Histological Recurrence Of Hepatitis Research Articles

Immunological dysfunction during or after antiviral therapy for recurrent hepatitis C reduces graft survival.

Pegylated interferon and ribavirin (PEGIFN/RBV) therapy for recurrent hepatitis C after liver transplantation (LT) is associated with a lower sustained virological response (SVR) rate as well as more frequent side effects compared to non-transplant patients. We aimed to determine the incidence and clinical characteristics of LT recipients with recurrent hepatitis C who developed immunological dysfunction (ID) during or after PEG-IFN/RBV therapy and to assess its impact on patient and graft survival. Seventy-four deceased donor LT recipients with histological recurrence of hepatitis C were treated with PEG-IFN/RBV from 1/00 to 12/08. ID was defined as biopsy-proven rejection or moderate plasma cell hepatitis. Patients were followed up until death, re-LT or 30 September 2011. Twelve patients (16 %) had ID, 8 (10.7 %) had cholestasis without ID, while 54 had no ID/cholestasis during or after discontinuation of PEG-IFN/RBV therapy. Biopsy-proven acute cellular rejection prior to (hazard ratio = 4.87, p = 0.009) and type of immunosuppression at the time of initiation of PEG-IFN/RBV were the only independent predictors of ID. Patients who were on tacrolimus at the time of initiation of PEG-IFN/RBV had a significantly lower risk of ID compared to those who were on cyclosporine (HR 0.254, p = 0.023). Patients with ID had a trend toward a lower SVR rate (25 vs. 54 %, p = 0.18) and a significantly higher rate of graft failure (33 vs. 4 %, p = 0.004) compared to patients with no ID/cholestasis. ID is common during or after PEG-IFN/RBV therapy for recurrent hepatitis C and frequently associated with decreased graft survival, trending toward low rates of SVR. Careful monitoring of liver biochemistries during or after PEG-IFN/RBV therapy with a low threshold to biopsy patients and particularly those receiving cyclosporine-based immunosuppression may improve outcomes in these patients.

Use of hepatitis C-positive donors in transplantation

Transplantation (Tx) is a therapeutic alternative intervention for terminal organ dysfunction, fatal disease or, in some cases, to improve the quality of life and reduce the risk of complications from chronic diseases. One of the major limitations in performing transplants is obtaining donor organs because of the difficulties in the process of organ donation of deceased donors and the unavailability of compatible living donors. In Brazil, there are many more patients on waiting lists, especially for liver and kidney transplants, than the number of procedures performed. Therefore, non-ideal donors are sometimes considered for transplantation, including those with a higher risk of primary graft dysfunction and infection transmission, such as hepatitis C virus (HCV)-seropositive donors. HCV-seropositive donors have routinely been used by a few groups or in cases of extreme urgency. However, the safety of transplantation from HCV-positive donors has not been clearly determined and may vary according to the type of transplant. To establish a set of recommendations, we performed an analysis based on the data available in the literature. The following items were considered according to the type of transplantation: 1) the position on the list, 2) the urgency of transplantation, 3) the HCV infection status of the donor (serology, viral replication and histological activity), 4) the HCV infection status of the recipient (serology, viral replication and histological activity) and 5) the safety data available regarding the use of HCV-seropositive donors. We analyzed liver, kidney, heart, lung and hematopoietic stem cell transplants (HSCTs). The IDSA (Infectious Diseases Society of America) rating system was used to establish levels of evidence. 1. Liver Transplantation Chronic liver disease due to HCV accounts for almost one-half of liver Tx indications. The risk of the histological recurrence of hepatitis after transplantation is approximately 70%. The graft and recipient survival is lower compared with other etiologies. Descriptive and comparative studies and case-control analyses have shown that the use of seropositive donors for seropositive recipients does not interfere with graft or patient survival. 2. Kidney Transplantation Some descriptive studies have shown that the use of seropositive donors for seropositive recipients does not interfere with graft or patient survival. However, one publication described five cases of discordant donor and recipient genotypes: in three of these cases, elevated enzyme levels and genotype substitution or association were observed in the recipient after transplant. 3. Heart Transplantation Little data are available regarding heart Tx. One multicenter study reported a lower survival rate in patients who received organs from seropositive donors, regardless of the HCV serostatus of the recipient. 4. Lung Transplantation Little data are also available regarding lung Tx. However, in a multicenter survey, 72% of the participating groups considered the use of HCV-seropositive donors for HCV-seropositive recipients. Nevertheless, there have been no descriptions of liver disease progression or graft and patient survival in positive viremia recipients. It is important to consider that treatment with interferon-gamma is usually not recommended after lung Tx due to the high risk of acute cellular rejection. 5. Hematopoietic Stem Cell Transplantation (HSCT) In HSCT, there have been reports of a significantly increased risk of hepatitis in HCV-seronegative recipients of seropositive donors, especially when there is evidence of viral replication. Because HSCT often involves situations in which there is an imminent risk of death and the need for an HLA-matched living donor, the decision should be based on the urgency of the Tx and level of viremia in the donor.

Steroid minimization in liver transplant recipients: impact on hepatitis C recurrence and post‐transplant diabetes

Steroid minimization regimens have become increasingly popular for kidney transplant recipients. We studied outcomes for liver transplant recipients with a regimen using rapid discontinuation of prednisone (RDP). The study group consisted of 83 recipients transplanted between June 2004 and January 2006. Immunosuppression consisted of tacrolimus, MMF, and two doses of basiliximab with six d of steroids. Patients with underlying autoimmune disorders (PSC, autoimmune hepatitis) were not included as they were maintained on steroids. The control group consisted of 83 recipients transplanted between January 2002 and May 2004. Immunosuppression consisted of tacrolimus, MMF and steroids, with no antibody induction. Mean MELD score at time of transplant was significantly higher in the steroid free group vs. the control group (28 vs. 23, p = 0.02); mean donor age was also higher (42 vs. 37 yr, p = 0.02). Other characteristics including recipient age, cold ischemic time, donor source, and cause of liver disease were similar (p = ns). Mean length of follow-up was 16.1 months in the RDP group and 32 months in the control group; a minimum of six months follow up was present for all patients. Patient and graft survival rates were not statistically different in the two groups (p = ns). Biopsy proven rejection was low in both groups and not significantly different (at one yr post-transplant 11% in the RDP group vs. 12% in control, p = 0.53). Based on protocol biopsy data, histologic recurrence of hepatitis C was demonstrated in 56% of the control group hepatitis C positive recipients vs. 39% in the RDP group (p = 0.05). There was a significantly lower incidence of post-transplant diabetes (PTDM) in the RDP vs. control group (at 6 months post-transplant 12% vs. 32%, p = 0.004). Rapid discontinuation of prednisone in liver transplant recipients is not associated with an increased risk of rejection, and may be associated with lower morbidity, especially PTDM and hepatitis C recurrence.

Hépatite C et transplantation hépatique: Histoire naturelle et traitement ou comment améliorer la prise en charge ?

Hepatitis C virus-related end-stage liver disease, alone or in combination with alcohol, has become the leading indication for liver transplantation in most transplant programs accounting for approximately half of transplants performed in European centers. Hepatitis C virus infection recurs virtually in every post-transplant patient. The natural history of hepatitis C after liver transplantation is variable. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Several factors, including those related to the virus, the host, the environment and the donor, are probably implicated in the outcome. The immune status represents the main significant variable in influencing disease severity in hepatitis C virus-infected patients; with higher HCV viral load and the significant association described between the degree of immunosuppression and disease severity. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. In this article we present a comprehensive review of post-transplant hepatitis C virus infection; in particular fibrosis progression and the major challenges according to treatment.

Natural history of hepatitis C following liver transplantation.

Currently, chronic hepatitis C virus-infection-related cirrhosis is the most common indication for liver transplantation in the USA and most parts of the world. While the incidence of new hepatitis C virus cases has decreased, the prevalence of infection will not peak until the year 2040. In addition, as the duration of infection increases, the proportion of new patients with cirrhosis will double by 2020 in an untreated patient population. If this model is correct, the projected increase in the need for liver transplantation secondary to chronic hepatitis C virus infection will place an impossible burden on an already limited supply of organs. In this article we present a comprehensive review of post-transplant hepatitis C virus infection and address the major challenges that face the transplant community. Hepatitis C virus infection recurs virtually in every post-transplant patient. Typically, serum levels of hepatitis C virus RNA increase rapidly from week 2 post-liver transplant, achieving 1-year post-liver transplant levels that are 10-20-fold greater than the mean pre-liver transplant levels. Progression of chronic hepatitis C virus is more aggressive after liver transplantation with a cumulative probability of developing graft cirrhosis estimated to reach 30% at 5 years. Approximately 10% of the patients with recurrent disease will die or require re-transplantation within 5 years post-transplantation. Interventions to prevent, improve, or halt the recurrence of hepatitis C virus infection have been evaluated by multiple small studies worldwide with similar overall rates of virological clearance of approximately 9-30%. Current consensus recommends combination therapy with pegylated interferon and ribavirin for those patients with histological recurrence of hepatitis C virus infection and fibrosis of >/= 2/4. Therapy is adjusted to tolerance and rescued with granulocyte colony-stimulating factor and erythropoietin for bone marrow suppression. The major challenges that face the transplant community in the coming years include new strategies to meet the growing demand for limited organ donor supplies and improvement of treatment for those patients in whom recurrence of viral disease has occurred. Only with improved antiviral treatments and strategies will we make a significant impact on this problem.

LIVER TRANSPLANTATION WITH THYMOGLOBULIN INDUCTION AND LOW-DOSE POSTOPERATIVE IMMUNOSUPPRESSION: EARLY RESULTS ON HCV RECURRENCE.

O33 Aims: Recent reports demonstrate the efficacy of induction immunosuppression with Thymoglobulin, a potent anti-thymocyte policlonal antibody, in allowing alloengraftment and acquired tolerance, by means of a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression. The effect of this novel approach in terms of recurrence of hepatitis C viral disease after liver transplantation has never been investigated. We report the preliminary results of a retrospective analysis aimed to discovery a relationship between thymoglobulin immunosuppression and pattern of recurrence of hepatitis C after liver transplantation Methods: From October 2002, we used Thymoglobulin induction + Tacrolimus monotherapy in a group of 22 HCV+ patients receiving liver transplantation (Thymoglobulin group); 32 historical HCV+ patients who received a different Tacrolimus based immunosuppression represented the comparison group. Results: Patients survival did not differs among the two groups, with 1-year survival rate of 82% (Thymoglobulin group) versus 86% in the non-Thymoglobulin group (p=ns). Five patients (22,7%) of the Thymoglobulin group experienced mild acute cellular rejection whereas 10 patients (31,3%) of the non-Thymoglobulin group experienced mild or moderate acute cellular rejection; among all Thymoglobulin patients, rejection grade was generally mild, requiring steroid recycle in 3 patients (13,6%), whereas 60% of patients in the non-Thymo group experienced moderate or severe acute rejection, requiring steroid recycle in all cases and OKT3 administration in one. Clinically HCV recurrence rate was equal in the two group (57% vs 55% of patients), although the pattern of recurrence was distinct. With respect of mean ALT and AST elevation, patients in the Thymo group reached higher levels than in the non-Thymo group (respectively mean ALT level: Thymo 326±65 UI/mL, non-Thymo 94±78 UI/mL, p=0,001; mean AST level: Thymo 202±71 UI/mL, non-Thymo 152±81 UI/mL, p=0,03). Patients in the Thymoglobulin group expressed earlier increase of HCV viral RNA load in a median time of 96 days (range 21-284 days) when compared with non-Thymoglobulin group (187 days; range 13-838; p=0,044); interestingly the mean peak viral RNA load was lower in Thymoglobulin patients than in the non-thymoglobulin patients (1494 U/L vs 3516 U/L; p=0,017). Histological recurrence of hepatitis C was also earlier in Thymoglobulin treated patients with a median disease-free survival of 113 days (range 25-204) when compared with the other group (327 days; range 31-752, p=0,001). However although a distict biochemical and virological pattern, no significant difference was observed in mean Ishak’s histological grading (4 in both groups) and staging (Thymo S=1, non-Thymo S=2) of HCV recurrence. Conclusions: Induction immunosuppression with Thymoglobulin in liver transplant recipients is effective in protecting against rejection whereas demonstrated a peculiar relationship with HCV recurrence that deserves further investigations.

The impact of advancing donor age on histologic recurrence of hepatitis C infection: The perils of ignored maternal advice

Recurrent hepatitis occurs in the majority of patients undergoing liver transplantation for hepatitis C virus (HCV) cirrhosis, with progression to cirrhosis in up to 30% after 5 years. Based on these data, a decrease in survival can be anticipated with prolonged follow-up. Furthermore, posttransplantation HCV-fibrosis progression has been shown in recent years to increase. Our aims were (1) to describe the natural history of HCV-infected recipients, particularly to determine whether survival has decreased in recent years; (2) to compare this outcome with that observed in non-HCV-infected cirrhosis controls; and (3) to determine the factors associated with disease severity and survival. Among 522 cirrhotic patients undergoing transplantation between 1991 and 2000, 283 (54%) were infected with HCV. Yearly biopsies were performed in these recipients and at 1 and 5 years in the remainder. With similar follow-up, the percentage of deaths in the HCV(+) group was signifi cantly higher than in the HCV-group (37% vs. 22%, P <.001), and patient survival was lower (77%, 61%, 55% vs. 87%, 76%, 70% at 1, 5, and 7 years, respectively; P =.0001). Although survival has increased in the HCV- group in recent years, it has significantly decreased in HCV recipients (P <.0001). The main cause of death among the latter was decompensated graft cirrhosis (n = 23/105, 22%), whereas that of HCV-patients was infections (n = 10/52, 19%). Reasons for the recent worse outcome in HCV+ recipients include the increased donor age and stronger immunosuppression. In conclusion, patient survival is lower among HCV+ recipients than among HCV- ones and has been decreasing in recent years. The aging of donors is a major contributor to this worse outcome.Background and Aim: Cirrhosis with liver failure due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT). Reinfection of the transplanted liver by HCV is inevitable, and aggressive hepatitis with accelerated progression to graft cirrhosis may be observed. Of concern, recent reports suggest that the outcome of LT for HCV may have deteriorated in recent years. Determinants of rate of progression to cirrhosis in the immunocompetent non-transplant patient are well defined, and the most powerful determinant is patient age at the time of infection. Following LT for HCV, recipient age does not affect outcome of HCV reinfection. However, the impact of donor age on graft fibrosis progression rate following LT has not been examined. Methods: We have examined post-transplant biopsies to assess histological activity, including fibrosis stage (scored 0-6 units, 6 representing established cirrhosis), and to calculate fibrosis progression rates in 101 post-transplant specimens from 56 HCV infected LT patients. Univariate and multivariate analyses examined the impact of parameters including recipient and donor age and sex on fibrosis progression rate, and on predicted time to cirrhosis. Results: For the cohort, median fibrosis progression rate was 0.78 units/year, and median interval from transplantation to development of cirrhosis was 7.7 years. In multivariate analysis, donor age (not recipient age) was a powerful determinant (P = 0.02) of fibrosis progression rate. When the liver donor was younger than 40 years, median progression rate was 0.6 units/year and interval to cirrhosis was 10 years. When the donor was aged 50 years or more, median progression rate was 2.7 units/year and interval to cirrhosis only 2.2 years. During the observation period there has been a significant increase in donor age (P = 0.01) but date of transplantation per se is not a determinant of progression rate when included in multivariate analyses. Conclusions: Donor age has a major influence on graft outcome following transplantation for HCV. The changing organ donor profile will affect the long term results of LT for HCV. These observations have important implications for donor liver allocation.

Histological recurrence and progression of hepatitis C after orthotopic liver transplantation: influence of immunosuppressive regimens.

Post-orthotopic liver transplantation (OLT) recurrence of hepatitis C is virtually universal, but histological progression of disease is not. This study examines long-term clinical and liver histological features at and after OLT to elucidate factors predictive of hepatitis C recurrence and progression after OLT. A blinded retrospective review of clinical, serological, and histopathologic features of 65 patients who underwent OLT for hepatitis C and Non A Non B hepatitis was conducted. Histological findings of recurrent hepatitis C and progression (fibrosis, >or= grade 2 by last follow-up) were correlated with clinical parameters. Histological recurrence of hepatitis C was seen in 43 of 65 patients, with progression in 19 patients. Histological findings in the native liver and post-OLT biopsy specimen at the time of recurrence showed no correlation with hepatitis C recurrence and progression. Patients treated with azathioprine (AZA)-containing immunosuppressive regimens experienced less recurrence (6 of 17 v 37 of 48 patients; P < .005) and progression (1 of 17 v 18 of 48 patients; P = .014) than those without AZA as part of their immunosuppressive regimen. No difference was seen between patients treated with cyclosporine versus those administered FK506 (P > .05). Histological recurrence of hepatitis C after OLT is seen in 66% of patients with progressive disease and 29% of all patients. The grade of inflammation in the native liver at the time of OLT and time of recurrence is not predictive of progression. AZA-containing regimens reduce histological recurrence and progression of hepatitis C in post-OLT patients.

The association of HLA haplotypes in liver transplant donors and recipients on biochemical and histologic recurrence of hepatitis C

The association of HLA haplotypes in liver transplant donors and recipients on biochemical and histologic recurrence of hepatitis C