Publications by authors named "Juan Manuel Pascasio"

30 Publications

  • Page 1 of 1

A 2-Step Strategy Combining FIB-4 With Transient Elastography and Ultrasound Predicted Liver Cancer After HCV Cure.

Am J Gastroenterol 2021 Sep 9. Epub 2021 Sep 9.

Hospital Universitario Virgen del Rocio, Universidad de Sevilla, Spain.

Introduction: Despite the direct-acting antiviral therapy has dramatically decreased the likelihood of having liver-related complications and extrahepatic outcomes, the risk of developing hepatocellular carcinoma (HCC) is not totally eliminated after sustained virological response (SVR). We aimed to develop an easy-to-apply strategy to be adopted in clinical practice for accurately classifying the HCC risk in hepatitis C virus patients after SVR.

Methods: Prospective and multicenter study enrolling hepatitis C virus patients with advanced fibrosis (transient elastography [TE] > 10 kPa) or cirrhosis by ultrasound showing SVR. They were followed up until HCC, liver transplantation, death, or until October 2020, which occurred first, with a minimum follow-up period of 6 months after SVR (follow-up: 49 [interquartile range 28-59] months).

Results: Patients with cirrhosis by ultrasound represented 58% (611/1,054) of the overall cohort. During the study, HCC occurrence was 5.3% (56/1,054). Multivariate analyses revealed that Fibrosis-4 (FIB-4) > 3.25 (hazard ratio [HR] 2.26 [1.08-4.73]; P = 0.030), TE (HR 1.02 [1.00-1.04]; P = 0.045) and cirrhosis by ultrasound (HR 3.15 [1.36-7.27]; P = 0.007) predicted HCC occurrence. Baseline HCC screening criteria (TE > 10 kPa or cirrhosis) identified patients at higher risk of HCC occurrence in presence of FIB-4 > 3.25 (8.8%; 44/498) vs FIB-4 < 3.25 (2.4%; 12/506), while those with only FIB > 3.25 had no HCC (0%; 0/50) (logRank 22.129; P = 0.0001). A combination of baseline FIB-4 > 3.25 and HCC screening criteria had an annual incidence >1.5 cases per 100 person-years, while the rest of the groups remained <1 case. Patients who maintained post-treatment FIB-4 > 3.25 and HCC screening criteria remained at the highest risk of HCC occurrence (13.7% [21/153] vs 4.9% [9/184]; logRank 7.396, P = 0.007).

Discussion: We demonstrated that a two-step strategy combining FIB-4, TE, and ultrasound could help stratify HCC incidence risk after SVR.
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http://dx.doi.org/10.14309/ajg.0000000000001503DOI Listing
September 2021

Prediction of liver stiffness by serum indexes in HCV-infected patients with or without HIV coinfection.

Medicine (Baltimore) 2021 Nov;100(46):e27838

Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa Zaragoza, Spain IIS Aragón, Zaragoza, Spain.

Abstract: Identification of advanced fibrosis/cirrhosis in hepatitis C virus (HCV)-infected patients should be a mainstay before starting treatment; however, the limited access of many centres to transient elastography (TE) is often a barrier for early assessments. We aimed to investigate the diagnostic accuracy of serum indexes for predicting liver stiffness.Retrospective analysis of HCV patients (with or without HIV coinfection) routinely assessed in 7 centres in Spain. The diagnostic accuracy of aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4), and their combinations was evaluated using a recent TE examination as a reference test (liver stiffness ≥ 9.5 kPa and ≥12.5 kPa for advanced fibrosis and cirrhosis, respectively). In addition to area under the receiving operating characteristic curves, sensitivity, specificity, and negative predictive value (NPV) and positive predictive value were estimated.The analysis included 1391 patients: 346 (25%) HIV-positive, 732 (53%) people who inject drugs, and 178 (13%) incarcerated. Advanced fibrosis and cirrhosis were found in 557 (40%) and 351 (25%) patients, respectively. APRI < 0.5 (n = 595; 43%) had an NPV of 95% for excluding cirrhosis. Combined FIB-4 < 1.45 with APRI < 0.5 (n = 467; 34%) had an NPV of 87% for excluding advanced fibrosis. Combined APRI > 2 and FIB-4 > 3.25 (n = 134; 10%) had a positive predictive value of 89% for advanced fibrosis. Globally, this approach would avoid the need for TE in 53% of patients. HIV coinfection did not influence diagnostic accuracy.Inexpensive and simple serum indexes confidently allowed identifying the absence of cirrhosis and the presence of advanced fibrosis in 53% of a heterogeneous series of real-world HCV patients with or without HIV infection.
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http://dx.doi.org/10.1097/MD.0000000000027838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601296PMC
November 2021

JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection.

Gastroenterology 2020 08 25;159(2):521-533.e9. Epub 2020 Apr 25.

Janssen Biopharma Inc., South San Francisco, California.

Background & Aims: JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection.

Methods: We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period.

Results: Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed.

Conclusions: In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. ClinicalTrials.gov identifier: NCT02662712.
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http://dx.doi.org/10.1053/j.gastro.2020.04.036DOI Listing
August 2020

Prophylaxis and treatment in liver transplantation. VII Consensus Document of the Spanish Society of Liver Transplantation.

Gastroenterol Hepatol 2020 Mar 21;43(3):169-177. Epub 2020 Feb 21.

Unidad de Trasplante Hepático, Hospital Clínic, IDIBAPS, CIBERehd, Univ. Barcelona, Barcelona, España. Electronic address:

Whilst prophylaxis of hepatitis B is universally accepted after liver transplantation (LT), national recommendations for the prophylaxis and treatment of hepatitis B virus (HBV) infection after LT are lacking in Spain. The aim of the VII consensus meeting organised by the Spanish Society of Liver Transplantation (SETH) was to set recommendations on the prophylaxis and treatment of hepatitis B after LT. The scientific evidence and strength of recommendations was evaluated by using the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) system. This document describes the recommendations and their level of evidence for: the definition and risk factors for hepatitis B recurrence after LT, monitoring and prophylaxis of hepatitis B recurrence at different periods after LT, treatment of hepatitis B before and after LT, and the prophylaxis of HBV infection by the recipients of LT with hepatitis B core antigen positive donors.
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http://dx.doi.org/10.1016/j.gastrohep.2019.11.005DOI Listing
March 2020

Deep-sequencing reveals broad subtype-specific HCV resistance mutations associated with treatment failure.

Antiviral Res 2020 02 16;174:104694. Epub 2019 Dec 16.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Hospital Universitario La Fe, Valencia, Spain.

A percentage of hepatitis C virus (HCV)-infected patients fail direct acting antiviral (DAA)-based treatment regimens, often because of drug resistance-associated substitutions (RAS). The aim of this study was to characterize the resistance profile of a large cohort of patients failing DAA-based treatments, and investigate the relationship between HCV subtype and failure, as an aid to optimizing management of these patients. A new, standardized HCV-RAS testing protocol based on deep sequencing was designed and applied to 220 previously subtyped samples from patients failing DAA treatment, collected in 39 Spanish hospitals. The majority had received DAA-based interferon (IFN) α-free regimens; 79% had failed sofosbuvir-containing therapy. Genomic regions encoding the nonstructural protein (NS) 3, NS5A, and NS5B (DAA target regions) were analyzed using subtype-specific primers. Viral subtype distribution was as follows: genotype (G) 1, 62.7%; G3a, 21.4%; G4d, 12.3%; G2, 1.8%; and mixed infections 1.8%. Overall, 88.6% of patients carried at least 1 RAS, and 19% carried RAS at frequencies below 20% in the mutant spectrum. There were no differences in RAS selection between treatments with and without ribavirin. Regardless of the treatment received, each HCV subtype showed specific types of RAS. Of note, no RAS were detected in the target proteins of 18.6% of patients failing treatment, and 30.4% of patients had RAS in proteins that were not targets of the inhibitors they received. HCV patients failing DAA therapy showed a high diversity of RAS. Ribavirin use did not influence the type or number of RAS at failure. The subtype-specific pattern of RAS emergence underscores the importance of accurate HCV subtyping. The frequency of "extra-target" RAS suggests the need for RAS screening in all three DAA target regions.
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http://dx.doi.org/10.1016/j.antiviral.2019.104694DOI Listing
February 2020

Prevalence of resistance associated substitutions and efficacy of baseline resistance-guided chronic hepatitis C treatment in Spain from the GEHEP-004 cohort.

PLoS One 2019 30;14(8):e0221231. Epub 2019 Aug 30.

Infectious Diseases Unit, University Hospital Nuestra Señora de Valme, Sevilla, Spain.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221231PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716636PMC
March 2020

High efficacy of resistance-guided retreatment of HCV patients failing NS5A inhibitors in the real world.

J Hepatol 2019 11 4;71(5):876-888. Epub 2019 Jul 4.

Clinical Microbiology Unit, University Hospital San Cecilio, Instituto de Investigacion Biosanitaria Ibs.Granada, Granada, Spain. Electronic address:

Background & Aims: 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 sofosbuvir/velpatasvir/voxilaprevir may not be available.

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 (SVR) 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%) were studied. After a resistance report, 186 patients were retreated. An 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 paritaprevir-ritonavir+ombitasvir±dasabuvir±ribavirin.

Conclusions: In our study, we show how resistance-guided retreatment in conjunction with an interpreted report allows patients to achieve 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: Hepatitis C infection can be cured with currently available antiviral agents. Only a small proportion of patients experience treatment failure, however, in absolute numbers, a high number of patients may require retreatment. Highly effective combinations of antivirals are also available for retreatment. However, these antivirals might not be available in resource-limited settings. Herein, we show how, by analyzing the cause of resistance, retreatment efficacy with old drugs can get very close to the efficacy of new drug combinations.
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http://dx.doi.org/10.1016/j.jhep.2019.06.022DOI Listing
November 2019

Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs.

J Hepatol 2019 10 14;71(4):666-672. Epub 2019 Jun 14.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Hospital Universitario Virgen del Rocío, Seville, Spain.

Background & Aims: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting.

Methods: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded.

Results: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific.

Conclusion: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group.

Lay Summary: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.
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http://dx.doi.org/10.1016/j.jhep.2019.06.002DOI Listing
October 2019

The simplification of the diagnosis process of chronic hepatitis C is cost-effective strategy.

Enferm Infecc Microbiol Clin (Engl Ed) 2019 Dec 11;37(10):634-641. Epub 2019 Apr 11.

Unidad de Gestión Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Jerez, Jerez de la Frontera, Cádiz, España.

Background: The cascade of care of the hepatitisC are complex. The diagnosis of active infection in the same serum sample would simplify the process establishing a rapid access for patients to treatment. Our objective was to estimate the impact on healthcare and economic outcomes of the diagnosis of chronic infection in one-step diagnosis compared to standard diagnosis in Andalusia (8.39 million people).

Methods: A decision tree was developed to estimate the referral of patients with chronic infection, loss of follow-up, access to treatment and costs of the diagnosis of the infection, for both processes. The unit costs (€, 2018) of the health resources (medical visits, antibodies, viral load and genotype), without considering the pharmacological cost, were obtained form public sources in Andalusia.

Results: Of the total estimated population (269,526 patients), 1,389 patients would be referred to the specialised care in the one-step diagnosis and 1,063 in de standard diagnosis, being treated 1,320 and 1,009, respectively. In one-step diagnosis, no negative viral loud patient would be referred to specialist versus 540 with standard diagnosis. One-step diagnosis would generate a cost saving of €184,928 versus standard diagnosis (€15,671,493 vs €15,856,421). When compared one-step diagnosis to standard diagnosis, the savings per patient with positive viral load referred to specialist would be €3,634 (€11,279 vs €14,923).

Conclusion: The one-step diagnosis will achieve an increase in diagnosed patients, will increase the access of chronic patient to treatment and will generate cost savings, demonstrating its efficiency in the system in Andalusia.
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http://dx.doi.org/10.1016/j.eimc.2019.03.001DOI Listing
December 2019

Increasing importance of European lineages in seeding the hepatitis C virus subtype 1a epidemic in Spain.

Euro Surveill 2019 Feb;24(9)

KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Clinical and Epidemiological Virology, Leuven, Belgium.

BackgroundReducing the burden of the hepatitis C virus (HCV) requires large-scale deployment of intervention programmes, which can be informed by the dynamic pattern of HCV spread. In Spain, ongoing transmission of HCV is mostly fuelled by people who inject drugs (PWID) infected with subtype 1a (HCV1a).AimOur aim was to map how infections spread within and between populations, which could help formulate more effective intervention programmes to halt the HCV1a epidemic in Spain.MethodsEpidemiological links between HCV1a viruses from a convenience sample of 283 patients in Spain, mostly PWID, collected between 2014 and 2016, and 1,317, 1,291 and 1,009 samples collected abroad between 1989 and 2016 were reconstructed using sequences covering the NS3, NS5A and NS5B genes. To efficiently do so, fast maximum likelihood-based tree estimation was coupled to a flexible Bayesian discrete phylogeographic inference method.ResultsThe transmission network structure of the Spanish HCV1a epidemic was shaped by continuous seeding of HCV1a into Spain, almost exclusively from North America and European countries. The latter became increasingly relevant and have dominated in recent times. Export from Spain to other countries in Europe was also strongly supported, although Spain was a net sink for European HCV1a lineages. Spatial reconstructions showed that the epidemic in Spain is diffuse, without large, dominant within-country networks.ConclusionTo boost the effectiveness of local intervention efforts, concerted supra-national strategies to control HCV1a transmission are needed, with a strong focus on the most important drivers of ongoing transmission, i.e. PWID and other high-risk populations.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.9.1800227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402173PMC
February 2019

Impact of comorbidities on patient outcomes after interferon-free therapy-induced viral eradication in hepatitis C.

J Hepatol 2018 05 28;68(5):940-948. Epub 2017 Dec 28.

Unit of Digestive Diseases, Virgen del Rocio University Hospital, Sevilla, Spain; Institute of Biomedicine of Seville and University of Sevilla, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jhep.2017.12.019DOI Listing
May 2018

Tenofovir lamivudine plus adefovir in chronic hepatitis B: TENOSIMP-B study.

World J Gastroenterol 2017 11;23(41):7459-7469

Division of Gastroenterology and Hepatology, Complejo Asistencial Universitario de León, León 24001, Spain CIBERehd and IBIOMED León.

Aim: To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) 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 24.22 ± 8.38, LAM+ADV, = 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 37.5%, LAM+ADV, = 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 ( = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 €5811 ± 1538, respectively, < 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.
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http://dx.doi.org/10.3748/wjg.v23.i41.7459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685852PMC
November 2017

Reply to: "Extended DAA indications for hepatitis C patients awaiting liver transplantation and further statistical considerations".

J Hepatol 2018 03 14;68(3):627-628. Epub 2017 Nov 14.

UGC Digestive Diseases, Hospital Universitario Virgen del Rocío, IBIS, CIBERehd, Sevilla, Spain.

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http://dx.doi.org/10.1016/j.jhep.2017.10.009DOI Listing
March 2018

Hepatopulmonary syndrome: which blood gas analysis criteria and position should we use for diagnosis?

Rev Esp Enferm Dig 2017 Dec;109(12):843-849

Medicina Interna, Hospital Virgen de Valme.

Introduction: Different blood gas criteria have been used in the diagnosis of hepatopulmonary syndrome (HPS).

Patients And Methods: Arterial blood gases were prospectively evaluated in 194 cirrhotic candidates for liver transplantation (LT) in the supine and seated position. Three blood gas criteria were analyzed: classic (partial pressure of oxygen [PaO2] < 70 mmHg and/or alveolar-arterial gradient of oxygen [A-a PO2] ≥ 20 mmHg), modern (A-a PO2 ≥ 15 mmHg or ≥ 20 mmHg in patients over 64) and the A-a PO2 ≥ threshold value adjusted for age.

Results: The prevalence of HPS in the supine and seated position was 27.8% and 23.2% (classic), 34% and 25.3% (modern) and 22.2% and 19% (adjusted for age), respectively. The proportion of severe and very severe cases increased in a seated position (11/49 [22.4%] vs 5/66 [7.6%], p = 0.02). No difference was observed in the pre-LT, post-LT and overall mortality in patients with HPS, regardless of the criteria used.

Conclusion: Obtaining blood gas measurements in the supine position and the use of modern criteria are more sensitive for the diagnosis of HPS. Blood gas analysis with the patient seated detects a greater number of severe and very severe cases. The presence of HPS was not associated with an increase in mortality regardless of blood gas criterion used.
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http://dx.doi.org/10.17235/reed.2017.4930/2017DOI Listing
December 2017

Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation.

J Hepatol 2017 12 24;67(6):1168-1176. Epub 2017 Aug 24.

Liver Unit, Hospital Clinic, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address:

Background & Aims: Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients.

Methods: Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain.

Results: In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT.

Conclusions: Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need.

Lay Summary: Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.
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http://dx.doi.org/10.1016/j.jhep.2017.08.008DOI Listing
December 2017

Efficacy and safety of daclatasvir-based antiviral therapy in hepatitis C virus recurrence after liver transplantation. Role of cirrhosis and genotype 3. A multicenter cohort study.

Transpl Int 2017 Oct 27;30(10):1041-1050. Epub 2017 Jul 27.

Liver Transplant Unit and Digestive Disease Department, Facultad de Medicina Universidad Complutense, IISGM, CIBERehd, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Direct-acting antiviral agents (DAA) combining daclatasvir (DCV) have reported good outcomes in the recurrence of hepatitis C virus (HCV) infection after liver transplant (LT). However, its effect on the severe recurrence and the risk of death remains controversial. We evaluated the efficacy, predictors of survival, and safety of DAC-based regimens in a large real-world cohort. A total of 331 patients received DCV-based therapy. Duration of therapy and ribavirin use were at the investigator's discretion. The primary end point was sustained virological response (SVR) at week 12. A multivariate analysis of predictive factors of mortality was performed. Intention-to-treat (ITT) and per-protocol SVR were 93.05% and 96.9%. ITT-SVR was lower in cirrhosis (n = 163) (96.4% vs. 89.6% P = 0.017); the SVR in genotype 3 (n = 91) was similar, even in advanced fibrosis (96.7% vs. 88%, P = 0.2). Ten patients (3%) experienced virological failure. Therapy was stopped in 18 patients (5.44%), and ten died during treatment. A total of 22 patients (6.6%) died. Albumin (HR = 0.376; 95% CI 0.155-0.910) and baseline MELD (HR = 1.137; 95% CI: 1.061-1.218) were predictors of death. DCV-based DAA treatment is efficacious and safe in patients with HCV infection after LT. Baseline MELD score and serum albumin are predictors of survival irrespective of viral response.
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http://dx.doi.org/10.1111/tri.12999DOI Listing
October 2017

The utility of the macro-aggregated albumin lung perfusion scan in the diagnosis and prognosis of hepatopulmonary syndrome in cirrhotic patients candidates for liver transplantation.

Rev Esp Enferm Dig 2017 May;109(5):335-343

Medicina Interna, Hospital Virgen de Valme.

Background: The macro-aggregated albumin lung perfusion scan (99mTc-MAA) is a diagnostic method for hepatopulmonary syndrome (HPS).

Goal: To determine the sensitivity of 99mTc-MAA in diagnosing HPS, to establish the utility of 99mTc-MAA in determining the influence of HPS on hypoxemia in patients with concomitant pulmonary disease and to determine the correlation between 99mTc-MAA values and other respiratory parameters.

Methods: Data from 115 cirrhotic patients who were eligible for liver transplantation (LT) were prospectively analyzed. A transthoracic contrast echocardiography and 99mTc-MAA were performed in 85 patients, and 74 patients were diagnosed with HPS.

Results: The overall sensitivity of 99mTc-MAA for the diagnosis of HPS was 18.9% (14/74) in all of the HPS cases and 66.7% (4/6) in the severe to very severe cases. In HPS patients who did not have lung disease, the degree of brain uptake of 99mTc-MAA was correlated with the alveolar-arterial oxygen gradient (A-a PO2) (r = 0.32, p < 0.05) and estimated oxygen shunt (r = 0.41, p < 0.05) and inversely correlated with partial pressure of arterial oxygen (PaO2) while breathing 100% O2 (r = -0.43, p < 0.05). The 99mTc-MAA was positive in 20.6% (7/36) of the patients with HPS and lung disease. The brain uptake of 99mTc-MAA was not associated with mortality and normalized in all cases six months after LT.

Conclusions: The 99mTc-MAA is a low sensitivity test for the diagnosis of HPS that can be useful in patients who have concomitant lung disease and in severe to very severe cases of HPS. It was not related to mortality, and brain uptake normalized after LT.
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http://dx.doi.org/10.17235/reed.2017.4219/2016DOI Listing
May 2017

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

Clin Gastroenterol Hepatol 2017 Jun 24;15(6):945-949.e1. Epub 2017 Feb 24.

Department of Gastroenterology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.

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.
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http://dx.doi.org/10.1016/j.cgh.2017.02.020DOI Listing
June 2017

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: Results from a Spanish real-world cohort.

J Hepatol 2017 06 9;66(6):1138-1148. Epub 2017 Feb 9.

Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain.

Background & Aims: Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice.

Methods: Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded.

Results: The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%.

Conclusions: In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles.

Lay Summary: In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.
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http://dx.doi.org/10.1016/j.jhep.2017.01.028DOI Listing
June 2017

Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of model for end-stage liver disease: Analysis of data from the Hepa-C registry.

Hepatology 2017 06 28;65(6):1810-1822. Epub 2017 Apr 28.

Liver Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Universidad Autónoma de Madrid and CIBERehd, Madrid, Spain.

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).
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http://dx.doi.org/10.1002/hep.29097DOI Listing
June 2017

The effectiveness of daclatasvir based therapy in European patients with chronic hepatitis C and advanced liver disease.

BMC Infect Dis 2017 01 7;17(1):45. Epub 2017 Jan 7.

Liver Unit, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Madrid, Spain.

Background: There is limited evidence for the effectiveness of daclatasvir in patients whose hepatitis C threatens their life expectancy. The Named Patient Program in Europe included patients with advanced chronic hepatitis C, a life expectancy of less than 12 months and no other treatment options.

Methods: A retrospective multi-country cohort of patients with chronic hepatitis C who received daclatasvir as part of the Named Patient Program in Austria, Denmark, Spain, Sweden, Switzerland and the United Kingdom. Treatment response was defined as a sustained virologic response (unquantifiable hepatitis C RNA) at 12 weeks post treatment. We summarised the characteristics of the patients in this cohort and estimated the rate of sustained virologic response for patients receiving daclatasvir and sofosbuvir with or without ribavirin using hierarchical Bayesian modelling.

Results: The 249 patients included had a median age of 56 years; most were male (78%), hepatitis C genotype 1 (75%), treatment experienced (65%) and with decompensated cirrhosis (59%). Many had had a liver transplant before receiving daclatasvir (40%). Of the 249 patients, 242 patients received daclatasvir and sofosbuvir and either reached 12 weeks post treatment or died during (n = 9) or after treatment (n = 4) or were lost to follow up during treatment (n = 1). The estimated rate of sustained virologic response at 12 weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis.

Conclusions: Daclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis.
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http://dx.doi.org/10.1186/s12879-016-2106-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5219681PMC
January 2017

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

World J Gastroenterol 2015 Aug;21(30):9163-74

Javier Salmerón, Carmen Vinaixa, Juan Manuel Pascasio, Manuel Romero-Gómez, José Antonio Pons, Francisco Jorquera, Ana Gila, Paloma Muñoz de Rueda, Rosa Quiles, CIBERehd, Instituto de Salud Carlos III, 28029 Madrid, Spain.

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.
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http://dx.doi.org/10.3748/wjg.v21.i30.9163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533049PMC
August 2015

High efficacy and safety of triple therapy in HCV genotype 1 and moderate fibrosis: a multicenter study of clinical practice in Spain.

Ann Hepatol 2015 Jul-Aug;14(4):477-86

Hospital Universitario de Canarias. Tenerife. Spain.

Background And Rational: Telaprevir-based therapy (TBT) has been extensively evaluated in clinical trials. So we designed a study to compare the efficacy and safety of TBT between patients with moderate fibrosis and those suffering from advanced fibrosis in clinical practice. A multicenter observational and ambispective study was conducted. It included 582 patients with chronic hepatitis C genotype 1, 214 with fibrosis F2, and 368 with F3/F4 (F3: 148; F4: 220).

Results: The mean patient age was 55 years, 67% male. Type of prior response was 22% naïve, 57% relapsers, and 21% partial/null responders, 69% had high viral load (> 800,000 IU/mL). HCV genotypes were 1a (19%), 1b (69%), and 1 (12%), respectively. Sixty-five percent were non-CC IL28B genotype. Week-12 sustained virologic response (SVR12) was significantly higher among F2-naïve patients (78%) compared with F3/F4-naïve patients (60%; p = 0.039) and among F2 non-responders (67%) compared with F3/F4 non-responders (42%; p = 0.014). SVR12 among relapsers was remarkably high in both groups (F2:89% vs. F3/F4:78%). Severe anemia and thrombocytopenia were more frequent among patients with F3/F4 than those with F2 (p < 0.01). Overall, 132 patients (22%) discontinued treatment: 58 due to adverse effects, 42 due to the stopping-rule, and 32 due to breakthrough. Premature discontinuation was more frequent among patients with F3/F4 (p = 0.028), especially due to breakthrough (p < 0.001).

Conclusions: This multicenter study demonstrates high efficacy and an acceptable safety profile with regard to TBT in F2-patients in clinical practice.
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February 2016

Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation.

Liver Int 2012 May 4;32(5):712-31. Epub 2012 Jan 4.

Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH)

In November 2010, the Spanish Society of Liver Transplantation (Sociedad Española de Trasplante Hepático, SETH) held a consensus conference. One of the topics of debate was liver transplantation in patients with hepatitis C. This document reviews (i) the natural history of post-transplant hepatitis C, (ii) factors associated with post-transplant prognosis in patients with hepatitis C, (iii) the role of immunosuppression in the evolution of recurrent hepatitis C and response to antiviral therapy, (iv) antiviral therapy, both before and after transplantation, (v) follow-up of patients with recurrent hepatitis C and (vi) the role of retransplantation.
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http://dx.doi.org/10.1111/j.1478-3231.2011.02731.xDOI Listing
May 2012

[Treatment approach of hepatocellular carcinoma in Spain. Analysis of 705 patients from 62 centers].

Med Clin (Barc) 2010 May 29;134(13):569-76. Epub 2009 Dec 29.

Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias, Oviedo, España.

Background And Objective: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis and its current situation in Spain is not well known. Therefore, a national registry was created to assess the characteristics of patients with de novo HCC.

Patients And Method: Between 1/10/2008 and 31/1/2009, 62 centers reported the baseline demographic, clinical and tumor characteristics, the first choice of treatment and eligibility for transplantation (OLT) of HCC diagnosed during this time.

Results: There were 705 new cases of HCC, 78% men, mean age 65 years, 89% cirrhosis (58% Child-Pugh class A, 42% HCV, 30% alcohol). Only 334 cases (47%) were diagnosed by screening. The size of the main nodule and BCLC stage were significantly lower in the screening group than in the rest (p<0.001). The applicability of radical therapies (resection and percutaneous ablation) was significantly higher (47.5% versus 24.6%, p<0.001) as well as the evaluation for OLT (31% versus 12%, p<0.001). The screening did not differ according to gender (p=0.204) or age (<50 years, <65, <75, >75 years) (p=0.171). Chemoembolization was the most common treatment: initial tumors (46.4%), tumors >5 cm (15.7%), multifocal HCC (37.9%) and as a bridge to OLT (33%).

Conclusion: The majority of HCC patients are diagnosed in Spain out of early detection programs, and this limits the chance for early diagnosis and effective therapy.
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http://dx.doi.org/10.1016/j.medcli.2009.10.042DOI Listing
May 2010

[Blood coagulation factor levels in candidates for liver transplantation: correlation with disease severity].

Gastroenterol Hepatol 2009 Aug-Sep;32(7):465-71

Hospital Universitario Virgen del Rocío, Sección de Hepatología, Sevilla, España.

Objective: To correlate blood coagulation factor levels with disease severity in cirrhotic patients evaluated as candidates for liver transplantation.

Material And Method: We included 87 patients (75.9% men) with a mean age of 54+/-9.4 years. Etiology and Child-Turcotte-Pugh (CTP) class were as follows: alcohol-related (36.8%), hepatitis C virus infection (35.6%), hepatitis B virus infection (11.5%) and other (16.1%); class A (13.8%), class B (40.2%) and class C (46%), respectively. The mean value of the Model for End-Stage Liver Disease (MELD) score was 14.5+/-5.9. Levels of factors II, V, VII, VIII, IX and X were compared between each CTP grade and with the MELD score.

Results: Except for factor VIII, all the clotting factors were reduced in our series (in particular factors II, V and VII) and deficiencies in these factors were closely related to CTP grade with statistical significance for stage C (p <0.05). We also found a marked inverse correlation between the MELD score and factors II, V, VII, IX and X values (p <0.05).

Conclusions: A correlation was found between reduced levels of factors II, V, VII, IX and X in liver cirrhosis and the severity of liver disease.
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http://dx.doi.org/10.1016/j.gastrohep.2009.02.016DOI Listing
January 2010

[Descriptive study of infectious complications in 109 consecutive liver transplant recipients].

Enferm Infecc Microbiol Clin 2009 Apr 9;27(4):199-205. Epub 2009 Apr 9.

Servicio de Enfermedades Infecciosas, Hospital Universitario Virgen del Rocío, Sevilla, España.

Introduction: Infectious disease is a common, serious complication in liver transplant recipients. The etiology of these infections undergoes changes related with technical advances, prophylaxis, and local epidemiology.

Methods: Prospective study in patients who underwent liver transplantation from July 2003 to December 2005 at the Hospital Universitario Virgen del Rocío. An observational description of infections occurring during the first 2 years following transplantation was carried out.

Results: The incidence of infection was 1.32 episodes per patient over follow-up (443 +/- 248 days). The most frequent infections were surgical site (16%), cytomegalovirus (CMV) (14%), and urinary tract (11%). Etiologies included bacterial (64%), viral (31%), and fungal (5%) causes. The most common pathogens were CMV (21%), Escherichia coli (20%), among which, 40% were extended-spectrum beta-lactamase ESBL-producers, and Enterococcus spp. (11%). More than half the infectious episodes (58%) occurred in the first 4 months after transplantation. The 30-day mortality rate was 18%. In the group with infection, patient and graft survivals were 75% and 73% at the end of follow-up, and in the group without infection, survival was 80% in both cases (P=NS).

Conclusions: The most common infectious syndromes following liver transplantation were surgical site infection, CMV infection, and urinary tract infection. Bacteria were the most commonly isolated microorganisms, and there was a high rate of ESBL-producing E. coli.
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http://dx.doi.org/10.1016/j.eimc.2008.09.005DOI Listing
April 2009

[Hepatopulmonary syndrome in patients with advanced hepatic disease: study of a series of 24 cases].

Med Clin (Barc) 2008 Feb;130(3):98-102

Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Hospitales Universitarios Virgen del Rocío, Sevilla, España.

Background And Objective: To describe the characteristics observed in patients diagnosed of hepatopulmonary syndrome (HPS) waiting for orthotopic liver transplantation and those who underwent liver trasplantation.

Patients And Method: An observational prospective descriptive study was carried out of patients waiting for liver transplantation in whom data of liver illness and lung function tests were analyzed.

Results: 107 patients of 53.69 years average age were studied (7.7 standard deviation). 24 of them (22.4%) had criteria of HPS. Ortodeoxia was present in the 34% of cases. The lung function tests were normal. In the comparative study between patients with HPS and no HPS, differences in diffusion were found (7.1 vs. 8.6 mmol/min/kPa; p = 0.04), as well as in the shunt (8% vs. 5.3%; p = 0.05) and the forced expiratory volume in one second (2,390 vs. 2,743 ml; p = 0.03). Seven patients were transplanted with correction of oxygenation and vascular dilatations in all of them.

Conclusions: HPS is a frequent illness in patients waiting for orthotopic liver transplantation. The main alteration in the blood oxygenation seems owe to shunt, and the diffusion tests is the analysis that could best differentiate patients with HPS. Orthotopic liver transplantation corrects the syndrome in all cases.
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http://dx.doi.org/10.1157/13115351DOI Listing
February 2008

Model for end-stage liver disease score-based allocation of donors for liver transplantation: a spanish multicenter experience.

Transplantation 2006 Dec;82(11):1429-35

Liver Transplant Unit, Reina Sofía University Hospital, Córdoba, Spain. 2Andalusian Transplant Coordinating Office, Sevilla, Spain.

Background: Prioritizing the liver transplant waiting list (WL) is subject to great variability. We present the experience of four transplant centers in Andalusia (Southern Spain) with a new consensus model of WL management based on the Model for End-Stage Liver Disease (MELD) score.

Methods: The initial criteria for local prioritizing were: a) cirrhosis with MELD score > or =24, and b) all hepatocellular carcinoma (HCC) admitted to the WL. Fourteen months later new criteria were established: a) cirrhosis with MELD score > or =18, and b) uninodular HCC between 3-5 cm or multinodular HCC (2-3 nodules <3 cm). Access to regional priority was scheduled after three months for patients with cirrhosis or six months for patients with HCC. We analyzed the WL mortality rate, posttransplant survival rate, and overall survival rate over three 14-month periods: A (before implementation of priority criteria), B (initial criteria), and C (current criteria).

Results: Priority was given to 36% of recipients in period B and 47% in period C. The WL mortality rate (including removals from WL) was 12.9%, 12.9%, and 10.7% in periods A, B, and C, respectively. One-year graft survival was 79.7%, 72.6%, and 81.2% in the same periods. The overall one-year survival rate for new cases on the WL was 74.9% in period A, 68.6% in period B, and 82.2% in period C.

Conclusions: The allocation system and WL management with the current criteria resulted in lower waiting list mortality without reducing posttransplant survival, leading to better survival for all patients listed.
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http://dx.doi.org/10.1097/01.tp.0000244559.60989.5aDOI Listing
December 2006
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