Prevention of recurrent exposure to hepatitis B virus (HBV) is essential after liver transplantation (LT) in patients infected with HBV. Many protocols for HBV prophylaxis after LT include the administration of hepatitis B immunoglobulin (HBIG).1234 HBIG treatment has been used for a long time because of its effectiveness, but it has major drawbacks including high cost, resistant viral mutation, and a cumbersome injection process.125 However, the route of HBIG administration has evolved to improve patient compliance.

In Korea, HBIG agents were initially developed for intramuscular injection in small doses. Thus long infusion periods of up to 4–8 hours were required for the administration of 10,000 IU HBIG in order to prevent adverse events. Following the development of more purified HBIG agents suitable for intravenous injection, the infusion time was successfully shortened to 1–2 hours, and with increased experience, we adopted an ultra-rapid infusion for 30 minutes.6 This shortened duration of infusion allowed us to utilize the hospital facility more effectively and enabled us to organize patient-friendly HBIG infusion schedules.

However, a progressive increase in LT recipients requiring regular HBIG infusions forced us to further modify the HBIG infusion protocol to be more efficient in terms of time and effort. In order to reduce the infusion time as well as the patients' wait time, and to improve the efficiency of our facility, we evaluated the outcome of simplified ultra-rapid HBIG infusion protocol administered to HBV-associated adult LT recipients visiting the outpatient clinic.

This single-arm study intended to evaluate the patient safety and the efficiency of facility utilization following simplified ultra-rapid intravenous infusion of HBIG in HBV-associated adult LT recipients who visited our outpatient clinic.

At our institution, 10,000 IU HBIG was infused during the anhepatic phase of LT operation, daily during the first week, once weekly for the next 1 month, and once monthly after that. After the first year of LT, the interval period between regular HBIG infusions was gradually increased to 8–16 weeks on a patient-by-patient basis, in order to maintain a trough serum antibody to hepatitis B surface antigen (anti-HBs) titer ≥500 IU/L. A high-genetic barrier nucleos(t)ide analog (entecavir or tenofovir) has often been added as combination therapy, especially in LT recipients showing rapid HBIG consumption or risk of hepatocellular carcinoma recurrence.78

We previously presented the protocol for conventional ultra-rapid HBIG infusion,6 in which 50 ml volume of 10,000 IU HBIG (collection of 5 bottles of 10 ml HBIG 2,000 IU without dilution) was continuously infused without using an infusion pump for 25 minutes, followed by a 5-minute wash-out of the infusion line with 50 ml 5% dextrose water. To ensure safety, this ultra-rapid infusion was performed in patients on bed-rest. From March 2010 to September 2016, more than 30,000 sessions of ultrarapid HBIG infusion were performed in more than 2,500 LT recipients.

In our simplified ultra-rapid infusion method, two points were modified as follows: wash-out of the infusion line was omitted, and sitting/ambulation was permitted during the HBIG infusion. Thus, 50 ml volume of 10,000 IU HBIG (prefilled at the institutional pharmacy through collection of 5 bottles of 10 ml HBIG 2,000 IU) was directly infused for 20–25 minutes on an ambulatory basis.

After a preliminary evaluation for 3 months with alternating administration of the conventional and simplified infusion methods, since January 2017 the simplified method replaced the conventional method.

We retrospectively analyzed the medical records of adult LT recipients who were administered HBIG regularly at the outpatient clinic during the 18-month study period from January 2017 to July 2018. Patients who were administered HBIG alternatively at other institutions were excluded. Apart from that, five patients who were administered HBIG slowly for 2 hours due to a past history of HBIG-associated urticaria were also not included in this study. All adverse side-effects were recorded in the HBIG infusion sheet.

Continuous variables were reported as mean±standard deviation. p-value<0.05 was considered statistically significant. Statistical analyses were performed using SPSS (version 22; IBM, New York, NY). The study protocol was approved by the institutional review board of the Asan Medical Center (2018-0739).

HBIG infusion is currently used in many transplant centers as a component of combination therapy or monotherapy for post-transplant HBV prophylaxis.1234567 In the real-world practice, HBIG infusion is an important component to determine the intervals between outpatient clinic visits because self-administration of HBIG is not yet permissive. Prefilled intramuscular injections containing HBIG of very high concentration, similar to insulin, are currently under investigation, though not yet commercially available. Thus, it is necessary for LT patients to visit hospitals regularly in order to receive HBIG.

In order to enhance patient compliance, two factors should be considered. The first is easy patient-friendly administration of HBIG. In practice, patients prefer short appointments to receive HBIG for convenience. This was the primary reason for the introduction of the simplified ultra-rapid infusion method as an improvement in the administration of HBIG. The second is to prolong the intervals between HBIG infusions, making outpatient clinic visits less frequent. Since the efficacy of HBIG monotherapy is not high, an adequate target trough level of anti-HBs was set to prevent HBV recurrence. Antiviral agents are highly effective in suppressing HBV replication, thus it is reasonable to lower the target anti-HBs trough level in patients undergoing a combination therapy of HBIG with an antiviral agent.910111213 Our findings regarding the cross-sectional distribution of trough anti-HBs revealed that a majority of our patients were administered HBIG more often than required, indicating that individualized adjustments in the HBIG infusion intervals are necessary.

Our simplified ultra-rapid infusion protocol has proven to be convenient for patients because it reduces the time they spend at the outpatient clinic. Nearly all the patients treated using this protocol were satisfied and preferred it to the conventional infusion method. Occupancy of patient beds was one of the limiting factors for turnover of HBIG infusion in the outpatient clinic. For reasons of safety, although HBIG was infused under bed rest, sitting or ambulation was usually allowed in the patients with no physical problems, and was proven to be safe following numerous sessions of HBIG infusion in this study. At our institution, the number of LT recipients visiting the outpatient clinic has increased progressively,1415 making it difficult to arrange HBIG infusion schedules at their convenience. We believe that our simplification of the ultra-rapid infusion method does not lower patient safety.

There was one significant reason for abandoning the wash-out procedure with 50 ml 5% dextrose water in our simplified method. This wash-out procedure was intended to completely infuse the expensive HBIG into the recipient without any amount of the solution remaining in the infusion line. Our studies revealed that the mean amount of HBIG remaining in the infusion line was estimated to be less than 1.5 ml (<3%). This was considered to be negligible considering the additional effort required for the wash-out process. In addition, dilution of the HBIG with 5% dextrose water could produce faint floating substances in some rare instances, which were identified as immunoglobulin G. The Korean Pharmacopoeia suggests that 10,000 IU HBIG should be dripped after mixing with 150 ml of 5% dextrose water (permitted at December 2006). This protocol was observed in our institution before introduction of the ultra-rapid infusion method in February 2010, but was modified primarily for the purpose of avoiding the infusion pump. Furthermore, dilution or washing with 5% dextrose water was eliminated from our current simplified protocol. Based on these reasons, we suggest revising the recommendation for HBIG administration described in the Korean Pharmacopoeia.

A new HBIG product containing 50 ml of 10,000 IU HBIG will be available soon in the market in Korea. Considering that regular infusion with a fixed dose of 10,000 IU HBIG has been routinely performed in Korea and collection of bottles with small dose is necessary, such a high-dose bottle agent will be helpful to perform ultra-rapid infusion as well as to prevent collection procedure-related contamination.

This study has some limitation. This study is a high-volume study but performed in a single institution. This study is a retrospective study, thus a prospective study design is necessary for follow-up studies. This study did not include all sessions of HBIG infusion in our institution because data collection was performed on only patient base not infusion session base.

In conclusion, our high-volume study indicated that the rapid infusion of highly purified HBIG within 30 minutes was well tolerated by nearly all LT recipients. This suggests that it would be reasonable to perform the simplified ultra-rapid infusion protocol widely for patient convenience.