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Biomedical subjects

Marina Berenguer

Publications and source records attributed to Marina Berenguer.

At least 19 recordsLinked to original sources
PubMed2007

Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.

Biopsy↗
PubMed2006

Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression.

BACKGROUNDS/AIMS: Recurrent HCV-cirrhosis occurs in a substantial proportion of transplant recipients, with higher rates reported in patients who had recently received a transplant. Over-immunosuppression has been implicated in this more unfavorable outcome. To determine whether the implementation of specific measures aimed at reducing or avoiding negative predictive variables is associated with an improvement in the outcome of recurrent hepatitis C. METHODS: Comparative study between a cohort of patients who had recently received a transplant (2001-2004) and a historical group of HCV-infected patients transplanted before the implementation of two simple measures (1999-2000): (i) use of dual initial immunosuppression (steroids + cyclosporine neoral or tacrolimus); (ii) slow steroid tapering (>6 months). Yearly biopsies were performed in these recipients, and only those with at least one protocol biopsy and those with cholestatic hepatitis (regardless of follow-up) were included in the study. End-point: rate of HCV-related severe disease (defined as bridging fibrosis, cirrhosis or fibrosing cholestatic hepatitis) within the first year post-transplantation. RESULTS: Severe disease was significantly lower in this cohort compared to the historical group (26/90, 29% vs 25/52, 48%; p=0.02). While other factors remained unchanged between the two cohorts, the proportion of patients on triple-quadruple regimes and the number of boluses of methyl-prednisolone were lower and the duration of prednisone therapy longer in more patients who had recently received a transplant. CONCLUSIONS: Improving the outcome of recurrent hepatitis C may be achieved by reducing overall immunosuppression and avoiding abrupt variations in immunosuppression.

Adult↗
PubMed2006

Effect of calcineurin inhibitors on survival and histologic disease severity in HCV-infected liver transplant recipients.

The severity of recurrent hepatitis C virus (HCV) is likely related to several factors. Controversial results have been reported regarding the effect of specific calcineurin-inhibitors. The aim of this research was to determine whether there are differences on posttransplantation outcome in HCV-infected patients based on initial immunosuppression. Prospective randomized trial comparing tacrolimus vs. cyclosporine-based immunosuppression in a cohort of patients undergoing primary orthotopic liver transplantation between 2001 and 2003 was used. Yearly biopsies were performed. Patients with at least 1 protocol biopsy and those with very severe recurrence despite a follow-up of less than 1 yr (cholestatic hepatitis, progression to bridging fibrosis/cirrhosis) were included. Baseline characteristics (demographics, liver function at transplantation, genotype distribution, donor, surgery, immunosuppression except for the type of calcineurin inhibitor) did not differ between the 2 groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, and/or death due to recurrent disease in the first year) was present in 27 in 90 (30%), and was equally distributed in the cyclosporine and tacrolimus groups (15/46 vs. 12/44, respectively). A total of 33 in 90 (37%) patients had no fibrosis in the first year biopsy with no difference between the cyclosporine and tacrolimus groups (36.5 vs. 37%). The percentage of patients developing recurrent acute hepatitis was also similar (32% vs 35%); time to acute hepatitis though was shorter in the tacrolimus group (59 days [35-185] vs. 92 days [39-343] in the cyclosporin group; P = 0.02). Cholestatic hepatitis was observed in 4 of 44 and 5 of 46 patients under cyclosporine and tacrolimus, respectively (P = not significant). In conclusions, the short-term posttransplantation course of hepatitis C is not related to the calcineurin inhibitor used.

Adult↗
PubMed2006

Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C.

There are unresolved issues regarding sustained virological response (SVR), tolerance and risk of rejection following antiviral therapy in liver transplantation (LT). The aim of our study was to determine efficacy, rejection risk and factors associated with SVR. HCV-infected LT patients with at least 6 months of follow-up following end-of-therapy (EOT) received combination therapy of ribavirin (Rbvr) + standard (n = 31)/pegIFN (n = 36) between 1999 and 2004 (95% genotype 1). An EOT and SVR was obtained in 46% and 33%, respectively. Type of antiviral therapy, use of erythropoietin, compliance, and early virologic response (EVR) were predictive of SVR, but only the latter remained in the multivariate analysis. Premature discontinuation, not impacted by the use of erythropoietin or GCSF, occurred in 40% patients. None of the variables predicted rejection (acute n = 2, chronic n = 4). A SVR occurred in 3/4 patients with chronic rejection. In conclusion, the efficacy of pegIFN-Rbvr is similar to the non-transplant population. An EVR at 3 months is useful to predict lack of response. The type of calcineurin inhibitor and history of prior non-response to IFN before LT do not influence the outcome of therapy. Severe rejection may lead to graft loss, a complication difficult to predict.

Adult↗
PubMed2006

Treating hepatitis C infection in liver transplant recipients.

Chronic infection with hepatitis C virus (HCV) is a growing problem worldwide, with up to 300 million individuals infected, and those with chronic infection are at risk for cirrhosis and hepatocellular carcinoma. HCV infection is the most common indication for liver transplantation in the United States and Europe. Unfortunately, although transplantation is effective for treating decompensated cirrhosis and limited hepatocellular carcinoma associated with hepatitis C, HCV reinfection is virtually the rule among transplant recipients. Reinfection of the graft is associated with more rapidly progressive disease, with a median time to cirrhosis of 8 to 10 yr. Unfortunately, treatment of chronic HCV in liver transplant recipients is suboptimal. Combination therapy with interferon (pegylated and nonpegylated forms) plus ribavirin appears to provide maximum benefits. Drug therapy is usually administered for recurrent disease. No prophylactic therapy is available. Preemptive regimens offer no distinctive advantages over treatments begun for recurrent disease. Overall, treatment is poorly tolerated, with frequent need for dose reductions, especially from cytopenias, and drug discontinuations in up to 50% of patients. Optimizing drug doses is important in maximizing sustained virological response rates. Future therapies may include ribavirin alternatives with lower rates of anemia, alternative interferons with lower rates of cytopenias, and new antiviral drugs that can be used alone or in combination with either interferon or ribavirin to enhance sustained virological response rates and improve tolerability. Liver Transpl 12:1192-1204, 2006. (c) 2006 AASLD.

Antiviral Agents↗
PubMed2006

Prediction of significant fibrosis in hepatitis C virus infected liver transplant recipients by artificial neural network analysis of clinical factors.

OBJECTIVES: Interest in developing noninvasive markers of liver fibrosis continues to increase, especially in recurrent hepatitis C virus infection after liver transplantation. Recently, a model for predicting significant fibrosis (bridging fibrosis and cirrhosis) on the basis of logistic regression and routine laboratory data has been proposed (logit model). The aim of the present study was to evaluate the accuracy of an artificial neural network, a technique reported to work better than logit models in complex biological situations, built on those same clinical variables and data set of patients, in predicting significant fibrosis. METHODS: The neural network was constructed on the training set of 414 protocol biopsies, from liver transplant recipients, and then tested on the remaining 96 biopsies, as validation set. Model performances of neural network and logit model were evaluated and compared by means of areas under receiver operating characteristic curves. RESULTS: With a cutoff value of >0.4 to predict significant fibrosis, the neural network provided sensitivity, specificity, positive and negative predictive values, respectively, of 100, 79.5, 60.5 and 100%, in the validation set. The performance of the neural network was significantly better than that of the logit model (in the validation set area under the curve = 0.93 vs. 0.84; P = 0.045). CONCLUSIONS: Artificial neural network provides accurate prediction of the presence or absence of significant fibrosis from clinical variables, allowing theoretically protocol liver biopsy to be avoided in several instances, a result of particular interest, given the lack of other types of reliable noninvasive indexes of fibrosis in the setting of transplantation.

Adult↗
PubMed2005

[Liver retransplantation: outcome analysis in 50 patients].

BACKGROUND AND OBJECTIVE: Liver re-transplantation (re-LT) is an accepted indication for some (technical problems, primary non-function [PNF]) but not all indications, particularly recurrence of the original disease, such as hepatitis C. We aimed to determine in our center: a) the rate of survival following re-transplantation for all and each different indication; b) to compare it to that obtained by a control group; c) to assess whether late re-LT, excluding PNF and surgical problems, and re-LT in HCV (+) patients are associated with a higher mortality, and d) to estimate medical costs. PATIENTS AND METHOD: Form 1991 to April 2002, 50 re-LT were done (group 1). Group 2 consisted of 45 primary LT controlled by transplant date. Group 1 was divided in two subgroups: a) re-LT after 6 months of the first LT (recurrence of primary liver disease n = 20, chronic rejection n = 5), b) Re-LT in the first 6 months (PNF n = 13, artery thrombosis n = 12). We analyzed donor, recipient, surgical and immunosuppressive-related variables. RESULTS: The mean age was 50 years (range: 23-63) (72% men). Actuarial survival for re-LT was lower than for the control group: 64%, 57% and 50% vs 84%, 82% and 82% at 1st, 3rd and 5th year, respectively. By indication, the 3-year survival was: PNF: 61% (p = 0.05), HAT: 58% (p = 0.02), recurrence of primary disease: 52% (p = 0.001), chronic rejection: 60% (p = 0.346). Although not reaching statistical significance, survival was lower in late vs early re-LT (p = 0.16) and in HCV-infected versus non-infected patients (p = 0.08). In the HCV (+) group, there were no differences by re-transplant indication (p = 0.8). Medical costs and complications were substantially higher in group 1 vs group 2. CONCLUSIONS: Re-LT is associated with substantial medical costs and mortality, particularly in patients infected with HCV.

Adult↗
PubMed2005

Aceruloplasminemia in an asymptomatic patient with a new mutation. Diagnosis and family genetic analysis.

A 39-year-old asymptomatic man showed elevated serum ferritin levels, mild hypertransaminasemia and serum ceruloplasmin almost undetectable. There was histological iron accumulation within the hepatocytes and also in the central nervous system (MRI). A genetic analysis revealed a new missense mutation in the ceruloplasmin gene. Two of the other four siblings were also affected by this mutation.

Adult↗
PubMed2005

Prediction of fibrosis in HCV-infected liver transplant recipients with a simple noninvasive index.

Recurrent hepatitis C is a frequent event in liver transplantation (LT). Serial liver biopsies remain the best way of monitoring disease progression. Due to the limitations of a liver biopsy, there is an interest in developing noninvasive markers of liver fibrosis. While several models for predicting fibrosis have been constructed in patients who have not undergone transplantation, these are lacking in the transplant population. The aim of this study was to construct one simple model based on routine laboratory data to predict fibrosis in hepatitis C virus (HCV)-infected LT patients. A total of 510 yearly protocol liver biopsies performed in 188 LT patients (67% male; median age 54 years) were divided into 2 groups: training set (n = 414) and validation set (n = 96). Laboratory variables at time of biopsies were recorded. Multivariate analysis identified 4 variables as independent predictors of fibrosis: prothrombin time (PT), albumin/total protein ratio, aspartate aminotransferase (AST), and time since LT. The area under the receiver operating characteristic (ROC) curves (AUCs) were 0.80 and 0.84 for the training and the validation set, respectively. In the training set, using a cutoff of 0.2, the model had a sensitivity, specificity, positive predictive value, and negative predictive value of 74%, 69%, 42%, and 90%, respectively, to differentiate significant (bridging fibrosis and cirrhosis) from mild fibrosis (none or portal). In the validation cohort, these values increased to 87%, 71%, 49%, and 95%, respectively. In conclusion, in the LT setting, a simple fibrosis index is useful to select HCV-infected patients with a very low risk of significant fibrosis in whom protocol liver biopsies may be avoided.

Adult↗
PubMed2005

Treatment of hepatitis C after liver transplantation.

This article summarizes the current therapies, with particular emphasis on antiviral therapy. Because these alternatives have substantial limitations, pretransplant or early post-transplant recognition of patients with high risk of severe post-transplantation outcome is desirable to target these patients for intervention. Alternatively, the implementation of measures aimed at reducing or avoiding factors known to be associated with an aggressive recurrence is an additional strategy that needs to be explored.

Antiviral Agents↗
PubMed2004

Genetic variability of hepatitis C virus non-structural protein 3 and virus-specific CD8+ response in patients with chronic hepatitis C.

Hepatitis C virus (HCV) variation in specific T-cell epitopes may represent a mechanism of viral persistence in chronic infection. We examined the HCV non-structural protein 3 (NS3), including the immunologically relevant epitopes HCV NS3-2 KLVALGINAV (human leukocyte antigen [HLA]-A2-restricted) and HCV NS3-1391 LIFCHSKKK (HLA-A3-restricted), in 22 HLA-A2+ patients with chronic infection. Significant amino acid variation was found in HCV NS3-2 epitope sequences when compared to the HCV-1 prototype virus. Six of the nine different HCV NS3-2 peptide variants were identified in patients with HCV NS3-2-specific CD8+ cells, detected with an HLA-A2 tetramer made with the HCV-1 prototype peptide. Phylogenetic analysis, including HCV reference sequences other than HCV-1, suggested however that most of the variations in the HCV NS3-2 epitope could be related to genetic heterogeneity between HCV reference subtypes. Variation was less common when comparing HCV NS3-2 epitope sequences from the clinical isolates to the most-closely related HCV reference subtype in each case. Some subtype-independent variations were found in epitopic residues probably important for T-cell receptor interaction. In contrast, no significant variation was found in HLA primary anchor sites, flanking regions, or in the contiguous HLA A3-restricted CD8+ T-cell epitope. Ongoing variation was not evident in two selected patients with follow-up. In conclusion, (i) the HCV NS3-2 epitope is not conserved between different HCV strains/subtypes, and (ii) an HLA-A2 tetramer loaded with the HCV-1 prototype NS3-2 peptide may still detect NS3-specific CD8+ cells in some patients with variant viruses. These data may be useful to improve T-cell assays using HCV NS3 peptides, taking into account the genetic diversity of this virus.

Adult↗
PubMed2004

Genetic variability of hepatitis C virus NS3 protein in human leukocyte antigen-A2 liver transplant recipients with recurrent hepatitis C.

The association between the severity of chronic hepatitis C and the variability of the hepatitis C virus (HCV) genome remains controversial, but to our knowledge few data are available to date regarding T-cell epitope coding regions in transplant patients. In the current study, we identified 21 human leukocyte antigen (HLA)-A2-positive Spanish patients with chronic hepatitis C, 14 immunosuppressed liver transplant recipients, and 7 immunocompetent controls. Alanine aminotransferase, aspartate aminotransferase, viral load, and rate of fibrosis progression were determined. Genetic distances of HCV isolates and variations in epitopes of the HCV nonstructural 3 protein (NS3-1393 LIFCHSKKK and NS3-1406 KLVALGINAV) were compared between patients with slow or fast progression of fibrosis. Isolates from transplant patients with fast progression were found to be more divergent (P =.03), had a higher mean value of synonymous (dS) variations (P =.02), and some were differentiated in a phylogenetic tree, compared with isolates from patients with slow progression. The HLA-A2-restricted NS3-1406 epitope was found to be more variable (20 of 21 isolates differed from the prototype) compared with the A3-restricted NS3-1392 epitope (19% vs. 1.25% variation). A shift in the viral peptide was not detected in a subset of transplant patients, but was evident in two of three nontransplant patients with follow-up. There was no correlation noted between a particular amino acid variation and fibrosis progression (slow or fast) in either transplant or nontransplant patients. The results of the current study suggest that 1) there may be different HCV-1b strains in our geographic area, 2) immunosuppression appears to have little effect in amino acid variation at the HCV NS3-1406 epitope, and 3) variations over time might be more frequent in nonimmunosuppressed patients.

Adult↗
PubMed2004

The use of class-I HLA tetramers for the detection of hepatitis C virus NS3-specific CD8(+) T cells in patients with chronic infection.

BACKGROUND/AIMS: New methods to detect virus-specific T-cell responses have recently been developed. Several human leukocyte antigen (HLA)-peptide tetramers for the detection of hepatitis C virus (HCV)-specific CD8(+) T cells are under evaluation. METHODS: Evaluation of one HLA class I-tetramer (HCVNS3-2) for the detection of HCV NS3-specific CD8(+) T cells in a series of 38 HLA-A2(+) chronically infected patients. RESULTS: Almost half (42%) of the patients had detectable NS3-specific CD8(+) T cells. The frequencies of such cells ranged from 0.01% to 0.22% of total CD8(+) T cells. No significant differences in clinical features or mean viral load were detected between patients with or without tetramer + CD8(+) T cells. CONCLUSIONS: The tetramer HCVNS3-2 may be very useful for the study of the HCV-specific CD8(+) immune response. Combination of this reagent with other tetramers based on other HCV peptides may help in the understanding of the immune response to the virus. However, a panel of tetramers based on several parts of the HCV polyprotein may be a mandatory requirement to explore the whole breadth of the CD8(+) T-cell response against HCV and to detect that response in the majority of patients with chronic infection.

Adult↗
PubMed2004

Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy.

BACKGROUND: Recurrent hepatitis C is very common leading to graft cirrhosis in a significant proportion of patients. Preliminary reports of combination therapy with interferon-ribavirin have been promising but generally applied to selected patients with chronic mild disease. Little is known, however, about the efficacy and risk of adverse effects when it is used in general clinical practice. AIMS: To analyse the efficacy (biochemical, virological and histological response) and tolerance of combination therapy in patients with recurrent hepatitis C genotype 1b. METHODS: Twenty-four patients (mean age 54 years; range 37-67 years; 75% male) with recurrent hepatitis C virus (histology at baseline: acute hepatitis (n = 3); chronic hepatitis (n = 21) with F3 or 4 in 77%) were treated with 12 months interferon (1.5-3 MU thrice weekly) + ribavirin (600-1200 mg daily) followed by 6 months ribavirin (58%), at a median of 427 days (56-2812) after transplantation. RESULTS: Seven patients (29%) discontinued therapy due to side effects, mainly anaemia, at a median of 3 months since initiation. Dose modifications were required in 88% of those completing the whole course of therapy. Overall, the sustained virological and biochemical response was 12.5%. This rate was slightly higher (18%) if only the 17 patients who finished the whole course of therapy were analysed. Histological improvement was achieved in 31.5% of treated patients. CONCLUSIONS: Combination therapy has a very limited efficacy in the liver transplant setting, although some benefit may be achieved, even in those with advanced graft fibrosis. Tolerance, however, remains a matter of concern.

Acute Disease↗