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Keywords:

  • Hepatitis B virus;
  • hepatitis B immunoglobulin;
  • liver transplantation;
  • reinfection prophylaxis;
  • subcutaneous administration

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Life-long hepatitis B immunoglobulin (HBIG) administration is a main component of prophylactic strategy to prevent hepatitis B virus (HBV) reinfection after liver transplantation (LT). Long-term effects of HBIG treatment are known only for intravenous (IV) and intramuscular formulations. To evaluate safety and efficacy of self-administered SC HBIG, 135 LT patients receiving a 48-week treatment were analyzed. The dose of HBIG was 500 IU or 1000 IU if body weight was <75 kg or ≥75 kg, respectively. Patients were switched from the monthly IV HBIG treatment to weekly SC HBIG 2–3 weeks after the last IV dosage. All patients were able to SC self-injection after a single training. The treatment was effective in maintaining trough anti-HBs levels >100 IU/L. No severe drug-related side effects occurred. Fifteen injection-site small hematomas and four cases of mild itch occurred. At the end of the study, anti-HBs median titer was 232 IU/L (115–566 IU/L) and 97.8% of patients had an anti-HBs level >150 IU/L. Due to high mean level of anti-HBs titers observed during this study, individualized treatment schedules should be further investigated. In conclusion, SC HBIG for long-term prophylaxis of post-LT HBV reinfection resulted safe, well accepted, and effective in maintaining adequate anti-HBs levels.


Abbreviations
HBIG

hepatitis B immunoglobulins

HBV

hepatitis B virus

IM

intramuscular

IV

intravenous

LT

liver transplantation

SC

subcutaneous

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Advanced hepatitis B virus (HBV) liver disease is one of the leading indications for liver transplantation (LT). In the absence of prophylaxis, HBV reinfection after LT occurs in approximately 80% of patients resulting in dismal graft and patient survival [1, 2]. Life-long hepatitis B immunoglobulin (HBIG) administration represents the backbone of prophylactic strategy to prevent HBV reinfection. Although the mechanisms whereby HBIG prevent HBV recurrence post-LT are not well understood, their administration reduces reinfection rates to less than 10% [3-6]. HBIG can be administered by intravenous (IV), intramuscular (IM) and subcutaneous (SC) route. HBIG by IV route is very effective in maintaining adequate anti-HBs levels but it is the most expensive way of administration. Costs are mainly related to the need to administer HBIG at the hospital, to the time spent by the patient, and to the effects on the quality of life reducing patient autonomy in his daily life. Long-term prophylaxis with high-dose IV HBIG had been the standard of care to prevent HBV reinfection after LT until the introduction of lamivudine. Afterwards, several studies have shown that combining lower HBIG doses with lamivudine reduced reinfection rates to less than 5% [7-14]. This strategy allowed the reduction of HBIG doses probably because lamivudine blocked viral replication of occult HBV foci reducing HBIG consumption. The switch from IV to IM administration of HBIG is cost saving and improves flexibility of patient in his daily life [15, 16]. However, patients treated with IM HBIG compared to patients treated with IV HBIG had worse quality of life score on the side effects scale [16]. Main problems related to IM administration are injection-site pain, unsuitability to self-injection and contraindication in patients affected by coagulopathies or treated with anticoagulants. SC HBIG injection allows self-administration resulting in a better autonomy of the patients and it is well tolerated. In healthy volunteers, no relevant differences in pharmacokinetic characteristics between IM and SC application of HBIG after a single administration were found [17]. Efficacy, safety and feasibility of SC administration in patients after LT have been demonstrated in a recently published phase III study [18]. However, data on long-term treatment with SC HBIG are still lacking.

The aim of this study was to evaluate the long-term effects of HBIG home self-administration by SC route in LT-patients for HBV liver disease in practice field.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

This is a single center, investigator driven, prospective study. From February 2011 to March 2011, 135 liver transplanted patients for HBV-related liver disease and in long-term prophylaxis with IV HBIG were switched to SC HBIG and enrolled in the study. Main inclusion criteria were male and female patients >18 years old, liver transplanted from ≥12 months, long-term prophylaxis against HBV reinfection with an anti-HBs level >200 IU/L after the last administration of HBIG, HBsAg and HBVDNA negativity, and stable graft function. Exclusion criteria were HIV co-infection, recent rejection episode, pregnancy, severe decompensated cardiac, pulmonary, liver and renal pathology. Duration of the study was 48 weeks. The local ethics committee approved the study and all the patients gave their informed consent before enrollment in the study.

Study protocol

Patients were switched from the standard IV HBIG treatment with 6000 IU monthly to weekly SC HBIG administration 2–3 weeks after the last IV dosage in order to ensure adequate anti-HBs coverage during the transition from IV to SC dosing. The dose of SC HBIG was 500 IU (1 mL) for patients with body weight < 75 kg and 1000 IU (2 mL) for those with body weight ≥ 75 kg. In these last patients, HBIG was administered by two injections performed in the same day. A physician supervised the first SC HBIG administration and trained the patient on the correct mode of self-administration at home. During the first 2 months of the study, serum anti-HBs and HBsAg levels were determined every 2 weeks, the day prior to HBIG administration; thereafter these tests were repeated at 4-week intervals up to week 48. At the same time intervals, physical examination, compliance evaluation, recording of adverse events and laboratory parameters (blood cell count, aminotransferases, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, creatinin, glucose, urea, INR, lactate dehydrogenase, albumin) were performed. In this study we selected a safety level of anti-HBs titers ≥150 IU/L and when the anti-HBs titer was below this level the dose of HBIG was doubled. Serum anti-HBs levels were determined with the commercial Axsym AUSAB microparticle enzyme immunoassay (Abbott Diagnostics). HBV-DNA serum concentration was measured before the enrollment and at the end of the study period by Cobas Taqman HBV-DNA RT-PCR Assay (lower limit of detection 20 IU/mL). Maintenance immunosuppression regimens consisted of either a two-drug regimens (49 patients) that included cyclosporine or tacrolimus, and mycophenolate or everolimus, or single agent immunosuppression (86 patients) based on cyclosporine, tacrolimus or sirolimus. Concomitant treatment with nucleoside or nucleotide analogues was done in 104 (77%) of 135 patients (Table 1).

Table 1. Basal characteristics of patients
Patient characteristicsValue
  1. LAM = lamivudine; ADF = adefovir; ETV = entecavir; LdT = telbivudine.

Age, median (range), years57 (34–78)
Male gender, n (%)105 (77.8%)
Body weight, median (range), kg75 (50–117)
Body mass index, median (range)26.7 (18.4–39.7)
Indication to OLT 
Decompensated cirrhosis105
Hepatocellular carcinoma30
Etiology 
HBV65
HBV-HCV8
HBV-HDV55
HBV-HDV-HCV7
Years after LT 
<533
5–1061
>1041
Antiviral therapy 
LAM87
LAM-ADF7
ADF4
ETV4
LdT2
None31
Proteinuria 
- Yes/No33/102
- mg/L, Mean ± SD (Range)433.09 ± 314.72 (153–1296)

Investigational product

Zutectra® (Biotest AG, Dreieich, Germany) is a sterile solution containing a preparation of human HBIG (of which at least 96% is IgG) in a prefilled syringe of 1 mL; each syringe contains 500 IU Human HBIG obtained from plasma of donors anti-HBs positive. After SC administration, Zutectra is slowly absorbed, achieving a maximum peak after 2–7 days with a half-life of about 3–4 weeks [17]. These pharmacokinetic characteristics may vary from patient to patient.

Statistical analysis

Mean ± standard deviation, 95% confidence intervals, and median were calculated for descriptive purposes. Box plots were used to show graphically the trend of anti-HBs at different time intervals. Mann-Whitney nonparametric test was used to compare anti-HBs serum levels at different time points among patients treated versus patients untreated with antivirals, patients with HBV infection versus patients with HDV co-infection, and patients with proteinuria versus patients without proteinuria. A two-sided p value ≤ 0.05 was considered to indicate statistical significance. SPSS version 14.0 was used for data analysis.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

One hundred thirty-five patients gave their consent to participate into the study and received SC HBIG treatment: 80 patients at a dose of 500 IU and 55 at a dose of 1000 IU. Basal characteristics of patients are shown in Table 1. After a single training, all patients were able to SC HBIG self-administration. At baseline, anti-HBs median titer after the last IV HBIG dosage was 407 IU/L (range 211–869). In 5 (6.2%) of 80 patients treated with the HBIG dose of 500 IU, anti-HBs titers decreased to a level between 100 IU and 150 IU in a single determination at week 8 and 12. According to our protocol, in these patients the dose of HBIG was doubled. Among the 55 patients treated with HBIG dose of 1000 IU, anti-HBs levels never decreased below 150 IU and no dose modification was needed.

Anti-HBs median titer at the week 48 was 232 IU/L (115–566 IU/L) and 132 (97.8%) of 135 patients had an anti-HBs level >150 IU/L. Figure 1 illustrates the trend of anti-HBs concentrations during the 48 weeks of the study. No differences in mean anti-HBs levels at different time intervals between patients treated with antivirals or untreated and between patients with HBV or HBV-HDV co-infection were observed (Figure 2). At baseline, 33 patients had mild proteinuria. In these patients, differences in mean anti-HBs levels and in percent change of antibody titers at different time points as compared to patients without proteinuria were not statistically significant. No severe drug-related side effects occurred. During the study, overall 9296 injections were done. Fifteen cases of small hematomas at the injection site and four cases of mild itch, not definitely related to SC HBIG administration, were observed. In these last cases, no dose modification of SC HBIG was done and itch spontaneously resolved. During the study period, no changes in safety laboratory parameters and no premature treatment discontinuation due to adverse events or lack of efficacy occurred. Serum HBsAg and HBV-DNA remained negative in all patients and no laboratory or clinical signs of HBV reinfection were observed.

image

Figure 1. Variation of anti-HBs levels during the study in the overall population.

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image

Figure 2. Variation of anti-HBs levels according to etiology (A), antiviral therapy (B) and presence of proteinuria (C). Differences in median anti-HBs level resulted >0.2 in all figures at all time intervals.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Home self-administration of SC HBIG for long-term prophylaxis of post-LT HBV reinfection resulted safe, well accepted by patients and effective in maintaining adequate anti-HBs levels.

As observed in previous studies on small series, SC administration was painless and it was associated with mild adverse events (pruritus, small injection-site hematomas) only in 6.7% of patients. Self-injection of HBIG by SC route resulted an easy procedure and all our patients were able to do it after a single short training. Although a specific questionnaire was not used, SC administration was well accepted by all patients mainly because it improved their autonomy and quality of life as compared to the previous IV treatment. In a multicenter Italian study, patients treated with IM HBIG reported significantly better quality of life scores on the Flexibility and Negative Feelings scales mainly due to the favorable impact on daily flexibility as compared to patients treated with IV HBIG [16]. The SC administration route could be advantageous over IM administration because of the possibility of self-administration by the patient at home and absence of injection-site pain. Therefore, SC application seems to be the preferable route to administer HBIG.

During the study period, a progressive decrease in antibody levels from the baseline to the week 48 was observed (Figure 1; Table 2). This decline occurred because we choose as safety measure to start SC administration 2–3 weeks after the last IV dosage, when anti-HBs levels were high (median 407 IU). We believe that the slight progressive decrease in antiHBs titers was not due to lack of compliance because of the absence of sharp changes at monthly controls. The SC administration of HBIG was effective in maintaining at any time point in all cases trough anti-HBs levels above the level of 100 IU/L, that is commonly accepted as the threshold to prevent HBV reinfection in LT patients [19]. Furthermore, no clinically significant intraindividual changes of anti-HBs serum levels during the study period were observed. According to our protocol, HBIG dose was doubled in five patients because antibody titers decreased between 150 IU/L and 100 IU/L. Dose modification was required only among patients treated with 500 IU of HBIG. It is commonly accepted that antivirals may reduce HBIG consumption blocking viral replication of occult foci. However, in this study no differences in anti-HBs mean levels at different time intervals were observed between patients concomitantly treated with antivirals and patients who were untreated with these drugs. No statistically significant differences in anti-HBs serum concentration were found also between patients with HBV-HDV co-infection, who are associated with a lower HBV replication and rate of re-infection, as compared to HBV mono-infected patients. Furthermore, a more rapid decrease of anti-HBs level was not observed in patients with mild proteinuria as compared to patients without this finding. At the end of the study, 98% of patients had anti-HBs trough levels that were far higher than the safety threshold. Therefore, using this study protocol the majority of patients were over-treated and it may be conceivable that different dosing schedules (i.e. HBIG administration every 10 days or every 2 weeks) should be further investigated. Previous studies have demonstrated the efficacy of low-dose IM HBIG and lamivudine combination started 1 week after LT in preventing HBV reinfection [12, 14]. Due to the results of this study, it is very worthwhile to evaluate a similar strategy using SC HBIG in a prospective study.

Table 2. Anti-HBs serum levels at different time intervals
 Median (range)Mean ± DS95% CI
Baseline407 (211–869)434 ± 137411.3–456.6
Week 2356 (177–732)370 ± 113351.3–389.4
Week 4341 (160–764)354 ± 120334.2–374.8
Week 6372 (156–739)334 ± 122313.2–354.4
Week 8299 (120–713)321 ± 119300.8–341.1
Week 12295 (127–801)319 ± 122298.2–339.3
Week 24297 (150–693)314 ± 109295.6–333.2
Week 28283 (152–648)304 ± 98276.6–339.1
Week 32243 (150–565)264 ± 91225.6–281.1
Week 36250 (153–592)292 ± 113259.4–331.3
Week 40257 (159–513)287 ± 115229.5–323.4
Week 44255 (187–518)318 ± 113215.0–465.3
Week 48232 (115–566)264 ± 97247.2–281.7

The availability of new nucleoside/nucleotide analogues with high genetic barriers has disclosed new attracting perspectives to prevent HBV recurrence after LT. An Asian study of 80 patients receiving entecavir monotherapy have shown encouraging results [20]. Other two studies showed that entecavir, tenofovir and combination of new nucleoside/nucleotide analogues were safe and effective in patients who discontinue HBIG [21, 22]. Although no clinical manifestations of HBV recurrence were observed in these studies, 3.3–22% of patients were HBsAg positive with undetectable or low levels of HBV-DNA at the time of last follow-up. The importance of this virological status after LT remains unclear, therefore more studies and longer follow-up are needed before to recommend these HBIG-sparing protocols in daily clinical practice.

To our knowledge, this is the first study that has evaluated the effects of a 48-week treatment with SC HBIG in a large cohort of LT patients in practice field. We believe that this treatment represents a safe, effective and convenient option for life-long administration of HBIG with the potential to improve patient quality of life. Individualized dosing intervals may lower treatment costs and increase patient compliance.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References