Editorial: Multidisciplinary management of cancer patients with immune-related adverse events from checkpoint inhibitors

Cancer; Immunotherapy; ToxicityCáncer; Inmunoterapia; ToxicidadCàncer; Immunoteràpia; Toxicita

Immunotherapy and the Spectrum of Kidney Disease: Should We Individualize the Treatment?

Chronic kidney disease; Dialysis; ImmunotherapyEnfermedad renal cronica; Diálisis; InmunoterapiaMalaltia renal crònica; Diàlisi; ImmunoteràpiaThe new targeted cancer therapies including immune checkpoint inhibitors (ICIs) have been demonstrated to improve the survival of oncological patients, even in cases of metastatic cancer. In the past 5 years, several studies have revealed that ICI can produce several immune-mediated toxicities involving different organs, such as the skin, the gastrointestinal tract, the liver, and, of course, the kidney. The most frequent lesion of immunotoxicity in the kidney is acute interstitial nephritis (AIN), although other nephropathies have also been described as a consequence of the use of ICI, such as glomerulonephritis and acute thrombotic microangiopathy, among others. In addition, kidney rejection has also been reported in kidney transplant patients treated with ICI. Normally randomized clinical trials with ICI exclude patients with end-stage kidney disease, namely, patients undergoing dialysis and kidney transplant patients. Several important questions need to be addressed in relation to immunotherapy and patients with kidney disease: (a) when to start corticosteroid therapy in a patient with suspected acute kidney injury (AKI) related to ICI, (b) the moment of nephrologist referral and kidney biopsy indication, (c) management of ICI in patients undergoing dialysis, and (d) the effect of ICI in kidney transplantation, immunosuppressive personalized treatment, and risk of allograft rejection in kidney transplant patients. The objective of this review was to summarize the recently published literature on a wide spectrum of kidney disease patients with cancer and ICI. This review will address three main important groups of individuals with kidney disease and cancer immunotherapy, AKI associated with ICI, patients undergoing dialysis, and kidney transplant recipients. We believe that the information provided in this review will enlighten the personalized ICI treatment in individuals with a broader spectrum of kidney diseases.This research was funded by ISCIIII-FEDER and ISCIII-RETICS REDinREN, Grant Numbers PI17/00257, PI21/01292, RD16/0009/0030, and RICORS RD21/0005/0016. Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), enfermedades glomerulares complejas

Estudio de dos situaciones especiales en pacientes con infección crónica por el virus de la hepatitis B: Eficacia y seguridad de los análogos de nucleós(t)idos de segunda generación en una cohorte de práctica clínica real y nuevos biomarcadores para la identificación de portadores inactivos /

La hepatitis B es un problema de salud mundial, con unos 400 millones de personas infectadas crónicamente. En nuestro medio se calcula una prevalencia del 0.7%, siendo la mayoría de los sujetos HBeAg negativo. En esta fase de la infección, uno de los retos es distinguir entre aquellos sujetos portadores inactivos, que presentarán un buen pronóstico de la enfermedad a largo plazo, y los pacientes con hepatitis crónica HBeAg negativo, que tienen riesgo de desarrollar fibrosis hepática y por tanto precisar tratamiento antiviral. El primer trabajo se centró en pacientes bajo tratamiento antiviral con análogos de nucleós(t)idos de segunda generación (Entecavir y Tenofovir). Las hipótesis del mismo fueron que la eficacia y tasa de efectos adversos en práctica clínica era similar a la de los estudios de registro y la validación del modelo Page-B para predicción del riesgo de carcinoma hepatocelular (CHC). Para dicho fin se analizó la base CIBERHEP que incluye sujetos con infección crónica por el VHB, seleccionándose un total de 609 pacientes caucásicos en tratamiento con Tenofovir o Entecavir. Las tasas de respuesta virológica y bioquímica fueron altas, con pocos efectos adversos y discontinuación de tratamiento, sin observarse deterioro de la función renal. A pesar de la supresión de la replicación viral, se observaron 12 casos de CHC, número inferior a los estimados por la puntuación Page-B. Al igual que en la cohorte original, todos aquellos sujetos que presentaron CHC tenían basalmente una puntuación Page-B ≥10 puntos, confirmándose el valor predictivo negativo del 100% de dicho punto de corte. La hipótesis del segundo de los estudios, fue que los niveles séricos de antígeno de superficie (HBsAg) o antígeno relacionado con el core (HBcrAg) podrían ser útiles para identificar a los verdaderos portadores inactivos del VHB. Para ello se realizó un estudio prospectivo con al 3 determinaciones analíticas en 1 año para caracterizar a los sujetos como portadores inactivos (niveles de alanino transferasa persistentemente normales y ADN VHB≤2.000 UI/mL) o con actividad por el VHB. En primer lugar se observó que los niveles de HBsAg estaban influidos el por genotipo del VHB, dato que dificultó la búsqueda de un único punto de corte con altos índices diagnósticos en todos los genotipos, siendo el HBsAg 85% en todos los genotipos excepto el H o F (73%).Hepatitis B virus (HBV) infection is a worldwide health problem, with around 400 million people chronically infected. In our setting, the prevalence is 0.7% and the majority of subjects are HBeAg negative. In this stage of the disease, one of the most challenging issues is to discern between the inactive carriers, who have a long-term good prognosis of the disease, and patients with HBeAg negative chronic hepatitis B, who are at risk of fibrosis development and therefore may require antiviral therapy. The first study of this thesis is focus on patients undergoing antiviral therapy with second generation nucleos(t)tides analogs (Entecavir and Tenofovir). The hypotheses were that the effectiveness and rate of side effects in daily clinical practice were similar to the registration studies and the validation of the Page-B score for prediction of hepatocellular carcinoma (HCC) development. From the collaborative database CIBERHEP, 609 caucasian subjects with chronic hepatitis B treated with Tenofovir or Entecavir were selected. The rates of biochemical and virological response were very high, and no worsening on renal function was observed. Despite suppression of viral replication, 12 cases of HCC were reported, a number lower to the estimated by the Page-B score. Similar to the original cohort, in the CIBERHEP all patients who developed HCC presented a baseline Page-B punctuation ≥10 points, supporting the previously described 100% negative predictive value of that cut-off. The hypothesis of the second study was that the serum levels of hepatitis B antigen (HBsAg) o core-related antigen (HBcrAg) could be useful for identification of HBV inactive carriers. To achieve this goal, a prospective work with 3 consecutive blood analyses throughout 1 year was carried out. Subjects were classified as inactive carriers (defined as persistently normal alanine transferase levels and HBV DNA ≤2.000 IU/mL) or subjects with HBV activity. Firstly, it was observed that HBsAg levels varied across the different HBV genotypes. This finding hindered the search of a unique HBsAg cut-off for diagnosing the inactive carrier state among the different HBV genotypes. Previously described HBsAg 3 logIU/mL was only useful of genotype D. However, HBcrAg did no vary among genotypes, and on the whole, the diagnostic accuracy of HBcrAg was higher than HBsAg levels. The combination on a single determination of HBcrAg ≤3 logU/mL plus HBV DNA ≤2.000 IU/mL presented a diagnostic accuracy ≥85% in all genotypes except H or F (73%)

Effectiveness, safety/tolerability of OBV/PTV/r ± DSV in patients with HCV genotype 1 or 4 with/without HIV-1 co-infection, chronic kidney disease (CKD) stage IIIb-V and dialysis in spanish clinical practice – Vie-KinD study

HIV and Hepatitis C Coinfection; Chronic Renal Failure; RibavirinCoinfecció VIH i Hepatitis C; Insuficiència Renal Crònica; RibavirinaCoinfección VIH y Hepatitis C; Insuficiencia Renal Crónica; RibavirinaBackground and aims: Limited data are available on the effectiveness and tolerability of direct-acting antivirals (DAAs) therapies in the real world for HCV-infected patients with comorbidities. This study aimed to describe the effectiveness of OBV/PTV/r ± DSV (3D/2D regimen) with or without ribavirin (RBV) in HCV or HCV/HIV co-infected patients with GT1/GT4 and CKD (IIIb-V stages), including those under hemodialysis and peritoneal dialysis in routine clinical practice in Spain in 2015. Material and methods: Non-interventional, retrospective, multicenter data collection study in 31 Spanish sites. Socio-demographic, clinical variables, study treatment characteristics, effectiveness and tolerability data were collected from medical records. Results: Data from 135 patients with a mean age (SD) of 58.3 (11.4) years were analyzed: 92.6% GT1 (81.6% GT1b and 17.6% GT1a) and 7.4% GT4, 14 (10.4%) HIV/HCV co-infected, 19.0% with fibrosis F3 and 28.1% F4 by FibroScan®, 52.6% were previously treated with pegIFN and RBV. 11.1%, 14.8% and 74.1% of patients had CKD stage IIIb, IV and V respectively. 68.9% of patients were on hemodialysis; 8.9% on peritoneal dialysis and 38.5% had history of renal transplant. A total of 125 (96.2%) of 135 patients were treated with 3D, 10 (7.4%) with 2D and 30.4% received RBV. The overall intention-to-treat (ITT) sustained virologic response at week 12 (SVR12) was 92.6% (125/135) and the overall modified-ITT (mITT) SVR12 was 99.2% (125/126). The SVR12 rates (ITT) per sub-groups were: HCV mono-infected (91.7%), HCV/HIV co-infected (100%), GT1 (92.0%), GT4 (100%), CKD stage IIIb (86.7%), stage IV (95%) and stage V (93%). Among the 10 non-SVR there was only 1 virologic failure (0.7%); 4 patients had missing data due lost to follow up (3.0%) and 5 patients discontinued 3D/2D regimen (3.7%): 4 due to severe adverse events (including 3 deaths) and 1 patient´s decision. Conclusions: These results have shown that 3D/2D regimens are effective and tolerable in patients with advanced CKD including those in dialysis with GT 1 or 4 chronic HCV mono-infection and HIV/HCV coinfection in a real-life cohort. The overall SVR12 rates were 92.6% (ITT) and 99.2% (mITT) without clinically relevant changes in eGFR until 12 weeks post-treatment. These results are consistent with those reported in clinical trials.MCL has served as consultant for AbbVie, MSD, Janssen, BMS and Gilead; MRB has received grant research from Gilead Science, and speaker fees from AbbVie, Gilead and MSD; MR has received speaker fees from AbbVie; MD has received grant support and consultancy fees from AbbVie, Bayer, Bristol-Myers Squibb, Gilead and Merck, Sharp & Dhome; FGR has served as speaker for AbbVie, Gilead and BMS; MLM has served as a speaker for AbbVie, BMS, Gilead, Janssen, MSD and ViiV; as a consultant for AbbVie, BMS and Janssen and has received research funding from FIPSE 36465/03, FIPSE 36680/07.-NEAT IG5 (NEAT is a project funded by the European Union under the 6th Framework programme) contract number LSHP-CT-2006-037570; MAC has served as a consultant for Gilead and and ViiV healthcare, and has received speaker fees from Janssens, Gilead, ViiV Healthcare; MMA reports personal fees from ViiV Healthcare, Gilead Sciences, Merck, Janssen, AbbVie and ABBOTT Laboratories, outside the submitted work; AR has received consultancy and speaker fees from AbbVie, Gilead Sciences and Merck Sharp & Dohme; JM has received honoraria, speaker fees, consultant fees or funds for research from AbbVie, BMS, Boehringer-Ingelheim, Gilead, Janssen, MSD, Roche and ViiV; EGP has received speaker fees from AbbVie and Gilead; LGB has served as consultant for AbbVie and Intercept and has received speaker fees from Gilead and MSD; AA, RMG, CB, TAE, MLG, BPL, IC, SB, LB, JGS, MJP, IMG, LM, IdlS, ML and JEL don't have a financial interest or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this paper; CdA and AM are paid employees of AbbVie and may hold stock or options. The specific roles of these authors are articulated in the 'author contributions' section. The design, study conduct, and financial support for the study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the manuscript

Impact of the COVID-19 pandemic on hepatitis B and C elimination: An EASL survey

Hepatitis B virus; Hepatitis C virus; COVID-19 pandemicVirus de la hepatitis B; Virus de la hepatitis C; Pandemia de COVID-19Virus de l'hepatitis B; Virus de l'hepatitis C; Pandèmia del COVID-19Background & Aims The World Health Organization (WHO) HBV and HCV elimination targets, set in 2016 and based on projections to 2030, were unable to consider the impact of intervening factors. To evaluate the impact of the COVID-19 pandemic on viral hepatitis elimination programs, the European Association for the Study of the Liver (EASL) conducted a survey in liver centers worldwide in 2021. Methods A web-based questionnaire was distributed (May-July 2021) to all EASL members representing clinical units providing HBV and HCV hepatitis care. Results are expressed as absolute numbers and reduction rates for each care activity. Results Data were collected from 32 European and 12 non-European clinical centers. Between January 2019 (pre-pandemic) and December 2020 (during the pandemic), chronic HBV consultations decreased by 32% and 26%, new referrals by 38% and 39%, HBV testing rates by 39% and 21% (for HBsAg detection) and 30% and 22% (for HBV DNA detection), and new HBV treatments by 20% and 44% (p = 0.328) in European and non-European centers, respectively. With regard to HCV during the same time frame, the overall reductions were 39% and 50% for consultations, 49% and 49% for new referrals, 11% and 38% for HCV RNA detection, and 51% and 54% for new HCV antiviral treatments for European and non-European Centers, respectively (p = 0.071). Conclusions All steps in the viral hepatitis care cascade have been hampered by the COVID-19 pandemic, with a comparable impact across different centers. These data reaffirm the pandemic’s major effect on global viral hepatitis elimination programs and suggest that actions to achieve the WHO 2030 targets should be reconsidered and revised to account for each country's progress relative to pre-pandemic values

Chronic hepatitis D associated with worse patient-reported outcomes than chronic hepatitis B

Hepatitis vírica; Qualitat de vida relacionada amb la salut; Malaltia hepàtica crònicaHepatitis viral; Calidad de vida relacionada con la salud; Enfermedad crónica del hígadoViral hepatitis; Health-related quality of life; Chronic Liver DiseaseBackground & Aims Health-related quality of life (HRQoL) determined by patient-reported outcomes (PROs) is impaired in chronic hepatitis B (CHB) and C patients, but there are no data regarding patients with chronic hepatitis D (CHD). The aim of this study was to assess PRO scores in untreated patients with CHD and compare them with those obtained for patients with CHB. Methods Patients with CHD completed 3 PRO instruments (Chronic Liver Disease Questionnaire [CLDQ], Functional Assessment of Chronic Illness Therapy–Fatigue [FACIT-F], and Work Productivity and Activity Impairment [WPAI]), and the results were compared with those of patients mono-infected with CHB. Results In total, 125 patients were included: 43 with CHD and 82 with CHB. Overall, baseline PROs showed differences between both groups. Several assessments, such as the worry score from CLDQ (p = 0.0118), functional well-being from FACIT-F (p = 0.0281), and activity impairment from WPAI (p = 0.0029) showed a significant trend to worse scores in patients with CHD than with CHB. In addition, the linear regression model supports the finding that having CHD as opposed to having CHB was a predictor of a higher worry score (CLDQ) and a higher activity impairment (WPAI). Conclusions In this first assessment in CHD, PROs recorded in patients with CHD showed a significant impairment in some domains of HRQoL questionnaires in comparison with those with CHB. Studies in larger cohorts with lengthier follow-up are needed to fully assess patient-reported quality of life over the course of CHD. Lay summary Chronic hepatitis D (CHD) is a viral disease that causes rapid evolution to liver cirrhosis, amongst other severe complications, when compared to patients with chronic hepatitis B (CHB). Health-related quality of life in chronic hepatitis C and CHB has been reported widely, but no studies have been performed on patient-reported outcomes in patients with CHD. Results showed that CHD patients reported worse outcomes in psychological domains such as worry and emotional well-being, as well as in physical domains such as abdominal symptoms, physical well-being, and activity impairment in comparison with patients with CHB

Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study

Early predictors; Corticosteroid; Autoimmune hepatitisPredictors primerencs; Corticosteroides; Hepatitis autoimmunePredictores tempranos; Corticosteroide; Hepatitis autoinmuneBackground and Aims To assess whether corticosteroids improve prognosis in patients with AS-AIH, and to identify factors at therapy initiation and during therapy predictive of the response to corticosteroids. Methods This was a retrospective cohort study including all patients with AS-AIH admitted to 13 tertiary centres from January 2002 to January 2019. The composite primary outcome was death or liver transplantation within 90 days of admission. Kaplan–Meier and Cox regression methods were used for data analysis. Results Of 242 consecutive patients enrolled (mean age [SD] 49.7 [16.8] years), 203 received corticosteroids. Overall 90-day transplant-free survival was 61.6% (95% confidence interval [CI] 55.4–67.7). Corticosteroids reduced the risk of a poor outcome (adjusted hazard ratio [HR] 0.25; 95% CI 0.2–0.4), but this treatment failed in 30.5%. An internally validated nomogram composed of older age, MELD, encephalopathy and ascites at the initiation of corticosteroids accurately predicted the response (C-index 0.82; [95% CI 0.8–0.9]). In responders, MELD significantly improved from days 3 to 14 but remained unchanged in non-responders. MELD on day 7 with a cut-off of 25 (sensitivity 62.5%[95% CI: 47.0–75.8]; specificity 95.2% [95% CI: 89.9–97.8]) was the best univariate predictor of the response. Prolonging corticosteroids did not increase the overall infection risk (adjusted HR 0.75; 95% CI 0.3–2.1). Conclusion Older patients with high MELD, encephalopathy or ascites at steroid therapy initiation and during treatment are unlikely to show a favourable response and so prolonged therapy in these patients, especially if they are transplantation candidates, should be avoided.This study was supported in part by grants from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, number PI20/01302, awarded to Agustín Albillos and number PI 21/01310, awarded to Luis Téllez. CIBEREHD is funded by the Instituto de Salud Carlos III using grants cofinanced by the European Development Regional Fund “A way to achieve Europe” (EDRF). María Carlota Londoño received support from the Plan Nacional de I+D+I co-funded by ISCIII-Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa") (PI17/00955). Laura Patricia Llovet received the Resident Award “Clínic-La Pedrera” granted by the Hospital Clínic de Barcelona, Research, Innovation and Education Department

Community Strategy for Hepatitis B, C, and D Screening and Linkage to Care in Mongolians Living in Spain

Mongolian community; Community program; Viral hepatitis screeningComunidad mongola; Programa comunitario; Cribado de hepatitis viralComunitat mongol; Programa comunitari; Cribatge de hepatitis viralMongolia has one of the highest viral hepatitis infection (B, C, and D) rates in the world. The aims of this study were to increase awareness of this disease and promote viral hepatitis screening in the Mongolian community living in Spain. Through a native community worker, Mongolian adults were invited to a community program consisting of an educational activity, an epidemiological questionnaire, and rapid point-of-care testing for hepatitis B and C. In those testing positive, blood extraction was performed to determine serological and virological parameters. In total, 280 Mongolians were invited to the program and 222 (79%) attended the event: 139 were women (63%), mean age was 42 years, and 78 (35%) had viral hepatitis risk factors. Testing found 13 (5.8%) anti-HCV-positive individuals, 1 with detectable HCV RNA (0.5%), 8 HBsAg-positive (3.6%), and 7 with detectable HBV DNA (3.1%). One additional individual had HBV/HCV co-infection with detectable HBV DNA and HCV RNA. Two subjects had hepatitis B/D co-infection (0.9%). The knowledge questionnaire showed a 1.64/8-point (20.5%) increase in correct answers after the educational activity. In summary, a viral hepatitis community program was feasible and widely accepted. It increased awareness of this condition in the Mongolian community in Spain and led to linkage to care in 22 participants, 50% of whom were unaware of their infection.This project was funded by GILEAD SCIENCES (GLD21/00139)