Hepatitis B Immune Globulin Therapy Research Articles

Nucleoside-Nucleotide Analog Combination Therapy Is Effective in Preventing Recurrent Hepatitis B After Liver Transplantation.

Hepatitis B immune globulin (HBIg) in combination with a nucleos(t)ide analog is the mainstay of prophylactic regimen to prevent recurrence of hepatitis B following orthotopic liver transplantation (OLT). HBIg therapy is costly and inconvenient for the patients. There is a growing experience converting HBIg/nucleos(t)ide to combination nucleotide/nucleoside analogs from. Twenty-six patients that underwent OLT between March 2001 and July 2011 who had received at least 12 months of HBIg and single nucleos(t)ide were enrolled. HBsAg and HBV DNA were undetectable, and anti-HBs were detectable at the time of switch. HBV DNA and HBsAg were measured every 3 months following discontinuation of HBIg and addition of nucleos(t)ide. Patients included 23 Asians/3 Caucasian, 21 males/5 females. Mean time of conversion from HBIg/nucleos(t)ide to nucleoside/nucleotide combination was 77.5 (range 11-132) months after OLT. Mean duration of follow-up after conversion was 31.9 (range 14-70) months. All patients had undetectable HBV DNA, and 24 patients remained HBsAg negative during follow-up. Two patients recurred 7 and 9 months later, respectively, with detectable HBsAg. Both patients continued to have undetectable HBV DNA and normal ALT. HBsAg was neutralized by reinfusion of HBIg. Nucleoside/nucleotide combination is an effective alternative to HBIg/nucleos(t)ide to prevent recurrence of hepatitis B after OLT.

Entecavir and hepatitis B immune globulin in patients undergoing liver transplantation for chronic hepatitis B

For patients undergoing liver transplantation (LT) for hepatitis B virus (HBV)–related liver disease, the current standard of care for preventing reinfection of the allograft is nucleoside analogue therapy combined with hepatitis B immune globulin (HBIG). Entecavir has demonstrated high efficacy and a favorable safety profile for chronic hepatitis B (CHB) treatment, but data for patients undergoing HBV-related LT are limited. This study assessed the safety and efficacy of entecavir combined with various HBIG regimens after CHB-related LT. In this phase 3b, single-arm, open-label study, 65 patients undergoing LT for CHB-related liver disease with an HBV DNA load <172 IU/mL at LT received entecavir (1.0 mg daily) for 72 weeks after LT. The primary endpoint was the proportion of evaluable patients (treated for ≥4 weeks) with virological recurrence (HBV DNA level ≥50 IU/mL) through week 72. Concomitant HBIG therapy was received by 64 of the 65 enrolled patients, and 44% of these patients received high-dose HBIG (any HBIG dose in the specified interval ≥10,000 IU). Through week 72, all 61 patients evaluable for the efficacy analysis had undetectable HBV DNA. The Kaplan-Meier estimate of patients without hepatitis B surface antigen (HBsAg) recurrence at week 72 was 0.9655. Two patients experienced a reappearance of HBsAg, but both remained HBV DNA− until the last follow-up. The frequency and nature of adverse events were consistent with those expected for this patient population. Serum creatinine increments ≥0.3 mg/dL and ≥0.5 mg/dL occurred in 62% and 39% of the patients, respectively, and all of these patients received calcineurin inhibitor therapy. In conclusion, in this population of patients treated with entecavir after CHB-related LT, entecavir was well tolerated and effective in maintaining viral suppression, even in individuals who experienced a reappearance of HBsAg. Liver Transpl 19:887–895, 2013. © 2013 AASLD.

Tenofovir-Emtricitabine Therapy for the Prevention of Hepatitis B Recurrence in Four Patients After Liver Transplantation

In patients infected with chronic hepatitis B virus (HBV) that goes untreated, therapeutic options are limited once the disease decompensates, and orthotopic liver transplantation is often the only treatment available to save the patient's life. After liver transplantation, combined therapy with hepatitis B immune globulin (HBIG) and a nucleos(t)ide analog is the standard of practice for the prevention of HBV recurrence. Historically, nucleos(t)ide analogs such as lamivudine and adefovir have been used with low-dose HBIG for the prevention of HBV recurrence after liver transplantation. However, these analogs are ineffective when used alone due the emergence of resistance mutations. Newer nucleos(t)ide analogs such as tenofovir disoproxil fumarate have demonstrated higher resistance thresholds and effective viral suppression when paired with low-dose HBIG. In this case series, we evaluated the safety and efficacy of switching four patients from low-dose HBIG plus nucleos(t)ide analog therapy for the prevention of HBV recurrence to a combination tenofovir-emtricitabine regimen. At the end of follow-up, all patients remained hepatitis B surface antigen negative and had HBV DNA levels of less than 10IU/ml. Additionally, no tenofovir-associated nephrotoxicity was observed among the four patients. Tenofovir-emtricitabine monotherapy in lieu of HBIG plus nucleos(t)ide analog therapy demonstrated prevention of HBV recurrence without tenofovir-associated nephrotoxicity after 9months of follow-up in all four patients and up to 15months in one patient.

Combination of lamivudine and adefovir without hepatitis B immune globulin is safe and effective prophylaxis against hepatitis B virus recurrence in hepatitis B surface antigen-positive liver transplant candidates

Without effective prophylaxis, liver transplantation for hepatitis B virus (HBV)-related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. Combination prophylaxis with hepatitis B immune globulin (HBIG) and lamivudine (LAM) reduces long-term recurrence rates below 10%; however, HBIG is costly and inconvenient to administer. We, therefore, conducted a multicenter, prospective study of outcomes with an HBIG-sparing regimen of LAM plus adefovir dipivoxil (ADV) initiated at the time of listing for liver transplantation and continued after transplantation. Twenty-six patients were recruited into this study at the time of listing for transplantation, and 20 subsequently underwent transplantation. Twelve of the 26 patients had LAM exposure before the study baseline, but none had LAM resistance. The median HBV viral load before the institution of antiviral therapy was approximately 4.0 log(10) IU/mL (range=2.3-7.5 log(10) IU/mL). To the 20 patients who underwent transplantation, 800 IU of intramuscular HBIG was given immediately after transplantation and daily for 7 days only (total HBIG dose=6400 IU). All transplant patients remained alive without HBV recurrence (they were negative for hepatitis B surface antigen, and HBV DNA was undetectable) after a median follow-up of 57 months after transplantation (range=27-83 months). The median serum creatinine level in these patients rose from 81 to 119 μmol/L over the course of the study. No patient required dose reduction or cessation. After the completion of this prospective study, the regimen was modified so that no perioperative HBIG was administered if the pretransplant serum HBV DNA level was suppressed below 3 log(10) IU/mL. Another 28 patients with HBV-related liver disease underwent transplantation (18 without HBIG). All remained alive and well without HBV recurrence after a median follow-up of 22 months after transplantation (range=10-58 months). In conclusion, a combination of LAM and ADV initiated at the time of wait listing provides safe and effective protection against recurrent HBV infection without the high costs and inconvenience associated with long-term HBIG therapy.

Evaluation of Blood Glucose Levels after Hepatitis B Immune Globulin Administration Utilizing Two Different Blood Glucose Monitoring Systems

Background Hepatitis B Immune Globulin (HBIG) is used post liver transplantation (OLT) in hepatitis B surface antigen-positive recipients to prevent recurrence of hepatitis B. One formulation of HBIG, HepaGam B, contains the disaccharide maltose, which can potentially falsely elevate glucose readings when glucose nonspecific point of care (GNSPOC) testing is used, such as a glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ)-based method. This can result in inappropriate administration of antidiabetic agents and resultant episodes of clinically significant hypoglycemia. Glucose specific point of care (GSPOC) testing, such as a glucose oxidase-based method, however, is not affected by the presence of maltose. The purpose of this study was to determine if there was a significant difference in glucose readings using GSPOC and GNSPOC monitoring devices after HBIG administration. Methods This is a nonrandomized, prospective study evaluating patients receiving maintenance HBIG therapy over 3 months post liver transplantation. Blood glucose levels in each subject were analyzed by GSPOC and GNSPOC devices at specific times around HBIG administration. Results Five adult OLT recipients receiving maintenance HBIG therapy were administered HepaGam B during the regularly scheduled outpatient visits. The median difference (GNSPOC minus GSPOC) predose as well as immediately, 60 minutes, and 120 minutes postdose were: −2, 11, 6, and 0 mg/dL, respectively. A random intercept model was used to fit the five subjects' glucose reading data over time. The Meter by Time interaction effect was not significant ( P = .59) and the Meter effect was not significant ( P = .46), which demonstrated no statistical difference between GNS and GS readings following HBIG administration. Conclusions Based on these results, there is not a significant difference between GSPOC and GNSPOC readings after administration of this HBIG formulation.

HBIg Discontinuation with Maintenance Oral Anti-viral Therapy and HBV Vaccination in Liver Transplant Recipients

Hepatitis B (HBV) is an uncommon indication for liver transplantation in the US accounting for approximately 5% of cases. Recurrence prophylaxis is typically long-term hepatitis B immune-globulin (HBIg) and an oral anti-HBV agent. Because of high HBIg costs and improving efficacy of new oral agents, there is increasing interest in HBIg discontinuation. To describe results of a protocol at our center including HBV vaccination and HBIg discontinuation. All patients received HBIg therapy and an oral anti-viral agent from the time of transplant. Patients transplanted for HBV with a stable post-operative clinical course underwent HBV vaccination and HBIg discontinuation. After HBIg discontinuation, patients were monitored for HBV recurrence for at least one year. Recurrence was defined as either viral (HBV-DNA 10(4) copies/ml on two consecutive occasions) or hepatitis (viral recurrence with elevated liver transaminases). Of 1182 recipients, 36 (3%) had HBV. Twenty-four were excluded from the protocol, and the remaining 12 patients underwent HBIg withdrawal. Median age at HBIg discontinuation was 56 (range, 36-70) years, median time from transplant to HBIg discontinuation was 62.8 (range, 27.5-128) months, and median time of follow-up after discontinuation was 27.4 (range, 13-69) months. Of the 12 patients vaccinated, no patients maintained HBSAb >or= 10 IU/l at last follow-up. There was no viral or hepatitis recurrence and no deaths or graft loss. HBIg discontinuation with maintenance oral anti-viral monotherapy is safe and effective for HBV liver transplant recipients. Vaccination is not effective in this population.

Hepatitis B virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: A survey of North American, European, and Asian-Pacific transplant programs

Prophylactic therapy is generally used to prevent reactivated hepatitis B after transplantation of an antibody to hepatitis B core antigen (anti-HBc)-positive liver. To gain insight into current practice, a questionnaire was e-mailed to 89 liver transplant physicians in the United States, Europe, and Asia/Australia and 4 hepatitis B experts. Addressees were asked if they prefer lamivudine or other nucleoside analogs and whether these drugs are used indefinitely. They were also questioned about the use of hepatitis B immune globulin (HBIg), the preferred duration of its administration, and whether treatment strategies differ according to the knowledge of the serologic status of the recipient. Responses were obtained from 78 physicians. All transplant physicians reported the use of nucleoside analog therapy, and 65% prefer lamivudine (58% versus 81% for US and non-US physicians, P = 0.05). Sixty-one percent use HBIg (38% always, 23% sometimes). HBIg was used more frequently in the United States than other parts of the world (69% versus 46%, P = 0.03). Eighty-one percent of transplant physicians use nucleoside analog therapy for an indefinite period, but the duration of HBIg treatment varies widely. Although some centers omit nucleoside analog or HBIg therapy in antibody to hepatitis B surface antigen-positive recipients, 90% will not omit these agents if the recipient is positive for anti-HBc alone. In conclusion, nucleoside analog therapy is nearly always used for anti-HBc-positive livers, and most transplant physicians treat for an indefinite period. Lamivudine continues to be preferred as first-line therapy. Many programs also use HBIg, but there is wide variation in the way this is administered. Further study is needed to determine the most cost-beneficial regimen.

Hepatitis B immune globulin and HBV-related liver transplantation

Post-transplant hepatitis B virus (HBV) recurrence prophylaxis is a sine qua non of liver transplantation for HBV-related liver disease because of high rate and aggressive course of HBV recurrence. Hepatitis B immune globulin (HBIG) is a polyclonal immune globulin solution obtained from plasma, donated by individuals with high titres of anti-HBs (hepatits B antibody). Although it was being used for postexposure prophylaxis against HBV since 1974, its use in post-transplant propyhlaxis of HBV infection was not until 1987. Long-term prophylaxis with HBIG alone had been the standard treatment in post-transplant HBV prophylaxis until the introduction of lamivudine. Combining HBIG with oral nucleotide/nucleoside analogues in post-transplant prophylaxis of recurrent HBV resulted in lower recurrence rates of infection. However, high cost and emergence of immune escape mutations are still the problems to be solved regarding HBIG therapy in post-transplant propyhlaxis of HBV recurrence.

Combination Therapy in Liver Transplant Recipients with Hepatitis B Virus Without Hepatitis B Immune Globulin

Conventional therapy to prevent HBV recurrence in liver transplant (LTx) recipients consists of Hepatitis B Immune Globulin (HBIg). The aim of this review is to investigate the safety and efficacy of converting HBIg and LAM therapy to ADV and LAM therapy. A retrospective review involving all liver transplant patients with HBV maintained on HBIg and LAM therapy. Results collected included: gender, age, HBV serological and DNA status (COBAS AmpliScreen PCR-based testing). Serologic testing was done every three months. Patients were followed for drug reactions, therapy compliance, and immune suppression compliance. A cost benefit analysis was done for drug comparisons using United States currency values. Patient demographics included: Male (n=6), Female (n=4), mean age 44 years (range 33 to 65). The mean length of follow up since therapy conversion (from HBIg and LMV to ADV and LMV) was 21 months (range 16 to 25 months). Serological status at time of conversion revealed that DNA status remained negative in all patients, HBsAg negative in 10/10, HB eAg (+) (5/10) and HBeAb (+)(5/10). None of the patients experienced an increase in transaminases while on dual ADV and LAM therapy. All patients were maintained on immune suppression monotherapy (tacrolimus) at 7-9 ng/mL. All patients reported compliance with the dual therapy and that they experienced no drug related side effects. Mean yearly costs for ADV and LAM was 7,235.00 United States dollars (range 6,550.00 to 8,225.00); while mean monthly costs for HBIg and LAM; 9225.00 (range 7205.00 to 12005.00). The above results demonstrate beneficial effects of ADV and LAM in place of the current standard of HBIg and LAM therapy. Safety and short term results show nucleoside therapy is adequate at preventing HBV viral recurrence. Lastly, the economic benefit for ADV and LAM vastly outweighed the HBIg and LAM group.

Outcomes of Hepatitis B Virus Recurrence After Liver Transplantation

The introduction of high doses of hepatitis B immune globulin (HBIG) and lamivudine for liver transplantation (OLT) prophylaxis has reduced the risk of hepatitis B recurrence and improved the survival of patients transplanted for hepatitis B virus (HBV)-related liver disease. But, posttransplant prophylaxis strategies to treat the recurrence of HBV have not yet been standardized. We analyzed 23 patients with HBV recurrence among 340 HBV-associated liver transplants performed from September 1996 to April 2004 (6.7%). Nine patients underwent deceased donor OLT and 14, living donor OLT. Mean follow-up was 37 months. Seroconversion after recurrence was observed in 6 of 23 patients (26%). Mean time to HBV recurrence tended to be shorter among the seroconversion (+) patients compared to seroconversion (−) patients (10 months vs 19.7 months; P = .062). Seroconversion rate after HBIG and lamivudine combination therapy for patients with HBV recurrence was 37.5% and time to seroconversion after HBV recurrence was 1.7 months. Seroconversion was best achieved when the pretransplant HBV DNA level was high and HBeAg was positive. Also, seroconversion rate was increased when HBV DNA level was low and the alanine transferase level high at the time of recurrence and when the time to recurrence after transplantation was short. Seroconversion after HBV recurrence, which was observed in 26%, may be increased in selected cases. Accordingly, aggressive treatment should be undertaken after HBV recurrence.

Prevention of hepatitis B virus infection from hepatitis B core antibody‐positive donor graft using hepatitis B immune globulin and lamivudine in living donor liver transplantation

Hepatic grafts from hepatitis B surface antigen-negative and anti-core antibody (HBcAb)-positive donors have been shown to transmit hepatitis B virus (HBV) infection. Recently, it has been reported that combined hepatitis B immune globulin (HBIG) and lamivudine therapy is effective in the prevention of hepatitis B recurrence after living donor liver transplantation (LDLT). In this report, we assessed the efficacy of combined HBIG and lamivudine therapy in preventing HBV transmission by graft with HBcAb-positive donors. We studied 22 patients who had undergone LDLT with allografts from HBcAb-positive living donors at Gunma University Hospital and Kyushu University Hospital. Long-term combined HBIG and lamivudine therapy were administrated to all recipients. Serum samples from the donor and recipient were tested for HBcAb, HBV DNA, and hepatitis B surface antibody. Liver biopsies from grafts were tested for HBV DNA. All recipients were HBcAb negative before LDLT. All of the donor livers were HBV DNA positive at the time of LDLT. All of the recipients had HBsAb titers greater than 300 mIU/ml 4 weeks after LDLT, and remained 100 mIU/ml thereafter. None of the recipients have become infected with HBV with a follow-up of 25-86 months. Perioperative combined HBIG and lamivudine therapy can prevent HBV infection in recipients who receive liver grafts from HBcAb-positive donors.

Management of the hepatitis B virus in the liver transplantation setting: A European and an American perspective

Management of the hepatitis B virus in the liver transplantation setting: A European and an American perspective

Outcomes in liver transplant recipients with hepatitis B virus: Resistance and recurrence patterns from a large transplant center over the last decade

Hepatitis B virus (HBV) recurrence following liver transplantation (LTx) has been controllable primarily with the use of hepatitis B immune globulin (HBIg) and lamivudine (LAM). However, HBV resistance to LAM and/or HBIg has become an increasing problem prompting the use of newer antiviral agents. The purpose of our study was to investigate the association between therapy, HBV breakthrough, and allograft / patient survival in HBV-positive liver transplant recipients. We performed a retrospective review of the medical records of patients that were transplanted for HBV from June 1994 to May 2003. A total of 92 patients, positive for either hepatitis B surface antigen (HBsAg) or HBV deoxyribonucleic acid (DNA) pretransplant, received LAM monotherapy or HBIg (6 months) plus LAM therapy post-liver transplant. HBV breakthrough post-LTx was noted in 14 patients. All patients had detectable HBV DNA prior to liver transplantation; none of the patients that were HBV DNA negative prior to transplant had detectable HBV DNA posttransplant. Of these 14, 9 patients (64%) were switched from LAM to adefovir dipivoxil (ADF) and 5 patients (36%) to tenofovir disoproxil fumarate (TNV). In conclusion, pre-LTx HBV viremia should be considered in planning post-LTx prophylaxis. Trials to evaluate oral antiviral agents in combination with or without HBIg therapy are needed.

Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immune globulin prophylaxis and lamivudine therapy.

Recurrent hepatitis B virus (HBV) infection after liver transplantation can be prevented by prophylactic hepatitis B immune globulin (HBIG) and lamivudine therapy. However, reinfection may still occur due to the emergence of immune escape mutants and mutants of the YMDD motif. The full spectrum of mutations within the HBV genome during recurrent HBV infection remains to be documented. In this study, serial HBV isolates were characterized from a patient with lamivudine resistance prior to liver transplantation who developed recurrent HBV infection within 2 months of transplantation despite a high dose of HBIG and lamivudine therapy. Sequence analysis of full-length viral genome before transplantation revealed many point mutations as compared with a wild-type genotype C sequence, including the T1753G/A1762T/G1764A triple mutation in the basal core promoter and the G1896A nonsense mutation in the precore region. After transplantation and therapy, several point mutations in the HBV genome emerged or became dominant. These mutations caused L426I/L526M/M550I triple mutation (equivalent to L428I/L528M/M552I in previous reports) in the polymerase, and D144E mutation in the "a" determinant of HBsAg. Transfection experiments revealed that the D144E mutation reduced HBsAg affinity to anti-HBs, confirming its active role for immune escape. Our study suggests that mutations in the HBsAg (D144E) and the polymerase (L426I/L526M/M550I) of HBV genome may be responsible for viral breakthrough despite HBIG prophylaxis and lamivudine therapy.

HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis

Long-term immunoprophylaxis with hepatitis B immune globulin (HBIG) is widely accepted for the prevention of recurrent hepatitis B virus (HBV) infection after liver transplantation in HBV-infected patients without viral replication. We report long-term results of HBIG administration in 284 hepatitis B surface antigen (HBsAg)-positive transplant patients. In protocol 1, 259 patients were given HBIG with the goal of maintaining the anti-HBs antibody (Ab) titer over 100 IU/L. After December 1993, 25 HBV DNA-positive patients received HBIG, with a target anti-HBs Ab titer over 500 IU/L, combined with posttransplantation antiviral therapy (protocol 2). At 10 years, 44 patients without recurrence were tested for the presence of HBV DNA in serum using real-time polymerase chain reaction (PCR); 28 were also tested in liver and peripheral blood mononuclear cells (PBMC). The overall 5- and 10-year posttransplantation actuarial rates of HBV recurrence were 24.2% and 25.4%, respectively. The 5-year recurrence rate in protocol 2 patients was 11.8%. On multivariate analysis, predictors of lower HBV recurrence risk were absence of serum HBV DNA before transplantation ( P < .0001), acute liver disease ( P = .0037), HDV superinfection ( P = .012), and protocol 2 therapy ( P < .0001). Low-level HBV DNA was detected by PCR in 45.4% of patients without HBV recurrence at 10 years. Overall actuarial 10-year survival was 74.4%. In conclusion, we confirm the efficacy of long-term HBIG immunoprophylaxis. Combination prophylaxis with HBIG and antiviral therapy is effective in patients with viral replication. Although there were only a few cases of HBV recurrence after 5 years, HBV DNA remained present in 45% of patients at 10 years. (H epatology 2003;38:86-95.)

Prevention of recurrent hepatitis B post–liver transplantation

1. Factors associated with a lower rate of recurrent hepatitis B post-liver transplantation (LT) are negative hepatitis B e antigen and/or serum hepatitis B virus DNA pre-LT, hepatitis D virus superinfection, and fulminant hepatitis B. 2. Long-term intravenous hepatitis B immune globulin (HBIG) monotherapy can reduce the overall rate of recurrent hepatitis B to 20% to 35%. 3. Long-term lamivudine monotherapy is associated with a risk for drug resistance and overall 3-year rate of recurrent hepatitis B of 40% to 50%. 4. Combination prophylaxis with HBIG and lamivudine can reduce the overall rate of recurrent hepatitis B to 0% to 10%. 5. The dose and duration of HBIG therapy needed when used in combination with lamivudine may be lower, but the optimal regimen remains to be determined. 6. Lamivudine resistance before LT is associated with an increased risk for recurrent hepatitis B post-LT. 7. A cost-effective prophylactic regimen to prevent recurrent hepatitis B should be tailored according to risk.

Safe use of livers from donors with positive hepatitis B core antibody.

Thirty-five patients received liver transplants using liver donors who had positive test results for the hepatitis B core antibody (HBcAb). In the same time frame, 195 patients received HBcAb-negative liver donors. Mean follow up for patients receiving HBcAb-positive donors was 25 months. All patients receiving HBcAb-positive donors were monitored for recurrence of hepatitis B (HBV) with HBV DNA assays. There was no de novo HBV in recipients of HBcAb-negative grafts. In the group of patients receiving HBcAb-positive donors, 4 of 35 patients died within 3 months after transplant with no evidence of HBV recurrence at time of death. Four patients were transplanted for HBV-related disease and were postoperatively placed on lamivudine and hepatitis B immune globulin (HBIG). HBV recurrence was seen in one of these patients. Of the remaining 27 patients, three of three mismatched patients (HBcAb-positive donor to HBcAb-negative recipient) developed de novo HBV (100%). Of 24 matched patients (HBcAb-positive donor to HBcAb-positive recipient), only two (7%) developed recurrent HBV allograft reinfection. All de novo and recurrent HBV infections were successfully managed with HBIG and lamivudine therapy. Survival for this subgroup of patients receiving HBcAb-positive donors for non-HBV-related liver disease was 100%. We conclude that the judicious use of HBcAb-positive donors is reasonably safe and associated with low morbidity and mortality, with the appropriate follow-up protocols. Additionally, lamivudine use can be reserved for those cases with de novo or recurrent HBV in the liver allograft, or, selectively, as prophylaxis in those recipients patients who are naïve to HBV and receive an HBcAb-positive donor.

Favorable outcome of orthotopic liver transplantation in a patient with subacute liver failure due to the emergence of a hepatitis B YMDD escape mutant virus

Background/Aims : Patients with end-stage liver disease due to chronic hepatitis B infection in whom a YMDD escape hepatitis B virus (HBV) mutant has emerged under lamivudine treatment are generally denied liver transplantation (OLT). Methods : We report the case of a male patient who was started on prophylactic treatment with lamivudine in the context of recurrent episodes of HBV reactivation during high dose immunosuppressive therapy for relapsing severe pulmonary sarcoidosis. Results : Following the emergence of a YMDD escape mutant virus under lamivudine treatment, he developed subacute liver failure requiring liver transplantation. The patient was treated with a combination of intravenous hepatitis B immune globulin (HBIG) which was started perioperatively and also continued lamivudine after OLT. Twelve months after OLT, there was no evidence of HBV reinfection of the liver graft with the use of HBIG and lamivudine. Conclusions : This observation suggests that emergence of the YMDD mutation is not a contra-indication to OLT, providing adequate immunoprophylaxis using HBIG and lamivudine combination therapy.

Liver transplantation for chronic hepatitis B infection with the use of combination lamivudine and low-dose hepatitis B immune globulin.

Current protocols for prophylaxis against allograft reinfection after liver transplantation for chronic hepatitis B virus (HBV) infection include the administration of large doses of hepatitis B immune globulin (HBIG), with considerable associated economic costs. Monotherapeutic prophylaxis with lamivudine has been complicated by the development of resistant strains of HBV. We studied the effectiveness of a posttransplantation prophylaxis protocol using combination lamivudine and low-dose HBIG in 7 consecutive patients with chronic HBV infection, 4 of whom were serum HBV DNA positive before pretransplantation lamivudine therapy. All patients were serum HBV DNA negative at transplantation and received lamivudine, 100 mg/d, posttransplantation. HBIG, 2170 IU, was administered intramuscularly intraoperatively and daily for 14 days. Maintenance HBIG therapy consisted of 2170 IU intramuscularly twice weekly, tapered to every 2 to 4 weeks by 12 months posttransplantation. Target serum HBIG (HBV surface antibody) titers were less than 500 IU/L for 6 months, then greater than 300 IU/L until 12 months posttransplantation. Induction serum HBIG titers were determined daily in 5 patients, and both serum HBIG and hepatitis B surface antigen were determined every 4 weeks in all patients. One patient died 61 days posttransplantation; the surviving patients (n = 6) were followed up for a mean of 532 days (range, 395 to 648 days). No patient has developed allograft reinfection. In the induction period, a target HBIG titer of greater than 500 IU/L was not achieved until a mean of 6.8 days (range, 5 to 10 days). In the maintenance period, all patients achieved the target HBIG titer. This suggests combination lamivudine and low-dose HBIG is effective in preventing allograft reinfection by HBV.

Prevention of de novo hepatitis B infection in recipients of hepatic allografts from anti-HBc positive donors.

The shortage of donor organs occasionally mandates the use of hepatic allografts from anti-HBc+ donors in recipients who are susceptible to de novo hepatitis B virus (HBV) infection. The efficacy of hepatitis B immune globulin and lamivudine to prevent de novo HBV infection in anti-HBs negative recipients of allografts from anti-HBc+ donors has not been investigated. After liver transplantation with an allograft from a donor positive for anti-HBc, recipients who were anti-HBs-, HbsAg- received hepatitis B immune globulin (HBIG) 10,000 IU i.v. daily for 7 days and monthly for 6 months. After 6 months, 1000 IU of HBIG was given IM. every 2 weeks for 18 months. Patients transplanted after 4/1/97 were given lamivudine 150 mg daily starting postoperative day 1. Between 8/14/96 and 6/10/98, 264 orthotopic liver transplants were performed and 16 anti-HBs-, HbsAg- patients received an hepatic allograft from a donor positive for anti-HBc. HBIG mono-therapy was administered to one patient. HBIG and lamivudine combination therapy was administered to 15 patients. Of the 16 patients, 8 were positive only for anti-HBc before transplant, and 8 were naive (anti-HBs-, anti-HBc-). The single patient who received HBIG monotherapy became HbsAg+ at 6 months. All patients receiving combination therapy with HBIG and lamivudine have remained HbsAg-. The average follow-up is 459 days (range 170-754). Two patients died from unrelated causes. Combination therapy with HBIG and lamivudine may prevent de novo HBV infection in anti-HBs-, HbsAg- recipients of hepatic allografts from anti-HBc+ donors.