Adjuvanted recombinant HBV vaccine (HBV-AS04) is effective over extended follow-up in dialysis population. An open-label non randomized trial.

BACKGROUND: Patients on regular dialysis show a poor response to hepatitis B vaccine due to uremia. A recombinant HB vaccine (containing an improved adjuvant system AS04, HBV-AS04) has been licensed but the evidence on its efficacy and safety in dialysis population over the long term is extremely limited. AIM: We have measured antibody (anti-HBs) persistence for up to 72 months in a large cohort of patients on long-term dialysis (with susceptibility to HBV infection) who underwent vaccination with HBV-AS04 vaccine. METHODS: Patients were prospectively recruited to receive four 20-mcg doses of HBV-AS04 by intramuscular route (deltoid muscle). Two vaccine schedules were adopted: 0,1,2, and 3 month (n=217 patients) and 0,1,2, and 6 month (n=31 patients). Anti-HBs antibody concentrations were tested at 1,2,3, 4, 7 and 12 months and then every year up to 72 months. Multivariate analysis was made to find the baseline parameters that were associated with the immune response to HBV-AS04 vaccine. RESULTS: Two hundred and seventy-two patients were included and 248 completed the study. At completion of vaccine schedule, the frequency of responders (anti-HBs titers≥10mIU/mL) was 81.5% (202/248) (mean anti-HBs antibody titers, 384.9±391.9mIU/mL), according to per-protocol analysis. On the grounds of univariate analysis, age was lower in responder than non- responder patients to HBV AS04 even if no statistical significance was achieved (P=0.09). The sero-protection rate at month 72 was 77% (7/9) (anti-HBs antibody titers, 184.9±360.1mIU/mL, P=0.001). Multivariate analysis found a relationship between sero-response rate and age (P=0.04). No major side effects and no de novo HBV episodes were observed. CONCLUSIONS: Our open-label nonrandomized trial performed in a 'real-world' practice showed the persistence of anti-HBs antibody among responder patients over a very long follow-up. Studies with longer observation periods are under way.

Efficacy and safety of direct-acting antiviral agents for HCV in mild-to-moderate chronic kidney disease.

BACKGROUND AND AIMS: The advent of direct-acting antiviral agents promises to change the management of hepatitis C virus infection (HCV) in patients with chronic kidney disease (CKD), a patient group in which the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' cohort of patients with CKD. METHODS: We performed an observational single-arm multi-centre study in a large (n=198) cohort of patients with stage 1-3 CKD who underwent antiviral therapy with DAAs for the treatment of HCV. The primary end-point was sustained virologic response (serum HCV RNA <15IU/mL, 12 weeks after treatment ended) (SVR12). We collected data on on-treatment adverse events (AEs), severe AEs, and laboratory abnormalities. RESULTS: The average baseline eGFR (CKD-EPI equation) was 70.06±20.1mL/min/1.72m2; the most common genotype was HCV 1b (n=93, 51%). Advanced liver scarring was found in 58 (46%) patients by transient elastography. Five regimens were adopted: elbasvir/grazoprevir (n=5), glecaprevir/pibrentasvir (n=4), ritonavir-boosted paritaprevir/ombitasvir/dasabuvir (PrOD) regimen (n=40), simeprevir±daclatasvir (n=2), and sofosbuvir-based combinations (n=147). The SVR12 rate was 95.4% (95% CI, 93.8%; 96.8%). There were nine virological failures - eight being relapsers. Adverse events occurred in 30% (51/168) of patients, and were managed clinically without discontinuation of therapy or hospitalization. One of the most common AEs was anaemia (n=12), which required discontinuation or dose reduction of ribavirin in some cases (n=6); deterioration of kidney function occurred in three (1.7%). CONCLUSIONS: All-oral, interferon-free therapy with DAAs for chronic HCV in mild-to-moderate CKD was effective and well-tolerated in a 'real-world' clinical setting. Studies are in progress to address whether sustained viral response translates into better survival in this population.

Gastrointestinal lesions in chronic kidney disease patients with anaemia. / Lesiones gastrointestinales en pacientes con enfermedad renal crónica y anemia.

INTRODUCTION: Despite the frequency with which anaemia is present in patients with chronic kidney disease (CKD), its relationship with gastrointestinal lesions has not been studied. METHOD: A cross-sectional, analytical, observational study involving one year of recruitment was carried out to determine the prevalence of endoscopic gastrointestinal lesions and associated risk factors in asymptomatic patients with chronic kidney disease stages 1-5 and anaemia who had a positive qualitative immunochemical faecal occult blood test. RESULTS: A total of 9,658 patients with CKD were analysed, of which 286 (2.9%) had anaemia; 198 had a positive faecal occult blood test (47% male, 71.1±11.8 years). The endoscopic study revealed 255 lesions, with at least one lesion in 68.2% of patients, with the most prevalent being: adenomatous colorectal polyps (39.6%), acute lesions of the gastric mucosa (22.6%), neoplastic lesions 15.1%), angiodysplasia (14.4%), oesophagitis (8.4%), inflammatory bowel disease (4.8%) and ischaemic colitis (3.1%). Uraemia and acetylsalicylic acid were identified as risk factors for acute gastric mucosal lesions. Angiodysplasia was associated with alcoholism, a more advanced stage of chronic kidney disease, anaemia, and lack of response to erythropoiesis-stimulating agents. Age and refractory anaemia were risk factors for adenomatous polyps and colorectal cancer. CONCLUSION: Renal patients with anaemia could benefit from an endoscopic study due to their high prevalence of gastrointestinal lesions, particularly adenomatous polyps and colorectal cancer, which are more common in those over 50 years of age with CKD stages 3-5.

'Real-life' experience with direct-acting antiviral agents for hepatitis C virus in end-stage renal disease.

BACKGROUND AND AIMS: The advent of direct-acting antiviral agents promises to change the management of hepatitis C in patients with end-stage renal disease, a patient group where the treatment of hepatitis C was historically challenging. We investigated the safety and efficacy of all-oral, interferon-free direct-acting antiviral agents for the treatment of hepatitis C in a 'real-world' group of patients with end-stage renal disease. METHODS: We performed a single-arm, multi-centre study in a cohort (n=30) of patients with advanced chronic kidney disease (mostly on dialysis) who underwent antiviral therapy with direct-acting antiviral agents. The primary end-point was sustained virologic response (serum hepatitis C virus RNA < 15 mIU/mL, 12 weeks after treatment ended). We collected data on on-treatment adverse events, serious adverse events and laboratory abnormalities. RESULTS: In total, 23 (77%) and 7 (23%) patients underwent regular dialysis and had chronic kidney disease at pre-dialysis stage, respectively. Six regimens were adopted: elbasvir/grazoprevir ( n = 6), ledipasvir/sofosbuvir ± ribavirin ( n = 4), PrOD regimens ± ribavirin ( n = 10), simeprevir + daclatasvir ( n = 3), sofosbuvir + daclatasvir ± ribavirin ( n = 3), sofosbuvir + ribavirin ( n = 4). The SVR12 rate was 90% (95% confidence interval, 74%; 96%). A total of 27 (90%) patients achieved SVR12; there were three virologic failures - two were non-responders and one had a viral breakthrough while on therapy. Adverse events occurred in 53% (16/30) (95% confidence interval, 0.39; 0.73) of patients and were managed clinically without discontinuation of therapy or hospitalization. The most common adverse event was anaemia ( n = 12) that required blood transfusions in seven individuals; deterioration of kidney function occurred in one (14%). CONCLUSION: All-oral, interferon-free therapy with direct-acting antiviral agents for chronic hepatitis C virus in advanced chronic kidney disease was effective and well tolerated in a 'real-life' clinical setting. Careful monitoring of haemoglobin and serum creatinine during therapy with direct-acting antiviral agents is suggested. Studies are under way to address whether sustained viral response translates into better survival in this population.

Recommendations for the treatment of hepatitis C virus infection in chronic kidney disease: a position statement by the Spanish association of the liver and the kidney.

Hepatitis C virus (HCV) infection is one of the main causes of liver cirrhosis worldwide. The long-term impact of HCV infection is highly variable, ranging from minimal histological changes to extensive fibrosis with hepatocellular carcinoma. The development of HCV drugs has increased dramatically in recent years, even in special populations such as chronic kidney disease patients. Classical treatment of chronic hepatitis C was based on the administration of interferon and ribavirin for 24-48 weeks, which was associated with a poor viral response and a high rate of side effects, especially in patients with a lower estimated glomerular filtration rate. The current high availability of the new direct-acting antivirals renders the classification of these agents for this special population necessary. The Spanish Association of the Liver and the Kidney has produced a position statement on the treatment of HCV infection in chronic kidney disease patients since the evidence to guide this treatment is scant and what evidence does exist is weak. The recommendations are based on the results of clinical trials and controlled studies conducted to date, with data published hitherto by the authors of these studies. Since the indications for treatment have been evaluated by other societies or are dependent on internal clinical protocols, the main goal of this position statement is to assist in decision-making when choosing a therapeutic option.

Spanish multicentre PIBHE study: Prevalence and immunization of chronic hepatitis B in haemodialysis patients in Spain.

INTRODUCTION: The PIBHE study, promoted by the Spanish Liver and Kidney Association and the Dialysis Virus Group of the Spanish Society of Nephrology, is the first study to determine the status of haemodialysis patients with chronic HBV infection and the immunisation against the vaccine. METHOD: The study has a national multicentre, observational, cross-sectional design and was carried out between January 2013 and 2014. A data collection folder was sent to all the nephrology departments and outpatient haemodialysis units in Spain, to be completed based on patient medical files after informed consent. The data were recorded in a central database. RESULTS: A total of 215 centres participated (15,645 patients), with an HBV prevalence of 1.03%. HCV or HIV was present in 7.2% of the HBV(+) patients. Viral load was below 2,000 IU/ml in 80%. GOT and GPT levels were 19.1±10.1 and 15.9±9.6 IU/ml, respectively. Liver biopsy was performed in 7.1%. Antiviral treatment was prescribed in 30% and suspended in 12.5%: entecavir (13.3%), lamivudine (10%), adefovir and tenofovir (6.7%), and interferon (3.3%). A total of 34.5% were candidates for renal transplantation and 6.9% had not been evaluated; 64.3% were followed up by a gastroenterologist; 27.2% of HBV(-) patients without immunisation had not been vaccinated. Fourteen different immunisation schedules had been used, with an immunisation rate of 58.8%. Mean anti-HBs stood at 165.7±297.8mIU/ml. A total of 72.7% of patients had received a vaccination course; 26.4%, 2 cycles; 1.0%, 3 cycles; and 11.6%, a booster dose. A total of 28.3% had a poor response (anti-HBs 10-99mIU/ml); 22.4%, an optimal response (anti-HBs 100-999mIU/ml); and 7.9%, an excellent response (anti-HBs ≥ 1,000mIU/ml). Age was significantly associated with response to vaccination; the mean age of nonresponders was significantly higher than patients who had a response of any kind (P<.05). The highest probability of an immune response was achieved with 4 doses of 40 mcg of adjuvanted vaccine (OR: 7.3; 95% CI 3.4 to 15.7), for the same age and number of cycles and boosters. Age, adjuvanted vaccine, dose and vaccination schedule influenced the immune response and the anti-HBs titres reached (P<.05). CONCLUSION: The prevalence of chronic HBV infection in haemodialysis in Spain is low and so are the rates of immunisation against the virus. The vaccination schedules used are very diverse and have been observed to correlate with the immune response. It would therefore be necessary to establish a protocol for the most effective vaccination schedule to increase immunisation in these patients.

Exocrine pancreatic insufficiency and chronic pancreatitis in chronic alcoholic liver disease: coincidence or shared toxicity?

OBJECTIVES: The aims of this study were to determine the prevalence of exocrine pancreatic insufficiency (EPI) and chronic pancreatitis (CP) in patients with chronic alcoholic liver disease and to analyze the possible associated factors. METHODS: This is an analytical observational study of cases and controls for a sample of patients with chronic alcoholic and nonalcoholic liver disease. Exocrine pancreatic insufficiency was diagnosed using the C mixed-triglyceride breath test. Patients with abdominal pain underwent endoscopic ultrasonography for CP evaluation using the Wiersema criteria. RESULTS: A total of 154 patients were included, 129 with alcoholic liver disease (83 with cirrhosis) and 25 with nonalcoholic liver disease. Exocrine pancreatic insufficiency was found in 55.2% versus 16.7% (P < 0.001), 70% of patients without cirrhosis compared with 46.2% of patients with cirrhosis had pancreatic insufficiency (P = 0.017), and 82.7% of patients with alcoholic liver disease and abdominal pain had CP (P < 0.001). Exocrine pancreatic insufficiency was associated with the male sex, alcohol intake, abdominal pain, degree of liver failure, and the absence of portal hypertension. Chronic pancreatitis was correlated with age younger than 55 years and abdominal pain. CONCLUSIONS: Patients with alcoholic liver disease had a high prevalence of EPI and CP; this prevalence was even higher in patients who have not yet developed cirrhosis with liver failure or portal hypertension.

Predominio del gen de la hemocromatosis en pacientes con hepatitis tóxicas / HFE genotype prevalence in patients with drug-induced hepatotoxicity

La toxicidad hepática por fármacos y su mecanismo han sido durante mucho tiempo desconocidos. Se ha observado que los pacientes con hepatitis aguda elevan los niveles séricos de ferritina. El objetivo de este estudio es determinar si existe una asociación de hepatotoxicidad por medicamentos y las mutaciones en el gen HFE asociadas con la hemocromatosis hereditaria. Material y métodos: Se analizaron10 pacientes ingresados en nuestro hospital con el diagnóstico de hepatitis aguda inducida por fármacos. A todos se les hicieron pruebas de laboratorio para el estudio de enfermedades hepáticas, la mutación del gen HFE y las características histopatológicas. Resultados: Un paciente con hepatitis secundaria a fármacos era heterocigoto para la mutación C282Y y uno heterocigoto para las mutaciones C282Y y H63D. Hubo un paciente homocigoto para la mutación H63D y seis fueron heterocigotos para la mutación H63D. La prevalencia general de las mutaciones del gen HFE en pacientes con enfermedad hepática inducida por fármacos fue del 90%. Conclusiones: La prevalencia de las mutaciones del gen HFE asociadas con hemocromatosis hereditaria está muy aumentada entre los pacientes que presentan hepatotoxicidad por medicamentos. Las mutaciones del gen HFE podrían estar involucradas en la hepatotoxicidad por fármacos...

SHECTS multi-centre Spanish study: liver situation of patients with chronic hepatitis from HCV on renal replacement therapy with haemodialysis.

INTRODUCTION: The SHECTS study, approved by the Spanish Society of Nephrology, has the goal of analysing the level of examination and follow-up of patients with chronic hepatitis C virus (HCV) infections on haemodialysis, and to determine the current prevalence of these patients. METHOD: A national, multi-centre, cohort study carried out between September 2010 and September 2011. We sent a data collection folder to all Spanish haemodialysis units to include information regarding each centre and the nephrological/hepatological situation of their HCV-positive patients. RESULTS: A total of 187 haemodialysis units (71 hospital-based) participated in the study. The global prevalence of HCV was estimated at 5.6%. The most common cause of chronic kidney disease was glomerular (25%); of the 72.1% of patients who had undergone a renal biopsy, 23.2% had glomerulonephritis that could have been associated with HCV. Genotyping had not been carried out in 64%, liver ultrasound had not been applied in 61.3%, and liver biopsies were not performed in 87.7%. One-third of all patients received care from a gastroenterologist. Antiviral treatment was administered to 26.6% of patients, with a sustained viral response in 35.3% and suspension of treatment in 67.4%. CONCLUSION: The prevalence of HCV in patients on haemodialysis in Spain has decreased to the point of reaching similar rates to those of neighbouring countries. These patients receive incomplete analyses of liver condition, and individuals who receive antiviral treatment and untreated patients constitute a large proportion, despite having low viral loads and being candidates for kidney transplants.

[Microalbuminuria and renal insufficiency in chronic hepatitis C virus infection]. / Microalbuminuria e insuficiencia renal en la infección crónica por el virus de la hepatitis C.

INTRODUCTION: Chronic hepatitis C virus (HCV) infection is associated with glomerular disease, which is manifested by proteinuria with or without renal dysfunction. METHOD: To determine the prevalence of HCV-associated renal injury and associated risk factors, we performed an observational, analytic, cross-sectional study of 120 HCV-positive patients and 145 HCV-negative controls. Data were gathered from medical records and history-taking and at least three blood and urine analyses were performed over a 1-year period. Renal insufficiency was defined as an estimated glomerular filtration rate of less than 60ml/min/1.73 m2 and/or microalbuminuria of more than 20mg/l or a microalbumin/creatinine ratio higher than 30 mcg/mg. RESULTS: The prevalence of microalbuminuria and renal insufficiency was 19.3% and 11.7% in HCV-positive patients versus 10.5% and 0.7% in HCV-negative controls (p 0.04), respectively. A total of 26.1% of HCV-positive patients had signs of renal injury compared with 11.8% of HCV-negative controls (p 0.003). HCV infection was independently and significantly associated with the probability of worsening of renal function. The prevalence of microalbuminuria and renal insufficiency progressively increased with greater age. CONCLUSION: HCV-positive patients show a high prevalence of microalbuminuria and renal insufficiency compared with HCV-negative individuals. The risk of HCV-associated renal insufficiency is independent of the presence of other predisposing factors such hypertension and diabetes.

[Reversibility of hepatitis B virus-induced liver cirrhosis after prolonged antiviral therapy]. / Desaparición de cirrosis hepática por VHB tras tratamiento prolongado con antivirales.

Reversibility of liver fibrosis or cirrhosis involves complete restoration of normal liver architecture. This phenomenon has been well documented in chronic liver diseases such as autoimmune hepatitis, biliary obstruction, hemochromatosis, nonalcoholic steatohepatitis, and viral hepatitis. There are very few reports of reversal of cirrhosis after antiviral therapy in patients with chronic hepatitis B virus (HBV) infection. We report a case of disappearance of HBV-induced liver cirrhosis after years of treatment with distinct antiviral drugs, documented by successive biopsy results. This disappearance was accompanied by normalization of platelet count, gammaglobulin titers, and radiologic findings.