Access to direct-acting antivirals for the treatment of hepatitis C in a country with limited resources. / Evaluación del acceso a antivirales para el tratamiento de la hepatitis C en un país con recursos limitados.

AIMS: To estimate the number of patients that have access to treatment of hepatitis C with direct-acting antivirals in Argentina and evaluate the factors associated with the lack of access. MATERIALS AND METHODS: A cross-sectional cohort study was conducted that included all the consecutive prescriptions of direct-acting antivirals issued at health centers that participated in the ECHOTM telemedicine project directed by the Hospital Italiano de Buenos Aires, within the time frame of January 2016 and February 2017. RESULTS: A total of 143 treatment prescriptions were included and overall access was 70% (95% CI 62-77%). The only independent factor associated with a lack of treatment access was coverage by a public healthcare system (OR 4.98 [95% CI 2.05- 12.09]). CONCLUSION: Patients with hepatitis C that were covered by a public healthcare system had a 4 times higher chance of not having access to treatment with direct-acting antivirals than patients covered by other healthcare systems (private insurance or the social welfare system).

Distinctive intrahepatic characteristics of paediatric and adult pathogenesis of chronic hepatitis C infection.

Mechanisms leading to liver damage in chronic hepatitis C (CHC) are being discussed, but both the immune system and the virus are involved. The aim of this study was to evaluate intrahepatic viral infection, apoptosis and portal and periportal/interface infiltrate in paediatric and adult patients to elucidate the pathogenesis of chronic hepatitis C. HCV-infected, activated caspase-3(+) and TUNEL(+) hepatocytes, as well as total, CD4(+), CD8(+), Foxp3(+) and CD20(+) lymphocytes infiltrating portal and periportal/interface tracts were evaluated in 27 paediatric and 32 adult liver samples by immunohistochemistry or immunofluorescence. The number of infected hepatocytes was higher in paediatric than in adult samples (p 0.0078). In children, they correlated with apoptotic hepatocytes (activated caspase-3(+) r = 0.74, p < 0.0001; TUNEL(+) r = 0.606, p 0.0017). Also, infected (p = 0.026) and apoptotic hepatocytes (p = 0.03) were associated with the severity of fibrosis. In adults, activated caspase-3(+) cell count was increased in severe hepatitis (p = 0.009). Total, CD4(+), CD8(+) and Foxp3(+) lymphocyte count was higher in adult samples (p < 0.05). Paediatric CD8(+) cells correlated with infected (r = 0.495, p 0.04) and TUNEL(+) hepatocytes (r = 0.474, p = 0.047), while adult ones correlated with activated caspase-3(+) hepatocytes (r = 0.387, p 0.04). In adults, CD8(+) was associated with hepatitis severity (p < 0.0001) and correlated with inflammatory activity (CD8(+) r = 0.639, p 0.0003). HCV, apoptosis and immune response proved to be involved in CHC pathogenesis of both paediatric and adult patients. However, liver injury in paediatric CHC would be largely associated with a viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.

Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir.

Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.

Use of liver grafts from anti-hepatitis B core-positive donors: a multicenter study in Argentina.

Liver transplantation success is limited by the availability of donors. To overcome this limitation, anti-core-positive donors are increasingly being accepted, but underutilization of this resource still occurs. We performed the current study to determine the prevalence of anti-core-positive donors in our region and to describe the management of these donors and their recipients. Between January 2005 and July 2011, the national transplant database included 2,262 registered liver donors among whom 106 (4.7%) were anti-core-positive including 59 (56%) discarded and 47 (44%) implanted organs. A median of 14.5 offers (range 4-60) were rejected before harvesting and implanting the accepted grafts. The only difference between the implanted and the discarded grafts was found for the alanine aminotransferase level, which was higher among the discarded ones (50 ± 59 UI/L vs 25 ± 16, P < .05). Among 40 recipients included in the study, 5 (12.5%) did not receive any prophylaxis; 18 (45%) a nucleos(t)ide analog 11 (25.5%), heptitis B immunoglobulin and nucleos(t)ide analogs and 6 (15%) pretransplant hepatitis B vaccination. Over a mean follow-up of 871 ± 585 days, 4 de novo hepatitis B cases were identified at 545, 720, 748, and 1,080 days posttransplantation. None of these patients had received any prophylaxis. In all cases entecavir successfully controlled viral replication. We believe that better utilization of these donors and careful management of their recipients represent safe strategies to expand the liver donor pool in Argentina.

[Recurrence of vesicular microlithiasis. Controlled study with different dosis of ursodeoxycholic acid]. / Recidiva de la microlitiasis vesicular. Estudio controlado con diferentes doses de ácido ursodesoxicólico.

Recurrent gallstones are the limiting factor for every non surgical treatment. In order to determine the optimal prevention therapy, 30 patients after successful dissolution therapy of microcholelithiasis (MCL) with ursodeoxycholic acid (UDCA), were randomized by the double blind method to receive UDCA therapy. This was administered either as 150 mg (N = 15, group I) or 300 mg per day (N = 15, group II). There was a follow-up period of 12 months with clinical examination every month and upper abdominal sonography on days 180 and 360. Recurrent gallstones, after a 12-month period, was 6.7% (1/15) in group II versus 66% (10/15) in group I (P < 0.005). When recurrence was examined according to the number of gallstones, it reached 8% (1/12) in the solitary MCL vs 55.5% (10/18) in multiple MCL (P < 0.005). The recurrence was always symptomatic (biliary pain) and developed in 11 out of 30 pts, as MCL in 7 and as biliary sludge in the remainder 4. We conclude that a daily dose of 300 mg of UDCA was effective in reducing the recurrent gallstones in more than 90% of cases treated for 12 months. The significant risk factors associated with recurrence were the UDCA low dose and multiple stones. Biliary sludge represented 36% of the recurrence.

Insuficiencia renal en pacientes con trasplante hepatico: incidencia y factores predisponentes / Renal failure in patients with liver transplat: incidence and predisposing factors

En los pacientes que son sometidos a un trasplante hepático se desarrolla con frecuencia insuficiencia renal. Sin embargo, su incidencia y los factores predisponentes al desarrollo de esta complicación no han sido bien establecidos. Por tanto, nuestro estudio ha sido dirigido a clarificar ambos aspectos en pacientes que han sido sometidos a un trasplante hepático en el Hospital Italiano de Buenos Aires. Para ello, se evaluaron em forma retrospectiva 38 pacientes adulltos receptores de un trasplante hepático durante su estadía en el hospital (40 + 10 días) (media + DS). En el an lisis final se excluyeron 3 pacientes (1 hepatitis fulminante y 2 con sobrevida menor a 72 hs). El tratamiento inmunosupresor se basó en el triple esquema: ciclosporina, corticoides y azatioprina. La presencia de insuficiencia renal se definió como la existencia de una creatinina sérica > 1.5 mg/dl y/o urea > 80 mg/dl. La insuficiencia renal se clasificó cronológicamente como precoz (días 0-6) y tardia (luego del día 6). Los siguientes par metros fueron evaluados en relación a la insuficiencia hepática: preoperatoria (función hepatocelular mediante la clasificación de Chil-Pugh y renal), intraoperatorios (cantidad de hemoderivados transfundidos, episodios de hipotensión, "by-pass" venovenoso, duración de la cirugía y de la fase anhepática) y postoperatorios (sepsis, rechazo, niveles plasm ticos de ciclosporina y uso de drogas nefrotóxicas). En veintiuno de los 35 pacientes (60 por ciento) con trasplante hepático se desarrolló insuficiencia renal. En 6 pacientes fue precoz y en 15 tardía. En la serie global, los pacientes con insuficiencia renal presentaron un mayor deterioro de la función hepática en el preoperatorio (8.6 + 0.3 vs 7.8 + 0.4, p<0.05), en el intraoperatorio un mayor requerimiento de hemoderivados (13.1 + 4.3 vs 10.1 + 3.8 unidades, p<0.05) y en el postoperatorio in nivel más elevado de ciclosporina (624 + 60 vs 430 + 30 ng/ml, p<0.05) que aquellos pacientes en quienes no se desarrolló complicación. Asimismo, en los pacientes que presentaron la insuficiencia renal en forma precoz se observó un mayor deterioro de la función hepatocelular y un mayor requerimiento de hemoderivados durante la cirugía. De otra parte, en los pacientes que la desarrollaron en forma tardía, la etiopatogenia de esta complicación fue multifactorial (falla del injerto, uso de drogas nefrotóxicas y ciclosporina). En 1 paciente hubo necesidad de realizar hemodiálisis y en otro hemofiltración...

Insuficiencia renal en pacientes con trasplante hepatico: incidencia y factores predisponentes / Renal failure in patients with liver transplat: incidence and predisposing factors

En los pacientes que son sometidos a un trasplante hepático se desarrolla con frecuencia insuficiencia renal. Sin embargo, su incidencia y los factores predisponentes al desarrollo de esta complicación no han sido bien establecidos. Por tanto, nuestro estudio ha sido dirigido a clarificar ambos aspectos en pacientes que han sido sometidos a un trasplante hepático en el Hospital Italiano de Buenos Aires. Para ello, se evaluaron em forma retrospectiva 38 pacientes adulltos receptores de un trasplante hepático durante su estadía en el hospital (40 + 10 días) (media + DS). En el an lisis final se excluyeron 3 pacientes (1 hepatitis fulminante y 2 con sobrevida menor a 72 hs). El tratamiento inmunosupresor se basó en el triple esquema: ciclosporina, corticoides y azatioprina. La presencia de insuficiencia renal se definió como la existencia de una creatinina sérica > 1.5 mg/dl y/o urea > 80 mg/dl. La insuficiencia renal se clasificó cronológicamente como precoz (días 0-6) y tardia (luego del día 6). Los siguientes par metros fueron evaluados en relación a la insuficiencia hepática: preoperatoria (función hepatocelular mediante la clasificación de Chil-Pugh y renal), intraoperatorios (cantidad de hemoderivados transfundidos, episodios de hipotensión, "by-pass" venovenoso, duración de la cirugía y de la fase anhepática) y postoperatorios (sepsis, rechazo, niveles plasm ticos de ciclosporina y uso de drogas nefrotóxicas). En veintiuno de los 35 pacientes (60 por ciento) con trasplante hepático se desarrolló insuficiencia renal. En 6 pacientes fue precoz y en 15 tardía. En la serie global, los pacientes con insuficiencia renal presentaron un mayor deterioro de la función hepática en el preoperatorio (8.6 + 0.3 vs 7.8 + 0.4, p<0.05), en el intraoperatorio un mayor requerimiento de hemoderivados (13.1 + 4.3 vs 10.1 + 3.8 unidades, p<0.05) y en el postoperatorio in nivel más elevado de ciclosporina (624 + 60 vs 430 + 30 ng/ml, p<0.05) que aquellos pacientes en quienes no se desarrolló complicación. Asimismo, en los pacientes que presentaron la insuficiencia renal en forma precoz se observó un mayor deterioro de la función hepatocelular y un mayor requerimiento de hemoderivados durante la cirugía. De otra parte, en los pacientes que la desarrollaron en forma tardía, la etiopatogenia de esta complicación fue multifactorial (falla del injerto, uso de drogas nefrotóxicas y ciclosporina). En 1 paciente hubo necesidad de realizar hemodiálisis y en otro hemofiltración...(AU)

Daily variation in portal blood flow and the effect of propranolol administration in a randomized study of patients with cirrhosis.

A nocturnal increase in portal pressure and blood flow was demonstrated in patients with cirrhosis, suggesting that these hemodynamic changes may contribute to the triggering of the hemorrhagic episodes observed during the night in these patients. It is known that propranolol reduces portal flow, thus reducing the risk of variceal bleeding. In a double-blind, placebo-controlled study, we evaluated the effect of long-term propranolol administration on the daily fluctuation of systemic and splanchnic hemodynamic parameters in 14 patients with cirrhosis. Cardiac output and portal blood flow were measured by the Doppler technique. A daily fluctuation of both cardiac output and portal blood flow was observed, peaking at midnight. beta-Adrenergic blockade was manifested by a significant reduction in heart rate (-21% +/- 4%, P < .01) and cardiac output (-12% +/- 2%, P < .05). A significant decrease in portal blood flow (-20% +/- 4%, P < .01) was also observed in these patients. Propranolol administration blunted the time-related changes in cardiac output and portal blood flow. In contrast, patients receiving placebo had a nocturnal peak of both parameters similar to that observed under basal conditions. Our study shows that chronic propranolol administration abolishes the nocturnal peak of portal blood flow in patients with cirrhosis and indicates a preventive effect of propranolol in these patients.

[Renal failure in patients with liver transplant: incidence and predisposing factors]. / Insuficiencia renal en pacientes con trasplante hepático: incidencia y factores predisponentes.

Renal failure is a common finding in patients undergoing orthotopic liver transplantation. The aim of the present study was to evaluate the incidence, prognostic value of pre, intra and postoperative factors and severity of renal dysfunction in patients who undergo liver transplantation. Therefore, the records of 38 consecutive adult patients were reviewed. Renal failure was defined arbitrarily as an increase in creatinine (> 1.5 mg/dl) and/or blood urea (> 80 mg/dl). Three patients were excluded of the final analysis (1 acute liver failure and 2 with a survival lower than 72 hs.) Twenty one of the 35 patients has renal failure after orthotopic liver transplantation. Six of these episodes developed early, having occurred within the first 6 days. Late renal impairment occurred in 15 patients within the hospitalization (40 +/- 10 days) (Mean +/- SD). In he overall series, liver function, evaluated by Child-Pugh classification, a higher blood-related requirements and cyclosporine levels were observed more in those who experienced renal failure than those who did not (p < 0.05). Early renal failure was related with preoperative (liver function) and intraoperative (blood requirements) factors and several causes (nephrotoxic drugs and graft failure) other than cyclosporine were present in patients who developed late renal impairment. No mortality. No mortality was associated with renal failure. We conclude that renal failure a) is a common finding after liver transplantation, b) the pathogenesis of this complication is multifactorial and, c) in not related with a poor outcome.

[Role of nitric oxide in alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension]. / Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal.

Recent experimental studies have suggested that an increase in the synthesis of nitric oxide, a powerful vasodilator secreted by endothelial cells, plays a role in the hemodynamic disturbances associated to portal hypertension. The present study was addressed to investigate the effects of L-NNA (a specific inhibitor of nitric oxide) on systemic and splanchnic hemodynamics in portal hypertensive rats, induced by partial portal vein ligation. Intravenous infusion of L-NNA (50 ug/kg/min) significantly increased systemic blood pressure and decreased cardiac output as measured by radiolabeled microspheres. A significant increase in systemic and splanchnic vascular resistance was also observed in L-NNA-treated rats; whereas portal blood flow decreased significantly, L-NNA did not modify portal pressure. Pretreatment with L-arginine (300 mg/Kg, i.v.) prevented the hemodynamic changes induced by L-NNA. Similar values of endotoxin levels were detected in both groups of animals. In the control group, L-NNA caused a mild but significant increase of mean arterial pressure; no significant changes on the other hemodynamic parameters were observed. These results suggest that an increase in endogenous synthesis of nitric oxide may play an important role in hemodynamic disturbances associated with chronic portal hypertension.

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal / Role of nitric oxide in the alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension

Se evaluó el efecto de la Nw-Nitro-L-arginina (L-NNA), un inhibidor específico de la síntesis de óxido nítrico, sobre la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal (ligadura parcial de la vena porta). La administración de L-NNA en los animales con hipertensión portal ocasionó un aumento significativo de la presión arterial media, una reducción del gasto cardíaco y un aumento de la resistencia vascular periférica. A nível de la hemodinámica esplácnica la L-NNA ocasionó un marcado incremento de la resistencia vascular esplácnica con la consecuente disminución del flujo sanguíneo portal. No se observaron cambios singnificativos en la presión portal. El pretratamiento con L-arginina inhibió los efectos hemodinámicos de la L-NNA. Similares niveles plasmáticos de endotoxina se detectaron en ambos grupos de animales. En el grupo control La L-NNA produjo un aumento de la presión arterial media; sin embargo, y a diferencia de lo observado en los animales on hipertensión portal, la administración de L-NNA no se acompaño de cambios significativos en el gasto cardíaco, flujo sanguíneo portal ni resistencia vascular esplácnica. Nuestros resultados sugieren que las alteraciones, tanto de la hemodinámica sistémica como esplácnica, asociadas a la hipertensión portal, pueden ser atenuadas mediante la administración de L-NNA. Asimismo, el aumento de la síntesis de óxido nítrico puede jugar un papel importante en la fisiopatogenia de estos trastornos hemodinámicos

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal. / [Role of nitric oxide in alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension]

Recent experimental studies have suggested that an increase in the synthesis of nitric oxide, a powerful vasodilator secreted by endothelial cells, plays a role in the hemodynamic disturbances associated to portal hypertension. The present study was addressed to investigate the effects of L-NNA (a specific inhibitor of nitric oxide) on systemic and splanchnic hemodynamics in portal hypertensive rats, induced by partial portal vein ligation. Intravenous infusion of L-NNA (50 ug/kg/min) significantly increased systemic blood pressure and decreased cardiac output as measured by radiolabeled microspheres. A significant increase in systemic and splanchnic vascular resistance was also observed in L-NNA-treated rats; whereas portal blood flow decreased significantly, L-NNA did not modify portal pressure. Pretreatment with L-arginine (300 mg/Kg, i.v.) prevented the hemodynamic changes induced by L-NNA. Similar values of endotoxin levels were detected in both groups of animals. In the control group, L-NNA caused a mild but significant increase of mean arterial pressure; no significant changes on the other hemodynamic parameters were observed. These results suggest that an increase in endogenous synthesis of nitric oxide may play an important role in hemodynamic disturbances associated with chronic portal hypertension.

Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal / Role of nitric oxide in the alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension

Se evaluó el efecto de la Nw-Nitro-L-arginina (L-NNA), un inhibidor específico de la síntesis de óxido nítrico, sobre la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal (ligadura parcial de la vena porta). La administración de L-NNA en los animales con hipertensión portal ocasionó un aumento significativo de la presión arterial media, una reducción del gasto cardíaco y un aumento de la resistencia vascular periférica. A nível de la hemodinámica esplácnica la L-NNA ocasionó un marcado incremento de la resistencia vascular esplácnica con la consecuente disminución del flujo sanguíneo portal. No se observaron cambios singnificativos en la presión portal. El pretratamiento con L-arginina inhibió los efectos hemodinámicos de la L-NNA. Similares niveles plasmáticos de endotoxina se detectaron en ambos grupos de animales. En el grupo control La L-NNA produjo un aumento de la presión arterial media; sin embargo, y a diferencia de lo observado en los animales on hipertensión portal, la administración de L-NNA no se acompaño de cambios significativos en el gasto cardíaco, flujo sanguíneo portal ni resistencia vascular esplácnica. Nuestros resultados sugieren que las alteraciones, tanto de la hemodinámica sistémica como esplácnica, asociadas a la hipertensión portal, pueden ser atenuadas mediante la administración de L-NNA. Asimismo, el aumento de la síntesis de óxido nítrico puede jugar un papel importante en la fisiopatogenia de estos trastornos hemodinámicos (AU)