Rafael Bárcena

Hepatitis C Recurrence After Liver Transplantation: Viral and Histologic Response to Full‐Dose Peg‐Interferon and Ribavirin

Hepatitis C recurrence after liver transplantation (LT) is universal, and frequently leads to cirrhosis and death. The aim of our study was to assess the efficacy and safety of 48‐weeks of full‐dose peg‐interferon‐α‐2a (n = 4) or α‐2b (n = 51) plus ribavirin (>11 mg/kg/day) in a multicentric cohort of 55 patients ≥12 months after LT. All subjects had histologically proven HCV recurrence, excluding severe cholestatic recurrence. Mean age was 54.3 ± 9.7, 77% male, 90.9% genotype 1, 32.7% cirrhotics. All but 5 patients received monotherapy with tacrolimus (54.5%), cyclosporine (30.7%) or mycophenolate mofetil (5.5%). The rates of end‐of‐treatment response and sustained virological response (SVR) were 66.7% and 43.6%, respectively. Low baseline HCV‐RNA (p = 0.005) and a length from LT to therapy between 2–4 years (p = 0.011) were predictors of SVR. The lack of achieving a viral load decrease ≥1‐log10 at week 4 and/or 2‐log10 at week 12 was 100% predictive of failure. The most frequent side effects were neutropenia (76,4%), anemia (60%) and infectious complications (30.9%). Toxicity led to peg‐interferon withdrawal in 16 (29%) subjects. In 15 patients with post‐treatment biopsy, the histological activity index was significantly improved (p = 0.006), whereas fibrosis did not change (p = 0.14). Three patients died (cholangitis, hepatic artery thrombosis and lung cancer). In conclusion, HCV therapy after LT was very effective, although it led to a significant rate of toxicity.

Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C

BACKGROUND/AIMS To investigate the effect of sustained virological response (SVR) on impaired fasting glucose (IFG) and/or type 2 diabetes (T2DM); to assess the influence of glucose abnormalities on the SVR rate. METHODS 1059 patients with chronic HCV; normal glucose (< 100 mg/dl) in 734, IFG (between 100 and 125 mg/dl) in 218, and T2DM (126 mg/dl) in 107 cases, were treated with interferon plus ribavirin over 24 or 48 weeks, depending on viral genotype. RESULTS The SVR rate was lower in patients with IFG and/or T2DM than in patients with normal glucose concentrations [143/325 (44%) vs. 432/734 (58.8%); P=0.002]. In the follow-up, abnormal glucose concentrations were observed in 74 of 304 (24.3%) non-responders and in 49 of 430 (11.4%) sustained responders (log-rank: 13.8; P=0.00002). Reverse stepwise logistic regression analysis identified the independent variables predictive of IFG or T2DM development as: sustained response (OR: 0.44; 95%CI=0.20-0.97; P=0.004) and fibrosis stage (OR: 1.46; 95%CI=1.06-2.01;P=0.02). Family history of DM, steatosis, gender, HCV viral load, genotype, triglycerides, cholesterol and BMI did not enter the multivariate analysis equation. CONCLUSIONS SVR reduces the risk of IFG and/or T2DM development in patients with chronic hepatitis C while altered glucose metabolism impairs sustained response to viral treatment.

Peginterferon Plus Ribavirin and Sustained Virological Response in HCV-Related Cirrhosis: Outcomes and Factors Predicting Response

OBJECTIVES Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.OBJECTIVES:Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.METHODS:Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.RESULTS:Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1–81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353–7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752–5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418–6.927); baseline viral load <6 × 105 (OR=2.597; 95% CI: 1.583–4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26–3.39). No patient with a HCV-RNA decline <1 log10 at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32–5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81–5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546–4). Improved outcome was more evident in responders with less advanced disease at baseline.CONCLUSIONS:SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.

Liver Transplantation in HIV-infected recipients

Liver transplantation is being evaluated as a therapeutic option for human immunodeficiency virus (HIV)‐infected patients with end‐stage liver disease, but experience is still scarce. We describe the outcome of 4 HIV‐infected patients who underwent liver transplantation in our hospital between July 2002 and April 2003. HIV‐infected liver transplant recipients meet the same standard criteria for transplantation as do HIV‐negative candidates. In addition, HIV infected persons are required to have a CD4 T‐cell count greater than 100/mL (CD4 T‐cells are targets for HIV infection). Immunosuppressive regimens, perioperative surgical prophylaxis, and prophylaxis for opportunistic infections are standard in the Liver Transplantation Unit in our hospital. Four patients, including 3 former intravenous drug users, received a liver transplant (2 from deceased donors and 2 from living donors), with a median follow‐up of 510 days. Three patients (75%) are alive, with 1 death occurring 17 months posttransplantation in a patient who developed fibrosing cholestatic hepatitis. Rejection occurred in 1 patient, and was managed with no complications. Hepatitis C virus (HCV) recurrence occurred in 3 patients. HIV‐infection has remained under control with antiretroviral treatment. A combination of 3 nucleoside analogs was used in 3 patients, with no need for drug adjustments. No opportunistic infections or other significant infectious complications developed. In conclusion, orthotopic liver transplantation seems a safe therapeutic option in the short term for HIV‐infected persons with end stage liver disease, including patients with a history of drug abuse. If indicated, an antiretroviral regimen consisting of 3 nucleosides could be used to avoid interactions with immunosuppressive drugs. (Liver Transpl 2005;11:76–81.)

Pegylated interferon α2b plus ribavirin for the treatment of chronic hepatitis C in HIV-infected patients

Background: Hepatitis C virus (HCV) and HIV coinfection constitutes an important epidemiological and clinical problem. We evaluated the safety and efficacy of Pegylated interferon α2b (Peg-IFN) and a fixed dose of ribavirin in the treatment of chronic hepatitis C in HIV coinfection. Methods: Open, prospective study in HCV–HIV coinfected patients with persistently elevated alanine aminotransferase (ALT) levels and a liver biopsy showing either portal or bridging fibrosis. Therapy included Peg-IFN (50 μg weekly) with ribavirin 800 mg for 48 weeks. The primary end point was sustained virological response (SVR). Univariate and multivariate analyses were performed to determine factors associated with response. Results: By intent-to-treat analysis, 11 of 35 patients (31%) reached SVR. SVR was significantly better for genotypes 2/3 than for genotype 1 (54% versus 21%; P < 0.05). By multivariate logistic regression analysis, only a non-1 genotype was an independent factor for SVR [odds ratio (OR), 6; 95% confidence interval (CI), 1.1–31.7; P < 0.005]. A decrease of at least 1.5 log10 HCV RNA at week 12 of therapy was highly predictive of SVR (OR, 49.9; 95% CI, 4.9–508.2; P < 0.001). Most patients developed adverse events, although only six patients (17%) discontinued treatment due to toxicity. Conclusions: The combination of low doses of Peg-IFN plus a fixed dose of ribavirin resulted in a rate of SVR similar to that obtained with higher doses of the drugs in HIV-infected patients and lower than those obtained in non-HIV patients. Response at week 12 may be useful to help guide therapy in HCV–HIV co-infected patients.

Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients

The pharmacokinetics of mycophenolate mofetil (MMF) in liver transplant recipients may change because of pharmacokinetic interactions with coadministered immunosuppressants or because changes in the enterohepatic anatomy may affect biotransformation of MMF to mycophenolic acid (MPA) and enterohepatic recirculation of MPA through the hydrolysis of mycophenolate acid glucuronide to MPA in the gut. In the latter case, the choice of formulation (oral versus intravenous) could have important clinical implications. We randomized liver transplant patients (n = 60) to standard (10–15 ng/mL) or reduced (5–8 ng/mL) trough levels of tacrolimus plus intravenous MMF followed by oral MMF (1 g twice daily) with corticosteroids. Pharmacokinetic sampling was performed after the last intravenous MMF dose, after the first oral MMF dose, and at selected times over 52 weeks. The efficacy and safety of the 2 regimens were also assessed. Twenty‐eight and 27 patients in the tacrolimus standard‐dose and reduced‐dose groups, respectively, were evaluated. No significant differences between the tacrolimus standard‐dose and reduced‐dose groups were seen in dose‐normalized MPA values of the time to the maximum plasma concentration (1.25 versus 1.28 hours), the maximum plasma concentration (15.5 ± 7.93 versus 13.6 ± 7.03 μg/mL), or the area under the concentration‐time curve from 0 to 12 hours (AUC0–12; 53.0 ± 20.6 versus 43.8 ± 15.5 μg h/mL) at week 26 or at any other time point. No relationship was observed between the tacrolimus trough or AUC0–12 and MPA AUC0–12. Exposure to MPA after oral and intravenous administration was similar. Safety and efficacy were similar in the two treatment groups. In conclusion, exposure to MPA is not a function of exposure to tacrolimus. The similar safety and efficacy seen with MMF plus standard or reduced doses of tacrolimus suggest that MMF could be combined with reduced doses of tacrolimus. Liver Transpl 15:136–147, 2009.

Improved graft function in liver‐transplanted patients after partial splenic embolization: reversal of splenic artery steal syndrome?

Abstract:  Aim:  To describe the functional effect of partial splenic embolization (PSE) in liver‐transplanted (LT) patients with hypersplenism and hepatitis C virus (HCV) recurrence.

Partial Splenic Embolization for the Treatment of Hypersplenism in Liver Transplanted Patients with Hepatitis C Virus Recurrence before peg-interferon Plus Ribavirin

Reinfection of the graft follows liver transplantation (LT) patients with HCV, with an accelerated course of the disease due to immunosuppressive treatment (1). Progression to cirrhosis is increased, more than 20% of patients present severe graft damage at 5 years post-LT (2), and the rate of death and allograft failure is increased when compared with other indications (3). The lack of an efficient strategy to prevent graft reinfection and the aggressive course of HCV after LT indicate the need for an effective antiviral therapy able to preserve the viability of the graft. Recent data on the use of peg-IFN plus ribavirin (RBV) after LT are encouraging, with rates of sustained virological response (SVR) over 30%, improved graft function, and a beneficial effect on the histological disease progression (4). Therapy, however, is limited by the high rate of peg-IFN and/or RBV-related hematological toxicity leading to dose reductions and/or administration of hematopoietic growth factors, such as erythropoietin (EPO), or granulocyte-colonies stimulating factor (G-CSF) (5). To date, severe thrombocytopenia remains as an absolute contraindication for HCV therapy. Partial splenic embolization (PSE) seems to be an effective alternative to surgical splenectomy for the treatment of hematologic disorders in cirrhotic patients with hypersplenism, especially against thrombocytopenia (6), and improves liver functions (7). We aimed to evaluate the safety and effectiveness of PSE before peg-IFN/RBV in three liver recipients with HCV recurrence and hypersplenism. After pneumococcal vaccination, PSE was performed under intravenous antibiotic, sedative, and antiemetic therapy. A femoral artery approach was used for superselective distal catheterization of the splenic artery, with injection of polyvinyl-alcohol particles (355 to 500 ) suspended in a solution of penicillin, gentamicin, and non-ionic iodine contrast, to obtain an splenic infarction ratio between 50% and 80%. Contrast-enhanced abdominal CT scan and Doppler ultrasound studies were performed before PSE and during follow-up, to assess the presence of complications. At a mean of 12 weeks after PSE all patients started weight-adjusted RBV plus peg-IFN-2b and were assessed in a monthly basis, including

Is Liver Transplantation Advisable for Isoniazid Fulminant Hepatitis in Active Extrapulmonary Tuberculosis

Antituberculous treatment is a well‐known cause of fulminant hepatic failure (FHF). This could lead to liver transplantation as the only possible treatment, which on the other hand could be contraindicated due to active tuberculosis. The risk of aggressive dissemination of the disease after transplantation is not clearly determined by the current second‐line antituberculous therapies. We report a case of vertebral tuberculosis treated with rifampin, isoniazid and pyrazinamide. He developed an FHF that was treated with urgent liver transplantation. Despite the immunosuppression, the disease was well controlled with ciprofloxacin, ethambutol and streptomycin and the patient is in good health 23 months after transplantation. In conclusion, active extrapulmonary tuberculosis should perhaps be considered for liver transplantation when FHF develops due to anti‐tuberculous drugs.

Safety and anti-HCV effect of prolonged intravenous silibinin in HCV genotype 1 subjects in the immediate liver transplant period

BACKGROUND & AIMS Reinfection of the graft is the rule in patients with HCV cirrhosis undergoing liver transplantation, and HCV-RNA reaches pre-transplantation levels within the first month. Short-term intravenous silibinin monotherapy is safe and shows a potent in vivo anti-HCV effect. We aimed at evaluating the safety and antiviral effect of prolonged intravenous silibinin, started immediately before liver transplantation. METHODS Single centre, prospective, pilot study, to assess the safety and effect on HCV-RNA kinetics during at least 21 days of intravenous silibinin monotherapy (20 mg/kg/day) in 9 consecutive HCV genotype 1 subjects, in comparison to a control, non-treated group of 7 consecutive prior transplanted subjects under the same immunosuppressive regimen (basiliximab, steroids, delayed tacrolimus, micophenolate). RESULTS Intravenous silibinin led to significant, maintained and progressive HCV-RNA decreases (mean HCV-RNA drop at week 3, -4.1 ± 1.3 log(10)IU/ml), and lack of viral breakthrough during administration. Four patients (44%) reached negative HCV-RNA, maintained during silibinin treatment, vs. none in the control group, but HCV-RNA relapsed in all of them after a median of 21 days (16-28), following silibinin withdrawal. Partial responders to silibinin showed marked decreases in HCV-RNA when compared to controls, but lower than complete responders. There were no clinical adverse effects, and silibinin led to asymptomatic transient hyperbilirubinemia (week 2, 4.2 ± 2.2 vs. 2.5 ± 3.6 mg/dl; p=0.02). CONCLUSIONS Prolonged intravenous silibinin monotherapy was safe in the immediate liver transplantation period, leading to a potent and time dependent antiviral effect and lack of HCV-RNA breakthrough during administration. However, HCV-RNA rebounded after withdrawal, and silibinin monotherapy did not avoid reinfection of the graft.