 0.26). In conclusion, corticosteroid treatment caused a significant initial decrease in transaminases, non-significant changes in HCV RNA, and a trend to a slower fibrosis progression in comparison to a control group. Therefore, corticosteroids did not accelerate progression of chronic hepatitis C.