‘Real-life’ experience with direct-acting antiviral agents for HCV after kidney transplant

Introductions and Objectives: The introduction of direct-acting antiviral (DAA) agents promises to change dramatically the management of hepatitis C in kidney transplant recipients, a patient group where the treatment of hepatitis C is historically challenging. The purpose of the current study was to assess (in a ‘real-life’ setting) the safety and efficacy of all-oral, interferon-free, direct-acting antiviral agents in kidney transplant recipients with HCV. Material and Methods: We performed a single-arm, multi-center study in a cohort (n = 95) of kidney transplant recipients who underwent antiviral therapy with DAAs. The primary end-point was sustained virologic response (SVR) (serum HCV RNA < 15 IU/mL, 12 weeks after treatment ended; SVR12). We recorded data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. Results: Various regimens were adopted at the discretion of the treating physician: elbasvir/grazoprevir (n = 11), paritaprevir/ritonavir/ombitasvir/dasabuvir (PrOD) regimens ± ribavirin (n = 23), and sofosbuvirbased regimens ± ribavirin (n = 61). The SVR12 rate was 93.7% (89/95) (95% CI, 88%; 98%), according to intention-to-treat analysis; three patients without viral response (n = 3) were found. Ribavirin was administered in 8 (8.4%) allograft recipients. The frequency of drop-outs was 4.2% (4/95) (95% CI, 0.2%; 8.2%); these were related to arthralgia/myalgia (n = 2), fatigue (n = 1), and lowered estimated glomerular filtration rate (eGFR) (n = 1). There were no differences with regard to serum creatinine and eGFR before and after antiviral therapy and during follow-up in the whole cohort. The patient who interrupted antiviral treatment due to raised serum creatinine was on sofosbuvir/daclatasvir regimen; one of the four dropouts obtained SVR. Conclusions: All-oral, interferon-free therapy with DAAs for chronic HCV after kidney transplantation was effective and well-tolerated in a ‘real–life’ clinical setting. Identical results have been observed in patients with intact kidneys or advanced chronic kidney disease. Careful evaluation of kidney function over follow-up in kidney transplant recipients who received DAAs regimens is recommended. Clinical trials aimed to assess whether sustained viral response translates into improved patient/graft survival are under way

Serious liver injury induced by Nimesulide: an international collaboration study reporting 57 cases

Nimesulide is a non-steroidal anti-inflammatory drug still marketed in many countries. We aim to analyze the clinical phenotype, outcome, and histological features of nimesulide-induced liver injury (nimesulide-DILI). We analyzed 57 cases recruited from the Spanish and LATIN DILI registries. Causality was assessed by the RUCAM scale. Mean age of the whole case series was 59 years (86% women) with a median time to onset of 40 days. A total of 46 patients (81%) were jaundiced. Nimesulide-DILI pattern was hepatocellular in 38 (67%), mixed in 12 (21%), and cholestatic in 7 (12%) cases. Transaminases were elevated with a mean of nearly 20-fold the upper limit of normality (ULN), while alkaline phosphatase showed a 2-fold mean elevation above ULN. Total bilirubin showed a mean elevation of 13-fold the ULN. Liver histology was obtained in 14 cases (25%), most of them with a hepatocellular pattern. Median time to recovery was 60 days. Overall, 12 patients (21%) developed acute liver failure (ALF), five (8.8%) died, three underwent liver transplantation (5.3%), and the remaining four resolved. Latency was ≤15 days in 12 patients (21%) and one patient developed ALF within seven days from treatment initiation. Increased total bilirubin and aspartate transaminase levels were independently associated with the development of ALF. In summary, nimesulide-DILI affects mainly women and presents typically with a hepatocellular pattern. It is associated with ALF and death in a high proportion of patients. Shorter (≤15 days) duration of therapy does not prevent serious nimesulide hepatotoxicity, making its risk/benefit ratio clearly unfavorable.The present study has been supported by grants of Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional - FEDER (contract numbers: PI18-00901; PI 18/01804; PT20/00127) and Agencia Española del Medicamento. Plataforma ISCiii de Investigación Clínica and CIBERehd are funded by ISCIII. MRD holds a Joan Rodes (JR16/00015)/Acción B clinicos investigadores (B-0002-2019) research contract from ISCIII and Consejería de Salud de Andalucía, IAA holds a Sara Borrell research contract from the National Health System, ISCIII (CD 20/00083)

Efficacy, tolerability and safety in the treatment of chronic hepatitis C with combination of PEG-Interferon – Ribavirin in daily practice

Background. Efficacy and safety of Pegylated Interferon alfa (PegIFN)-Ribavirin (RBV) for the treatment of chronic hepatitis C (CHC) in routine clinical practice seems to be comparable with results of randomizedcontrolled trials.Aims. To evaluate the efficacy, tolerability and safety of CHC treatment with PegIFN + RBV in “real world” patients in Argentina and to analyze factors associated with SVR.Methods. Medical records of patients treated according to current guidelines from 2001 to 2008 were reviewed.Results. 235 patients were included and 80.8% completed treatment. Discontinuation occurred in 7.6% due to adverse events (AE), and 1.2% dropped-out treatment. Overall SVR was 60.8%. Multivariate analysis demonstrated that being naive (p 0.031) and low basal viral load (p 0.006) were associated with SVR, whereas F3-F4 (p 0.001) and elevated ALT (p 0.023) were associated with non-response. 80% of planned doses completed was associated with 74% SVR (p <0.001). At least one AE was reported in 93.6% of the patients: neutropenia in 27.6%, thrombocytopenia in 15.3%, anemia in 38.7%, psychiatric symptoms in 63.4%, thyroid dysfunction in 10.2%.Conclusion. Efficacy, tolerability and safety of treatment of CHC in daily practice in Argentina are similar to those reported in randomized controlled trials

Natural history of hepatitis C virus infection in a cohort of asymptomatic post-transfused subjects

Background &amp; aims. Studies about the natural history of hepatitis C virus (HCV) infection report variable progression to cirrhosis depending on study design. Retrospective cross-sectional liver clinic studies overestimate the rate of fibrosis progression due to inclusion of patients with more severe disease leaving mild and asymptomatic patients underrepresented. We evaluated fibrosis progression in a group of “healthy” asymptomatic subjects, attending to a voluntary campaign for the detection of HCV infection.Material and methods. A detection campaign was launched on subjects transfused before 1993. Of 1699 volunteers, 61(3.6%) had HCV infection. A liver biopsy was performed in 40 (65%). Assessed risk factors for liver fibrosis were: sex, body mass index, alcohol consumption (> 20 g/d♀ - >40g/d♂), genotype, HLA-DRB1 alleles, present age, age at infection and duration of infection.Results. 25 (62.5%) were women with a median age of 52.5 years. The median duration of infection was 21.5 years with a median age at infection of 27 years. As regards fibrosis, 25 (62.5%) had a Low Stage (F0-F1), 8 patients, 20%, had severe fibrosis, one patient (2.5%) had cirrhosis. Alcohol consumption was the only risk factor associated with fibrosis progression.Conclusions. The low progression to cirrhosis may be explained by the clinical characteristics of ourpopulation: asymptomatic middle-aged “healthy” subjects infected at young age. The progression to severe fibrosis was noticeable; hence a longer follow-up might demonstrate changes in this outcome. Significant alcohol consumption clearly worsens the natural history of HCV infection; this is no so evident for occasional or mild alcohol consumers

Nitrofurantoin-induced liver injury: long-term follow-up in two prospective DILI registries

Nitrofurantoin is a synthetic antibiotic that is recommended as first-choice treatment for uncomplicated urinary tract infections. The prescription of this drug has increased dramatically, especially in Latin American countries. We described the demographics, clinical characteristics, biochemical features, and outcome of nitrofurantoin-induced liver injury. We analyzed 23 cases from the Latin American DILI Network (LATINDILI) and the Spanish DILI Registry. Causality was assessed with the RUCAM and RECAM scale. Of the 23 DILI cases included in our series, 96% patients were women, and the mean age of the whole cohort was 61 years. The median time of drug exposure was 175 days (interquartile range [IQR] 96–760), with 11 patients who were prescribed nitrofurantoin for more than six months. Hepatocellular damage was the most frequent pattern of liver injury (83%), and nearly half of the patients had an asymptomatic presentation (52%). Neither death nor liver transplantation was documented in this series. Overall, 65% of the patients (n = 15) presented with positive autoantibody titres. The median time to resolution was 81 days (IQR 57–141), and 15 patients (83%) recovered within six months. Five patients (22%) developed nitrofurantoin-induced autoimmune-like hepatitis (NI-AILH), of whom two were characterized by a persistent increase in transaminases that required immunosuppressive treatment to achieve normalization of liver enzymes. Clinicians who prescribe nitrofurantoin should be aware that patients who had taken nitrofurantoin for a long term may be at risk of developing nitrofurantoin-induced autoimmune-like hepatitis.Fil: Bessone, Fernando. Hospital Provincial del Centenario; ArgentinaFil: Ferrari, Antonella. Hospital Provincial del Centenario; ArgentinaFil: Hernandez, Nelia. Hospital de Clinicas Dr. Manuel Quintela; UruguayFil: Mendizabal, Manuel. Universidad Austral; ArgentinaFil: Ridruejo, Ezequiel. Centro de Educación Medica E Invest.clinicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zerega, Alina. Hospital Allende; ArgentinaFil: Tanno, Federico Carlos. Hospital Provincial del Centenario; ArgentinaFil: Reggiardo, María Virginia. Hospital Provincial del Centenario; ArgentinaFil: Vorobioff, Julio. Hospital Provincial del Centenario; ArgentinaFil: Tanno, Hugo Enrique. Hospital Provincial del Centenario; ArgentinaFil: Arrese, Marco. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Nunes, Vinicius. Universidade Federal da Bahia; BrasilFil: Tagle, Martin. Clínica Anglo Americana; PerúFil: Medina Caliz, Inmaculada. Universidad de Málaga; EspañaFil: Robles Diaz, Mercedes. Universidad de Málaga; EspañaFil: Niu, Hao. Universidad de Málaga; EspañaFil: Alvarez Alvarez, Ismael. Universidad de Málaga; EspañaFil: Stephens, Camilla. Universidad de Málaga; EspañaFil: Lucena, M. Isabel. Universidad de Málaga; EspañaFil: Andrade, Raul J.. Universidad de Málaga; Españ

Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma

Background & Aims: Data from Europe and North America have been published regarding the risk of developing hepatocellular carcinoma (HCC) after treatment with direct antiviral agents (DAA). We proposed to evaluate cumulative incidence and associated risk factors for de novo HCC. Methods: This was a prospective multicentre cohort study from Latin America including 1400 F1-F4-treated patients with DAAs (F3-F4 n = 1017). Cox proportional regression models (hazard ratios, HR and 95% CI) were used to evaluate independent associated variables with HCC. Further adjustment with competing risk regression and propensity score matching was carried out. Results: During a median follow-up of 16 months (IQR 8.9-23.4 months) since DAAs initiation, overall cumulative incidence of HCC was 0.02 (CI 0.01; 0.03) at 12 months and 0.04 (CI 0.03; 0.06) at 24 months. Cumulative incidence of HCC in cirrhotic patients (n = 784) was 0.03 (CI 0.02-0.05) at 12 months and 0.06 (CI 0.04-0.08) at 24 months of follow-up. Failure to achieve SVR was independently associated with de novo HCC with a HR of 4.9 (CI 1.44; 17.32), after adjusting for diabetes mellitus, previous interferon non-responder, Child-Pugh and clinically significant portal hypertension. SVR presented an overall relative risk reduction for de novo HCC of 73% (CI 15%-91%), 17 patients were needed to be treated to prevent one case of de novo HCC in this cohort. Conclusions: Achieving SVR with DAA regimens was associated with a significant risk reduction in HCC. However, this risk remained high in patients with advanced fibrosis, thus demanding continuous surveillance strategies in this population.Fil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Ridruejo, Ezequiel. Universidad Austral. Hospital Universitario Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; ArgentinaFil: Herz Wolff, Fernando. Universidade Federal do Rio Grande do Sul; BrasilFil: Ameigeiras, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Anders, Margarita. Hospital Aleman; ArgentinaFil: Schinoni, María Isabel. Universidade Federal da Bahia; BrasilFil: Reggiardo, Virginia. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Palazzo, Ana. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Videla, María. Sanatorio Sagrado Corazón; ArgentinaFil: Alonso, Cristina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Santos, Luisa. Fundación Cardioinfantil; ColombiaFil: Varón, Adriana. Fundación Cardioinfantil; ColombiaFil: Figueroa, Sebastián. Sanatorio Parque; ArgentinaFil: Vistarini, Cecilia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Adrover, Raúl. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Fernández, Nora. Hospital Británico de Buenos Aires; ArgentinaFil: Perez, Daniela. Gobierno de la Provincia de Tucumán. Hospital Ángel Padilla; ArgentinaFil: Tanno, Federico. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Hernández, Nelia. Universidad de la República. Facultad de Medicina. Hospital de Clínicas "Dr. Manuel Quintela"; UruguayFil: Sixto, Marcela. Provincia de Santa Fe. Ministerio de Salud. Hospital "Dr. José María Cullen"; ArgentinaFil: Borzi, Silvia. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Bruno, Andres. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Cocozzella, Daniel. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Soza, Alejandro. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Descalzi, Valeria. Fundación Favaloro; ArgentinaFil: Estepo, Claudio. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Zerega, Alina. Sanatorio Allende; ArgentinaFil: de Araujo, Alexandre. Hospital de Clinicas de Porto Alegre; BrasilFil: Cheinquer, Hugo. Universidade Federal do Rio Grande do Sul; BrasilFil: Silva, Marcelo. Universidad Austral. Hospital Universitario Austral; Argentin

Decompensated cirrhosis and liver transplantation negatively impact in DAA treatment response: Real-world experience from HCV-LALREAN cohort

Introduction: Although the effectiveness of direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) has been reported in real-world settings, predictive factors of treatment failure are lacking. Therefore, we sought to explore the baseline predictors of treatment response to DAAs. Methods: This was a prospective multicenter cohort study from the Latin American Liver Research Educational and Awareness Network (LALREAN) including patients who received DAA treatment from May 2016 to April 2019. A multivariate logistic regression model was conducted to identify variables associated with unachieved sustained virological response (SVR), defined as treatment failure (odds ratios [OR] and 95% confidence intervals [CIs]). Results: From 2167 patients (55.2% with cirrhosis) who initiated DAA therapy, 89.4% completed a full-course treatment (n = 1938). Median treatment duration was 12 weeks, and 50% received ribavirin. Definitive suspension due to intolerance or other causes was observed in only 1.0% cases (n = 20). Overall non-SVR12 was 4.5% (95% CI, 3.5-5.7). There were no significant differences in treatment failure according to HCV genotypes and the degree of fibrosis. Independently associated variables with DAA failure were liver function impairment according to the Child-Pugh score B OR, 2.09 (P =.06), Child-Pugh C OR, 11.7 (P <.0001); and liver transplant (LT) recipient OR, 3.75 (P =.01). Conclusion: In this real-life setting, higher DAA treatment failure rates were observed in patients with decompensated cirrhosis and in LT recipients. These predictive baseline factors should be addressed to individualize the appropriate time-point of DAA treatment (NCT03775798; www.clinicaltrials.gov).Fil: Ridruejo, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Piñero, Federico. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Mendizabal, Manuel. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Cheinquer, Hugo. Universidade Federal do Rio Grande do Sul; BrasilFil: Wolff, Fernando Herz. Universidade Federal do Rio Grande do Sul; BrasilFil: Anders, Margarita. Hospital Aleman; ArgentinaFil: Reggiardo, Virginia. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Ameigeiras, Beatriz. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Palazzo, Ana. Hospital Padilla; ArgentinaFil: Alonso, Cristina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Schinoni, María Isabel. Universidade Federal da Bahia; BrasilFil: Videla Zuain, María Grazia. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; ArgentinaFil: Tanno, Federico. Provincia de Santa Fe. Ministerio de Salud y Medio Ambiente - Rosario. Hospital Provincial del Centenario; ArgentinaFil: Figueroa, Sebastián. Hospital Dr. Arturo Oñativia - Salta Capital.; ArgentinaFil: Santos, Luisa. Fundación Cardioinfantil; ColombiaFil: Peralta, Mirta. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Soza, Alejandro. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Vistarini, Cecilia. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; ArgentinaFil: Adrover, Raúl. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Fernández, Nora. Hospital Británico de Buenos Aires; ArgentinaFil: Perez, Daniela. Hospital Padilla; ArgentinaFil: Hernández, Nelia. Universidad de la República. Facultad de Medicina. Hospital de Clínicas "Dr. Manuel Quintela"; UruguayFil: Estepo, Claudio. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Bruno, Andres. Gobierno de la Ciudad Autónoma de Buenos Aires. Hospital General de Agudos Doctor Cosme Argerich; ArgentinaFil: Descalzi, Valeria. Fundación Favaloro; ArgentinaFil: Sixto, Marcela. Provincia de Santa Fe. Ministerio de Salud. Hospital "Dr. José María Cullen"; ArgentinaFil: Borzi, Silvia. Gobierno de la Provincia de Buenos Aires. Ministerio de Salud. Hospital Interzonal General de Agudos "prof. Dr. Rodolfo Rossi".; ArgentinaFil: Cocozzella, Daniel. Gobierno de la Provincia de Buenos Aires. Hospital Interzonal de Agudos San Roque de Gonnet; ArgentinaFil: Zerega, Alina. Sanatorio Allende; ArgentinaFil: de Araujo, Alexandre. Hospital de Clinicas de Porto Alegre; BrasilFil: Varón, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Silva, Marcelo. Universidad Austral. Hospital Universitario Austral; Argentin

Drug-Induced Liver Injury in Latin America: 10-year experience of the Latin American DILI (LATINDILI) Network

Background and aims: Latin America is a region of great interest for studying the clinical presentation of idiosyncratic drug-induced liver injury (DILI). A comprehensive analysis of patients enrolled into the LATINDILI Network over a decade is presented. Methods: Demographics, clinical presentation, histological findings and outcome of prospectively recruited DILI cases in the LATINDILI Network were analyzed. Suspected culprit drugs were classified according to the Anatomical Therapeutic Chemical classification. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) scale. Results: Overall, 468 idiosyncratic DILI cases were analyzed (62% women, mean age 49 years). Hepatocellular injury predominated (62%), jaundice was present in 60% of patients and 42% were hospitalized. 4.1% of the cases had a fatal outcome, and 24 (12%) patients developed chronic DILI. The most common drug classes were systemic antiinfectives (31%), musculoskeletal agents (12%), antineoplastic and immunomodulating agents (11%), and herbal and dietary supplements (HDS, 9%). Notably, none of the patients with DILI due to antibacterials or immunosuppressants had a fatal outcome. In fact, Hy's law showed to have drug-specific predictive value, with anti-tuberculosis drugs, nimesulide and HDS associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin and diclofenac that fulfilled Hy's law did not have a fatal outcome. Conclusion: Features of DILI in Latin America are comparable to other prospective registries. However, the pattern of drugs responsible for DILI differs. An increasing incidence of HDS, with high mortality rate, and likewise nimesulide and nitrofurantoin was noted. Thus, public health policies should raise awareness of the potential adverse effects of these compounds.This work was supported by grants of Instituto de Salud Carlos III (ISCIII), cofounded by Fondo Europeo de Desarrollo Regional – FEDER, cofounded by European Union (grant number PI21/01248; PT20/00127; PT23/00137), and by the Agencia Española de Medicamentos y Productos Sanitarios. CIBERehd and Plataforma de Investigación Clinica are funded by ISCIII. JMPB holds a Rio Hortega contract (CM21/00074) and JSC a Juan Rodés contract (JR21/00066) from ISCIII and cofounded by the European Union. HN holds a postdoctoral research contract funded by Junta de Andalucía (POSTDOC_21_00780). This project has received funding from the European Horizon´s research and innovation program HORIZON-HLTH-2022-STAYHLTH-02 under agreement Nº 101095679. This study is funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. The funding sources had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the manuscript for publication