Marina Berenguer

HCV-related fibrosis progression following liver transplantation: increase in recent years

BACKGROUND/AIMS The natural history and predictors of HCV-related disease severity post-transplantation are uncertain. The aims of this study were to define the natural history of post-transplantation HCV infection by assessing the rate of fibrosis progression, to determine if the post-transplantation natural history differs from that observed pre-transplantation, and to identify predictors of post-transplantation disease progression. METHODS Post-transplantation biopsies (mean: 3+/-1.6/patient) from 284 patients were scored according to histologic stage, using the method of Desmet et al. Change in fibrosis score (fibrosis progression/year) post-transplantation was used as the primary outcome. Predictors analyzed included viral factors (genotype and viral load at transplantation), patient demographics, year of transplantation, country of transplantation, pre-transplantation fibrosis progression, immunosuppression and laboratory data. RESULTS There was a linear association between change in fibrosis score and time from transplantation, with a median rate of fibrosis progression per year of 0.3 (0.004-2.19/year). Using parametric time-to-event analysis, the expected median duration to cirrhosis was 10 years. The rate of post-transplantation fibrosis progression was significantly higher than pre-transplantation (0.2/year (0.09-0.8) p<0.0001), and higher in Spanish than US centers (0.48 (0.01-2.19) vs 0.28 (0.004-2.08); p=0.09) despite similar progression rates prior to transplantation. Variables independently associated with post-transplantation progression included year of transplantation (p=0.0001), race (p=0.02), number of methyl-prednisolone boluses (p=0.03), and HCV RNA levels at transplantation (p=0.01). CONCLUSIONS HCV-related disease progression is accelerated in immunocompromised compared to immunocompetent patients, with a progressive increase in patients who have recently undergone liver transplantation. Changes in patient management post-transplantation over time and between transplant centers may account for the increase in fibrosis progression observed in recent years.

Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin

The aim of our study was to conduct a systematic review of studies evaluating antiviral therapy with pegylated interferon (PEG-IFN) alfa in combination with ribavirin for the management of recurrent hepatitis C after liver transplantation. Data sources included electronic databases and a manual search. Studies evaluating the efficacy and tolerability of PEG-IFN alfa with ribavirin in patients with recurrent hepatitis C were selected for inclusion. The information extracted from each of the selected publications included study design details, patient characteristics, treatment regimens and efficacy and tolerability end points. Nineteen studies including 611 patients were identified. PEG-IFN alfa-2b was used in 16 studies. The mean rate of SVR was 30.2% (range, 8-50%). Dose reduction and discontinuation of treatment were common in these studies (73% and 27.6%, respectively). The lack of an early virologic response (EVR) at 3 months of therapy was the most frequently described predictive factor of nonresponse. Treatment discontinuation and dose reductions due to adverse events were frequent and possibly represent important obstacles to attainment of SVR. EVR at 3 months of treatment should be considered an important predictor of treatment outcome.

Contribution of obesity to hepatitis C-related fibrosis progression.

OBJECTIVE:Hepatitis C virus (HCV) disease progression is variable. Identification of factors predictive of rapid progression is an important goal for improving patient management. The aim of this study was to evaluate the predictive role of several variables, including some that are etiologically related to the nonalcoholic steatohepatitis (NASH) syndrome such us obesity, in fibrosis progression in both patients with elevated and normal transaminase levels.METHODS:A total of 114 chronic HCV-infected (HCV-RNA positive) patients were recruited prospectively between 2000 and 2001. All patients had at least one liver biopsy. The annual change in fibrosis stage (fibrosis progression rate) was assessed from the time of presumed infection (fibrosis = 0) among those who had only one biopsy (n = 97) or between two biopsies if these were available (n = 17). Based on published data, we arbitrarily defined a patient as a rapid progressor when the fibrosis progression rate was >0.2 U/yr. Potential predictors of rapid progression were: age at infection and biopsy, sex, significant alcohol intake (>50 g/day), risk factor of HCV acquisition (based on answers to a questionnaire), obesity (based on body mass index [BMI]), autoantibodies, iron overload (ferritin, transferrin saturation), diabetes, hyperlipidemia, anti-HBcore IgG, genotype, and viral load.RESULTS:The median fibrosis progression rate was 0.05 U/yr (range 0–1.58 yr). In all, 22 patients (19%) were rapid progressors. Variables associated with progression by multivariate analysis included: advanced age at infection (p = 0.0001), BMI ≥25 (p = 0.01), and ALT >1.5 times upper limit of normal (p = 0.01). Among patients with ALT >1.5 times upper limit of normal, these variables were advanced age at infection, BMI ≥25, diabetes and transferrin saturation >45. Among those with normal ALT levels, only BMI ≥30 was predictive of progression.CONCLUSIONS:Obesity, advanced age at infection, and elevated ALT levels predict rapid disease progression, suggesting that measures aimed at weight reduction may play a significant role in hepatitis C management. The natural history of hepatitis C is independent of the presence of autoimmunity markers.

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. Liver Transpl 12:1067–1076, 2006.

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.

De Novo Internal Neoplasms after Liver Transplantation: Increased Risk and Aggressive Behavior in Recent Years?

The goal of the study was to determine the incidence and variables associated with post‐liver transplantation (LT) de novo internal neoplasms development, excluding skin tumors and hepatocellular carcinoma. Medical records were reviewed for recipient/donor demographics, viral serology, cause of liver disease, interval from LT to tumor diagnosis, predisposing factors, immunosuppression and survival. Forty‐one neoplasms (31 solid and 10 hematologic) developed in 772 recipients (5.3%) transplanted between 1991 and 2001. Time to tumor diagnosis was longer in patients transplanted before 1995 than in those transplanted afterwards (58 vs. 22 months; p < 0.05). Hematologic neoplasms (HN) appeared earlier than solid (2 vs. 21 months; p < 0.001), were more prevalent in those transplanted after 1995 than before (32% vs. 12.5%), and had lower survival than solid (2 vs. 21 months, p < 0.001). While HCV was the most frequent indication in HN (70%), alcohol was that of solid tumors (71%). Overall, risk factors for de novo neoplasms included alcohol and immunosuppression (p < 0.01). In patients undergoing LT in recent years, there is a higher incidence of HN with de novo internal neoplasms developing at earlier time‐points than in those transplanted years ago. Risk factors for tumor development include alcohol, HCV and possibly strong immunosuppression.

Progression of liver fibrosis in post-transplant hepatitis C: Mechanisms, assessment and treatment

Liver fibrosis results from an excessive wound healing response in most chronic liver diseases, such as hepatitis C. Despite great advances in antiviral therapy in recent years, progressive liver fibrosis remains a major problem for patients with recurrent hepatitis C after liver transplantation. Liver biopsy remains a central tool in the management of HCV-positive liver transplant recipients, but reliable non-invasive methods for the assessment of liver fibrosis, such as ultrasound elastography, are increasingly being incorporated in the management of post-transplant patients, helping predict prognosis, guide treatment decisions, and stratify patients for emerging antifibrotic therapies. In this manuscript, we will review the natural history as well as tools to monitor fibrosis progression in the HCV-positive liver transplant recipient, the mechanisms underlying rapid fibrosis progression in up to 30% of these patients, the effect of antiviral therapies and highlight promising antifibrotic approaches.

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. Liver Transpl 12:762–767, 2006.

Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients

Hepatitis C virus (HCV) re-infection of the graft is universal and interferon based antiviral therapy remains at present the treatment of choice in HCV liver transplant recipients. Apart from the antiviral effects, interferon and ribavirin have both potent immunomodulatory properties resulting in a broad range of immune-related disorders including acute cellular rejection and chronic ductopenic rejection as well as de novo autoimmune hepatitis. Further complicating the picture, HCV infection per se is associated with a variety of autoimmune phenomena. We discuss here the immune-mediated complications and their relationship to chronic HCV and interferon based antiviral therapy.

Liver transplantation and hepatitis C.

Hepatitis C virus (HCV)-related end-stage cirrhosis with/without hepatocellular carcinoma is the primary indication for liver transplantation in many countries. Unfortunately, HCV is not eliminated by transplantation and graft re-infection is the rule, resulting in HCV-related graft disease. The natural history of recurrent hepatitis is variable; overall, progression to cirrhosis occurs in 20-30% and allograft failure in 10% after 5-10 years from transplantation. The use of poor quality organs, particularly from old donors, has a significant negative impact on disease severity and transplant outcome. In contrast, antiviral therapy, particularly if it results in permanent eradication of the virus, is associated with improved histology, reduced rate of graft decompensation and enhanced outcome. Disease monitoring, through protocol liver biopsies and new non-invasive tools, is essential to select patients at need of antiviral therapy. Peginterferon with ribavirin, used similarly to what is done in the non-transplant setting, is currently the treatment of choice; sustained viral response is achieved in about 35% of cases. Side effects, particularly anemia, are extremely frequent and sometimes severe (rejection, de novo autoimmune hepatitis). Retransplantation (RT) is the last option for the small subset of patients with allograft failure due to HCV recurrence who fulfil minimum criteria based on RT survival models.