Objectives: Hepatitis B immunoglobulin prophylaxis in combination with antiviral drugs is recommended for prevention of hepatitis B virus reinfection after liver transplant. However, there is no consensus on a standard prophylactic method, and controversy exists over the duration, dose, and route of administration. We conducted a prospective study to evaluate the safety and effectiveness of intramuscular hepatitis B immunoglobulin in combination with lamivudine and/or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year for prevention of hepatitis B virus reinfection.

Materials and Methods: Patients with hepatitis B-related liver cirrhosis who had undergone primary liver transplants were enrolled. The prophylactic protocol involved intraoperative intramuscular hepatitis B immunoglobulin at 10 000 IU, tapering to 5000 IU daily for the first 6 days, weekly for a month, every 2 weeks for the next month, and monthly for a year after liver transplant, in combination with antiviral drugs.

Results: From January 2002 until March 2014, two hundred sixty-eight liver transplants were performed. Forty-four patients (16.4%) who underwent liver transplants due to hepatitis B-related liver failure were enrolled. Five patients had hepatocellular carcinoma; 20 had both hepatitis D and hepatitis B virus infection. The median age was 47 years (range, 26-59 y) with a median model for end stage liver disease score of 20. Thirty-three patients were men (76%). Sixty-one percent of patients were negative for hepatitis B virus DNA at the time of transplant. The median follow-up was 13.6 months (range, 0-142 mo). Only 1 patient (2.3%) experienced hepatitis B virus reinfection (at 44.7 months posttransplant), which was successfully treated with tenofovir. Five patients died (11.4%) during the follow-up from nonhepatitis B causes.

Conclusions: Intramuscular hepatitis B immuno­globulin in combination with lamivudine or tenofovir and discontinuation of hepatitis B immunoglobulin after 1 year posttransplant may provide safe and cost-effective protection against posttransplant hepatitis B reinfection.

Key words : HBV reinfection, HBIg, Intramuscular HBIg

Introduction

Liver transplant is the treatment of choice for hepatitis B virus (HBV)-related liver failure;1 HBV accounts for approximately 5% to 10% of liver transplants in the United States. However, it is the leading indicator for liver transplant in Asia.^2,3 In our center, HBV-related liver failure is the third leading cause for liver transplants with a liver transplant rate of 19% after cryptogenic cirrhosis and autoimmune hepatitis (AIH).⁴ Our center for liver transplants was started in 2002. At that time, chronic hepatitis B disease was the second most common cause of primary liver disease for patients referred to our center for liver transplants. Since 2002, five hundred forty-three patients with cirrhosis have been registered on the waiting list, and after cryptogenic cirrhosis, hepatitis B- related cirrhosis is the second most common diagnosis as the primary cause of liver disease leading to a need for transplant. Other diagnoses—autoimmune hepatitis (AIH), hepatitis C virus (HCV), primary sclerosing cholangitis (PSC), and Wilson disease—are also linked to a need for liver transplant (Table 1).

Without prophylactic treatment, the rate of posttransplant allograft reinfection is as high as 80% to 100%, often leading to aggressive recurrent hepatitis, subsequent HBV-related liver failure, and death.^5-8 In the last 2 decades, with the advent of hepatitis B immunoglobulin (HBIg) and antiviral drugs as prophylaxis against HBV recurrence after liver transplants, the HBV reinfection and 5-year patient mortality rates have been reduced to 10% and 20%.^9,10

Hepatitis B immunoglobulin prophylaxis in combination with the nucleoside/nucleotide analogs (NAs) lamivudine or tenofovir is a well-accepted treatment recommended by many centers for prevention of HBV reinfection after liver transplants.¹¹ However, there is no consensus on a standard prophylactic method, and controversy over the duration, dose, and route of administration of HBIg exists among transplant centers.

We conducted this prospective study to evaluate the safety and effectiveness of intramuscular HBIg in combination with lamivudine or tenofovir and discontinuation of HBIg after 1 year, for prevention of HBV reinfection after liver transplants.

Materials and Methods

Patients with HBV-related liver failure who underwent primary liver transplants in the Imam Khomeini Hospital, Tehran University of Medical Sciences from 2002 to March 2014 were enrolled in the study. Data were recorded prospectively. All protocols, experimental studies, and clinical trials involving human subjects were approved by the ethics committee of the institution before the study began, and protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from patients or their guardians.

In a review of 82 medical files of patients with cirrhosis resulting from HBV, 52% had undetectable serum HBV-DNA and 95% were hepatitis B e antigen (HBe Ag) negative and 55% were on one anti-viral drug (tenofovir). Seventeen percent of hepatitis B patients with cirrhosis on the waiting list at our center also had hepatitis D; coinfection with HDV was significantly higher in patients with un­detectable virus. In our study, 2% of hepatitis B patients with cirrhosis had HCC as a complication resulting from cirrhosis. Patients with undetectable serum HBV DNA had a history of longer treatment duration with oral NAs. The median HBV viral load in HBV patients awaiting transplant was 10 000 copies/mL, and there was no significant difference between viral load in HBV patients with detectable or undetectable serum virus. Thus, the majority of candidate patients on the transplant waiting list had a low viral load and were considered at low risk for hepatitis B after liver transplant (Table 2).

The major concern for patients with hepatitis B is recurrence of HBV infection in the new liver. Hepatitis B immunoglobulin, in combination with NAs, has been the standard of care recommended by many centers for prevention of HBV recurrence and has resulted in a HBV reinfection rate of less than 10% at the 2-year point after transplant. However, there is no consensus on a standard prophylactic method. Controversy over the duration, dose, and route of administration of HBIg exists among transplant centers. Cost and access to intravenous (IV) HBIg are also concerns in some regions. Alternatively, low-dose intramuscular HBIg has been suggested as an equally effective, safe, less expensive, and more available substitution for IV HBIg which, in combination with NAs, can be the most cost-effective and efficient regimen for the prevention of posttransplant HBV recurrence. We used a prophylactic method of intra­operative intramuscular HBIg 10 000 IU followed by 5000 IU daily for the first 6 days and weekly for a month. Intramuscular HBIg was administered from the second month until 1 year posttransplant, if the anti-HBs titer was lower than 250 IU/L. After the first year, HBIg was completely discontinued. Lamivudine was administered to 11 patients before and after transplants. Patients who had undergone liver transplants from 2012 (n = 33) received tenofovir instead of lamivudine before and after transplants. In our study, the definition of HBV recurrence included detectable levels of HBV DNA and/or the persistence or reappearance of serum HBsAg after its initial loss with or without clinical evidence of recurrent disease.¹⁰

Immunosuppressive therapy included treatment with 1000 mg IV methylprednisolone during the anhepatic stage, followed by a 3-drug regimen of corticosteroid, calcineurin inhibitor, and myco­phenolate mofetil. Corticosteroid was tapered off after the first month, and mycophenolate mofetil was tapered after year 1.

Results

From January 2002 until March 2014, two hundred sixty-eight liver transplants were performed. Forty-four patients (16.4%) who underwent liver transplants due to HBV-related liver failure were enrolled in the study. Five patients had hepato­cellular carcinoma and, in addition to HBV infection, twenty had hepatitis D virus. The median age was 47 years (range, 26-59) with a median model for end stage liver disease (MELD) score of 20. Thirty three patients were males (76%). Sixty-one percent of patients were negative for HBV DNA at the time of transplant. The median follow-up was 13.6 months (range, 0-142) (Table 3). HB Ab titers were recorded at week 1, month 1, month 6, and month 12. Additional doses of intramuscular HBIg were prescribed for certain patients (Figure 1). At 44.7 months post­transplant, 1 patient experienced HBV reinfection, but survived. He had received lamivudine before and after transplant and was successfully treated with the addition of tenofovir to lamivudine (Table 4). Thus, the overall rate of HBV reinfection was 2.3%. Five patients (11.4%) died during the follow-up from non-HBV causes. Deaths occurred at 1, 12, 19, 60, and 150 days posttransplant due to primary nonfunction, cardiac failure, hepatic artery thrombosis-related sepsis, sepsis, and posttransplant lymphoproliferative disorder (Table 5).

Discussion

Controversy exists over the best standard prophylactic method to prevent HBV reinfection after liver transplant; there is also little consensus among transplant centers concerning the duration, dose, and route of administration of HBIg and the type of NAs to be used. Major disadvantages of using HBIg for prevention of recurrent post­transplant HBV infection are its inconvenience administration, limited supply and very expensive costs. Thus, withdrawal from HBIg treatment is highly desirable; however, the safety, efficacy and timing of withdrawal are not well-understood.

Samuel and associates demonstrated that a high-dose IV HBIg protocol, including 10 000 IU intraoperatively daily for the first posttransplant week followed by 10 000 IU monthly thereafter, resulted in 29% HBV reinfection rate after 2 years of transplant.¹² However, major disadvantages of high-dose IV HBIg for prevention of posttransplant HBV reinfection include its high cost, decreased efficacy in patients who are HBVDNA/HBeAg positive at time of transplant, and development of resistance due to genetic HBV mutants.^12-14

To reduce the amount of HBIg needed, individualized doses of HBIg are based on anti-HB titers; many transplant centers adjust the dose of HBIg accordingly, to maintain the anti-HB titer at a protective level.¹⁵ Additionally, intramuscular administration of HBIg reduces the amount of HBIg needed. In some studies, intramuscular HBIg during the posttransplant period is equally effective to IV HBIg; it has resulted in reduction of anti-HB titers to the same levels as IV HBIg, to a 0% to 24% HBV reinfection rate after liver transplant.^16-19 The great advantage of intramuscular administration of HBIg, compared to the IV route, is a substantial reduction in HBIg dose needed to achieve adequate titers, as well as cost reduction. However, intramuscular administration involves a painful injection.²⁰ The combination of HBIg and NAs is more effective against HBV reinfection after liver transplant than HBIg alone, because of synergistic activity; the combination results in a greater reduction in the needed time course and doses of HBIg.^11,21 The combination of HBIg and lamivudine has been the standard of care recommended by many centers against HBV reinfection, with recurrence rate of less than 10% at 2 years after liver transplant.²² However, there is an increasing interest among liver transplant centers in using more potent NAs, such as adefovir, tenofovir and entecavir, instead of lamivudine.

A recent systematic review by Cholongitas and associates, showed that HBIg could safely be replaced with potent NAs, however the timing of HBIg withdrawal is not clear and further studies are required.²³ In a randomized trial by Buti and associates, HBIg was discontinued in 20 patients soon after liver transplant and lamivudine was continued indefinitely; in 9 other patients, HBIg with lamivudine were continued. At 91 months of follow-up, 15% of patients for whom HBIg was discontinued showed signs of HBV reinfection, a rate similar to the 11% of patients receiving HBIg with lamivudine.²⁴ In another randomized study,^25,18 patients received HBIg with lamivudine, but HBIg was replaced with adefovir at the 1 year posttransplant. These patients were compared to 18 patients who received HBIg in combination with lamivudine indefinitely. After 24 months, HBV reinfection rates were similar in both groups (1/18 vs 0/18). In a prospective study of 58 patients, a prophylactic method included lamivudine in combination with IV HBIg 10 000 IU intraoperatively, 2000 IU daily for a week, 2000 IU (when anti-HB titers were less than 100 IU/L), and discontinuation of HBIg at the 1 year posttransplant timepoint. After 4 years of follow-up, 6.8% of patients were positive for HBV reinfection.26 In 2011, Stravitz and associates showed that HBIg withdrawal and continuing tenofovir with emtricitabine is a safe and effective method against HBV reinfection.²⁷ In our study, after approximately 2 years of HBIg withdrawal and prophylactic treatment with lamivudine or tenofovir, only 1 patient experienced HBV reinfection.

Hepatitis B virus antiviral therapy combined with potent NAs before transplant decreases both the viral load and the risk of reinfection; it achieves this by lowering the amount of circulating virus at the time of transplant and by prolonging the half-life of HBIg. Low dose intramuscular HBIg combined with NAs has been successful in preventing reinfection in patients with low detectable HBV DNA (particularly those with a viral load less than 10 000 copies/mL) and negative HBe Ag pretransplant. Antiviral therapy with tenofovir, a potent drug with a very low risk for resistance, could result in complete viral suppression after liver transplants. With increased availability of tenofovir and other potent NAs, the role of HBIg is evolving. Potent NAs alone without HBIg might suffice in preventing recurrent hepatitis B, but longer follow ups and precautions are needed in patients with HDV, HIV, and HCC hepatitis B.

This current prospective study suggests that the use of intramuscular HBIg in combination with lamivudine or tenofovir, and discontinuation of HBIg after 1 year posttransplant, may be a safe and cost-effective method to prevent HBV reinfection in patients who are HBV DNA negative at the time of transplant. These findings require follow-up to confirm their clinical significance.

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