Hepatitis C virus infection in Argentina: Burden of chronic disease.

AIM: To estimate the progression of the hepatitis C virus (HCV) epidemic and measure the burden of HCV-related morbidity and mortality. METHODS: Age- and gender-defined cohorts were used to follow the viremic population in Argentina and estimate HCV incidence, prevalence, hepatic complications, and mortality. The relative impact of two scenarios on HCV-related outcomes was assessed: (1) increased sustained virologic response (SVR); and (2) increased SVR and treatment. RESULTS: Under scenario 1, SVR raised to 85%-95% in 2016. Compared to the base case scenario, there was a 0.3% reduction in prevalent cases and liver-related deaths by 2030. Given low treatment rates, cases of hepatocellular carcinoma and decompensated cirrhosis decreased < 1%, in contrast to the base case in 2030. Under scenario 2, the same increases in SVR were modeled, with gradual increases in the annual diagnosed and treated populations. This scenario decreased prevalent infections 45%, liver-related deaths 55%, liver cancer cases 60%, and decompensated cirrhosis 55%, as compared to the base case by 2030. CONCLUSION: In Argentina, cases of end stage liver disease and liver-related deaths due to HCV are still growing, while its prevalence is decreasing. Increasing in SVR rates is not enough, and increasing in the number of patients diagnosed and candidates for treatment is needed to reduce the HCV disease burden. Based on this scenario, strategies to increase diagnosis and treatment uptake must be developed to reduce HCV burden in Argentina.

Fibrosis progression in maintenance liver transplant patients with hepatitis C recurrence: a randomised study of everolimus vs. calcineurin inhibitors.

BACKGROUND & AIMS: Robust clinical data evaluating fibrosis progression in hepatitis C virus (HCV) liver transplant patients receiving an mTOR inhibitor vs. calcineurin inhibitor (CNI) are lacking. To evaluate fibrosis progression in maintenance liver transplant patients receiving everolimus- or CNI-based immunosuppression. METHODS: In a randomised, multicentre, open-label study, 43 maintenance liver transplant patients with recurrent HCV infection were randomised to continue CNI-based immunosuppression or switch to everolimus. RESULTS: For patients with biopsy data at month 12, mean Ishak-Knodell fibrosis score at baseline was 2.6 ± 0.9 (n = 14) with everolimus vs. 1.9 ± 1.1 (n = 18) with CNI (P = 0.043), and 1.9 ± 1.2 vs. 2.2 ± 1.3 at month 12. Ishak-Knodell fibrosis score decreased from baseline to month 12 by a mean of -0.7 ± 1.1 with everolimus, but increased by 0.2 ± 1.2 with CNI (P = 0.046). No acute rejection or graft losses occurred up to month 12. Estimated GFR at month 12 was 65.6 ml/min/1.73 m² with everolimus and 62.2 ml/min/1.73 m² with CNI [mean difference 3.4 ml/min/1.73 m² compared to CNI control group, 95% CI -4.9, 11.8 ml/min/1.73 m², P = 0.411 (analysis of covariance adjusting for baseline GFR)]. Adverse events occurred in 95.5% of everolimus patients and 71.4% of CNI patients (serious adverse events 31.8% and 0.0%, respectively). Adverse events led to everolimus discontinuation in five patients (22.7%). CONCLUSIONS: This exploratory study suggests that conversion from CNI to everolimus reduces progression of liver fibrosis, and preserves renal function without jeopardising efficacy in liver transplant recipients with recurrent HCV, but is associated with a higher incidence of adverse events and serious adverse events. These preliminary findings merit examination in a larger trial.

Improved waiting-list outcomes in Argentina after the adoption of a model for end-stage liver disease-based liver allocation policy.

In July 2005, Argentina became the first country after the United States to introduce the Model for End-Stage Liver Disease (MELD) for organ allocation. In this study, we investigated waiting-list (WL) outcomes (n = 3272) and post-liver transplantation (LT) survival in 2 consecutive periods of 5 years before and after the implementation of a MELD-based allocation policy. Data were obtained from the database of the national institute for organ allocation in Argentina. After the adoption of the MELD system, there were significant reductions in WL mortality [28.5% versus 21.9%, P < 0.001, hazard ratio (HR) = 1.57, 95% confidence interval (CI) = 1.37-1.81] and total dropout rates (38.6% versus 29.1%, P < 0.001, HR = 1.31, 95% CI = 1.16-1.48) despite significantly less LT accessibility (57.4% versus 50.7%, P < 0.001, HR = 1.53, 95% CI = 1.39-1.68). The annual number of deaths per 1000 patient-years at risk decreased from 273 in 2005 to 173 in 2010, and the number of LT procedures per 1000 patient-years at risk decreased from 564 to 422. MELD and Model for End-Stage Liver Disease-Sodium scores were excellent predictors of 3-month WL mortality with c statistics of 0.828 and 0.857, respectively (P < 0.001). No difference was observed in 1-year posttransplant survival between the 2 periods (81.1% versus 81.3%). Although patients with a MELD score > 30 had lower posttransplant survival, the global accuracy of the score for predicting outcomes was poor, as indicated by a c statistic of only 0.523. Patients with granted MELD exceptions (158 for hepatocellular carcinoma and 52 for other reasons) had significantly higher access to LT (80.4%) in comparison with nonexception patients with equivalent listing priority (MELD score = 18-25; 54.6%, P < 0.001, HR = 0.49, 95% CI = 0.40-0.61). In conclusion, the adoption of the MELD model in Argentina has resulted in improved liver organ allocation without compromising posttransplant survival.

Hepatitis C virus diversification in Argentina: comparative analysis between the large city of Buenos Aires and the small rural town of O'Brien.

BACKGROUND: The estimated prevalence of HCV infection in Argentina is around 2%. However, higher rates of infection have been described in population studies of small urban and rural communities. The aim of this work was to compare the origin and diversification of HCV-1b in samples from two different epidemiological scenarios: Buenos Aires, a large cosmopolitan city, and O'Brien, a small rural town with a high prevalence of HCV infection. PATIENTS AND METHODS: The E1/E2 and NS5B regions of the viral genome from 83 patients infected with HCV-1b were sequenced. Phylogenetic analysis and Bayesian Coalescent methods were used to study the origin and diversification of HCV-1b in both patient populations. RESULTS: Samples from Buenos Aires showed a polyphyletic behavior with a tMRCA around 1887-1900 and a time of spread of infection approximately 60 years ago. In contrast, samples from ÓBrien showed a monophyletic behavior with a tMRCA around 1950-1960 and a time of spread of infection more recent than in Buenos Aires, around 20-30 years ago. CONCLUSION: Phylogenetic and coalescence analysis revealed a different behavior in the epidemiological histories of Buenos Aires and ÓBrien. HCV infection in Buenos Aires shows a polyphyletic behavior and an exponential growth in two phases, whereas that in O'Brien shows a monophyletic cluster and an exponential growth in one single step with a more recent tMRCA. The polyphyletic origin and the probability of encountering susceptible individuals in a large cosmopolitan city like Buenos Aires are in agreement with a longer period of expansion. In contrast, in less populated areas such as O'Brien, the chances of HCV transmission are strongly restricted. Furthermore, the monophyletic character and the most recent time of emergence suggest that different HCV-1b ancestors (variants) that were in expansion in Buenos Aires had the opportunity to colonize and expand in O'Brien.

[Indications and timing of liver transplantation]. / Indicaciones y oportunidad del trasplante hepático.

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

Indicaciones y oportunidad del trasplante hepático / Indications and timing of liver transplantation

El trasplante hepático (TH) está indicado en pacientes con enfermedades hepáticas agudas o crónicas severas e irreversibles para las cuales no exista un tratamiento alternativo y en ausencia de contraindicaciones. Las indicaciones de TH pueden ser agrupadas en cuatro categorías: cirrosis hepática, hepatitis fulminante, tumores hepáticos y defectos genéticos de origen hepático que producen daño en otros órganos. Deben ser derivados para TH los pacientes con cirrosis que desarrollen cualquier complicación mayor o coagulopatía. La derivación precoz es "la clave del éxito" en la hepatitis fulminante por el alto riesgo de muerte y por tener una evolución mayormente impredecible. La oportunidad del TH es el momento en la historia natural de la hepatopatía cuando la sobrevida esperada es mayor con TH que en lista de espera. Estudios recientes han sugerido que el máximo beneficio del TH se obtiene en pacientes con MELD >15. Sin embargo, en algunos casos sin riesgo de muerte inminente, el objetivo del TH es mejorar la calidad de vida o prevenir contraindicaciones como la progresión del hepatocarcinoma cuando el tiempo de espera excede los 8 meses. Actualmente existe una marcada desproporción entre el número de donantes disponibles y el número creciente de potenciales receptores, lo que ha determinado un incremento progresivo del tiempo y mortalidad en lista. La racionalidad de distribuir los órganos en base al score de MELD es otorgar prioridad en la lista a los candidatos más enfermos y a aquellos que no pueden esperar como los pacientes con hepatocarcinoma.

Liver transplantation (OLT) is indicated in patients with severe and irreversible acute or chronic liver disease without alternative therapy and in the absence of contraindications. Indications for OLT can be grouped in four categories, namely cirrhosis, fulminant hepatitis, malignant hepatic tumors and liver-based genetic defects that trigger damage of other organs. Patients with cirrhosis should be referred for OLT after the onset of any of the major complications or coagulopathy. Early referral is crucial in fulminant hepatitis due to the high mortality with medical therapy and the unpredictable nature of this condition. Ideal timing for OLT is the moment in the natural history of the disease when the expected survival of patients on the waiting list is higher with than without OLT. Recent data suggest that maximal benefit of OLT is obtained in patients with a MELD score >15. However, in some cases with no imminent risk of death, OLT is indicated to improve quality of life or to prevent contraindications such as progression of hepatocellular carcinoma. At present, there is a marked disproportion between the number of donors available and the growing number of patients listed worldwide, which in turn has resulted in prolongation of the time-interval to OLT and waitlist mortality. The rationale of allocation systems utilizing the MELD score is to prioritize on the waiting list patients with severe liver dysfunction ("the sickest first") and those with hepatocellular carcinoma who may loose the benefits of OLT when waitlist time exceeds eight months.

Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico / Prevalence of liver diseases in a small rural community isolated in tne mountain heights: clinical, biochemical and ultrasonographic study

En este estudio clínico, bioquímico y ecográfico se evaluó la prevalencia de hepatopatías en Lara, una comunidad rural aislada de alta montaña en Tucumán, provincia con la máxima prevalencia de infección por HAV en niños de Argentina. Lara carece de agua potable, electricidad y cloacas. Se estudiaron 102 habitantes, lo que representa el 41% de la población. El anti-HBc y anti-HCV fueron negativos en todos los casos. Ningún niño presentó anormalidades hepáticas. El 41% de los adultos refirió ingesta alcohólica y el 12% transfusiones. Se observó incremento leve de ALT en 3 casos (6%). La ecografía demostró esteatosis en 8 individuos (16%), litiasis vesicular en 7 (14%), microcalcificaciones en 5 (10%) y quistes de aspecto parasitario en 4 (8%). La prevalencia de infección por HAV en Lara fue de 89% en adultos y 35% en niños, siendo significativamente menor que la de los niños de la ciudad de Tucumán con nivel socioeconómico medio / alto (53%, p = 0.05) o bajo (74%, p = 0.0006). La diferencia fue más evidente en niños menores de 5 años (0%, 53% y 75% respectivamente). La serología para hidatidosis fue positiva en 3/4 individuos con quistes, 2/5 con microcalcificaciones y 17/85 (20%) con ecografía normal, lo que sugiere que la técnica de Elisa utilizada se asocia a frecuentes resultados falsos positivos. El estudio poblacional de Lara demostró una elevada prevalencia de esteatosis, litiasis vesicular e hidatidosis en adultos, ausencia de infección por HBV y HCV, y una baja exposición al HAV en niños, especialmente en menores de 5 años.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p=0.05) and low (74%, p=0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged <5 years (anti-HAV in 0%, 53% y 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absenceof HBV and HCV infection and low exposure to HAV in children especially in those aged <5 years.

[Prevalence of liver diseases in a small rural community isolated in the mountain heights: clinical, biochemical and ultrasonographic study]. / Prevalencia de enfermedades hepáticas en una población rural de alta montaña: estudio clínico, bioquímico y ecográfico.

The goal of this population-based clinical, biochemical and ultrasonographic study was to assess the prevalence of liver diseases in Lara, a small rural community isolated in the mountain heights of Tucumán, a Province of Argentina with the highest reported rates of HAV infection in children. Inhabitants of Lara lack electricity, potable water and a sewer system. The study included 102 individuals representing 41% of the total population. Anti-HBc and anti-HCV were negative in all cases. No children showed clinical, biochemical or ecographic abnormalities. Among adults, 41% referred alcohol consumption and 12% blood transfusions. Only 3 adults (6%) had mildly elevated ALT. Ultrasound showed steatosis in 8 individuals (16%), gallstones in 7 (14%), parenchymal micro-calcifications in 5 (10%) and parasitic cysts in 4 (8%). Prevalence of HAV infection in Lara was 89% in adults and 35% in children, being significantly lower than that of children of medium/high (53%, p = 0.05) and low (74%, p = 0.0006) socioeconomic level from the city of Tucumán (control groups). These differences were more marked in children aged < 5 years (anti-HAV in 0%, 53% and 75% respectively). Serologic tests for echinoccocal disease were positive in 3/4 individuals with parasitic cysts, 2/5 with micro-calcifications and 17/85 (20%) with normal ultrasound, thus suggesting a high rate of false-positive results of the Elisa test utilized. This study showed that in Lara there is a high prevalence of steatosis, gallstones and equinoccocal disease in adults, absence of HBVand HCV infection and low exposure to HAV in children especially in those aged < 5 years.

Análisis de la morbi-mortalidad en 225 resecciones hepáticas / Results of liver resections

Antecedentes: La mortalidad en hepatectomías electivas se encuentra en cifras inferiores al 5 por ciento en pacientes seleccionados. Existen condiciones clínicas que implican un mayor riesgo de morbimortalidad. Las resecciones en donantes vivos para trasplantes hepáticos crean una nueva situación: exponer a individuos sanos a una cirugía compleja. Objetivo: Evaluar los resultados obtenidos en resecciones hepáticas en diferentes situaciones clínicas. Lugar de aplicación: Unidad de cirugía hepatobiliar. Diseño: Retrospectivo estratificado. Población: 225 resecciones hepáticas en 217 pacientes. Métodos: Estratificación en: grupo 1 (n=79) donantes vivos; grupo 2 (n=49) resecciones por patología benigna; grupo 3 (n=53) resecciones por tumores malignos sobre hígado normal; y grupo 4 (n=49) resecciones por tumores malignos sobre disfunción hepática. Variables analizadas: edad; riesgo quirúrgico (ASA); tipo de resección; tiempo de internación postoperatoria; complicaciones intra y postoperatorias y mortalidad a 60 días. Análisis estadístico: chi cuadrado, tests de Fisher, Student y estudios de regresión uni y multivariada. Resultados: La morbilidad global fue de 26,6 por ciento. El 19 por ciento se relacionó con el procedimiento quirúrgico. La morbilidad intraoperatoria fue 1,3 por ciento. Los pacientes ASA 3 y 4 (único predictor independiente) y las resecciones en hígados patológicos estuvieron significativamente asociados al riesgo de desarrollar complicaciones y/o muerte. La mortalidad global fue de 2 por ciento, siendo nula en los grupos 1 y 2, 1,8 por ciento en el grupo 3 y 8 por ciento en el grupo 4. Hubo una tendencia, aunque no significativa, a observar fístulas biliares en pacientes del grupo 1 y en resecciones múltiples. Conclusiones: En pacientes con co-morbilidad, las resecciones hepáticas son factibles con una adecuada selección