This method requires only clinically available parameters, including gender, body weight, hematocrit, interval period of HBIG administration and trough anti-HBs titer. For Part 4 of this study, we recruited more than 150 patients who passed 5 years of LT without any eventful episode and performed a prospective study to extend the intervals of HBIG infusion to 12 weeks (94 days) with target trough anti -HBs titer of 200 IU/L since January 2016. Thus, the peak anti-HBs titer shortly after HBIG infusion is the sum of pre-existing trough titer and additional peak titer of HBIG infusion (Fig. 1A).
Simulation of anti-HBs pharmacokinetics with calculation of half-life (A) and use of simulative half-life (B). PK study to assess the accuracy of simulative anti-HBs peak titer and SHL (part 1 study). All patients underwent regularly administered HBIG infusion and measurement of trough anti-HBs titer each time.
The trough anti-HBs titer and intervals of HBIG infusion from overall 1000 measurement sessions in 100 patients (study cohort 3) are depicted in Fig. Scatter diagram showing the association between the trough anti-HBs titer and HBIG infusion intervals in the 100 patients of study cohort 2. If the target trough anti-HBs titer is 500 IU/L and SHL is 15 versus 20 days, the infusion interval becomes 52 versus 70 days, respectively.
We performed a prospective study to extend HBIG infusion intervals to 12 weeks (94 days) with a target trough anti-HBs titer of 200 IU/L. During the follow-up period, progressive prolongation of the HBIG interval lowered the trough anti-HBs titer in line with the target trough titer. The lowest anti-HBs levels among the last three measurements were used to calculate SHL.
The distribution of infusion intervals and nadir anti-HBs levels are shown in the figure. Scatter plot shows the relationship between nadir anti-HBs titer and HBIG infusion intervals in 114 patients from study cohort 3. Nine transplant surgeons at our institution independently determined the HBIG infusion interval for each patient individually according to a simplified principle to maintain a nadir serum anti-HBs titer ≥ 500 IU/l.
Scatter diagram showing the association between the trough anti-HBs titer and HBIG infusion intervals after stratification according to concomitant use of nucleos(t)ide analogue (NA) in the 660 patients of study cohort 4. Thus, a mean interval of 10 weeks can be applied to achieve a trough anti-HBs level of 500 IU/L. Consequently, an average interval of 13 weeks can be applied to reach a lowest anti-HBs level of 200 IU/L.
Scatter plot showing the relationship between simulated HBIG half-life and HBIG infusion intervals against target anti-HBs titers in 660 patients from Study Cohort 4.
Cohort 2 Cohort 3 Cohort 4
Thus, HNCT has begun to simply add an NA to HBIG monotherapy, with or without lowering the target anti-HBs titer. In real-world practice in Korea, most LT centers have still adopted high-dose HBIG prophylactic therapy, with or without NA, because there is no consensus or practical guideline to lower the target titer to anti-HBs levels, mainly due to low medical cost, with patients paying only US$70–140 for 10,000 IU HBIG (5–10% of total cost). We believe that the anti-HBs titer target would have been lowered earlier if the medical cost for HBIG infusion was not so low in Korea.
Given the high efficacy of HNCT, it should be reasonable that the target anti-HBs trough titer is lower than that of HBIG monotherapy. Consequently, there is a need to develop a practical method to logically adjust the target anti-HBs trough titer in LT recipients routinely given HBIG. Because the in vivo half-life of HBIG varies greatly by occasion or time, as well as by person, it is difficult to reliably approximate the nadir anti-HBs titer to the target level.
Previously, it was assumed that the anti-HBs titer is proportional to the effectiveness of preventing HBV recurrence, which explains the much higher anti-HBs titer than the target trough level, but such a concept is no longer valid in the current clinical field of LT. In part 1 of this study, we demonstrated that there was only a 4.4% difference between the estimated and actually measured additional rise in anti-HBs titer after infusion of 10,000 IU HBIG. A Korean prospective multicenter study found that the nadir anti-HBs titer stabilized after 16 weeks of LT according to the conventional protocol described in the methods section of this study. (10) Therefore, individualized adjustment of HBIG infusion intervals towards a specific target nadir titer can be reliably determined by adopting SHL 1 year after LT.
The required parameters were gender, body weight, hematocrit, SHL and target trough anti-HBs titer. Based on our long-term experience, we set the interval of HBIG infusion to 8–12 weeks for a target trough anti-HBs titer of 500 IU/L, which often resulted in the actual trough anti-HBs titer between 500 and 1000 IU/L. Although the target trough anti-HBs titer was set at 500 IU/L, the actual level in clinical practice was usually higher than the target level.
To increase the cost-effectiveness of HBV prophylaxis, we intended to lower the target trough anti-HBs titer towards 200 IU/L in part 4 of this research. Given that only 11.1% of measurement sessions showed anti-HBs trough titers <500 IU/L (Part 2 of this work), we believe that a majority of our patients are indicated for prolongation of HBIG infusion intervals. If the target trough anti-HBs titer is set at 200 IU/L, the interval for HBIG infusion will be prolonged in almost all of our patients.
If the nadir anti-HBs titer falls to 200 IU/L, 94.4% of patients can be indicated for prolongation of the interval by ≥7 days while only 0.2% can be indicated for shortening the interval by ≥7 days. Considering the high effectiveness of NA prophylaxis, there is no reason to keep the low anti-HBs titer as high as that in HBIG monotherapy.
