RESUMEN
BACKGROUND: Despite the current highly effective therapies with direct-acting antiviral agents (DAAs), some patients with chronic hepatitis C virus (HCV) infection still do not achieve sustained virological response (SVR) and require retreatment. Sofosbuvir/velpatasvir/voxilaprevir (SVV) is recommended as the first-line retreatment option for most patients. The aim of this study was to evaluate the efficacy of SVV as salvage therapy after at least one course of DAA. METHODS: Data were collected on all HCV-infected patients who failed DAAs and were prescribed SVV from a prospective Canadian registry (CANUHC) including 17 sites across Canada. Factors associated with failure to achieve SVR with SVV therapy and the utility of RAS testing and ribavirin use were evaluated. RESULTS: A total of 128 patients received SVV after non-SVR with DAA treatment: 80% male, median age 57.5 (31-86), 44% cirrhotic, and 17 patients post liver transplant. First line regimens included: sofosbuvir/velpatasvir (27.3%), sofosbuvir/ledipasvir (26.5%), grazoprevir/elbasvir (12.5%), other (33.5%). Ribavirin was added to SVV in 26 patients due to past sofosbuvir/velpatasvir use (nâ =â 8), complex resistance associated substitution profiles (nâ =â 16) and/or cirrhosis (nâ =â 9). Overall SVR rate was 96% (123/128). Of 35 patients who previously failed sofosbuvir/velpatasvir, 31 (88.5%) achieved SVR compared to 92 of 93 (99%) among those receiving any other regimen (Pâ =â .01). CONCLUSIONS: Similar to reports from phase 3 clinical trials, SVV proved highly effective as salvage therapy for patients who failed a previous DAA therapy. Those who failed SVV had at least 2 of the following factors: genotype 3, presence of cirrhosis, past liver transplantation, past exposure to sofosbuvir/velpatasvir and/or complex resistance profiles.
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Antivirales , Hepatitis C Crónica , Ácidos Aminoisobutíricos , Antivirales/uso terapéutico , Canadá , Carbamatos , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Masculino , Persona de Mediana Edad , Prolina/análogos & derivados , Estudios Prospectivos , Quinoxalinas , Sistema de Registros , Terapia Recuperativa , Sofosbuvir/uso terapéutico , SulfonamidasRESUMEN
BACKGROUND: Diabetes mellitus (DM) is said to adversely affect transplant outcomes. The aim of this study was to investigate the impact of pre-existing and new-onset DM on liver transplantation (LT) recipients. METHODS: A single-center retrospective analysis of prospectively collected data of LT recipients (1990-2015) was undertaken. RESULTS: Of the 2209 patients, 13% (n = 298) had Pre-DM, 16% (n = 362) developed post-transplant diabetes mellitus (PTDM), 5% (n = 118) developed transient hyperglycemia (t-HG) post-LT, and 65% (n = 1431) never developed DM (no DM). Baseline clinical characteristics of patients with PTDM were similar to that of patients with Pre-DM. Incidence of PTDM peaked during the first year (87%) and plateaued thereafter. On multivariate analysis (Bonferroni-corrected), nonalcoholic fatty liver disease and the use of tacrolimus and sirolimus were independently associated with PTDM development. Both Pre-DM and PTDM patients had satisfactory and comparable glycemic control throughout the follow-up period. Those who developed t-HG seem to have a unique characteristic compared with others. Overall, 9%, 5%, and 8% of patients developed end-stage renal disease (ESRD), major cardiovascular event (mCVE), and de novo cancer, respectively. Both Pre-DM and PTDM did not adversely affect patient survival, retransplantation, or de novo cancer. The risks of ESRD and mCVE were significantly higher in patients with Pre-DM followed by PTDM and no DM. CONCLUSIONS: In this largest nonregistry study, patients with Pre-DM and PTDM share similar baseline clinical characteristics. Pre-DM increases the risk of ESRD and mCVE; however, patient survival was comparable to those with PTDM and without diabetes. Understanding the impact of PTDM would need prolonged follow-up.
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Diabetes Mellitus/etiología , Rechazo de Injerto/complicaciones , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias/etiología , Receptores de Trasplantes , Diabetes Mellitus/epidemiología , Enfermedad Hepática en Estado Terminal/cirugía , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND & AIMS: Radiofrequency ablation (RFA) is an effective treatment for single hepatocellular carcinoma (HCC) ≤3â¯cm. Disease recurrence is common, and in some patients will occur outside transplant criteria. We aimed to assess the incidence and risk factors for recurrence beyond Milan criteria in potentially transplantable patients treated with RFA as first-line therapy. METHODS: We performed a retrospective cohort study of potentially transplantable patients with new diagnoses of unifocal HCC ≤3â¯cm that underwent RFA as first-line therapy between 2000-2015. We defined potentially transplantable patients as those aged <70â¯years without any comorbidities that would preclude transplant surgery. Incidence of recurrence beyond Milan criteria was compared across 2 groups according to HCC diameter at the time of ablation: (HCC ≤2â¯cm vs. HCC >2â¯cm). Competing risks Cox regression was used to identify predictors of recurrence beyond Milan criteria. RESULTS: We included 301 patients (167 HCC ≤2â¯cm and 134 HCC >2â¯cm). Recurrence beyond Milan criteria occurred in 36 (21.6%) and 47 (35.1%) patients in the HCC ≤2â¯cm and the HCC >2â¯cm groups, respectively (pâ¯=â¯0.01). The 1-, 3- and 5-year actuarial survival rates after RFA were 98.2%, 86.2% and 79.0% in the HCC ≤2â¯cm group vs. 93.3%, 77.6% and 70.9% in the HCC >2â¯cm group (pâ¯=â¯0.01). Tumor size >2â¯cm (hazard ratio 1.94; 95%CI 1.25-3.02) and alpha-fetoprotein levels at the time of ablation (100-1,000â¯ng/ml: hazard ratio 2.05; 95%CI 1.10-3.83) were found to be predictors of post-RFA recurrence outside Milan criteria. CONCLUSION: RFA for single HCC ≤3â¯cm provides excellent short- to medium-term survival. However, we identified patients at higher risk of recurrence beyond Milan criteria. For these patients, liver transplantation should be considered immediately after the first HCC recurrence following RFA. LAY SUMMARY: Radiofrequency ablation and liver transplantation are treatment options for early stages of hepatocellular carcinoma (HCC). After ablation some patients will experience recurrence or metastatic spread of the initial tumor or may develop new tumors within the liver. Despite close follow-up, these recurrences can progress rapidly and exceed transplant criteria, preventing the patient from receiving a transplant. We identified that patients with HCC >2â¯cm and higher serum alpha-fetoprotein are at greater risk of recurrence beyond the transplant criteria. These data suggest that liver transplantation should be considered immediately after the first HCC recurrence for these patients.
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Carcinoma Hepatocelular/cirugía , Ablación por Catéter/métodos , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Estudios Retrospectivos , alfa-Fetoproteínas/análisisRESUMEN
OBJECTIVES: We assessed the impact of sofosbuvir-based regimens on renal function in liver transplant recipients with recurrent hepatitis C virus and the role of renal function on the efficacy and safety of these regimens. MATERIALS AND METHODS: In an expanded pan-Canadian cohort, 180 liver transplant recipients were treated with sofosbuvir-based regimens for hepatitis C virus recurrence from January 2014 to May 2015. Mean age was 58 ± 6.85 years, and 50% had F3/4 fibrosis. Patients were stratified into 4 groups based on baseline estimated glomerular filtration rate (calculated by the Modification of Diet in Renal Disease formula): < 30, 30 to 45, 46 to 60, and > 60 mL/min/173 m2. The primary outcome was posttreatment changes in renal function from baseline. Secondary outcomes included sustained virologic response at 12 weeks posttreatment and anemia-related and serious adverse events. RESULTS: Posttreatment renal function was improved in most patients (58%). Renal function declined in 22% of patients, which was more marked in those with estimated glomerular filtration rate < 30 mL/min/173 m2, advanced cirrhosis (P = .05), and aggressive hepatitis C virus/fibrosing cholestatic hepatitis (P < .05). High rates (80%-88%) of sustained virologic response at 12 weeks posttreatment were seen across all renal function strata. Cirrhotic patients with glomerular filtration rates < 30 mL/min/173 m2 had sustained virologic response rates at 12 weeks posttreatment comparable to the overall patient group. Rates of anemia-related adverse events and transfusion requirements increased across decreasing estimated glomerular filtration rate groups, with notably more occurrences with ribavirin-based regimens. CONCLUSIONS: Sofosbuvir-based regimens improved overall renal function in liver transplant recipients, with sustained virologic response, suggesting an association of subclinical hepatitis C virus-related renal disease. Sustained virologic response rates at 12 weeks posttreatment (80%-88%) were comparable regardless of baseline renal function but lower in cirrhosis.
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Antivirales/uso terapéutico , Tasa de Filtración Glomerular/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Enfermedades Renales/fisiopatología , Riñón/efectos de los fármacos , Trasplante de Hígado/efectos adversos , Sofosbuvir/uso terapéutico , Anciano , Antivirales/efectos adversos , Canadá/epidemiología , Quimioterapia Combinada , Femenino , Hepatitis C/diagnóstico , Hepatitis C/epidemiología , Hepatitis C/virología , Humanos , Riñón/fisiopatología , Enfermedades Renales/diagnóstico , Enfermedades Renales/epidemiología , Masculino , Persona de Mediana Edad , Recuperación de la Función , Recurrencia , Estudios Retrospectivos , Sofosbuvir/efectos adversos , Respuesta Virológica Sostenida , Factores de Tiempo , Resultado del TratamientoRESUMEN
Portal vein thrombosis (PVT) is a severe complication after liver transplantation that can result in increased morbidity and mortality. Few data are available regarding risk factors, classification, and treatment of PVT after living donor liver transplantation (LDLT). Between January 2004 and November 2014, 421 adult-to-adult LDLTs were performed at our institution, and they were included in the analysis. Perioperative characteristics and outcomes from patients with no-PVT (n = 393) were compared with those with de novo PVT (total portal vein thrombosis [t-PVT]; n = 28). Ten patients had early portal vein thrombosis (e-PVT) occurring within 1 month, and 18 patients had late portal vein thrombosis (l-PVT) appearing later than 1 month after LDLT. Analysis of perioperative variables determined that splenectomy was associated with t-PVT (hazard ratio [HR], 3.55; P = 0.01), e-PVT (HR, 4.96; P = 0.04), and l-PVT (HR, 3.84; P = 0.03). In contrast, donor age was only found as a risk factor for l-PVT (HR, 1.05; P = 0.01). Salvage rate for treatment in e-PVT and l-PVT was 100% and 50%, respectively, without having an early event of rethrombosis. Mortality within 30 days did not show a significant difference between groups (no-PVT, 2% versus e-PVT, 10%; P = 0.15). No significant differences were found regarding 1-year (89% versus 92%), 5-year (79% versus 82%), and 10-year (69% versus 79%) graft survival between the t-PVT and no-PVT groups, respectively (P = 0.24). The 1-year (89% versus 96%), 5-year (82% versus 86%), and 10-year (79% versus 83%) patient survival was similar for the patients in the no-PVT and t-PVT groups, respectively (P = 0.70). No cases of graft loss occurred as a direct consequence of PVT. In conclusion, the early diagnosis and management of PVT after LDLT can lead to acceptable early and longterm results without affecting patient and graft survival.
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Trasplante de Hígado/efectos adversos , Donadores Vivos , Vena Porta , Esplenectomía/efectos adversos , Trombosis de la Vena/etiología , Adulto , Femenino , Supervivencia de Injerto , Humanos , Circulación Hepática , Trasplante de Hígado/métodos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Ontario , Vena Porta/diagnóstico por imagen , Vena Porta/fisiopatología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Esplenectomía/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular , Trombosis de la Vena/diagnóstico por imagen , Trombosis de la Vena/mortalidad , Trombosis de la Vena/fisiopatologíaRESUMEN
Immunotherapy with immune checkpoint inhibitors (ICIs) may be considered as a treatment option for various types of tumors, but the transplant recipient population as well as patients requiring long-term systemic immunosuppression for other reasons have been systematically excluded from clinical trials involving ICIs. We report a case of successful treatment with ICI in a liver transplant recipient diagnosed with a rare subtype of melanoma. This patient had not required any modification to her antirejection immunosuppression before or during immunotherapy, had not experienced any serious immune-related adverse event, and had a durable objective response for nearly 1.5 year now. A summary of a literature review on other case reports is included to show that ICIs can be safe and provide clinically meaningful benefit in transplant patients, although acute rejection and graft loss remain a significant risk. Given the serious complication of graft failure, a detailed discussion of risks and benefits with immunotherapy needs to be made for an informed consent. Nevertheless, transplant recipients with cancer should not be deprived of this potentially life-saving or life-prolonging treatment, and inclusion of this population in future clinical trials should be considered.
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Antineoplásicos Inmunológicos/uso terapéutico , Ipilimumab/uso terapéutico , Neoplasias Hepáticas/terapia , Trasplante de Hígado , Melanoma/terapia , Antígeno CTLA-4/antagonistas & inhibidores , Terapia Combinada , Femenino , Humanos , Neoplasias Hepáticas/secundario , Melanoma/patología , Persona de Mediana Edad , PronósticoRESUMEN
Whether and when recovery beyond the need for transplant may occur in patients listed for decompensation remains unclear. This study aimed to investigate the characteristics of patients delisted following recompensation. Seventy-seven patients who were listed between 2005 and 2015 for decompensation, but later delisted following recompensation were included. Alcohol-related liver disease (ALD) was the underlying etiology in the majority (n = 47, 61%). Listing characteristics of these patients were compared with those of decompensated ALD patients who either underwent deceased donor liver transplantation or died on the waiting list. The model for end-stage liver disease (MELD) score <20 and serum albumin ≥32 g/l at listing were the only independent predictors of recompensation/delisting in ALD. The probability of recompensation was 70% when both factors were present at listing. Interestingly, about a tenth of decompensated ALD patients who died on the waiting list (median duration on waiting list 11 months) and a quarter of decompensated ALD patients who underwent living donor liver transplantation (median duration on waiting list 2 months) also had both factors at listing. In conclusion, ALD seems to be the most favorable etiology for recompensation beyond the need for transplantation. Both MELD and serum albumin at listing independently predict recompensation/delisting in ALD. It seems advisable to implement a period of observation for ALD patients with both favorable factors, before embarking on living donor liver transplantation.
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Hepatopatías Alcohólicas , Trasplante de Hígado/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Remisión Espontánea , Estudios Retrospectivos , Listas de EsperaRESUMEN
BACKGROUND: In parallel with the obesity epidemic, liver transplantation for nonalcoholic steatohepatitis (NASH) is increasing dramatically in North America. Although survival outcomes are similar to other etiologies, liver transplantation in the NASH population has been associated with significantly increased resource utilization. We sought to compare outcomes between live donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) at a high volume North American transplant center, with a particular focus on resource utilization. METHODS: The study population consists of primary liver transplants performed for NASH at Toronto General Hospital from 2000 to 2014. Recipient characteristics, perioperative outcomes, graft and patient survivals, and resource utilization were compared for LDLT versus DDLT. RESULTS: A total of 176 patients were included in the study (48 LDLT vs 128 DDLT). LDLT recipients had a lower model for end-stage liver disease score and were less frequently hospitalized prior to transplant. Estimated blood loss and early markers of graft injury were lower for LDLT. LDLT recipients had a significantly shorter hospitalization (intensive care unit, postoperative, and total hospitalization). CONCLUSIONS: LDLT for NASH facilitates transplantation of patients at a less severe stage of disease, which appears to promote a faster postoperative recovery with less resource utilization.
RESUMEN
Trichodysplasia spinulosa (TS) is a rare dermatologic complication associated with the immunosuppressive therapy used in solid organ transplantation. The distinctive clinical manifestation of this condition is spiny follicular papules on the face, ears, extremities, and trunk. Histopathologically, abnormally maturing hair follicles with hyperkeratotic material are noted. The condition is produced by the trichodysplasia spinulosa-associated polyomavirus. Treatment of this condition in the past has entailed a reduction in immunosuppression, topical agents such as cidofovir or retinoids, or oral valganciclovir. Herein, we report a case of generalized TS treated successfully with leflunomide.
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Enfermedades del Cabello/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Isoxazoles/uso terapéutico , Trasplante de Hígado/efectos adversos , Infecciones por Polyomavirus/tratamiento farmacológico , Prurito/tratamiento farmacológico , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Diagnóstico Diferencial , Enfermedades del Cabello/diagnóstico , Enfermedades del Cabello/patología , Enfermedades del Cabello/virología , Folículo Piloso/patología , Humanos , Terapia de Inmunosupresión , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Leflunamida , Masculino , Infecciones por Polyomavirus/diagnóstico , Infecciones por Polyomavirus/patología , Infecciones por Polyomavirus/virología , Prurito/diagnóstico , Prurito/patología , Prurito/virologíaRESUMEN
BACKGROUND: Patients with hepatocellular carcinoma (HCC) beyond the traditional criteria (advanced HCC) are typically offered palliation, which is associated with a 3-year survival rate lower than 30%. This study aimed to describe the outcomes for a subset of patients with advanced HCC who satisfied the Extended Toronto Criteria (ETC) and were listed for liver transplantation (LT). METHODS: All patients listed in the Toronto liver transplantation program with HCC beyond both the Milan and University of California, San Francisco criteria were included in this study. Data were extracted from the prospectively collected electronic database. All radiologic images were reviewed by two independent radiologists. The primary end point was patient survival. RESULTS: Between January 1999 and August 2014, 96 patients with advanced HCC were listed for LT, and 62 (65%) of these patients received bridging therapy while on the waiting list. Bridging therapy led to a significant reduction in tumor progression (p = 0.02) and tumor burden (p < 0.001). The majority of those listed underwent LT (n = 69, 72%). Both tumor progression on waiting list (hazard ratio [HR] 4.973; range1.599-15.464; p = 0.006) and peak alpha-fetoprotein (AFP) at 400 ng/ml or higher (HR, 4.604; range 1.660-12.768; p = 0.003) were independently associated with waiting list dropout. Post-LT HCC recurrence occurred in 35% of the patients (n = 24). Among those with HCC recurrence, survival was significantly better for those who received curative treatment (p = 0.004). The overall actuarial survival rates from the listing were 76% at 1 year, 56% at 3 years, and 47% at 5 years, and the corresponding rates from LT were 93, 71, and 66%. CONCLUSION: Liver transplantation provides significantly better survival rates than palliation for patients with selected advanced HCC.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Selección de Paciente , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: This study evaluates the efficacy, safety, and tolerability of regimens containing sofosbuvir (SOF) in the treatment of hepatitis C virus (HCV) recurrence in all genotypes in patients outside of clinical trials in all Canadian transplant centers. METHODS: One hundred twenty liver transplantation recipients from across Canada with HCV recurrence were started on SOF-based regimens (SOF + simeprevir ± ribavirin (RBV), n = 53; SOF + pegylated interferon + RBV, n = 25; SOF + RBV, n = 36; and SOF + ledipasvir, n = 6) between January and November 2014. Mean age 58 ± 6.85 years, majority (83%) were genotype 1, male (81%), and treatment experienced (82%). Twenty-seven percent had fibrosing cholestatic hepatitis/early aggressive HCV in the graft, and 48% had F3/4 fibrosis. The primary outcomes included patient and graft survival, on- and end-of-treatment response and sustained virological response at 12 weeks after treatment end (SVR12), and adverse events. RESULTS: One hundred thirteen of 120 (94%) patients were HCV RNA undetectable at end of treatment, and SVR12 was achieved in 102/120 (85%) patients, with 7 relapses, 1 nonresponder, and 10 deaths (liver-related complications). Sixty-three percent had HCV RNA levels below the lower limit of quantification at week 4. Serum creatinine levels remained stable throughout the treatment. Severe anemia occurred in 13% of patients, primarily in RBV-based regimens. CONCLUSIONS: Sofosbuvir-based antiviral therapy for HCV recurrence after liver transplantation was well tolerated, with an overall high SVR12 rate (85%) including patients with severe disease recurrence and F3-4 cirrhosis. The response rate was higher (91%) in mild HCV recurrence, suggesting earlier treatment might be beneficial.
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Antivirales/administración & dosificación , Hepatitis C/tratamiento farmacológico , Trasplante de Hígado , Sofosbuvir/administración & dosificación , Anciano , Biopsia , Canadá , Creatinina/sangre , Femenino , Fibrosis , Genotipo , Tasa de Filtración Glomerular , Hepatitis C/cirugía , Humanos , Interferones/administración & dosificación , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/análisis , Recurrencia , Ribavirina/administración & dosificación , Simeprevir/administración & dosificaciónRESUMEN
BACKGROUND: The literature regarding post-transplant lymphoproliferative disorder (PTLD) in liver transplant recipients (LTRs) is limited. OBJECTIVES: To study the incidence, predictors and outcomes of PTLD after liver transplantation in a single, large-volume centre. METHODS: The charts of all LTRs (n=1372) in the authors' centre between January 2000 and June 2012 were retrospectively reviewed and those who developed PTLD were identified. Demographic, clinical and treatment data were prospectively collected. Responses to treatment, including complete response, no response, relapse and survival, were recorded. RESULTS: The incidence of PTLD in LTRs was 32 in 1372 (2.3%). Overall, median survival was 37 months (range 0.5 to 195 months), with one-, three- and five-year survival rates of 81%, 74% and 60%, respectively. Epstein-Barr virus (EBV)-negative patients had a better mean (± SD) survival (95±79 months) than EBV-positive patients (41±42 months) (P=0.02). For stage I/II PTLD, one-, three- and five-year actuarial survival was 87%, 87% and 75%, compared with 50%, 30% and 0% for stage III/IV PTLD, respectively (P=0.001). In patients with complete response, median survival was 58 months (range 10 to 195 months); and one-, three- and five-year actuarial survival was 100%, 94% and 76%, respectively, after diagnosis of PTLD. Changing immunosuppression (IS) from calcineurin inhibitor to sirolimus at the time of diagnosis may have improved survival (seven of seven survivors) compared with only decreasing or stopping IS (14 of 25 survivors) (P=0.07). CONCLUSIONS: This series from a single large-volume centre showed excellent short and long-term survival after PTLD in adult LTRs who were EBV negative, had early disease and showed complete response. Consistent with the known in vitro antiproliferative effect of sirolimus, switching IS from calcineurin inhibitor to sirolimus may improve survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Hígado , Trastornos Linfoproliferativos/terapia , Complicaciones Posoperatorias/terapia , Rituximab/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Inhibidores de la Calcineurina/efectos adversos , Inhibidores de la Calcineurina/uso terapéutico , Quimioradioterapia , Ciclofosfamida/uso terapéutico , Bases de Datos Factuales , Doxorrubicina/uso terapéutico , Infecciones por Virus de Epstein-Barr/inducido químicamente , Infecciones por Virus de Epstein-Barr/epidemiología , Femenino , Rechazo de Injerto/prevención & control , Enfermedad de Hodgkin/inducido químicamente , Enfermedad de Hodgkin/epidemiología , Enfermedad de Hodgkin/terapia , Hospitales de Alto Volumen , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Incidencia , Linfoma de Células B Grandes Difuso/inducido químicamente , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/terapia , Linfoma no Hodgkin/inducido químicamente , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/terapia , Trastornos Linfoproliferativos/inducido químicamente , Trastornos Linfoproliferativos/epidemiología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/inducido químicamente , Complicaciones Posoperatorias/epidemiología , Prednisona/uso terapéutico , Estudios Retrospectivos , Sirolimus/efectos adversos , Sirolimus/uso terapéutico , Vincristina/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: The optimal cutoff of each value in configuring selection criteria for pre-transplant assessment of hepatocellular carcinoma (HCC) remains uncertain. METHODS: To build a predictive model for recurrent HCC, we performed data mining analysis on patients who underwent LT for HCC at University Health Network (n = 246). The model was externally validated using a cohort from the Scientific Registry of Transplant Recipients (SRTR) database (n = 9,769). RESULTS: Among 246 patients, 14.6% (n = 36) experienced recurrent HCC within 2.5 years post-LT. The risk prediction model for recurrent HCC identified two subgroups with low-risk (total tumor diameter [TTD] <4 cm and serum alpha-fetoprotein [AFP] <73 ng/ml, n = 135) and with high-risk (TTD >4 cm and/or AFP >73 ng/ml, n = 111). The reproducibility of the model was validated through the SRTR database; overall patient survival rate was significantly better in low-risk group than high-risk group (P < 0.0001). Using Cox regression model, this yardstick, not Milan criteria, was revealed to efficiently predict post-transplant survival independent of underlying characteristics (P < 0.0001). CONCLUSIONS: Grouping LT candidates with pre-LT HCC by the cutoffs of TTD 4 cm and AFP 73 ng/ml which were unearthed by data mining analysis efficiently classify patients according by the post-transplant prognosis.
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Carcinoma Hepatocelular/cirugía , Minería de Datos/métodos , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/mortalidad , Recurrencia Local de Neoplasia/cirugía , Selección de Paciente , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Treatment outcomes of recurrent HCV genotype 3 (GT-3) after liver transplantation (LT) are ill-defined. AIMS: To determine efficacy, predictors, and long-term survival after treatment of recurrent HCV GT-3 infection, post-LT, with a combination of pegylated interferon (PEG) and ribavirin (RBV). METHODS: We studied all LT recipients (LTR) in our program treated with PEG and RBV for recurrent HCV GT-3 between Jan 1st 2002 and Dec 31st 2013. Antiviral therapy (AVT) was started if histology showed recurrent HCV with ≥ stage 2 fibrosis. Treatment was intended for 24 or 36 weeks, depending on early virologic response, and/or 24 weeks consolidation. Primary endpoint was sustained virological response (SVR). We also studied predictors of SVR and long-term patient survival. RESULTS: Among 492 LT for HCV-related cirrhosis and/or hepatocellular carcinoma performed during the study period, 110 (22%) had HCV GT-3 infection. Fifty-two (10.5%) HCV GT-3 patients had indications for AVT. Six were unable to complete the AVT, three because of clinical decompensation and one each because of metastatic disease involving the brain, lung cancer, and ductopenic rejection. Forty-seven (90%) patients achieved early virological response (EVR) and 37 (71%) achieved SVR. Predictors of SVR were EVR (p < 0.001), stage ≤ 3 fibrosis (p = 0.008), and 36 weeks treatment duration (p < 0.001). Less advanced fibrosis ≤ 3 was independent predictor of SVR (OR 0.18, 95% CI 0.05-0.67). SVR patients had actuarial (Kaplan-Meier) 1, 3, and 10 year post-treatment survival of 100, 100, and 95%, compared with 87, 78, and 20% for non-SVR patients (p < 0.001, log rank test). CONCLUSION: Efficacy of AVT for recurrent HCV GT-3 post-LT is high, and comparable with that for non-transplant patients. Less advanced fibrosis is an independent predictor of SVR. SVR improves long-term survival.
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Antivirales/uso terapéutico , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Trasplante de Hígado , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Adulto , Anciano , Carcinoma Hepatocelular/cirugía , Femenino , Genotipo , Hepacivirus/genética , Hepatitis C Crónica/cirugía , Hepatitis C Crónica/virología , Humanos , Interferón alfa-2 , Cirrosis Hepática/patología , Cirrosis Hepática/cirugía , Cirrosis Hepática/virología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , ARN Viral/sangre , Proteínas Recombinantes/uso terapéutico , Recurrencia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Hepatitis C (HCV) continues to be the leading indication for liver transplantation (LT). Sustained virological response (SVR) rates to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy for recurrent HCV in Genotype 1 (G1) LT recipients have been disappointing (30-40%). Experience with triple therapy using protease inhibitors (PI) boceprevir (BOC), telaprevir (TVR) in these patients has been limited. MATERIAL AND METHODS: This national multicenter retrospective study included 76 patients (64 male, mean age 57 ± 6 years), treated for G1 HCV recurrence with either BOC (n = 41) or TVR (n = 35), who were non-responders or relapsers (n = 54), treatment naïve (n = 22) or had fibrosing cholestatic HCV (n = 3). 53 patients were on cyclosporine, 22 on tacrolimus and one patient on prednisone alone. RESULTS: On treatment virologic response was observed in 84% (64/76), 83% in BOC and 85% in TVR group. A higher week 4 response after starting triple therapy (RVR) was noted in TVR group 25/35 (81%) as compared to BOC group 26/41 (63%); p value = 0.02. The end of treatment response was 78% and 75% in BOC and TVR group, respectively. SVR 12 weeks after treatment discontinuation was observed in 59.5% (22/37); 58.3% in the BOC group and 61.5% in TVR group. Treatment was discontinued early in 23 patients (serious adverse effects n = 19, treatment failure n = 4). Infections occurred in 5 patients with 2 deaths (all in BOC). Anemia was the most common side effect (n = 55, 72%) requiring erythropoietin and RBV dose reduction. In the BOC group, cyclosporine dose reduction was 2.2 ± 1.0 fold and 8.6 ± 2.4 fold with tacrolimus. In TVR group, dose reduction was 3.0 ± 1.4 with cyclosporine and 12 ± 5.7 fold with tacrolimus. CONCLUSIONS: PI-based triple therapy appears more effective in producing HCV-RNA clearance than dual therapy. Tolerability is a serious issue and drug-drug interactions are manageable with close monitoring.
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Antivirales/uso terapéutico , Enfermedad Hepática en Estado Terminal/cirugía , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Trasplante de Hígado/efectos adversos , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , Inhibidores de Proteasas/uso terapéutico , Activación Viral/efectos de los fármacos , Antivirales/efectos adversos , Canadá , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Enfermedad Hepática en Estado Terminal/virología , Femenino , Hepacivirus/enzimología , Hepacivirus/genética , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/diagnóstico , Humanos , Inmunosupresores/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Oligopéptidos/efectos adversos , Prolina/efectos adversos , Prolina/uso terapéutico , Inhibidores de Proteasas/efectos adversos , ARN Viral/sangre , Recurrencia , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Carga Viral , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismoRESUMEN
BACKGROUND: Hepatitis B immunoglobulin (HBIG) given in combination with a nucleos(t)ide analogue has reduced the rate of recurrent hepatitis B virus (HBV) infection following liver transplantation (LT); however, the most effective protocol remains unclear. OBJECTIVE: To evaluate the use of tenofovir disoproxil fumarate (TDF) in combination with one year of low-dose HBIG. METHODS: Twenty-four adults who underwent LT for HBV-related liver disease at the University Health Network (Toronto, Ontario) and received TDF (± lamivudine) and one year of HBIG to prevent recurrent HBV infection from June 2005 to June 2011 were evaluated. RESULTS: The median length of follow-up post-LT was 29.1 months. Three patients died during the follow-up period. Patient survival was 100% and 84.1% at one and five years, respectively. None of the patients developed recurrent HBV infection. No significant adverse event was observed due to TDF administration; renal function pre- and post-LT were also acceptably preserved. CONCLUSION: The present study demonstrated that a short, finite course of low-dose HBIG combined with maintenance of long-term TDF staring before LT is cost-effective and safe. However, further prospective study involving a larger patient cohort with a longer follow-up period is required to confirm the results.
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Adenina/análogos & derivados , Antivirales/uso terapéutico , Hepatitis B Crónica/terapia , Inmunoglobulinas/uso terapéutico , Trasplante de Hígado , Organofosfonatos/uso terapéutico , Adenina/uso terapéutico , Adulto , Anciano , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Prevención Secundaria , Tenofovir , Resultado del TratamientoRESUMEN
BACKGROUND: Hepatitis C virus (HCV) infection remains the leading indication for liver transplantation (LT) worldwide. Recurrent hepatitis C following LT is universal, and significant fibrosis (SF, Metavir fibrosis stage ≥2) apparent on protocol biopsy typically prompts antiviral therapy. OBJECTIVE: To determine the optimal timing of protocol liver biopsies in this setting. METHODS: A total of 151 patients who underwent LT related to HCV infection between July 2004 and December 2009 were analyzed retrospectively. Data regarding protocol liver biopsies at six, 12 and 24 months post-LT, conventional laboratory parameters and demographic information were obtained. RESULTS: The 151 patients included in the present study had significantly lower serum aspartate aminotransferase (AST) levels than the four patients who progressed to receive antiviral treatment for SF before six months post-LT (P<0.001). AST level, but not alanine aminotransferase level, histological activity or fibrosis stage at the six-month biopsy was independently associated with the progression to SF at 12 months (P<0.05). However, AST level, histological activity and fibrosis stage at the 12-month biopsy emerged as independent parameters associated with progression to SF at 24 months (P<0.05). CONCLUSION: The protocol liver biopsy at six months could be eliminated, especially in patients who consistently exhibit low AST levels. Histological activity, the presence or absence of fibrosis, and AST values at the 12-month biopsy may lead to the decision to defer the protocol biopsy at 24 months or result in earlier introduction of antiviral therapy.
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Aspartato Aminotransferasas/sangre , Hepatitis C Crónica/cirugía , Cirrosis Hepática/sangre , Trasplante de Hígado , Hígado/patología , Adulto , Anciano , Antivirales/uso terapéutico , Biomarcadores/sangre , Biopsia/estadística & datos numéricos , Protocolos Clínicos , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Humanos , Cirrosis Hepática/patología , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
The transition from regular use of cyclosporine to the newer calcineurin-inhibitors, such as tacrolimus, has been suggested as a contributing factor to the "era effect" of worsening outcomes of post-transplant HCV recurrence. This retrospective medical chart review of 458 patients was undertaken to evaluate the role of immunosuppressant choice (cyclosporine vs. tacrolimus) in determining virologic response and clinical outcomes of post-liver transplant HCV infection recurrence. Our results showed that patients undergoing interferon-based treatment taking cyclosporine have significantly better odds (OR: 2.59, P = 0.043) of presenting a sustained viral response (66.7%) compared to tacrolimus (52.8%). This did not result in a significant effect on post-liver transplantation clinical events including HCV-related deaths, graft loss, fibrosing cholestatic hepatitis, hepatocellular carcinoma or graft rejection. Other variables, which showed a significant relationship with the achievement of sustained viral response included donor age (OR 0.96, P = 0.001) and HCV genotype 1 infection (OR 0.05, P < 0.001). The observed significant increase in the odds of acute/hyperacute (OR 6.49, P = 0.001) and chronic rejection (OR 10.45, P < 0.001) in the cyclosporine to tacrolimus switch group, accompanied by an increase in the odds of HCV-related death (OR 2.30, P < 0.047) compared to tacrolimus merits further study. A significant increase (P < 0.044) in new-onset diabetes mellitus with tacrolimus (28.3%) compared to cyclosporine (18.7%) was also observed. Pre-transplant diabetes mellitus was associated with a significantly increased likelihood of graft fibrosis (HR 1.95, P = 0.003).
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Ciclosporina/uso terapéutico , Hepatitis C/complicaciones , Inmunosupresores/uso terapéutico , Trasplante de Hígado/inmunología , Tacrolimus/uso terapéutico , Adulto , Antivirales/uso terapéutico , Biomarcadores/sangre , Canadá , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/virología , Distribución de Chi-Cuadrado , Ciclosporina/efectos adversos , Diabetes Mellitus/etiología , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/virología , Hepacivirus/genética , Hepatitis C/diagnóstico , Hepatitis C/tratamiento farmacológico , Hepatitis C/mortalidad , Hepatitis C/virología , Humanos , Inmunosupresores/efectos adversos , Estimación de Kaplan-Meier , Cirrosis Hepática/inmunología , Cirrosis Hepática/virología , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/virología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , ARN Viral/sangre , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Tacrolimus/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Carga ViralRESUMEN
Recurrent hepatitis C virus (HCV) infection occurs universally and is regarded as a major cause of mortality after liver transplantation (LT) for HCV-related end-stage liver disease. We conducted this large, single-center, retrospective study to ascertain the long-term impact of virological response to treatment of recurrent hepatitis C on survival of LT recipients. From August 1987 to October 2011, 285 patients have received interferon-based antiviral therapy for recurrent hepatitis C. Of these 285, 245 patients were enrolled in this study. One hundred and twenty-six patients (51.4%) achieved sustained virological response (SVR). Relapsers (undetectable HCV-RNA at end of treatment, becoming positive afterward) comprised 9.0% (22/245), and nonresponse (NR; never achieving undetectable HCV-RNA) 39.6% (97/245). The median follow-up after completion of antiviral treatment was 2081 days. Using Kaplan-Meier method, patients who achieved SVR were shown to have significantly better 5-year patient survival (95.2%) than the NR group (49.9%) (P < 0.001), and a trend toward better 5-year survival than relapsers (87.5%) (P = 0.14); relapsers had a significantly longer survival than NR group (P = 0.005). When compared with NR, SVR and relapse appeared to be significant predictors of better survival, independent of underlying characteristics. In conclusion, virological response, especially SVR, translates into markedly improved long-term patient outcomes in patients transplanted for hepatitis C.
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Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Trasplante de Hígado/mortalidad , Adulto , Anciano , Femenino , Supervivencia de Injerto , Hepatitis C/virología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Recurrencia , Estudios Retrospectivos , Factores de TiempoRESUMEN
Hepatitis B immunoglobulin (HBIG), given in combination with nucleos(t)ide therapy, has reduced the rate of recurrent hepatitis B virus (HBV) following liver transplantation (LT), although the most effective protocol is unknown. We have retrospectively evaluated the use of long-term nucleos(t)ide analog in combination with one yr of low-dose HBIG. One hundred and fifty-two adults with HBV-related liver disease underwent LT in our center from January 1999 to August 2009; of these, 132 patients who received one yr of HBIG combined with long-term nucleos(t)ide analogs (largely on lamivudine [LAM] alone, n = 97) afterward were included for the purposes of this study. Median follow-up post-transplantation was 1752 d. Patient survival was 93.9%, 86.9% and 84.1% at 1, 5, and 10 yr, respectively; none of the 17 deceased patients had recurrent HBV. HBV recurrence was observed in nine patients (all received LAM+HBIG), yielding recurrence rates of 2.3%, 5.1%, and 8.6% at 1, 3, and 5/10 yr, respectively. All recurrences were successfully managed, usually with additional antiviral treatment. In conclusion, this study, with its long-term follow-up, demonstrates that short course of low-dose HBIG (without anti-HBs monitoring) combined with the use of long-term nucleos(t)ide analog is effective and less cumbersome than many protocols in current use.