Ruth Neuhaus

Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease

The relevance of sobriety for outcome after orthotopic liver transplantation (OLT) for alcoholic liver disease (ALD) is still discussed controversially. We conducted a retrospective analysis of 300 patients transplanted for ALD with regard to recurrent alcohol consumption, risk factors for drinking after OLT, and long‐term survival. The 300 patients underwent OLT for ALD between 1989 and 2002. Median follow‐up was 89 months. Incidence and severity of drinking, survival rates, and causes of death were assessed. Age, gender, duration of pretransplant sobriety, social support, presence of children, and the results of psychosomatic evaluation were analyzed for their impact on recurrent alcohol consumption after OLT. Drinking of various degrees was observed in 19% of ALD patients after OLT. Pretransplant sobriety of less than 6 months, absence of companion in life, presence of young children, and a predicted poor psychosomatic prognosis were associated with an increased risk of recurrent alcohol consumption, whereas age and gender were not independent risk factors. Survival rates of patients who resumed abusive drinking were significantly lower than survival rates of abstinent patients or patients with minor lapses. Recurrent alcoholic liver disease accounted for the vast majority of deaths among patients who resumed abusive drinking after OLT, whereas malignant tumors, infections, and cardiovascular disease were the most common causes of death among abstinent patients. In conclusion, abusive drinking after OLT is associated with poor long‐term survival. Analysis of risk factors may help to identify patients with a high risk for recurrent alcohol abuse after OLT. Liver Transpl, 2006.

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.

Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient.

Acute hepatitis E virus (HEV) infection is a self-limiting symptomatic or asymptomatic disease. However, as recently observed, it can manifest itself as chronic hepatitis in patients receiving solid organ transplants as well as in patients with HIV infection or severe hematologic disorders. Here, we describe the clinical course of a 73-year-old male patient in whom HEV transmission occurred after receiving a HEV-infected liver from a donor with occult HEV infection, whereby the patient had tested negative for HEV RNA and anti-HEV antibodies shortly before explantation. Anti-HEV IgG, IgM, and HEV RNA were detected in the first tested serum sample of the liver recipient obtained 150 days after liver transplantation and remained positive (earlier samples after OLT were not available). Liver cirrhosis developed within 15 months and the patient died of septic shock. Based on phylogenetic analyses of the donor and recipients HEV strains, we were able to prove that the occult HEV infection was transmitted via the graft.

Treatment of Patients with Recurrent Hepatitis C after Liver Transplantation with Peginterferon Alfa-2b Plus Ribavirin

Background. Recurrent hepatitis C virus (HCV) after liver transplantation (OLT) is a major cause of graft loss in HCV-positive patients. In this study, we evaluated the efficacy and safety of pegylated interferon alfa-2b (peginterferon) and ribavirin treatment for recurrent HCV after OLT and analyzed the influence of antiviral treatment on the histological course of recurrent hepatitis. Methods. Twenty-five patients with recurrent HCV (genotype 1 n=20 and 2–4 n=5) received peginterferon (1 mg/kg/weekly) and ribavirin (600 mg) for 48 weeks. Viral load prior to treatment was below 1,000,000 (IU/ml) in 11 of 25 patients. Sustained antiviral response was defined as undetectable HCV-RNA in serum 6 months after stopping of therapy. All patients underwent liver biopsy prior to treatment and after 72 weeks. Results. Seventeen of 25 patients became HCV-RNA-negative after treatment (68%). Sustained virologic response (SVR) was achieved in 9/25 (36%) patients. Liver specimen showed increase of fibrosis from 1.7 to 2.0 within 72 weeks. Side effects like neutropenia (60%) and anemia (36%) were treated with G-CSF, erythropoietin, and dose reduction of peginterferon and ribavirin. Conclusions. The use of peginterferon is safe and effective in patients with recurrent HCV. Treatment of side effects, especially neutropenia or anemia, helped to maintain antiviral therapy. Despite a viral response of 68% during treatment, the patients showed further progress of recurrent hepatitis in liver specimen.

Rapid decline of antibodies after hepatitis A immunization in liver and renal transplant recipients.

Background. Hepatitis A vaccine is safe and achieves good seroconversion rates in liver (LTX) and renal (RTX) transplant recipients. Methods. A study was performed to determine the anti-hepatitis A virus (HAV) antibody decline in LTX and RTX patients, and in healthy controls who have been immunized with two doses of hepatitis A vaccine. Results. LTX and RTX patients had a satisfactory seroconversion rate after complete immunisation. However, 2 years later they had experienced a much more rapid antibody decline than controls, and only 59% of LTX and 26% of RTX seroconverters showed titres above the cut-off level defined as protective. Conclusions. Patients on immunosuppressive therapy may not be adequately protected against hepatitis A a few years after vaccination and alternative vaccination schemes may have to be considered.

Trends and experiences in liver retransplantation over 15 years

Compared to primary liver transplantation (LT), the inferior results in the outcome of liver retransplantation (re‐LT) continue to be a major challenge. The purpose of this study was to analyze changes in and outcomes of re‐LT over a period of 15 years at the Charité Virchow Clinic. Between 1989 and 2003, we performed 1,619 LTs and 157 re‐LTs (9.7%) in 1,462 patients. A total of 119 retransplants (50 females, 69 males) were analyzed after consideration of exclusion criteria: recipient age <16 years, second re‐LT, primary LT as split‐liver or living‐related LT, or combination with renal transplantation or Whipple operation. All patients received a whole‐size organ. Mean follow‐up was 62 months (6 days to 187 months). The main indications for re‐LT were initial nonfunction (26.9%), recurrence of viral‐induced hepatitis (20.2%), or acute and chronic rejection or thrombosis of the hepatic artery (both 16.8%). The main causes of death were bacterial infections (26.0%) as well as bleeding complications or recurrence of disease (both 16.0%) within the first postoperative month. Overall, 50 out of 119 patients (42%) died after re‐LT, 26 patients within the first 3 months and 38 within 1 year. Overall patient survival was 89.9% after 1 month, 78.2% after 1 year, and 67.1% after 5 years. In conclusion, our study showed good clinical results after re‐LT. Apart from the changing indications for re‐LT with an increasing amount of initial organ failure and hepatic artery thrombosis, the analysis also showed a decreasing amount of complications such as rejection, ischemic type biliary lesions, and recurrence of the disease with unchanged outcome over a period of 15 years. Liver Transpl, 2006.

LONG-TERM FOLLOW-UP OF HEPATITIS B VIRUS-INFECTED RECIPIENTS AFTER ORTHOTOPIC LIVER TRANSPLANTATION

The outcome after OLT was studied in 53 patients with chronic hepatitis B virus (HBV)* infection, 15 of whom had, in addition, evidence of hepatitis delta virus (HDV) superinfection. Nine of 53 patients received short-term immunoprophylaxis with anti-hepatitis B surface (HBs) hyperimmunoglobulin up to 1 week after OLT and 44 of 53 patients received long-term unlimited immunoprophylaxis. Eight of 9 (89%) patients with short-term immunoprophylaxis showed reactivation of replication with HBV DNA in serum > 10 pg/ml independently of the preoperative HBV DNA level and HBsAg reappeared in all cases. Four (44%) patients in this group lost their graft because of fulminant hepatitis or cirrhosis and required retransplantation, and 2 patients (22%) died after reinfection in the second graft. Nineteen of 44 (43%) patients with long-term immunoprophylaxis developed HBV values > 10 pg/ml after transplant and 12 of 44 (27%) became HBsAg+ again. Most of them had quantifiable HBV DNA levels before OLT. Retransplantation was required in 5 of 44 (11%) patients and 4 of them died after HBV recurrence. The frequency of HBV reactivation and the development of viral hepatitis after OLT were associated with the preoperative presence of HBV, as determined by the molecular hybridization assay. With nested polymerase chain reaction, all 53 patients were HBV-DNA+ in the serum before and after OLT. with just one exception, none of the patients with HDV superinfection died, in spite of increased HDV replication after OLT. The data indicate that long-term immunoprophylaxis with anti-HBs hyperimmunoglobulin after OLT improves the prognosis in HBV-infected patients. The preoperative detection of HBV DNA in serum by molecular hybridization assay is correlated with graft infection and represents a prognostic parameter. The presence of HDV may have a protective effect after OLT.

Mycophenolatemofetil for immunosuppression after liver transplantation: A follow-up study of 191 patients

Background. Mycophenolatemofetil (MMF) combined with calcineurin inhibitors (CNIs) as immunosuppression after orthotopic liver transplantation (OLT) is still under discussion. We retrospectively investigated the immunosuppressive potency of MMF for treatment of steroid‐resistant acute rejection (AR) or chronic rejection (CR), chronic graft dysfunction, and CNI‐induced toxicity in patients after OLT. Methods. Between 1988 and 2001 we performed 1,386 OLTs in 1,258 patients. Since 1995, 191 patients have received MMF after OLT for steroid‐resistant AR or CR, chronic graft dysfunction (115 patients), and CNIinduced toxicity (76 patients). The mean follow‐up time was 56 months. Results. Of 47 patients with steroid‐resistant AR, 12 had been treated with OKT3, without resolving the rejection. Overall, bilirubin and transaminases decreased significantly within 2 weeks after the addition of MMF, and liver function normalized in 38 patients. Five of eight patients with CR demonstrated stable liver function after a follow‐up of 55±8 months; 52 of 60 patients with chronic graft dysfunction improved within 3 months; and 46 of 59 patients with CNI‐induced nephrotoxicity improved after MMF treatment and a reduction of CNIs (with a significant decrease in serum creatinine within 2 weeks and an increase of creatinine clearance within 3 months). Clinical symptoms improved in 10 of 12 patients with neurotoxicity and four of five patients with hepatotoxicity. Side effects of MMF, such as gastrointestinal disorders or bone marrow toxicity, occurred in 60 patients (31.4%). The incidence of infections did not increase. Patient survival was 93%, and graft survival was 88.2%. Conclusions. MMF is a potent and safe immunosuppressive agent in OLT recipients for rescue therapy in AR, CR, or chronic graft dysfunction and helps to reduce the serious toxic side effects of CNIs.

Preoperative antiviral treatment and postoperative prophylaxis in HBV-DNA positive patients undergoing liver transplantation.

BACKGROUND Despite passive immunoprophylaxis a significant number of patients, especially if hepatitis B virus (HBV) DNA is positive prior to transplantation, develop HBV recurrence. This number might be reduced by lowering viral replication pretransplant with antiviral agents and by postoperative combination of antiviral agents and passive immunoprophylaxis. PATIENTS AND METHODS A total of 74 HBV-DNA positive patients who underwent liver transplantation between 9/88 and 4/00 were analyzed retrospectively. Before lamivudine or famciclovir were available, in total 40 patients did not receive any preoperative antiviral therapy. Since 11/93, 17 patients were treated with famciclovir 1500 mg daily, after 4/96 17 patients with lamivudine 150 mg daily prior liver transplantation. Posttransplant all patients received passive immunoprophylaxis aiming at a titer of more than 100 U/liter. In the 34 patients with preoperative antiviral therapy an additional prophylaxis with the respective antiviral agent was applied. RESULTS Under preoperative famciclovir and lamivudine 30 and 71% of patients became HBV-DNA negative, respectively. Actuarial reinfection rate 2 years after liver transplantation was 48% without antiviral prophylaxis, which was not statistically different from 55% under perioperative famciclovir therapy. In contrast only 18% developed HBV recurrence under perioperative lamivudine treatment. During both antiviral regimens neither pre nor posttransplant severe side effects were observed. CONCLUSION Perioperative application of famciclovir is not recommendable, whereas lamivudine seems to lower recurrence rates significantly. Whether the observed effect is due to pre- or postoperative application remains to be addressed in further studies. In addition the long-term course has to be awaited.

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. Liver Transpl, 2011.