Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin.

Sustained virologic response (SVR) is the standard measure for evaluating response to therapy in patients with chronic hepatitis C (CHC). The aim of this study was to prospectively assess the durability of SVR in the pivotal studies of peginterferon (PEG-IFN) α-2b or IFN α-2b. We conducted two phase 3b long-term follow-up studies of patients previously treated for CHC in eight prospective randomized studies of IFN α-2b and/or PEG-IFN α-2b. Patients who achieved SVR [undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of treatment] were eligible for inclusion in these follow-up studies. In total, 636 patients with SVR following treatment with IFN α-2b and 366 with SVR following treatment with PEG-IFN α-2b were enrolled. Definite relapse (quantifiable serum HCV RNA with no subsequent undetectable HCV RNA) was reported in six patients treated with IFN α-2b and three patients treated with PEG-IFN α-2b. Based on these relapses, the point estimate for the likelihood of maintaining response after 5 years was 99.2% [95% confidence interval (CI), 98.1-99.7%] for IFN α-2b and 99.4% (95% CI, 97.7-99.9%) for PEG-IFN α-2b. Successful treatment of hepatitis C with PEG-IFN α-2b or IFN α-2b leads to clinical cure of hepatitis C in the vast majority of cases.

Severe sirolimus-related inflammatory state anemia in an HIV+ liver transplant patient with calcineurin inhibitor renal insufficiency: a case report.

Although multifactorial anemia is common following orthotopic liver transplantation (OLT), the late introduction of sirolimus (SRL) has been associated with high rates of anemia, whose pathogenic mechanisms have not been fully studied. Herein we have described a case of severe anemia in an HIV+ OLT patient who was switched from calcineurin inhibitors (CNI) to SRL due to severe nephrotoxicity. After 22 weeks of SRL, hemoglobin levels dropped 4 g/dL to a nadir of 6.5 g/dL. After discarding other causes for anemia, we concluded that it displayed the features of anemia of a chronic inflammatory state (ACIS): decreased mean corpuscular volume (MCV), low serum iron despite high ferritinemia, and elevated fibrinogen and C-reactive protein (CRP) levels. SRL trough levels were never above the therapeutic range. After blood transfusions and erythropoietin (EPO) use, SRL was maintained within the lower range of therapeutic levels, with significant improvement in renal function. As described among kidney transplant recipients, SRL-related anemia in this HIV+ patient with CNI nephrotoxicity after OLT showed features of ACIS. Blood transfusions and EPO use allowed SRL maintenance.

Clinical trial: pharmacodynamics and pharmacokinetics of re-treatment with fixed-dose induction of peginterferon alpha-2a in hepatitis C virus genotype 1 true non-responder patients.

BACKGROUND: Patients infected with hepatitis C virus genotype 1 who are true non-responders to previous therapy suffer from a very difficult-to-cure disease. New approaches to treatment are necessary. AIM: To explore the efficacy, pharmacokinetics and safety of fixed-dose induction with peginterferon alpha-2a and ribavirin in this difficult-to-cure population. METHODS: Seventy-five hepatitis C virus genotype 1 true non-responder patients to a previous interferon-based combination regimen were randomised to receive peginterferon alpha-2a 360, 270 or 180 microg/week for 12 weeks, followed by 180 microg/week for 36 weeks, in combination with ribavirin (1000/1200 mg/day). Peginterferon alpha-2a concentration was measured throughout the study. RESULTS: Sustained virological response rates were 38%, 30% and 18%, in the 360, 270 and 180 microg/week groups, respectively (relapse rates: 25%, 50% and 64%, respectively). The area under the serum concentration-time curve of peginterferon alpha-2a from 0-12 weeks increased in a dose-dependent manner (P < 0.0001) and was associated with the sustained virological response (odds ratio: 1.35; 95% CI: 0.89, 2.06). The three regimens were equally well tolerated. CONCLUSION: Fixed-dose induction of peginterferon alpha-2a resulted in increased drug exposure and improved the likelihood of achieving a cure, without compromising safety in hepatitis C virus genotype 1 true non-responder patients.

[Hepatic encephalopathy secondary to porto-systemic shunt satisfactorily treated with interventionist radiology]. / Encefalopatía hepática secundaria a la existencia de un shunt portosistémico tratada satisfactoriamente mediante radiología intervencionista.

Hepatic encephalopathy is a reversible state of altered cognition that may occur in patients with acute or chronic liver disease or porto-systemic shunt, and in which known neurological or psychiatric signs may develop. Nitrogenated substances from intestinal digestion reach the brain without being cleared by their passage through the liver due to the presence of porto-systemic shunt. We report two cases of patients with porto-systemic shunt diagnosed with recurrent chronic hepatic encephalopathy refractory to conventional medical treatment. They were satisfactorily treated with shunt embolization using interventionist radiology techniques.

Scarce influence of corticosteroid boluses on long-term viral load and liver histology in transplanted patients with recurrent hepatitis C.

Corticosteroid boluses, which are the treatment for acute rejection episodes, have been shown to produce transient increases in viremia. However, their effect on long-term viral load, histological activity index (HAI), and fibrosis has not been well established. The aim of our study was to compare late viral load, HAI, and fibrosis in patients with versus without steroid boluses in the immediate posttransplant period. We analyzed patients transplanted due to hepatitis C virus. Inclusion criteria were: no change in immunosuppression (cyclosporine or tacrolimus with/without mycophenolate); no steroids in the previous 4 months; no antiviral treatment; liver biopsy and viral load determination >12 months after transplantation. Exclusion criteria were HIV, hepatitis B, and active cytomegalovirus infection. Nonparametric tests were used to compare viral load, HAI, and fibrosis (Ishak-score) among patients who received steroid boluses for an acute rejection episode (group 1) versus those who did not (group 2). Among the 48 selected patients were 38 men with the overall mean age of the entire group of 55.6 +/- 10.9 years. The mean period from liver transplantation was 53.25 +/- 33.4 months. Thirty-four (70.1%) were treated with tacrolimus and the rest, cyclosporine. Eleven (22.9%) had and 37 (77.1%) had not received corticosteroid boluses. The viral load was similar in groups 1 and 2 (5.74 +/- 0.54 vs 5.98 +/- 0.53 Log(10) IU per mL, P = .32). Fibrosis was also similar (2.5 +/- 1.6 vs 2.2 +/- 1.7, P = .56). However, HAI was higher in group 1 (7.5 +/- 1.7 vs 6.0 +/- 1.7, P = .026). In conclusion, although long-term viral load was similar in patients who had versus had not received one cycle of steroid boluses, the HAI was significantly higher in the former cohort, but had not resulted in greater fibrosis during the study follow-up.

Hepatitis C virus recurrence after liver transplantation: influence of immunosuppressive regimens on viral load and liver histology.

Cyclosporine has recently been reported to produce in vitro suppression of hepatitis C virus replication driven by blockade of cyclophilins, an effect not shown for tacrolimus. However, the clinical consequence of this in vitro finding have not been well studied in vivo. We compared viral load and fibrosis in transplanted patients receiving monotherapy with tacrolimus or cyclosporine. Patients with recurrent hepatitis C after transplantation were selected from two tertiary centers with the following inclusion criteria: monotherapy with tacrolimus or cyclosporine for more than 12 months before viral load measurement, no antiviral treatment, corticosteroids stopped within 12 months after transplantation. HIV, hepatitis B, and active infection by cytomegalovirus were excluded. Patient characteristics, viral load, and fibrosis were compared by univariate analysis between the cyclosporine and tacrolimus groups. Significant variables, viral load, and fibrosis were included in a multivariate model. Sixty-six patients were included, 46 on tacrolimus and 20 on cyclosporine. Fifty-six were male, and the mean age was 55.3 +/- 10.1 years. Fibrosis (Ishak score) was 3.9 +/- 1.9 in the cyclosporine group and 2.7 +/- 1.9 in the tacrolimus group (P = .019). Viral load (log(10)IU/mL) was 5.8 +/- 0.5 and 5.9 +/- 0.5, respectively (P = .7) and time since liver transplantation was 95.3 +/- 47.7 and 41.1 +/- 16.8 months (P = .0001). In the multivariate model, viral load (P = .65) and fibrosis (P = .24) were not significantly different and only time since transplantation remained significant (P = .0001). In conclusion, viral load was not different in patients with tacrolimus as compared with cyclosporine, and the lower fibrosis observed in the cyclosporine group lacked significance when considered together with time since liver transplantation.

Analysis of a quantitative PCR assay for CMV infection in liver transplant recipients: an intent to find the optimal cut-off value.

BACKGROUND: Preemptive therapy required highly predictive tests for CMV disease. CMV antigenemia assay (pp65 Ag) has been commonly used for rapid diagnosis of CMV infection. Amplification methods for early detection of CMV DNA are under analysis. OBJECTIVES: To compare two diagnostic methods for CMV infection and disease in this population: quantitative PCR (qPCR) performed in two different samples, plasma and leukocytes (PMNs) and using a commercial diagnostic test (COBAS Amplicor Monitor Test) versus pp65 Ag. STUDY DESIGN: Prospective study conducted in liver transplant recipients from February 2000 to February 2001. RESULTS: Analyses were performed on 164 samples collected weekly during early post-transplant period from 33 patients. Agreements higher than 78% were observed between the three assays. Optimal qPCR cut-off values were calculated using ROC curves for two specific antigenemia values. For antigenemia >or=10 positive cells, the optimal cut-off value for qPCR in plasma was 1330 copies/ml, with a sensitivity (S) of 58% and a specificity (E) of 98% and the optimal cut-off value for qPCR-cells was 713 copies/5x10(6) cells (S:91.7% and E:86%). Using a threshold of antigenemia >or=20 positive cells, the optimal cut-off values were 1330 copies/ml for qPCR-plasma (S 87%; E 98%) and 4755 copies/5x10(6) cells for qPCR-cells (S 87.5%; E 98%). Prediction values for the three assays were calculated in patients with CMV disease (9 pts; 27%). Considering the assays in a qualitative way, the most sensitive was CMV PCR in cells (S: 100%, E: 54%, PPV: 40%; NPV: 100%). Using specific cut-off values for disease detection the sensitivity, specificity, PPV and NPV for antigenemia >or=10 positive cells were: 89%; 83%; 67%; 95%, respectively. For qPCR-cells >or=713 copies/5x10(6) cells: 100%; 54%; 33% and 100% and for plasma-qPCR>or=1330 copies/ml: 78%, 77%, 47%, 89% respectively. CONCLUSIONS: Optimal cut-off for viral load performed in plasma and cells can be obtained for the breakpoint antigenemia value recommended for initiating preemptive therapy with high specificities and sensitivities. Diagnostic assays like CMV pp65 Ag and quantitative PCR for CMV have similar efficiency and could be recommended as methods of choice for diagnosis and monitoring of active CMV infection after transplantation.

Pegylated interferon and ribavirin for the recurrence of chronic hepatitis C genotype 1 in transplant patients.

The efficacy of pegylated interferon (p-IFN) and ribavirin (RB) in transplant patients is not well known. Chronic hepatitis C evolves in a more aggressive form after transplantation, causing a worse survival. Twenty-one naïve patients with recurrent chronic hepatitis C demonstrated by biopsy were treated for 48 weeks with p-IFN alpha2b (1.5 microg/kg/wk) and RB (>10.6 mg/kg/d). Quantification of RNA was performed (Amplicor Cobas 2.0 Roche) at baseline, 4, 12, 24, 48, and 72 weeks. A qualitative technique was used when quantitative levels were undetectable. At more than 1 year since liver transplantation we did not detect coinfection with human immunodeficiency virus or use steroid treatment. Among the cohort there were 16 men (76.2%). The mean overall age was 52 +/- 12 years. Time from liver transplant to treatment was 1637 +/- 1030 days. They were all infected with genotype 1. Eight patients received cyclosporine and the others tacrolimus. One patient was coinfected with hepatitis B virus and was receiving lamivudine. The mean initial histological activity index was 6.9 +/- 1.5 and fibrosis, 2.52 +/- 1.8 (Ishak). Two patients needed spleen embolization before the treatment. Two patients had to stop the treatment: one due to clinical intolerance, and the other one due to a cholangitis. In 14%, p-IFN doses were adjusted. In 32% RB was adjusted. Five (23.8%) did not respond at 24 weeks. Fourteen (66.7%) showed end-treatment responses but four relapsed at 72 weeks. A sustained viral response was achieved in 9 (42.8%). One patient died due to arterial thrombosis just after completing the treatment.

Study on the efficacy and safety of adefovir dipivoxil treatment in post-liver transplant patients with hepatitis B virus infection and lamivudine-resistant hepatitis B virus.

Hepatitis B virus (HBV) recurrence and de novo HBV infection are frequent events in liver transplantation recipients. Treatment with lamivudine is initially efficient in both infections but the incidence of lamivudine-resistant HBV emergence increases over time. Adefovir appears to be promising in post-liver transplantation patients with recurrent HBV infection and lamivudine-resistant HBV. This study analyzed adefovir treatment in 42 post-liver transplantation patients who developed recurrent HBV or de novo HBV infection with lamivudine-resistant HBV (54.8% HCV-coinfected). Patients received 10 mg of oral adefovir once daily for a mean period of time of 21.5 months (range from 12 to 31 months). In 62.9% of patients, ALT levels decreased significantly. Serum HBV-DNA was undetectable in 64% of the cases. Twenty percent of patients lost HBeAg marker and 13.3% of them developed anti-HBe. In 9.5% of recipients, HBsAg became negative. There was no significant change in serum creatinine levels. In only one patient was worsening of the renal function detected, making dose adjustment necessary. No other side effects were reported. Our results confirm the efficacy and safety of adefovir treatment in post-liver transplantation patients with lamivudine-resistant HBV, neither were adefovir-resistant mutations identified in patients after 21 months of therapy, nor were there adverse events, especially renal toxicity.

Posttransplant liver granulomatosis associated with hepatitis C?

BACKGROUND: Liver granulomatosis is an occasional finding in posttransplant liver biopsies. Its diagnosis is made more difficult by the variety of conditions that can lead to it. In the nontransplant setting, the association of liver granulomatosis and hepatitis C virus (HCV) infection has occasionally been described. METHODS: We describe the case of a patient with a liver transplantation for an HCV-associated cirrhosis who developed an alteration of liver tests. Granulomatosis was detected on the liver biopsy. RESULTS: Other causes of granulomatosis were satisfactorily excluded. The development of the lesions coincided with a viral flare-up. CONCLUSION: We think that HCV can be listed among the possible causes of liver granulomas in the posttransplant setting and that it must be considered in the differential diagnosis of this condition.

Aspergillus antigenemia sandwich-enzyme immunoassay test as a serodiagnostic method for invasive aspergillosis in liver transplant recipients.

BACKGROUND: Invasive aspergillosis (IA) is an important cause of mortality in liver transplant patients. Clinical and microbiological diagnosis is difficult, and it is frequently achieved only after autopsy. Early diagnosis and antifungal therapy could improve the survival of these patients. METHODS: A retrospective case-control study of IA in liver transplant recipients (OLT) was performed to determine the value of the detection of galactomannan Aspergillus antigen in serum using a sandwich-ELISA test (Platelia, Sanofi Diagnostic Pasteur). Stored frozen serum specimens obtained during the posttransplantation period were used. RESULTS: Fourteen cases of IA were diagnosed in 240 OLT recipients (IA incidence: 5.8%) during 5 years with 13 deaths (mortality: 93%). Nine case patients and 33 control patients met the criteria required for being considered "valid" for antigenemia analysis. In five of the nine case patients, a serum sample was positive for Aspergillus antigenemia detection. The median value was 5.7 ng/ml (range: 1.6-6.6). Sensitivity of the test was 55.6%, specificity was 93.9%, the positive predictive value was 71.4%, and the negative predictive value was 88.6%. The likelihood ratio of a positive test was 9.2. CONCLUSIONS: Galactomannan detection in serum could be useful for an early diagnosis of IA in OLT recipients.

Long survival of diarrhea-associated hepatocarcinoma treated with Adriamycin and indomethacin. A case report.

The existence of tumors producing prostaglandins is well documented in the literature. At present, no case report of a prostaglandin-producing hepatocellular carcinoma has been published, to our knowledge. The authors report a patient with hepatocellular carcinoma associated with diarrhea mediated by prostaglandins, surviving 30 months after receiving treatment with indomethacin and Adriamycin. The authors will discuss the possible role played by indomethacin in the exceptional clinical course of the patient.

Liver transplantation for type Ib glycogenosis with reversal of cyclic neutropenia.

We describe a case of glycogen storage disease type Ib in 32-year old male patient with poor metabolic control in spite of medical and nutritional management and the use of recombinant granulocyte stimulating factor. Because of this, liver transplantation was considered as a definitive treatment. We comment on the metabolic results of liver transplantation performed, with reversal of hypoglycemia, hyperuricemia, hypertriglyceridemia and cyclic neutropenia, all of which persist 4 years post-transplant. In view of this case, we believe that liver transplantation is a feasible option to consider in patients with type Ib glycogenosis as a definitive therapeutic procedure.

Role of Helicobacter pylori infection and its eradication in patients with subclinical hepatic encephalopathy.

AIMS: Helicobacter pylori infection in cirrhotic patients has been associated with episodes of hepatic encephalopathy (HE), although conclusive data are still lacking. This prospective study has evaluated the prevalence of H. pylori infection in 37 patients with advanced cirrhosis of the liver and subclinical hepatic encephalopathy (SHE), diagnosed by changes in psychometric tests and/or electrophysiological tests, as well as the repercussion of H. pylori eradication on ammonaemia and the evolution of this disorder. RESULTS: A positive result for H. pylori infection was obtained in 22/37 (59%) patients. Initial fasting blood levels of ammonia were high in both groups. Infected and non-infected patients showed similar levels (62.05 mmol/l v. 62.5 mmol/l), which were lowered by the standard diet, although statistical significance was only reached in the infected patient group (53.05 +/- 26 mmol/l; P < 0.05). Infection was eradicated in 19 patients, but no reduction of blood levels of ammonia was observed after H. pylori eradication among infected patients (52.37 +/- 29 mmol/l). No change has been found in either group after the administration of diet or antimicrobials with regard to psychometric and/or electrophysiological tests. CONCLUSIONS: H. pylori infection does not contribute significantly to high blood levels of ammonia in patients with advanced cirrhosis and SHE. Likewise, H. pylori eradication does not induce any improvement in the psychometric and/or electrophysiological tests used to define SHE.

Survival and complication rates in liver transplant patients showing primary dysfunction versus normofunction.

AIMS: To determine rates of vascular and biliary duct complications, acute rejection, and graft and patient survival according to function status following liver transplantation. METHODS: We classified 248 consecutive liver transplants performed at the Hospital Ramón y Cajal, Madrid, over a 79-month period according to initial function as primary function (NP) versus dysfunction (PD). The latter group was subdivided into grafts showing primary failure (PF) or inadequate function (IPF). The classes NP and IPF were distinguished according to whether transaminase (GOT or GPT) levels and prothrombin activity were above or below 2000 IU and 50%, respectively. RESULTS: There were 23 (9.3%) patients with PD, of whom 12 (4.8%) showed PF. The incidence of vascular and biliary duct complications was similar in both groups, although acute rejection showed a significant difference (PD 3/23 versus NP 98/225; odds ratio =.18). In contrast, the mean survival rates of the grafts (NP 60.37 versus IPF 39.90 months) or patients (NP 63.02 versus PD 47.10 months) were not significantly different. Only 1- and 3-month graft survival rates significantly differed between the NP and IPF groups (NP 95% versus IPF 63%; P=.03 and NP 89% versus IPF 58%; P=.02, respectively). CONCLUSIONS: Recipients with PD or NP after liver transplant showed no differences in the incidence of vascular or biliary duct complications. These groups did vary, however, in terms of rates of acute rejection episodes. No differences in graft and patient survival rates were observed except a significantly lower graft survival at 1 and 3 months, among patients with inadequate primary function.

Beneficial effects of HLA class II incompatibility in living donor liver transplantation.

OBJECTIVE: To analyze the impact of HLA matching in both patient and graft evolution after LDLT. MATERIAL AND METHODS: Twenty recipients underwent LDLT with follow-up of 3 to 30 months. HLA typing was performed on all donor-recipient pairs; class I antigens were typed using serological methods and class II loci (DRB1 and DQB1) using low-resolution molecular typing. Recipient sera were cross-matched with donor lymphocytes. Antigen mismatches were analyzed for each locus individually, for each class as a whole and for HLA class I immunogenic triplets according to HLA Matchmaker software. RESULTS: Eighteen of 20 donor-recipient pairs were HLA haploidentical. All but one of the recipients had a negative cross-match before transplantation. While there was not a statistically significant correlation between HLA class I mismatches and the incidence of acute rejection episodes, HLA class II matching in DRB1 and DQB1 loci appeared to be associated with a higher incidence of acute rejection episodes after LDLT. Both host-versus-graft (HvG) and graft-versus-host (GvH) HLA class II compatibilities correlated with rejection episodes, especially for the GvH direction. CONCLUSIONS: HLA class II matching for DRB1 and DQB1 loci appears to be associated with a higher incidence of acute rejection episodes after LDLT. In this study, mismatches in class I HLA antigens are not related to an higher incidence of acute rejection episodes nor other complications after LDLT. Further studies are needed to unveil the role of HLA matching in LDLT.

Effect of exogenous fibrolytic enzyme on ruminal fermentation and digestibility of alfalfa and rye-grass hay fed to lambs.

This experiment was carried out to study the effect of a directly fed exogenous fibrolytic enzyme on intake and digestion of DM, OM, protein, NDF, ADF, and hemicellulose of alfalfa and ryegrass hay by sheep. Four diets were randomly assigned to four ruminally cannulated lambs using a 4 x 4 Latin square design, repeated in time, with a factorial arrangement (2 x 2) of diets: 1) alfalfa hay; 2) alfalfa hay + exogenous fibrolytic enzymes (enzyme); 3) ryegrass hay; and 4) ryegrass hay + enzyme. Lambs consumed more DM and OM from alfalfa than from ryegrass hay (P < 0.001). The ADF intake was not different between the hays, but NDF intake was lower for alfalfa (P < 0.001). For both hays, the enzyme increased intake of DM (P < 0.01), as well as OM and CP (P < 0.05); however, NDF and ADF intake were not changed. Alfalfa hay had higher apparent digestibility of DM, OM, and CP (P < 0.001), but lower digestibility for NDF, ADF, and hemicellulose. The enzyme increased apparent digestibility of CP, hemicellulose (P < 0.05), and NDF (P < 0.10) for alfalfa. Also, for both hays, the enzyme improved N balance because lambs retained more N (P < 0.05). The enzyme increased (P < 0.05) total VFA concentration (3 and 6 h) for both hays. Results from this trial indicate that directly fed exogenous fibrolytic enzymes may change ruminal fermentation, intake, and digestibility of forages with different nutritive value.

Sleep electroencephalogram alterations disclose initial stage of encephalopathy.

UNLABELLED: Minimal hepatic encephalopathy is often present in patients with chronic liver disease. The aim of this work was to determine changes in the dynamics of sleep electroencephalogram (EEG) in cirrhotic patients without overt encephalopathy. Twenty such cirrhotic subjects included in the protocol of hepatic transplantation of our hospital were studied and compared with 20 age-matched healthy volunteers. Spectral analysis of all-night EEG was estimated by computing the fast-Fourier transform in 2-second epochs, and averaging every 60 seconds. Artifacts were off-line suppressed, sleep stages (stage 2, stage 3-4 and REM) were determined, and the EEG mean dominant frequency (MDF) was calculated in each of these stages. Results show that in cirrhotic patients, nocturnal MDF evolution discloses a clear alteration of the ultradian EEG frequency oscillations present in controls. Also, the mean value of MDF in REM episodes was larger in cirrhotics than the corresponding value in controls. CONCLUSIONS: 1) sleep EEG evidences the existence of minimal hepatic encephalopathy; 2) the spectral analysis of EEG in minimal hepatic encephalopathy showed that the changes of MDF during sleep are an early marker of cerebral dysfunction in cirrhotic patients.