J.M. Pascasio

Efficacy and tolerability of interferon-free antiviral therapy in kidney transplant recipients with chronic hepatitis C

BACKGROUND & AIMSnThe development of direct-acting antiviral agents (DAAs) is a major step forward in the treatment of hepatitis C (HCV). The aims of the study were to evaluate the efficacy and tolerability of DAAs in kidney transplant (KT) recipients.nnnMETHODSnHepa-C is a Spanish registry of patients treated with DAAs in which clinical, virological and analytical data were prospectively included. We report on the data from 103 KT recipients who received DAAs.nnnRESULTSnThe most commonly used DAAs combinations were sofosbuvir/ledipasvir (n=59, 57%) and sofosbuvir+daclatasvir (n=18, 17%). Ribavirin was used in 41% of patients. Sustained viral response after 12weeks (SVR12) rate was 98%. Grade 2 or 3 anemia appeared in 14 (33%) of patients receiving ribavirin and in 9 (15%) without (p=0.03). There were three episodes of acute humoral graft rejection. No patient discontinued therapy due to adverse events. Importantly, 57 (55%) patients required immunosuppression dose adjustment. Overall, there were no statistically significant differences in the mean level of serum creatinine, eGFR and proteinuria before and after treatment. Nonetheless, seventeen (16%) patients experienced renal dysfunction (increase in serum creatinine >25%) during antiviral therapy, of whom 65% were cirrhotic in comparison with only 29% cirrhotic patients who did not develop significant renal dysfunction (p=0.004).nnnCONCLUSIONSnAntiviral therapy with DAAs was highly efficacious and safe in KT recipients. Nevertheless, a non-negligible number of patients, most of them cirrhotic, developed mild allograft dysfunction and a significant proportion of patients required immunosuppression dose adjustment, warranting a close follow-up during therapy.nnnLAY SUMMARYnInfection by hepatitis C virus is often found in kidney transplant patients and its presence increases mortality and graft failure. We investigated the efficacy and safety of the new direct-acting hepatitis C antivirals in this population, in which previous information is scarce. Our data shows that, as occurs in the non-transplant setting, new anti-HCV antivirals are highly efficacious kidney transplant patients. Overall, this therapy is also quite safe, although worsening of renal function is observed in 16% of patients warranting a close follow-up observation of graft function during antiviral therapy.

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

AIMnTo 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.nnnMETHODSnProspective 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.nnnRESULTSnOne 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).nnnCONCLUSIONnIn 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.

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

BackgroundThere 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 12xa0months and no other treatment options.MethodsA 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 12xa0weeks 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.ResultsThe 249 patients included had a median age of 56xa0years; 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 12xa0weeks post treatment or died during (nu2009=u20099) or after treatment (nu2009=u20094) or were lost to follow up during treatment (nu2009=u20091). The estimated rate of sustained virologic response at 12xa0weeks post treatment was 87% (95% credible interval 75 to 94%) for previously treated genotype 1 patients with decompensated cirrhosis.ConclusionsDaclatasvir with sofosbuvir is an effective treatment in clinical practice for hepatitis C genotype 1 patients with decompensated cirrhosis.

Síndrome hepatopulmonar en pacientes con hepatopatía avanzada: estudio de 24 casos

Fundamento y Objetivo Describir las caracteristicas clinicas y funcionales de pacientes con sindrome hepatopulmonar (SHP) en lista de espera para trasplante ortotopico hepatico y los cambios producidos en ellas en un grupo de pacientes que recibio el trasplante. Pacientes y metodo Se ha realizado un estudio observacional, transversal y descriptivo con caracter prospectivo de pacientes en lista de espera para trasplante hepatico, en quienes se analizaron datos de enfermedad hepatica y de pruebas de funcion respiratoria. Resultados Se ha estudiado a 107 pacientes, con una edad media (desviacion estandar) de 53,69 (7,7) anos, de los que 24 (22,4%) cumplian criterios de SHP. La ortodesoxia estaba presente en el 34% de los pacientes. Las pruebas de funcion respiratoria estaban dentro de la normalidad. En el estudio comparativo entre los pacientes afectados de SHP y el resto se encontraron diferencias en la difusion de monoxido de carbono (7,1 frente a 8,6 mmol/min/kPa; pxa0=xa00,04), la cuantia del cortocircuito pulmonar (un 8 frente al 5,3%; pxa0=xa00,05) y el volumen espiratorio forzado en el primer segundo (2.390 frente a 2.743 ml; pxa0=xa00,03). En 7 pacientes con SHP que recibieron el trasplante se corrigieron la oxigenacion y las dilataciones vasculares. Conclusiones El SHP es una entidad frecuente en pacientes en espera de trasplante ortotopico hepatico. La principal alteracion en la oxigenacion sanguinea parece ser debida al efecto cortocircuito. Las pruebas de difusion de monoxido de carbono son las que parecen tener mayor caracter discriminativo entre los pacientes con y sin SHP. Tras el trasplante desaparece el sindrome en todos los pacientes.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.

Liver Transplantation for Hepatocellular Carcinoma: Results of a Multicenter Study With Common Priorization Criteria

OBJECTIVEnTo evaluate the results of liver transplantation (OLT) performed for hepatocellular carcinoma (HCC) among a multicenter cohort of patients with predefined common inclusion and priorization criteria.nnnPATIENTS AND METHODSnOver a 5-year period (January 2002-December 2006), 199 HCC patients underwent OLT in four centers in Andalusia. The morphological (Milan) inclusion criteria were priorized in two consecutive periods, according to the Model for End-stage Liver Disease score: group I, 53 patients (HCC < 2 cm = 24 points; > or = 2 cm or multinodular = 29 points) and group II, 146 cases (HCC < 3 cm without priorization; HCC > or = 3 cm or multinodular = 18 points).nnnRESULTSnAmong the 199 HCCs, 186 (93.5%) subjects were transplanted and 13 (6.5%) were excluded. There were 18 cases (9.7%) where the diagnosis was incidental and 168 were known HCC cases; 144 (85.7%) complied with the Milan criteria (Milan+); 24 (14.3%) exceeded there criteria (Milan-). According to preoperative imaging, the number of nodules and tumor mean sizes among the excluded-Milan+ and Milan- groups-were 1.8/5.3 cm, 1.4/3.5 cm, and 2.3/6.7 cm, respectively (P < .001). Percutaneous treatment during listing was delivered to 55% of the excluded cases: 49% of Milan+ and 96% of Milan-. The median time on the list was 88 days for known HCC (53 days for group I, and 97 days for group II), and 172 days for the incidental HCCs. Staging (pTNM) was correct in 64% of cases: 23% were understaged and 13% were overstaged. Overall mortality within the first 90 days was 9%, and transplant patient survival at 5 years was 61%. No differences were observed in survival rates between both study periods, although there were differences between the Milan+ (65%) and Milan- (23%) groups (P < .04). In addition, the difference in the recurrence rates was also significant between the Milan+ (7%), Milan- (24%), and the incidental (25%) groups (P < .02).nnnCONCLUSIONSnA common priorization policy of HCC for OLT based on morphological criteria results in a low exclusion rate on the waiting lists (6.5%). The Milan criteria are still a good cutoff to stratify the risk of recurrence, despite preoperative tumor staging being correct in only two-thirds of cases.

P1200 EFFECTIVENESS OF TRIPLE THERAPY WITH BOCEPREVIR OR TELAPREVIR IN A MULTICENTRE CLINICAL PRACTICE COHORT OF HCV TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED HEPATIC FIBROSIS. SVR-12W AFTER TREATMENT

P1200 EFFECTIVENESS OF TRIPLE THERAPY WITH BOCEPREVIR OR TELAPREVIR IN A MULTICENTRE CLINICAL PRACTICE COHORT OF HCV TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED HEPATIC FIBROSIS. SVR-12W AFTER TREATMENT C. Fernandez, P. Munoz de Rueda, S. Alonso, M. Prieto, A. Martin-Alvarez, J. Pons, J. Pascasio, M. Serra, M. Romero, P. Conde, I. Carmona, M. Diago, M. Testillano, J. NavarroJarabo, J. Sanchez Ruano, J. Sousa, F. Nogueras, R. Granados, G. Sanchez Antolin, R. Andrade, H. Hallal, M. Marti Arribas, M. del Moral, J. Salmeron. Servicio de Aparato Digestivo, HU Fundacion de Alcorcon, Madrid, Unidad de Apoyo a la Investigacion, HU San Cecilio, Ciber de Enfermedades Hepaticas y Digestivas (CIBERehd), Granada, Unidad de Gestion Cĺinica de Enfermedades Digestivas, H La Fe, Valencia, Unidad de Hepatoloǵia, H Virgen de Arrixaca, Murcia, Unidad de Hepatoloǵia, H Virgen del Rocio, Sevilla, H Cĺinico de Valencia, Valencia, H Nuestra Senora de Valme, CIBERehd, Sevilla, H Virgen de la Concha, Zamora, Servicio de Aparato Digestivo, HU Virgen de la Macarena, Sevilla, H General de Valencia, Valencia, HU de CRUCES, Bilbao, Vizcaya, Unidad de Aparato Digestivo, Agencia Sanitaria Costa del Sol, Marbella, Malaga, Servicio de Aparato Digestivo, Complejo Hospitalario de Toledo, Toledo, Servicio de Digestivo, HU Virgen de las Nieves, Granada, HU Gran Canaria Dr. Negŕin, Las Palmas de Gran Canaria, Unidad de Hepatologia, HU Ŕio Hortega, Valladolid, HU Virgen de la Victoria, Malaga, H Morales Meseguer, Murcia, HU Salamanca, Salamanca, Unidad de Gestion Cĺinica de Aparato Digestivo, HU San Cecilio, Ciber de Enfermedades Hepaticas y Digestivas (Ciberehd), Granada, Spain E-mail: fsalmero@ugr.es

Effectiveness of ribavirin use associated with direct-acting antivirals in the treatment of non-cirrhotic patients with genotype 1a or 4 HCV infection in real-world practice

effectiveness. Methods: Retrospective, multicentric national study that included patients treated according to clinical practice in Spain. Data were collected from the HEPA-C National Registry (AEEH-CIBERehd). The study evaluated data from patients with genotype 1 or 4 treated in 41 Spanish centers, from1April to 30October 2016. Theprimaryendpoint for effectiveness was sustained viral response at week 12 (SVR12). Results: A total of 3,412 patients were included in the study, 56.4% males, mean age of 58 years, most of the genotype 1b (68.8%) (genotype 1a:22%; genotype 4:7%). Patient distribution according to the degree of fibrosis: F4 (52%), F3 (18%), F2 (19%) and F0–1 (9%). 27.2% of patients received LDV/SOF, 27.4% LDV/SOF + RBV, 24.8% OBV/ PTV/rtv/DSV + RBV, 17.5% OBV/PTV/rtv/DSV and 2.6% OBV/PTV + RBV. 54.8% received RBV. Regarding treatment duration, 82.9% of patients received 12 weeks of treatment, 14.3% 24 weeks and 2.8% 8 weeks. 72.4% were treated according to the SmPC. The most frequent reason for lack of adherence to the SmPC was the addition of RBV (84% of prescriptions were non-concordant), followed by not adding RBV when it was recommended (6.9%), prolonged treatment duration (4.5%) and shortened treatment duration (2.5%). SVR12 in patients treated according to SmPC was 96.1%, while in patients with nonconcordant prescriptions was 96.7% (p = 0.44). In patients with shortened treatment duration, SVR12 was significantly lower than in the rest of patients (82.6% vs. 97%, p < 0.05). Conclusions: 72.4% of patients received treatment according to the SmPC. Themajority of deviations were due to RBV use. Therewere no statistically significant differences in SVR between patients treated according to the SmPC and those receiving non-concordant prescriptions. However, there was an impact in SVR for patients who were treated for less time than recommended.

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

BACKGROUND & AIMSnPatients 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.nnnMETHODSnThis 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.nnnRESULTSnA 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; pu202f=u202f0.0001), bilirubin (HR 1.39; 95% CI 1.11-1.75; pu202f=u202f0.004), age (HR 1.06 95% CI 1.02-1.11; pu202f=u202f0.005), international normalized ratio (HR 3.49; 95% CI 1.36-8.97; pu202f=u202f0.010), and albumin (HR 0.18; 95% CI 0.09-0.37; pu202f=u202f0.0001). 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.nnnCONCLUSIONSnThe 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.nnnLAY SUMMARYnThe 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.

Efficacy and Safety of Therapy With Simeprevir and Sofosbuvir in Liver Transplant Recipients Infected by Hepatitis C Virus Genotype 4: Cohort Spanish Society of Liver Transplantation Cohort

BACKGROUNDnPatients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of 2nd-generation direct-acting antivirals (DAAs), and more data are needed to help guide treatment decisions. We still have even fewer data concerning liver transplant patients. Simeprevir (SIM) and sofosbuvir (SOF) combination is useful to treat this genotype. The aim of this study was to know the efficacy and safety of the combination SIMxa0+ SOF ± ribavirin (RBV) in a group of liver transplant patients with HCV genotype 4 infection in Spain in real life.nnnMETHODSnThis was a multicenter retrospective study, including 28 HCV genotype 4 patients from 11 liver transplant centers who were treated with SIMxa0+ SOF ± RBV. We included in the analysis demographic, clinical, and virologic data and details of serious adverse events (SAEs), including mortality rate 6 months after treatment.nnnRESULTSnAll patients were male, mean age 52 ± 9.43 years, and 50% were IL28B CT and 37.5% TT; 46.42% of them were pretreated and 76.9 were null responders. Fibrosis stage 4 was found in 38.7% of patients; in 67.8% of those cases the diagnosis of fibrosis was made with the use of Fibroscan, in 21.4% by liver biopsy. The average Fibroscan was 13.86 KPa. The average Model for End-Stage Liver Disease (MELD) score of cirrhotic patients was 10.9 and the Child-Pugh score was A in 70%, B in 20%, and C in 10%. We included RBV in 75% of patients, and treatment duration was 12 weeks in all patients. The sustained virologic response at week 12 (SVR12) was 95.23%. There were no discontinuations due to SAEs, but the mortality rate at 6 months after treatment was 7.14%. All deceased patients were cirrhotic, Child C, and with an average MELD score ofxa020.nnnCONCLUSIONSnThe combination SIMxa0+ SOF ± RBV to treat HCV genotype 4 in liver transplant patients is an option with high rates of SVR12 and very safe, similarly to genotype 1. There was no treatment-related mortality, but when it is administered in advanced stages of fibrosis it may not be enough to prevent mortality associated with cirrhotic hepatitis Cxa0recurrence after transplantation.

24 HIGHER SUSTAINED VIROLOGIC RESPONSE AND HISTOLOGIC IMPROVEMENT IN RECURRENT HEPATITIS C AFTER PEGYLATED INTERFERON PLUS RIBAVIRIN THERAPY UNDER CYCLOSPORINE-BASED VERSUS TACROLIMUS-BASED IMMUNOSUPPRESSIVE THERAPY

24 HIGHER SUSTAINED VIROLOGIC RESPONSE AND HISTOLOGIC IMPROVEMENT IN RECURRENT HEPATITIS C AFTER PEGYLATED INTERFERON PLUS RIBAVIRIN THERAPY UNDER CYCLOSPORINE-BASED VERSUS TACROLIMUS-BASED IMMUNOSUPPRESSIVE THERAPY M. Navasa, T. Casanovas, M. Berenguer, I. Fernandez, M. Salcedo, L. Castells, J. Pascasio, J. Fernandez, I. Herrero, A. Otero, S. Tome, M. de la Mata, R. Barcena, I. Banos, M. Guilera, on behalf of ReViS-TC Study Group. Hospital Clinic i Provincial, Barcelona, Hospital de Bellvitge, L’Hospitalet de Llobregat, Hospital La Fe, Valencia, Hospital 12 de Octubre, Hospital Gregorio Maranon, Madrid, Hospital Vall d’Hebron, Barcelona, Hospital Virgen del Rocio, Sevilla, Hospital de Cruces, Bilbao, Cĺinica Universitaria Navarra, Pamplona, Hospital Juan Canalejo, A Coruna, Hospital Santiago, Santiago de Compostela, Hospital Reina Sofia, Cordoba, Hospital Ramon y Cajal, Hospital Puerta Hierro, Madrid, Novartis Farmaceutica, S.A., Barcelona, Spain E-mail: teresacasanovas@bellvitgehospital.cat