Robert W. McGory

Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization

Passive immunization with hepatitis B surface antibody (anti-HBs) is important to prevent hepatitis B virus (HBV) recurrence after orthotopic liver transplantation for chronic HBV cirrhosis. Hepatitis B immune globulin (HBIG) dosing regimens have been poorly defined, utilize numerous routes of administration, and result in a high rate of HBV relapse and mortality. Twenty-five of 27 (93%) patients transplanted (four retransplants) for chronic HBV cirrhosis show no evidence of recurrent HBV (range, 2-55 months). Anti-HBs titers necessary to minimize the risk of hepatitis B surface antigen detectability were >500 IU/L for days 0 to 7, >250 IU/L for days 8 to 90, and >100 IU/L thereafter. Pretransplant HBV E antigen (HBeAG)-positive patients required more HBIG to achieve these goals than HBeAG-negative individuals. The elimination of anti-HBs changed continually for the initial 3 posttransplant months. The anti-HBs half-life increased from 0.7 days to 14.1 days. Anti-HBs elimination was significantly different in HBeAG+ and HBeAG- patients for the first week, but was subsequently indistinguishable after week 1. After 3 months, the half-life was statistically less for HBeAG+ patients, but the difference did not influence the clinical treatment regimens. Quantitative hepatitis B DNA levels did not predict the amount of HBIG required. HBV recurrence after orthotopic liver transplantation can be reduced by aggressive passive immunization. Pharmacokinetic analysis of anti-Hbs elimination can improve immunoglobulin therapy and prevent recurrence of clinical hepatitis.

Retransplantation of patients with severe posttransplant hepatitis B in the first allograft

BACKGROUND The outcome of orthotopic liver transplantation (OLTX) in patients retransplanted for severe hepatitis B virus (HBV) in the first allograft has been poor due to high rates of HBV reinfection and even more aggressive disease in the second graft. Recent data suggest that hepatitis B immunoglobulin (HBIg) given after transplantation can be successful in delaying or preventing HBV reinfection in patients transplanted for chronic hepatitis B cirrhosis. We report the successful retransplantation of patients who developed recurrent or de novo hepatitis B after OLTXY. METHODS Using similar HBIg regimens, two centers retransplanted seven patients after they developed recurrent or de novo hepatitis B in the first allograft. At retransplantation all seven patients were HBs antigen (Ag) positive; four patients were positive for HBeAg and HBV DNA by immunoblot assay, two patients were negative for HBeAg and HBV DNA, and one patient was positive for HBV DNA and negative for HBeAg. All patients were either HDV Ag or anti-HDV negative. One patient was anti-HCV positive. All patients received HBIg infusions after retransplantation to maintain serum anti-HBs levels >500 IU/L indefinitely. RESULTS After retransplantation, six of seven patients are alive (86%): all are without evidence of HBV recurrence with serum negative for HBsAg, HBeAg, and HBV DNA by immunoblot assay. Liver biopsies are normal on routine studies with immunohistochemical stains for HBcAg and HBsAg also being negative. Mean follow-up of these six patients is 40.1 months (range 21-63 months). One patient (14%) developed HBV reinfection 7 months after his second transplant, in spite of maintaining target anti-HBs levels. He maintained stable liver function with minimal evidence of clinical hepatitis B, but died 8 months later from an unrelated stroke. CONCLUSIONS We conclude that patients with recurrent or de novo hepatitis B after OLTX can be successfully retransplanted using aggressive immunoprophylaxis to prevent HBV reinfection. The failure of HBIg therapy in one patient underscores the need for other effective adjunctive anti-HBV modalities.

Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function

BACKGROUND An oral formulation of ganciclovir (GCV) was recently approved for the prevention of cytomegalovirus disease in solid organ transplant recipients. This study was designed to determine the bioavailability of GCV and to test a dosing algorithm in transplant and dialysis patients with different levels of renal function. METHODS Pharmacokinetic studies were carried out in 23 patients who were either a recipient of an organ transplant or on hemodialysis. Drug dosing was established by the following algorithm based on calculated creatinine clearance (CrCl): CrCl = [(140-age) x body weight]/(72 x Cr) x 0.85 for women that is, CrCl >50 ml/min, 1000 mg every 8 hr; CrCl of 25-50 ml/min, 1000 mg every 24 hr; CrCl of 10-24 ml/ min, 500 mg every day; CrCl < 10 ml/min (or on dialysis), 500 mg every other day after dialysis. GCV was taken within 30 min after a meal. The patients received oral GCV for between 12 days and 14 weeks. Serum specimens (or plasma from patients on hemodialysis) obtained at steady state were analyzed for GCV concentrations by high-performance liquid chromatography. In nine of the transplant recipients, absolute bioavailability was determined by comparing GCV levels after single oral and intravenous doses of GCV. RESULTS The following GCV concentrations (mean +/-SD) were determined: with CrCl of > or =70 ml/min, the minimum steady-state concentration (Cmin) and maximum concentration (Cmax) were 0.78+/-0.46 microg/ml and 1.42+/-0.37 microg/ml, respectively, with a 24-hr area under the concentration time curve (AUC0-24) of 24.7+/-7.8 microg x hr/ml; with CrCl of 50-69 ml/min, the Cmin and Cmax were 1.93+/-0.48 and 2.57+/-0.39 microg/ml, respectively, with an AUC0-24 of 52.1+/-10.1 microg x hr/ml; with CrCl of 25-50 ml/min, the Cmin and Cmax were 0.41+/-0.27 and 1.17+/-0.32 microg/ml, respectively, with an AUC0-24 of 14.6+/-7.4 microg x hr/ml. For one patient with a CrCl of 23.8 ml/min, the Cmin and Cmax were 0.32 and 0.7 microg/ml, respectively, with an AUC0-24 of 10.7 microg x hr/ml. With CrCl of <10 ml/min, the mean Cmin and Cmax were 0.75+/-0.42 and 1.59+/-0.55 microg/ml, respectively, with a mean AUC0-24 of 64.6+/-18.8 microg x hr/ml. Absolute bioavailability, for the nine patients so analyzed, was 7.2+/-2.4%. For those patients with end-stage renal failure, GCV concentrations fell during dialysis from a mean of 1.47+/-0.48 microg/ml before dialysis to 0.69+/-0.38 microg/ml after dialysis. CONCLUSIONS The bioavailability of oral GCV in transplant patients was similar to that observed in human immunodeficiency virus-infected patients. However, levels between 0.5 and 1 microg/ml (within the IC50 of most cytomegalovirus isolates) could be achieved with tolerable oral doses. The proposed dosing algorithm resulted in adequate levels for patients with CrCl greater than 50 ml/min and for patients on dialysis. For patients with CrCl between 10 and 50 ml/min, the levels achieved were low and these patients would likely benefit from increased doses.