Review of the use of hepatitis B core antibody–positive kidney donors

This article reviews the risks of transplanting hepatitis B core antibody (anti-HBc)–positive (+) kidneys and strategies to minimize the risks to the recipient. In the United States, there is a shortage of kidneys available for transplantation. Presently, 4% of kidneys transplanted are anti-HBc (+). In published retrospective studies, the serologic conversion rate for recipients of anti-HBc (+) kidneys varied between 0% and 27%; and the development of elevated hepatic transaminases varied between 0% and 26%. Only one published article had a trend toward increased risk of graft loss. Other published studies had no significant difference in graft or patient survival. Factors that influence the risk of transmission include hepatitis B viral load, vaccination, and antiviral therapy. If the donor is anti-HBc (+) and hepatitis B DNA negative, the risk of transmission is negligible; unfortunately, this information may not be available at the time of transplant. Vaccinated recipients with a protective hepatitis B surface antibody of at least 10 mIU/mL had a 4% conversion rate compared with 10% in recipients with antibody levels not exceeding 10 mIU/mL. Both hepatitis B immunoglobulin and lamivudine have been used in recipients of anti-HBc (+) kidneys to decrease seroconversion with success. The data do support the use of anti-HBc (+) kidneys if precautions are taken. The recipients should be informed of the risk, should be vaccinated with an adequate response, and should have surveillance serologies performed.     

Prophylaxis against de novo hepatitis B for liver transplantation utilizing hep B core (+) donors: does hepatitis B immunoglobulin provide a survival advantage?

Donor liver allografts with positive serology for hepatitis B core antibody [HBc (+)] have been increasingly used for liver transplantation. However, the optimal prophylactic regimen to prevent development of de novo hepatitis B has not been determined. To evaluate this, we screened United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) registry data for adult recipients of HBc (+) organs who were HBsAg (?), and evaluated the effects of using prophylactic anti‐viral therapies (HBIG and lamivudine) on patient and graft survival. Out of a total cohort of 958 patients transplanted since 2004, 61 received HBIG alone, 116 received lamivudine alone, 66 both, 509 neither and 206 were missing this information. Based on several multivariable Cox regression models, patients receiving HBIG therapy‐only were observed to have a statistically significant (approximately 70%) reduction in risk of mortality compared with patients receiving lamivudine‐only therapy [HR = 0.29, 95% CI (0.10, 0.86), P = 0.026], and a nonstatistically significant reduction in risk of graft failure. However, no graft failures were attributed to de novo hepatitis B, suggesting that any improved graft/patient survival possibly associated with HBIG therapy occurs independently of de novo hepatitis B virus (HBV) reduction. While this study cannot prove that HBIG therapy is protective for graft and patient survival after liver transplantation, these findings do highlight the need to further examine and study prophylactic use in recipients of HBc (+) donors.     

Can donors with high donor risk indices be used cost‐effectively in liver transplantation in US Transplant Centers?

In an effort to quantify the impact of donor risk factors on recipient outcomes, the donor risk index (DRI) was developed. A high DRI correlates with poorer post‐transplant survival. In this study, high‐DRI donors are classified as those having DRIs >2.0, while low‐DRI donors have DRIs <2.0. The aim of this study was to evaluate the cost‐effectiveness of high‐DRI donor use in US Transplant Centers. A Markov‐based decision analytic model was created to simulate outcomes for an allocation scheme using only low‐DRI donors versus a scheme using both low‐ and high‐DRI donors. Baseline values and ranges were determined from published data and Medicare cost data. Sensitivity analyses were conducted to test model strength and parameter variability. An allocation scheme in which only low‐DRI donors were used generated 5.2 quality‐adjusted life years (QALYs) at a cost of $83 000/QALY. An allocation scheme using both low‐ and high‐DRI donors generated 5.9 QALYs at a cost of $66 000/QALY. Sensitivity analyses supported the use of an allocation scheme using both low‐ and high‐DRI donors. The overall contribution of high‐DRI grafts to the donor pool and the resultant reduction in wait‐list mortality make them cost‐effective.     

Treatment of posttransplant lymphoproliferative disorder with the anti-CD20 monoclonal antibody rituximab alone in an adult after liver transplantation: a new drug in therapy of patients with posttransplant lymphoproliferative disorder after solid organ transplantation?

BACKGROUND: Posttransplant lymphoproliferative (PT-LPD) disorder is a life-threatening complication with an incidence of 1-10%. Uniform treatment, so far, does not exist. METHODS: In December 1996, 5 months after a liver transplant, a 43-year-old patient developed a PT-LPD with para-aortal lymphomas and splenomegaly. Histological investigations revealed a PT-LPD of a diffuse large B-cell type of the centroblastic variant. The patient received three cycles of a modified cyclophosphamide, doxorubicin, vincristine, and prednisone-regimen, resulting in complete remission but the patient withdrew from further treatment. In February 1998, the patient had a recurrence of PT-LPD with gastric involvement and parasplenic lymphomas. The patient rejected cytotoxic treatment because of her fear of drug-induced progressive myopathy, so we conducted treatment with the monoclonal antibody--directed against CD20-rituximab. RESULTS AND CONCLUSIONS: After 2 doses of rituximab, clinical symptoms had disappeared and after 6 doses, gastroscopy revealed no residual disease. At this time, the patient remains in remission, with a follow up of > or =6 months. Anti-CD20 monoclonal antibody rituximab is a new, well-tolerated drug for the treatment of lymphomas. In addition, this drug may offer an additional treatment option for patients with PT-LPDs.     

Hepatitis C–associated focal proliferative glomerulonephritis in an aviremic recipient of a hepatitis C–positive antibody donor liver

Shortage of organs for liver transplantation (LT) and the availability of highly efficient pan-genotypic direct-acting antivirals (DAAs) against hepatitis C virus (HCV) have allowed the use of livers from HCV-positive antibody/negative nucleic acid test donors (dHCV Ab+/NAT−) into aviremic HCV recipients over the last few years. We report the case of a patient who received an LT from an HCV Ab+/NAT− donor and, after HCV viremic conversion, developed a nephrotic syndrome due to a focal proliferative glomerulonephritis early after LT. Patient's renal function and proteinuria resolved after successful treatment with DAAs. Renal and hepatic function remain normal over 24 months of follow-up. This case restates the success of LT using livers from dHCV Ab+/NAT− in aviremic recipients in the context of DAAs while illustrating the risk for potential complications associated with the HCV transmission and reinforcing the importance of early initiation of anti-HCV therapy.     

Successful pregnancy in a liver transplant recipient treated with lamivudine for de novo hepatitis B in the graft

Pregnancy is often successful after liver transplantation, despite the potentially toxic effects of immunosuppressive drug therapy. Liver transplant recipients with recurrent hepatitis C or hepatitis B nonetheless appear to be at risk of a worse graft function in the event of pregnancy, and antiviral drugs are generally contraindicated in pregnancy because of their teratogenic effects. A 33-year-old woman had undergone liver transplantation for Carolis disease 6 years previously. Two years later the patient experienced de novo HBV hepatitis. Lamivudine treatment (100 mg/day) was started and clearance of HBsAg was documented 1 year later. Four years after starting antiviral treatment the patient became pregnant, despite of the risk of teratogenic effects; lamivudine, cyclosporine and azathioprine were not discontinued for risk of break-through hepatitis and acute or chronic rejection. The course of gestation was uneventful and caesarean section was performed after 36 weeks. The newborn infant was a healthy male weighing 3,080 g and measuring 50 cm.     

Is hepatitis B immunoglobulin prophylaxis needed for liver transplantation in the era of new antivirals?

Chronic infection with hepatitis B virus (HBV) is one of the most common causes of cirrhosis of the liver and hepatocellular carcinoma worldwide, frequently requiring liver transplantation. Other nonliver organ transplants get infected de novo or through reactivation from previous active or inactive infections. With significant improvements in the surgical techniques and immunosuppressive regimens over the last 20 years, organ transplantation has become the most effective and lifesaving therapy for patients with chronic renal failure, cirrhosis, hepatocarcinoma, and heart failure. Until recently chronic HBV infection was considered a formal contraindication for liver transplantation, since recurrence of infection without prophylaxis occurs in 75% to 90% of the patients, with significant morbidity and mortality and few therapeutic alternatives. However, the introduction of hepatitis B immunoglobulin (HBIG) a decade ago to reduce the risk of reinfection of liver grafts, and more recently the availability of nucleoside analogues with few side effects and easy administration, have led to a dramatic improvement in patient outcomes with a risk of long-term HBV reinfection of less than 10% with combined HBIG and lamivudine prophylaxis. Chronic HBV infection in kidney, heart, and other organs has become a serious long-term problem and one of the most frequent and important comorbidities affecting graft and patient survival. Fortunately the introduction of nucleoside analogues allows significant control of viral replication and prevents progression of liver disease and other organ damage. In the present article we discuss the current indications for HBV prophylaxis and treatment prior to and after organ transplantation, as well as the most cost-effective way to apply different regimens to reduce side effects and improve survival and quality of life after transplantation.     

What is the biopsychosocial role of human immunodeficiency virus positivity in patients with end-stage liver disease who undergo orthotopic liver transplantation?

INTRODUCTION: Since 2003 the National Research Program for Solid Organ Transplantation in patients with human immunodeficiency virus (HIV) is active at our liver transplantation center. Patients with HIV who enter this protocol are assessed by the Consultation Liaison Psychiatry Service. The aim of the present study was to evaluate their psychiatric comorbidity. METHODS: An observational prospective study was conducted comparing end-stage liver disease (ESLD) patients with and without HIV. After the assessment, the psychiatrist compiled the Transplant Evaluation Rating Scale (TERS) and the Montgomery Asberg Depression Rating Scale (MADRS). Baseline evaluation was made before inclusion on the OLT waiting list and the follow-up evaluation was made 12 months later. RESULTS: From January 2003 to December 2006 we assessed 553 patients: 39 (6%) with HIV and 361 (94%) without HIV. The 2 groups were homogeneous for gender (75% of male patients; P=not significant [NS]) but not for age (46+/-5 vs 56+/-9; P=NS). Psychiatric history was negative in 176 (49%) patients without HIV and in 6 (15%) patients with HIV (P< .001). At baseline psychiatric comorbidity was present in 33 HIV patients (85%) and in 148 non-HIV patients (41%; P< .001). At follow-up MADRS highlighted an improvement in all of the items for HIV patients. In the non-HIV group, the variation was as follows: baseline, 7.10; follow-up, 8.15. In the HIV group, the variation was as follows: baseline, 10.20; follow-up, 4.09 (P< .001). The average score at TERS was higher among patients with HIV (43+/-9 vs 35+/-9; P=NS). CONCLUSIONS: At baseline HIV patients with ESLD showed a higher rate of psychopathology, but they improved at follow-up; the contrary happened in the non-HIV group.     

Hepatocellular carcinoma: Can it be considered a controversial indication for liver transplantation in centers with high rates of hepatitis C?

Hepatocellular carcinoma (HCC) is still considered a controversial indication for liver transplantation (LT), mainly because of long waiting times and underlying viral cirrhosis. The goal was to evaluate the outcome of LT in 104 patients with HCC and cirrhosis, mainly hepatitis C virus (HCV)–related, in a center with a short waiting time (median, 105 days). Four groups were formed according to the HCC and HCV status: HCV positive with HCC (group 1, n = 81), HCV negative with HCC (group 2, n = 23), HCV positive without HCC (group 3, n = 200), and HCV negative without HCC (group 4, n = 207). Predictive factors of tumor recurrence were demographics, tumor related (size or number of nodules, capsule, bilobar involvement, vascular or lymphatic invasion, clinical and pathologic TNM staging, pre-LT percutaneous ultrasound-guided ethanol injection or transarterial chemoembolization, α-fetoprotein levels), donor and surgery related, and year of transplantation. The same variables and “tumor recurrence (yes/no)” were applied to evaluate the effect on survival. The median follow up was 29 months (range, 0 to 104 months). Patient survival was 70% at 1 year and 59% at 5 years for group 1, 87% at 1 year and 77% at 5 years for group 2, 81% at 1 year and 64% at 5 years for group 3, and 88% at 1 year and 77% at 5 years for group 4 (P = .013). Survival was significantly lower in patients with HCC than in those without (74% and 63% versus 85% and 70%, at 1 and 5 years, respectively; P = .05). The causes of death in those with and without HCC were tumor recurrence (24%) and recurrent HCV (8%) versus sepsis (34%) and recurrent HCV (14%). HCC recurrence occurred in 12 patients (11.5%) at a median of 14 months (range, 3 to 60 months) with a probability increasing from 8% at 1 year to 16% at 5 years. In patients with HCC, tumor recurrence was associated with vascular invasion (P = .0004) by multivariate analysis; variables predictive of survival were donor old age (P = .01), viral-related etiology (P = .02), and tumor recurrence (P = .001). Although LT still remains an adequate indication for HCC in centers with high prevalence of HCV infection and short waiting times, both tumor and HCV-related recurrent diseases hamper significantly the outcomes of these patients. (Liver Transpl 2002;8:1020-1027.)     

The effect and safety of the treatment of recurrent hepatitis C infection after orthotopic liver transplantation with pegylated interferon α2b and ribavirin

Introduction

Recurrent hepatitis C infection in the posttransplant setting is a serious problem. The aim of this study was to evaluate the efficacy, safety, indications, optimal time of administration and adequate duration of antiviral therapy with pegylated interferon alpha 2 b (PEG-IFN) and ribavirin (RIB).

Patients and methods

Between 2003 and 2009, 16 patients received antiviral therapy (PEG-IFN: 0.8–1.6 μg/kg/wk, RIB 800–1200 mg/d) for at least 6 months. Patients with a biochemical without a virologicalresponse after 12 months of therapy received antiviral treatment for a further 6 months. Hepatitis C virus load was determined at 1, 3, 6, and 12 months after start of therapy. Liver biopsy was performed in all patients before the beginning and after the end of treatment.

Results

The mean period of antiviral therapy was 14 months. The four patients who received the full-length treatment (12 months, 33%) showed sustained virological responses (SVR) and 8 showed virological and biochemical responses (VR, BR). Patients with SVR showed significant improvement in the grading and staging of HAI (histological activity index; P = .03). Nine patients had several side effects under antiviral treatment. Acute rejection episodes were not observed.

Conclusion

The antiviral treatment combination using PEG-IFN and RIB for recurrent hepatitis C is effective procedure. The SVR of 33% after 12 months of treatment with significant improvement in HAI grading and staging and stable HAI in all treated patients favor early initiation and 12-month administration of antiviral treatment. Furthermore, all patients with BR without VR, who underwent antiviral treatment for a further 6 months, achieved a VR. However, the optimal duration of treatment needs to be investigated in large prospective studies.