Safety, Tolerability, and Outcomes of Tafamidis for the Treatment of Acquired Amyloid Neuropathy in Domino Liver Transplant Recipients.

INTRODUCTION: Acquired amyloid neuropathy is an iatrogenic disease that appears years after a domino liver transplant. The objectives of our study are to analyze the efficacy and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. This post-authorization, prospective, longitudinal study included seven domino liver transplant recipients with acquired amyloid neuropathy who received treatment with tafamidis for 18 months. METHODS: The primary endpoints were the response rate, defined as those patients with an increase of < 2 points on the Neurological Impairment Score (NIS) from baseline, and the change in the NIS score from baseline. Secondary endpoints included the Quantitative Sensory Test, 10-m walk test, quality of life (Norfolk), and disability (Rasch-built Overall Disability Scale). As safety parameters, the evidence of graft rejection, changes in immunosuppressive trough levels and changes in antiviral and allogeneic cellular immunity before and 12 months after tafamidis treatment were also assessed. RESULTS: Six patients (85.7%) had responded at 18-months. Compared to baseline, we observed non-statistically significant improvement in mean NIS score at 6 months (- 2.54 points, CI - 5.92 to 0.84), 12 months (- 3.25 points; CI - 6.63 to 0.13), and 18 months (- 2.35 points; CI - 5.74 to 1.02). Changes in the Quantitative Sensory Test, 10-m walk tests and the quality of life and disability questionnaires were not statistically significant. The use of tafamidis did not induce relevant side effects or drug interactions. Also, no acute rejections events nor changes in functional adaptive immunity were observed. CONCLUSION: Our study supports the safety and tolerability of tafamidis for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Tafamidis shows promise as a useful treatment in the clinical management of these patients. Future randomized placebo-controlled clinical trials with longer follow-up durations are needed.

Long-Term Effectiveness, Safety, and Patient-Reported Outcomes of Self-Administered Subcutaneous Hepatitis B Immunoglobulin in Liver Post-Transplant Hepatitis B Prophylaxis: A Prospective Non-Interventional Study.

BACKGROUND Self-administered subcutaneous hepatitis B immunoglobulin (s.c. HBIg) in combination with nucleos(t)ide analogs (NUCs) has proved to be effective and safe in preventing hepatitis B virus (HBV) reinfection after liver transplantation. MATERIAL AND METHODS This non-interventional, prospective, single-arm, multicenter, international study collected data on long-term effectiveness, safety, patient satisfaction (Treatment Satisfaction Questionnaire for Medication, TSQM-11), and quality of life (EQ-5D questionnaire) in routine practice over a 2-year treatment period. Data analysis was based on 195 adults (82.1% male) transplanted for HBV-related liver diseases and treated with s.c. HBIg with/without NUC(s). RESULTS HBV recurrence (seropositivity of HBV surface antigen and/or HBV DNA) was observed in 7/195 (3.6%) patients (annual rate: 2.01%). Hepatocellular carcinoma (HCC) recurred in 4/83 (4.8%) patients transplanted for HBV-HCC (annual rate: 2.88%). Twenty-nine adverse drug reactions occurred in 16/195 (8.2%) patients. Convenience and overall satisfaction scores of the TSQM-11 were significantly (P<0.05) improved under treatment at the 3-month, 2-year, and last follow-up visits. Quality of life remained constant over the entire observation period (EQ-5D index [P≥0.075]). S.c. HBIg was mainly self-administered (6458/9021 administrations, 71.6%) at home (8514/9021 administrations, 94.4%). CONCLUSIONS The results indicate long-term effectiveness and safety of s.c. HBIg in combination with NUC therapy in preventing post-transplant HBV reinfection under real-life conditions. The convenience of the therapy contributed to the high overall treatment satisfaction and acceptance by the patients.

Treatment With Diflunisal in Domino Liver Transplant Recipients With Acquired Amyloid Neuropathy.

Objectives: To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. Methods: We performed a retrospective longitudinal study of prospectively collected data for all domino liver transplant recipients with acquired amyloid neuropathy who received diflunisal at our hospital. Neurological deterioration was defined as an score increase of ≥2 points from baseline on the Neurological Impairment Scale/Neurological Impairment Scale-Lower Limbs. Results: Twelve patients who had received compassionate use treatment with diflunisal were identified, of whom seven had follow-up data for ≥12 months. Five patients (71.4%) presented with neurological deterioration on the Neurological Impairment Scale after 12 months (p = 0.0382). The main adverse effects were cardiovascular and renal, leading to diflunisal being stopped in five patients and the dose being reduced in two patients. Conclusion: Our study suggests that most domino liver transplant recipients with acquired amyloid neuropathy will develop neurological deterioration by 12 months of treatment with diflunisal. This therapy was also associated with a high incidence of adverse effects and low treatment retention. The low efficacy and low tolerability of diflunisal treatment encourage the search for new therapeutic options.

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study.

Domino liver transplantation (DLT) has been used widely in patients with hereditary amyloid transthyretin (ATTR) amyloidosis. New-onset polyneuropathy in recipients of DLT has been reported, but there are few cases of cardiac involvement reported. We aimed to perform a cross-sectional study for ATTR amyloidosis with cardiomyopathy (ATTR-CM) in DLT recipients. We evaluated 23 living DLT recipients a median of 9 years since DLT at 2 referral centers with a systematic cardiac evaluation, including bone scintigraphy. Median age was 72 years, 91% had hypertension, 35% had diabetes mellitus, 67% had chronic renal failure, and 8 patients (35%) developed new-onset polyneuropathy. Only 13% had a normal electrocardiogram and a normal echocardiography, and most of them showed some conduction disturbance or increase in left ventricular wall thickness, but only 1 patient with a Glu89Lys mutation developed ATTR-CM diagnosed by bone scintigraphy and endomyocardial biopsy. None of the recipients of a DLT with Val30Met mutation showed cardiac involvement by bone scintigraphy. In conclusion, DLT from Val30Met donors seems to be safe regarding the development of ATTR-CM. Evaluation of cardiomyopathy in DLT recipients is challenging due to concomitant comorbidities and in this context, bone scintigraphy can be helpful to evaluate ATTR-CM.

Interferon-Free Therapy in Elderly Patients With Advanced Liver Disease.

OBJECTIVES: Interferon-free therapies have an improved safety and efficacy profile. However, data in elderly patients, who have frequently advanced liver disease, associated comorbidities, and use concomitant medications are scarce. The im of this study was to assess the effectiveness and tolerability of all-oral regimens in elderly patients in real-life clinical practice. METHODS: Retrospective analysis of hepatitis C virus (HCV) patients aged ≥65 years receiving interferon-free regimens within the Spanish National Registry (Hepa-C). RESULTS: Data of 1,252 patients were recorded. Of these, 955 (76%) were aged 65-74 years, 211 (17%) were aged 75-79 years, and 86 (7%) were aged ≥80 years at the start of antiviral therapy. HCV genotype-1b was predominant (88%) and 48% were previous non-responders. A significant proportion of patients had cirrhosis (922; 74%), of whom 11% presented decompensated liver disease. The most used regimens were SOF/LDV (33%), 3D (28%), and SOF/SMV (26%). Ribavirin was added in 49% of patients. Overall, the sustained virological response (SVR12) rate was 94% without differences among the three age categories. Albumin ≤3.5 g/dl was the only independent negative predictor of response (0.25 (0.15-0.41); P<0.01). Regarding tolerability, the rate of severe adverse events increased with age category (8.8, 13, and 14%; P=0.04). In addition, the main predictors of mortality (2.3%) were age ≥75 years (2.59 (1.16-5.83); P =0.02) and albumin ≤3.5 (17 (6.3-47); P <0.01). CONCLUSIONS: SVR rates with interferon-free regimens in elderly patients are high and comparable to the general population. Baseline low albumin levels (≤3.5 g/dl) was the only predictor of treatment failure. Importantly, the rate of severe adverse events and death increased with age. Elderly patients (≥75 years) or those with advanced liver disease (albumin ≤3.5) presented higher mortality. Thus a careful selection of patients for antiviral treatment is recommended.

Rapid diagnosis of spontaneous bacterial peritonitis by use of reagent strips.

We studied the use of reagent strips for diagnosis of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites. A reagent strip for leukocyte esterase designed for the testing of urine with a colorimetric 5-grade scale (0 to 4) was used to evaluate ascitic fluid in 228 nonselected paracentesis performed in 128 cirrhotic patients. We diagnosed 52 SBP and 5 secondary bacterial peritonitis by means of polymorphonuclear cell count and classical criteria. When we considered positive a reagent strip result of 3 or 4, sensitivity was 89% (51 of 57), specificity was 99% (170 of 171), and positive predictive value was 98%. When we considered positive a reagent strip result of 2 or more, sensitivity was 96% (55 of 57), specificity was 89% (152 of 171), and negative predictive value was 99%. In conclusion, the use of reagent strips is a rapid, easy to use, and inexpensive tool for diagnosis of ascitic fluid infection. A positive result should be an indication for empirical antibiotic therapy, and a negative result may be useful as a screening test to exclude SBP.

Is MELD really the definitive score for liver allocation?

The best system for organ allocation is still a controversial issue. The aim of this study was to study the accuracy of four different scores to predict mortality on the waiting list and, thus, their usefulness to determine organ allocation. We retrospectively compared two groups of patients, those who died on waiting list (group D) and those who successfully underwent transplantation (group T) during the same time period. Four scores, at the time of entering the waiting list and just before liver transplantation or death, were evaluated. The evaluated scores were as follows: (1) the Child-Pugh classification; (2) the Model for End-Stage Liver Disease (MELD) score; (3) the Freeman scale; and (4) the Guardiola et al index. The mortality rate on waiting list was 15.9%. All studied scores, except Freeman scale, were higher in group D at the time of entrance on waiting list (MELD, 17.4 +/- 8 v 12.3 +/- 6, P = .02; Child, 9.9 +/- 2 v 7.7 +/- 2, P = .002; Freeman, 9.7 +/- 4 v 7.3 +/- 3.9, P = .09; Guardiola, 2.6 +/- 0.9 v 1.7 +/- 0.7, P = .001). C-statistics of all scores were similar and in all cases lower than 0.8 (MELD, 0.75; Child, 0.78; Freeman, 0.65; Guardiola, 0.79). None of the studied scores have an excellent accuracy to predict prognosis of patients on waiting list, mainly in case of populations with high proportion of hepatocellular carcinoma. Although the MELD score is rapidly available, standardized, and objective, it does not reflect the severity of patients with cancer or metabolic disorders.

[Surgical treatment of hepatocellular carcinoma. Long term results]. / Resultados a largo plazo del tratamiento quirúrgico del hepatocarcinoma.

BACKGROUND: Surgical treatment for hepatocellular carcinoma remains controversial due to a lack of prospective randomized studies. MATERIAL AND METHOD: Between January 1990 and December 2000, 121 liver transplantations (group 1) and 52 hepatectomies (group 2) were performed for hepatocellular carcinoma. Each surgical treatment was carried out depending on patients' and tumor's characteristics. RESULTS: Patients from group 1 had a more advanced tumoral grade, with higher involvement of two lobes (19 vs 4%; p = 0.015) and higher number of nodules (1.9 DE [2] vs 1.2 [0.6]; p = 0.001); yet the mean tumor size was lower (3 cm [1.5] vs 4.2 [3.2]; p = 0.006). Operative mortality (4% vs 2%; p = 0.66) and 5- and 10-years survival (68% and 42% vs 63% and 45%; p = 0.23) were similar between both groups. Nevertheless, 5- and 10-years recurrence rates (10.6% and 10.6% vs 50% and 65.5%; p < 0.0001) were more favourable in group 1. Prognostic factors of recurrence included microscopic vascular invasion (RR = 12.12; CI, 2.02-75.52) and alpha-fetoprotein levels higher than 300 ng/mL (RR = 7.12; 95% CI, 1.08-47.02) in group 1, and the pT3-4 stage (RR = 3.86; 95% CI, 1.06-14.03) in group 2. Mean time on waiting lists for liver transplantation was 3.06 (2.66) months and it has increased significantly in last years, especially among blood group 0 patients. However, this fact has not been associated with a worsening of survival rates (p = 0.98). CONCLUSIONS: After a good patient selection, either liver transplantation or hepatectomy achieve excellent long term survival rates in patients with hepatocellular carcinoma, though the former allows a better control of the tumoral disease. The increase of mean time on waiting lists for liver transplantation during the last years has not led to a worsening of survival results.

Resultados a largo plazo del tratamiento quirúrgico del hepatocarcinoma / Surgical treatment of hepatocellular carcinoma. Long term results

FUNDAMENTO: El tratamiento quirúrgico del hepatocarcinoma (HCC) sigue siendo un tema controvertido por falta de estudios prospectivos aleatorizados. PACIENTES Y MÉTODO: Entre enero de 1990 y diciembre de 2000 se realizaron en nuestro centro 121 trasplantes hepáticos (grupo I) y 52 hepatectomías (grupo II) por HCC. La indicación de una u otra técnica dependió de las características del paciente y del tumor. RESULTADOS: Los pacientes del grupo I presentaron un estadio tumoral más avanzado, con mayor incidencia de bilobularidad (19 frente a un 4 por ciento; p = 0,015) y un mayor número de nódulos (1,9 DE [2] frente a 1,2 [0,6]; p = 0,001), pero el tamaño tumoral medio fue inferior (3 cm [1,5] frente a 4,2 cm [3,2]; p = 0,006). La mortalidad operatoria (4 frente a un 2 por ciento; p = 0,66), y la supervivencia a los 5 y 10 años (68 y 42 por ciento frente a 63 y 45 por ciento; p = 0,23) fueron similares para los dos grupos. Sin embargo, la incidencia de recidiva a los 5 y 10 años (10,6 y 10,6 por ciento frente a 50 y 65,5 por ciento; p < 0,0001) fueron favorables al grupo I. Los factores pronósticos de recidiva en el grupo I fueron la invasión vascular microscópica (riesgo relativo [RR] = 12,12; intervalo de confianza [IC del 95 por ciento], 2,02-75,52) y un valor de alfafetoproteína superior a 300 ng/ml (RR = 7,12; IC, 1,08-47,02) y en el grupo II el estadio pT3-4 (RR = 3,86; IC del 95 por ciento, 1,06-14,03). El tiempo medio en lista de espera de los pacientes del grupo I fue de 3,06 (2,66) meses y se ha incrementado significativamente en los últimos años, especialmente entre los enfermos del grupo sanguíneo 0, sin que ello se haya asociado a un empeoramiento de la supervivencia (p = 0,98).CONCLUSIONES: Con una buena selección de los pacientes, tanto el trasplante hepático como la hepatectomía obtienen excelentes supervivencias a largo plazo en los pacientes con HCC, aunque el primero permite un mejor control de la enfermedad tumoral. Las causas de mortalidad son diferentes para cada uno de los tratamientos. La prolongación del tiempo en lista de espera de trasplante que se ha producido en los últimos años no ha originado un empeoramiento de los resultados de supervivencia. (AU)

Análisis de 500 trasplantes hepáticos en el Hospital de Bellvitge / Analysis of 500 liver transplantations in the Bellvitge Hospital, Spain

Fundamento: Se presenta la experiencia del programa de trasplante hepático del Hospital de Bellvitge en 500 trasplantes realizados durante 15 años, con el objetivo de poner de manifiesto los cambios que se han producido y exponer los resultados a largo plazo de esta terapéutica. Pacientes y método: Se consideraron y compararon 5 grupos de 100 trasplantes consecutivos (I-V). Resultados: Las indicaciones más frecuentes fueron el hepatocarcinoma (23 por ciento), la cirrosis alcohólica (22,8 por ciento) y la hepatopatía crónica por virus C (18,8 por ciento). En 59 pacientes se llevaron a cabo 65 retrasplantes (13 por ciento), cuyas indicaciones más frecuentes fueron la trombosis arterial (13 pacientes) y el fallo primario del injerto (10 pacientes). En 19 enfermos se realizó un trasplante combinado hepatorrenal. La causa más frecuente de muerte del donante en el grupo I fueron los traumatismos craneales (80 por ciento), mientras que en el grupo V fue la enfermedad vascular (52 por ciento). Otras diferencias significativas entre estos grupos se observan en la proporción de pacientes en estadio 2 y 3 de la clasificación UNOS (el 45 frente al 19 por ciento), en el consumo de hemoderivados (29,6 [26] frente a 4,6 [5,3] concentrados de hematíes), en la frecuencia de reintervenciones por hemoperitoneo (el 22 frente al 5 por ciento), en la estancia en UCI (13 [13] frente a 7,4 [11] días) y en el hospital 40 [52] frente a 23,7 [17] días), y en la incidencia de rechazo (el 46 frente al 20 por ciento) y de fallo primario del injerto (el 9 frente al 3 por ciento). Sin embargo, la prevalencia de infección (el 48 frente al 54,5 por ciento) y la incidencia de complicaciones biliares (el 26 frente al 20 por ciento) no han presentado variaciones significativas. La supervivencia actuarial de los pacientes trasplantados desde 1990 es del 83 y del 70 por ciento al año y a los 5 años, respectivamente. Conclusiones: Se observa una mejoría notable y progresiva de los resultados del trasplante hepático. Sin embargo, los tumores de novo, la recidiva de la hepatitis por virus C y el rechazo crónico pueden limitar los resultados a largo plazo. (AU)