The 28-year incidence of de novo malignancies after liver transplantation: A single-center analysis of risk factors and mortality in 1616 patients.

De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow-up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow-up. The median follow-up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3-81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A-treated compared with tacrolimus-treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow-up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404-1414 2017 AASLD.

Two-Year Follow-Up Analysis of Telaprevir-Based Antiviral Triple Therapy for HCV Recurrence in Genotype 1 Infected Liver Graft Recipients as a First Step towards Modern HCV Therapy.

Objective. The introduction of protease inhibitors telaprevir and boceprevir in 2011 had extended the antiviral treatment options especially in genotype 1 infected hepatitis C relapsers and nonresponders to interferon/ribavirin therapy. The aim of this study was to analyze the long-term treatment efficiency of telaprevir-based triple therapy for patients with hepatitis C reinfection after orthotopic liver transplantation. Patients and Methods. We included 12 patients with histologically confirmed graft fibrosis due to hepatitis C reinfection. The treatment duration was scheduled as 12 weeks of telaprevir-based antiviral triple therapy followed by 36 weeks of dual therapy with pegylated interferon/ribavirin. The patients were followed up for two years after the end of triple therapy. Results. Of the 12 patients, 6 (50%) completed the full 48 weeks of antiviral treatment. An end of treatment response and a sustained virological response 52 weeks after the end of the antiviral treatment course were achieved in 8/12 (67%) and 7/12 (58%) patients, respectively. Conclusion. Telaprevir-based triple therapy was shown to be a long-term effective but complex treatment option for individual patients with hepatitis C graft. With the recent improvements in hepatitis C therapy options telaprevir may not be recommended as a standard therapy for this indication anymore.

Incidence and long-term survival of patients with de novo head and neck carcinoma after liver transplantation.

BACKGROUND: Liver transplant recipients have an increased risk of developing de novo malignancies. METHODS: We conducted a prospective evaluation of clinicopathological data and predictors for overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) after liver transplantation (1988 to 2010). RESULTS: Thirty-three of 2040 patients who underwent liver transplantation (1.6%) developed de novo HNSCC. The incidence of HNSCC in liver transplant recipients with end-stage alcoholic liver disease (26) was 5%. After a median follow-up of 9 years, 1-year, 3-year, and 5-year OS rates were 74%, 47%, and 34%, respectively. Tumor size, cervical lymph node metastases, tumor site, and therapy (surgery only vs surgery and adjuvant radiotherapy [RT]/chemoradiotherapy [CRT] vs RT/CRT only; p < .0001) were significantly associated with OS in univariate analysis. However, surgery only predicted OS independently in multivariate analysis. CONCLUSION: Early diagnosis and surgical treatment of de novo HNSCC are crucial to the outcome. HNSCC risk should be taken into close consideration during posttransplantation follow-up examinations, especially among patients with a positive history of smoking and alcohol consumption.

Successful Treatment of Chronic Hepatitis E After an Orthotopic Liver Transplant With Ribavirin Monotherapy.

OBJECTIVES: Hepatitis E virus infection is increasingly reported as a cause of chronic hepatitis in organ transplant recipients. Besides reduction of immunosuppressive therapy or pegylated-interferon therapy, promising results have been reported for ribavirin monotherapy of hepatitis E virus after kidney transplant. To our knowledge, this is the first report of a successful ribavirin monotherapy for chronic hepatitis E virus infection after and orthotopic liver transplant. MATERIALS AND METHODS: This is a case report of a 55-year-old man with a diagnosis of chronic hepatitis E (genotype 3f) 26 months after an orthotopic liver transplant. A reduction of immunosuppressive therapy was not tolerated, and the patient did not qualify for pegylated-interferon therapy. Because of progressively elevated liver transaminases accompanied by histologic changes in the liver allograft, ribavirin monotherapy was undertaken for 16 weeks. RESULTS: We saw a decrease in liver enzymes after 1 week of ribavirin monotherapy. Hepatitis E virus RNA anti-HEV-IgM were tested after 8 weeks of ribavirin therapy, and were both negative. Antiviral therapy was continued for 16 weeks, and hepatitis E virus RNA remained undetectable; there also was a significant decrease in liver transaminases levels to normal values. In the 8-week and 8-month follow-ups at the end of antiviral therapy, the patient presented with normal liver enzymes and no detectable hepatitis E virus RNA. CONCLUSIONS: In conclusion, successful therapy of chronic hepatitis E after an orthotopic liver transplant may be achieved by ribavirin monotherapy and should be considered in patients who are sensitive to a reduction of immunosuppressive therapy or pegylated-interferon therapy.

Fcγ-receptor IIIA polymorphism p.158F has no negative predictive impact on rituximab therapy with and without sequential chemotherapy in CD20-positive posttransplant lymphoproliferative disorder.

We retrospectively analyzed the p.V158F polymorphism of Fcγ-receptor IIIA (FCGR3A, CD16) in patients with PTLD treated with rituximab monotherapy. Previous reports had indicated that the lower affinity F allele affects rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) and is linked to inferior outcome of rituximab monotherapy in B cell malignancies. 25 patients with PTLD after solid organ transplantation were included in this analysis. They had received 4 weekly doses of rituximab as part of two clinical trials, which had a rituximab monotherapy induction regimen in common. 16/25 patients received further treatment with CHOP-21 after rituximab monotherapy (PTLD-1, NCT01458548). The FCGR3A status was correlated to the response after 4 cycles of rituximab monotherapy. Response to rituximab monotherapy was not affected by F carrier status. This is in contrast to previous findings in B cell malignancies where investigators found a predictive impact of FCGR3A status on outcome to rituximab monotherapy. One explanation for this finding could be that ADCC is impaired in transplant recipients receiving immunosuppression. These results suggest that carrying a FCRG3A F allele does not negatively affect rituximab therapy in immunosuppressed patients.

YKL-40-gene polymorphism affects acute cellular rejection and fibrosis progression after transplantation for hepatitis C virus-induced liver disease.

BACKGROUND AND AIM: The development of end-stage graft disease is suspected to be partially determined by an individual genetic background. The aim of our study was to determine the prevalence of YKL-40-gene polymorphism in hepatitis C virus (HCV)-positive patients and its impact on the incidence of acute cellular rejection (ACR), graft fibrosis and antiviral treatment response. METHODS: A total of 149 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for YKL-40 (rs4950928; G/C) by TaqMan Genotyping Assay. The results were correlated with 616 post-transplant graft biopsies regarding inflammation, fibrosis and evidence for ACR. RESULTS: No association of YKL-40-genotypes was observed regarding mean inflammation grade (P = 0.216) and antiviral treatment outcome (P = 0.733). However, the development of advanced fibrosis (F3-4) was significantly faster in patients with YKL-40-G-allele: t(CC) = 4.6 versus t(CG/GG) = 2.4 years; P = 0.006. Patients with lower fibrosis (F0-2) compared to advanced fibrosis (F3-4) received significantly more frequent dual immunosuppression (calcineurin inhibitors [CNIs]/mofetile mycophenolate [MMF] vs CNIs; P = 0.003). ACR-occurrence was associated with YKL-40-genotypes (ACR: CC = 60.4%, CG = 25.0% and GG = 14.6% vs non-ACR: CC = 74.2%, CG = 23.8% and GG = 2.0%; P = 0.009) and with gender compatibility between donor and recipient (P = 0.012). CONCLUSION: Fibrosis progression and ACR-incidence after transplantation for HCV-induced liver disease seem to be under genetic control. The negative impact of G-allele on post-transplant events observed in our study, deserves attention and should be verified in larger liver transplantation-cohorts.

Genetic variants of STAT-4 affect the development of graft fibrosis after liver transplantation for HCV-induced liver disease.

BACKGROUND: Hepatitis C virus (HCV) reinfection after liver transplantation may lead to recirrhosis and seems to be influenced by genetic factors. The aim of our study was to evaluate the role of STAT-4-polymorphisms in the development of HCV-related graft disease based on protocol biopsies. METHODS: One hundred sixty transplant patients with HCV recurrence were genotyped for STAT-4 (rs7574865) by polymerase chain reaction. Fibrosis stages were determined based on Desmet and Scheuer classification. SPSS was used for the statistical analysis of genotype distribution and of time to the development of advanced fibrosis among the genotypes. RESULTS: During a comparable observation period of 86.2 months (P=0.654), 65 patients (46.5%) developed advanced fibrosis. Advanced fibrosis was observed significantly more frequent in patients (n=34) with at least one T-allele (53.1 vs. 32.3%; P=0.013) compared with homozygotes for G-allele (n=31). Significant differences in the duration of advanced fibrosis development were detected between patients with at least one T-allele compared with G-allele (34.4 vs. 49.0 months; P=0.022). No impact was observed regarding the outcome of interferon-based antiviral treatment (P=0.297) and the occurrence of acute cellular rejection (P=0.365). CONCLUSION: Present results indicate a possible impact of genetic confounders in the recipient on graft fibrogenesis, thus explaining significantly different graft behavior observed after transplantation for HCV-associated liver disease. STAT-4-T-allele is identified as fibrogenic factor and seems to have a negative impact on HCV-induced fibrosis development.

Role of IL28B polymorphism in the development of hepatitis C virus-induced hepatocellular carcinoma, graft fibrosis, and posttransplant antiviral therapy.

BACKGROUND: The development of liver graft disease is partially determined by individual genetic background. Interleukin 28B (IL28B) is strongly suspected to be involved in susceptibility for hepatitis C virus (HCV) infection, inflammation, and antiviral treatment response before and after liver transplantation (LT). Currently, the role of IL28B polymorphism (rs12979860) in the development of hepatocellular carcinoma (HCC) is unclear, and only limited data are available on the course of HCV recurrence. METHODS: One hundred sixty-seven HCV-positive patients after LT were genotyped for IL28B (C→T; rs12979860). Sixty-one patients with histologically confirmed HCC in the explanted liver were compared with 106 patients without HCC regarding IL28B genotypes. Among patients with HCC, IL28B genotypes were correlated with tumor histology and pretransplant α-fetoprotein (AFP) levels. Furthermore, the role of IL28B polymorphism was evaluated regarding interferon-based treatment success and fibrosis progression after LT. RESULTS: The prevalence of HCC in explanted livers was significantly higher among patients with TT genotype, suggesting a protective role of the C allele in HCC development (P=0.041). Median AFP level was closely to significance higher in the presence of T allele (P=0.052). Significant differences in IL28B genotype distribution were detected between AFP-negative and AFP-positive HCCs (<15 µg/L vs. >15 µg/L; P=0.008). Although no impact could be observed regarding acute cellular rejection (P=0.940), T allele was significantly associated with antiviral therapy failure (P=0.028) and faster development of advanced fibrosis (P=0.017) after LT. CONCLUSION: IL28B polymorphism seems to be involved in the development of HCV-induced HCC and in the course of HCV recurrence after LT. T allele may be regarded as a genetic risk factor for HCV-related carcinogenesis, posttransplant fibrosis progression, and antiviral therapy failure.

Burkitt post-transplantation lymphoma in adult solid organ transplant recipients: sequential immunochemotherapy with rituximab (R) followed by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP is safe and effective in an analysis of 8 patients.

BACKGROUND: Burkitt lymphoma post-transplantation lymphoproliferative disorder (Burkitt-PTLD) is a rare form of monomorphic B-cell PTLD for which no standard treatment has been established. Currently, the treatment of Burkitt lymphoma outside the post-transplantation setting involves high doses of alkylating agents, frequent dosing, and intrathecal and/or systemic central nervous system prophylaxis. In PTLD, however, such protocols are associated with considerable toxicity and mortality. METHODS: The authors present a retrospective series of 8 adult patients with Burkitt-PTLD. Six patients were reported to the prospective German PTLD registry or were enrolled in the PTLD-1 trial, and 2 patients had received treatment before 2000, thus allowing for comparison with the pre-rituximab era. RESULTS: Seven of the 8 patients were men. The median age at presentation was 38 years, and the median time since transplantation was 5.7 years. Five of 8 patients had histologically established, Epstein-Barr virus-associated disease, and 7 of 7 patients were positive for a MYC translocation. Five of 8 patients received sequential immunochemotherapy (4 courses of rituximab [R] followed by 4 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP] or R plus CHOP [R-CHOP]). In this group, 5 of 5 patients reached complete remission (CR), and their overall survival (OS) was significantly longer (P = .008) compared with the OS for 2 of 8 patients who received first-line CHOP and did not respond. One of 8 patients (who had stage IV disease with meningiosis) received combination therapy (cyclophosphamide pretreatment, rituximab, intrathecal chemotherapy, whole-brain irradiation, and radioimmunotherapy) and reached CR. Overall, 6 of 8 patients reached CR; and, after a median follow-up of 4.7 years (range, 1.7-4.8 years), the median OS was 36.7 months. There was no treatment-related mortality under first-line therapy. CONCLUSIONS: In the largest adult case series in Burkitt-PTLD to date, sequential immunochemotherapy with rituximab followed by standard CHOP or R-CHOP was a both safe and effective treatment.

Transforming growth factor-ß1-gene polymorphism in the development of kidney disease after liver transplantation.

BACKGROUND: The development of kidney dysfunction is one of the most important after liver transplantation (LT). Genetic variants of pathogenetically relevant cytokines may influence the development and course of the disease. The aim of our study was to evaluate the role of transforming growth factor-ß1 (TGF-ß1) polymorphism in this context. METHODS: Four hundred eighty-six liver graft recipients were genotyped for TGF-ß1 codon 25 (guanine → cytosine, G → C) by polymerase chain reaction. Renal function before and after LT was characterized by estimation of glomerular filtration rate (GFR) using four-parameter-modification of diet in renal disease formula on defined dates. GFR was compared among TGF-ß1-genotype groups of the entire cohort within the median observation period of 7 years. For the assessment of renal function recovery after LT, patients were divided into three groups by GFR difference (ΔGFR = ± 10 mL/min). RESULTS: Mean pretransplant GFR differed significantly among TGF-ß1-genotype groups (GG: 85.0 mL/min vs. GC/CC: 75.3 mL/min; P=0.016). The significance disappeared in the follow-up period. Although GG genotype demonstrated higher mean GFR levels, patients with GC/CC genotype tended to improve kidney function compared with GG genotype (P=0.013). Interestingly, lower mean GFR rates were observed among female compared with male recipients before (P=0.002), separately at all dates and cumulatively after LT (P<0.001). CONCLUSIONS: Genetic variants of one of the most important cytokine TGF-ß1 at codon 25 may have an impact on kidney function, suggesting an unfavorable effect of C allele in pretransplant setting and serve as marker for the recovery of renal function after LT. The identification of further confounders seems to be promising.

Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial.

BACKGROUND: Post-transplantation lymphoproliferative disorder (PTLD) develops in 1-10% of transplant recipients and can be Epstein-Barr virus (EBV) associated. To improve long-term efficacy after rituximab monotherapy and to avoid the toxic effects of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy seen in first-line treatment, we initiated a phase 2 trial to test whether the subsequent use of rituximab and CHOP would improve the outcome of patients with PTLD. METHODS: In this international multicentre open-label phase 2 trial, treatment-naive adult solid-organ transplant recipients diagnosed with CD20-positive PTLD who had failed to respond to upfront immunosuppression reduction received four courses of rituximab (375 mg/m(2) intravenously) once a week followed by 4 weeks without treatment and four cycles of CHOP every 3 weeks. In case of disease progression during rituximab monotherapy, CHOP was started immediately. Supportive therapy with granulocyte-colony stimulating factor after chemotherapy was mandatory and antibiotic prophylaxis was recommended. The primary endpoint was treatment efficacy measured as response rates in all patients who completed treatment with rituximab and CHOP, per protocol, and response duration, in all patients who completed all planned therapy and responded. Secondary endpoints were frequency of infections, treatment-related mortality, and overall survival. This study is registered at ClinicalTrials.gov, number NCT01458548. FINDINGS: 74 patients were enrolled between Dec 12, 2002 and May 5, 2008, of whom 70 patients were eligible to receive treatment. PTLD was of late type in 53 (76%) of 70 patients, monomorphic in 67 (96%) of 70, and histologically EBV associated in 29 (44%) of 66 cases. Four of 70 patients did not receive CHOP. 53 of 59 patients had a complete or partial response (90%, 95% CI 79-96), of which 40 (68%, 55-78) were complete responses. At data cutoff (June 1, 2011) median response duration in the 53 patients who had responded to treatment had not yet been reached (>79·1 months). The main adverse events were grade 3-4 leucopenia in 42 of 62 patients (68%, 55-78) and infections of grade 3-4 in 26 of 64 patients (41%, 29-53). Seven of 66 patients (11%, 5-21) had CHOP-associated treatment-related mortality. Median overall survival was 6·6 years (95% CI 2·8-10·4; n=70). INTERPRETATION: Our results support the use of sequential immunochemotherapy with rituximab and CHOP in PTLD. FUNDING: F Hoffmann-La Roche, Amgen Germany, Chugaï France.

Recurrent hepatocellular carcinoma in liver transplant recipients: parameters affecting time to recurrence, treatment options and survival in the sorafenib era.

BACKGROUND: A growing number of patients with hepatocellular carcinoma undergo liver transplantation, but there is little data on recurrence and its treatment in the posttransplant setting. METHODS: This article presents a retrospective analysis of adult hepatocellular carcinoma patients. The aim of the study was to characterize the clinical pattern of posttransplant hepatocellular carcinoma recurrence, treatment options in recurrence and overall survival after liver transplantation and after recurrence. RESULTS: A total of 139 patients with histological proven hepatocellular carcinoma was included in the study. The median follow-up after liver transplantation was 37.2 months. Twenty-four of 139 patients experienced a recurrence. In 72.7% of the cases, the hepatocellular carcinoma recurred outside the transplant. Median overall survival after recurrence was 23.1 months. A total of 68.2% of patients received a mean of 2.2 treatments for posttransplant hepatocellular carcinoma recurrence. While on treatment with sorafenib, the use of mTOR inhibitors and radiotherapy had no statistically significant effect on overall survival, complete surgical resection of metastatic lesions significantly improved overall survival. Non-resectable patients with isolated hepatic relapse also benefited from local control strategies. CONCLUSIONS: Posttransplant hepatocellular carcinoma recurrence frequently is located outside the transplant, and despite the proven efficacy of sorafenib, complete surgical resection of metastatic lesions remains the hallmark of treatment.

Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial.

BACKGROUND: Calcineurin inhibitors (CNIs) play the key role in immunosuppressive protocols yet are often associated with numerous side effects. Renal insufficiency, hypertension, hyperglycemia, and increased risk of secondary malignancy are major problems in short- and long-term follow-up of liver transplant patients. Mycophenolate mofetil (MMF) has proved to be a potent immunosuppressive agent free of the CNI-associated side effects. PATIENTS AND METHODS: One hundred fifty patients who received liver transplantation at our institution (1998-2003) were prospectively randomized: 75 patients continued CNI standard therapy, 75 patients were switched to MMF monotherapy, and follow-up was 5 years. Incidence of rejection, renal complication, cardiovascular, neurological and gastrointestinal adverse effects, and diabetes and malignancy development was recorded. Graft biopsies were performed every 2 to 3 years. RESULTS: No significant difference regarding the incidence of acute rejection was detected. A trend to higher rejection frequency was apparent in the MMF monotherapy group. Chronic rejection was absent; organ and patient survival were identical in the two groups. No significant difference occurred concerning the incidence of cardiovascular, gastrointestinal or neurological adverse effects, or the development of malignancies. Renal function improved significantly in patients with renal insufficiency when patients treated with CNI were switched to MMF monotherapy. CONCLUSION: MMF monotherapy may serve as safe long-term immunosuppression after liver transplantation for a subgroup of patients. Especially for patients with renal insufficiency MMF offers immunosuppression without the risk of nephrotoxicity.

Association of mannose-binding lectin-2 gene polymorphism with the development of hepatitis C-induced hepatocellular carcinoma.

BACKGROUND: Development of end-stage liver and graft disease is suspected to be partially determined by the individual genetic background. Mannose-binding lectin (MBL) is an important immunomodulatory factor, which is supposed to be involved in complement activation and oncogenesis. Genetic polymorphisms of MBL-2 alter MBL functionality. The aim of our study was to determine the prevalence of MBL-2 polymorphism (rs7096206) in hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) based on histological analysis of explanted livers in patients undergoing liver transplantation (LT). METHODS: One hundred and seventy-seven patients, who underwent LT for HCV-induced liver disease, were genotyped for MBL-2 by TaqMan genotyping assay. Sixty-two patients with histologically confirmed HCC were compared with 115 patients without HCC. MBL-2 genotypes were corelated with the growth patern, tumour size and pretransplant α-fetoprotein (AFP) level of HCC patients. RESULTS: The prevalence of GG/GC genotypes was significantly higher among HCC patients compared with tumour-free explanted livers (P = 0.004; odds ratio 2.5; 1.3-4.8). GG/GC genotype group was significantly associated with the size of HCC (P = 0.022), higher pretransplant AFP level (P = 0.010) and bilobar tumour growth (P = 0.038). Furthermore, CC genotype was found to be significantly more frequent in AFP-negative HCCs (P = 0.002). CONCLUSION: Mannose-binding lectin-2 polymorphism seems to be involved in the development of pretransplant HCV-induced HCC and should be further investigated as potential risk factor for HCV-associated carcinogenesis.

IL-6 and IL-10 in post-transplant lymphoproliferative disorders development and maintenance: a longitudinal study of cytokine plasma levels and T-cell subsets in 38 patients undergoing treatment.

IL-6 and IL-10 have previously been implicated in the pathogenesis of post-transplant lymphoproliferative disorders (PTLD) and, like peripheral lymphocyte populations, are markers of immune status that are amenable to study in vivo. Thus, we analyzed cytokine plasma levels as well as lymphocyte subsets in a longitudinal analysis of 38 adult transplant recipients undergoing treatment for PTLD. Pretherapeutically, we found significantly elevated IL-6 (13.8 pg/ml) and IL-10 plasma levels (54.7 pg/ml) - in the case of IL-10, even higher in treatment nonresponders than in responders (116 vs. 14 pg/ml). Over time, however, IL-10 levels did not correlate with the course of disease, whereas those of IL-6 did, falling in responders and rising in nonresponders. These findings were independent of histological EBV-status, treatment type, and total peripheral T-cell counts, which were significantly reduced in patients with PTLD. Our observations support the idea that although IL-10 is important for creating a permissive environment for post-transplant lymphoma development, IL-6 is associated with PTLD proliferation. The analysis of lymphocyte subsets further identified HLA-DR+ CD8+ lymphocyte numbers as significantly different in non-PTLD controls (33%), treatment responders (44%) and nonresponders (70%). Although the specificity of these cells is unclear, their increase might correlate with the impaired tumor-specific cytotoxic-T-lymphocyte (CTL)-response in PTLD.

Treatment of hepatitis C-virus-reinfection after liver transplant with silibinin in nonresponders to pegylated interferon-based therapy.

OBJECTIVES: Hepatitis C-virus-persistence after orthotopic liver transplant leads to reduced patient and graft survival compared to other indications. Current interferon-based antiviral therapy of hepatitis C-virus-infection posttransplant provides a sustained response rate of 30% to 40%. This study, performed in an hepatitis C-virus-reinfected liver transplant population, examines the antiviral effect of intravenously administered silibinin, recently reported to exhibit strong antiviral properties in the natural setting of hepatitis C-virus-related liver disease. PATIENTS AND METHODS: Four patients after orthotopic liver transplant with hepatitis C-virus-recurrence, previously having not responded to peg-interferon-ribavirin therapy, were treated with intravenous silibinin and additionally, after the 10th day, with standard interferon-based therapy. Aminotransferases and hepatitis C-virus-RNA were measured during treatment. RESULTS: All patients demonstrated normalization of liver enzymes and significant decline of hepatitis C-virus-RNA measured at day 10 (mean 2.8 logarithmic levels: 1.7, 2.3, 2.9, and 4.3) during silibinin monotherapy. One patient cleared hepatitis C-virus-RNA under silibinin monotherapy and another patient eliminated hepatitis C virus under subsequent interferon-based therapy. No adverse effects were observed during silibinin application. CONCLUSIONS: Intravenous silibinin is an effective therapeutic approach for treating hepatitis C-virus-reinfection after liver transplant and should be evaluated further.

Transforming growth factor ß1 polymorphisms and progression of graft fibrosis after liver transplantation for hepatitis C virus--induced liver disease.

Re-infection with the hepatitis C virus (HCV) is an important development after liver transplantation (LT); it can lead to graft fibrosis. The aim of this study was to assess the role of transforming growth factor ß1 (TGF-ß1) polymorphisms in the development of HCV-related graft disease by evaluating protocol liver biopsies. A total of 192 patients with a recurrence of HCV infection after LT were genotyped for TGF-ß1 codon 10 (C→T) and codon 25 (G→C) using the polymerase chain reaction. Histological evaluation of 614 protocol liver biopsies obtained from these patients was undertaken using the classification of Desmet and Scheuer to stage the degree of fibrosis. Mild stages of fibrosis (0-2) were compared to advanced stages of fibrosis (3-4) that developed during the period of infection with the virus. Correlations between the prevalence of TGF-ß1 genotypes and the different degrees of fibrosis that developed were determined. No statistically significant differences were found for genotype distributions (codons 10 and 25) with respect to recipient age, donor sex, occurrence of acute cellular rejection, and response to antiviral therapy. However, the C allele at codon 25 was significantly less frequent in the group with advanced fibrosis (P = 0.001). Furthermore, a positive association was found between progression of fibrosis and male recipient sex (P = 0.024), donor age (P = 0.041), and viral genotype 1b (P = 0.002). In conclusion, this study, in which the evolution of hepatic fibrosis was assessed histologically in a large cohort of patients with HCV re-infection after LT, has demonstrated that the C allele at codon 25 of the TGF-ß1 gene is a marker for the development of graft fibrosis.

Relationship between the interleukin-28b gene polymorphism and the histological severity of hepatitis C virus-induced graft inflammation and the response to antiviral therapy after liver transplantation.

Up to 30% of liver transplants will develop graft cirrhosis within 5 years after liver transplantation (LT) due to recurrent HCV-infection forwarding accelerated graft damage. Genetic variants of cytokines involved in the immune response may contribute to the degree of graft inflammation, fibrosis progression, and antiviral therapy outcome. The aim of our study was to analyze biochemical and histological inflammation extent based on protocol liver biopsies and to evaluate the role of genetic variants of IL-28b in HCV-related graft disease and antiviral treatment response. 183 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for IL-28b (rs8099917, G ≥ T) by TaqMan Genotyping Assay. 56 of 159 patients have been successfully treated with interferon-based antiviral therapy. 605 protocol liver biopsies performed 0.5 to 10 and more than 10 years after transplantation were evaluated according to Desmet and Scheuer classification of inflammation and fibrosis. Prevalence of IL-28b-genotypes was correlated with histological severity of graft damage, levels of aminotransferases, occurrence of acute cellular rejection, pre-treatment viremia, and antiviral therapy outcome. Significant association of IL-28b-genotype distribution was observed to the median grade of inflammation (p < 0.001), mean levels of aminotransferases (ALT: p = 0.001, AST: p = 0.003), median pre-treatment viremia level within 1 year after LT (p = 0.046) and interferon-based antiviral therapy failure (p < 0.001). Among successfully treated patients, G-allele was significantly less frequent, and the genotype GG was not present at all. No differences were observed regarding acute cellular rejection (p = 0.798) and fibrosis stages (p = 0.586). IL-28b polymorphism seems to influence the degree of graft inflammation at biochemical and histological levels. G-allele might serve as a marker for graft inflammation and as a predictor for unfavorable antiviral therapy outcome in HCV-re-infected LT-population.

Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study.

Hepatitis B re-infection prophylaxis is crucial for graft and recipient survival for transplanted patients and is administered routinely after liver transplantation for hepatitis B. Aim of the current study was the investigation of efficacy, safety and feasibility of home-treatment of a novel human hepatitis B immunoglobulin BT088 (Zutectra) after weekly subcutaneous application in liver-transplanted patients. A total of 23 patients (5 female, 18 male, median age 51 years) were enrolled and switched from monthly IV to weekly SC hepatitis B immunoglobulin administration. During a period of 18 weeks (optional 24 weeks) anti-HBs levels, signs of re-infection, adverse events and feasibility of self-administration were studied. After 8 weeks of training patients showing good compliance and stable antibody titres were allowed to start self-administration at home. All patients maintained a safety level of >100 U/l anti-HBs. No failure was noted, no re-infection occurred. A total of 10 treatment-emergent events were assessed as related to study drug application (injection-site haematoma, headache, abdominal pain, fatigue and haematuria). High numbers of self-administration (287 vs. 122 by staff) demonstrated general feasibility of SC administration. Weekly subcutaneous administration of BT088 (Zutectra - registered trade mark in the EU) is effective, safe and presents an easy-to-apply treatment option for combined hepatitis B virus re-infection prophylaxis in liver transplant patients (Eudra CT Number: 2005-003737-40).

ELISA-based detection of C4d after liver transplantation--a helpful tool for differential diagnosis between acute rejection and HCV-recurrence?

Hepatitis-C is the most common indication for liver transplantation. Recurrence of HCV is universal leading to graft failure in up to 40% of all patients. The differentiation between acute rejection and recurrent hepatitis-C is crucial as rejection treatments are likely to aggravate HCV-recurrence. Histological examination of liver biopsy remains the gold standard for diagnosis of acute rejection but has failed in the past to distinguish between acute rejection and recurrent hepatitis-C. In a retrospective study we have recently reported that C4d as a marker of the activated complement cascade is detectable in a hepatic specimen in acute rejection after liver transplantation and may serve as a valuable tool in differential diagnosis between ACR and HCV-recurrence. We performed a prospective analysis by ELISA measurement of C4d concentration in cryo-preserved liver biopsies of LTX patients who had either experienced acute rejection, hepatitis-C recurrence or displayed no pathological alterations (controls). Opposed to our immunohistologically based findings in paraffinized tissue we were unable to detect significant differences of C4d concentration in ELISA of cryo-preserved liver tissue. Consequently the role and potential value of C4d as a diagnostic marker may not be determined using ELISA-based tissue evaluation.