Efficacy and safety of early switching to subcutaneous HBIg after liver transplantation Back

Introduction

The history of the management of HBV infection in patients undergoing liver transplantation has been one of success. It was first shown in the early 1990s that long-term prophylaxis with intravenous HB immunoglobulin (HBIG) significantly reduced the risk of HBV recurrence and improved survival rates1 and the advent of combination therapy with oral antivirals reduced the long-term reinfection rate far below 10 per cent.2
Though effective, a fixed dose schedule of intravenous prophylaxis was expensive and efforts to contain costs led to the introduction of dosing adjusted according to anti-HB titre and subsequently to intramuscular administration of HBIG. This was followed in 2006 by the first case report of subcutaneous administration of HBIG and, in 2010, the introduction of Zutectra, the first formulation of HBIG intended for subcutaneous administration.3
Specialists attending the 51st International Liver Congress in Barcelona met at a Biotest Round Table on April 15th to discuss the latest evidence for the efficacy and safety of early switching to subcutaneous HBIG after liver transplantation and its impact on adherence and quality of life.

Management of liver transplantation patients with hepatitis B during perioperative and early follow-up phase

Professor Renato Romagnoli, Professor of Surgery, University of Turin

It is clear that early use of intravenous HBIG after transplantation is essential but, when HBsAg negative status has been achieved, it is advantageous to patients to switch to an intramuscular or subcutaneous regimen. The efficacy and safety of an early switch to subcutaneous administration was evaluated in ZEUS (Zutectra Early Use Study) trial.4 This was a prospective, open-label, single arm Phase III study over 6 months conducted in 17 centres in Italy, Spain, UK and France between December 2012 and September 2014. Patients undergoing liver transplantation who were HBsAg positive but had undetectable HBV DNA received standard treatment with intravenous HBIG for at least 8 days, then switched to subcutaneous administration when they were HBsAg negative and anti-HBs was >400 IU/L. Subcutaneous HBIG was administered once every 1 or 2 weeks at a dose adjusted to maintain serum anti-HBs at a level of >100 IU/l (up to a maximum 1,500 IU). After 4 weeks, the subcutaneous injection could be administered by the patient or a caregiver after training and assessment. Additional treatment with an oral nucleoside analogue was permitted according to local practice. Of the 49 patients who entered the study, one discontinued prematurely due to graft rejection and one was lost to follow up. The mean age was 52 years, 84 per cent were male and 92 per cent were Caucasian. Indications for liver transplantation included HBV-induced cirrhosis (92 per cent), hepatocellular carcinoma (49 per cent) and retransplantation (6 per cent). Coinfection with hepatitis D virus was present in 43 per cent and 82 per cent were being treated with antiviral therapy before surgery. The primary efficacy endpoint was treatment failure by month 6, defined as serum anti-HBs ≤100 IU/l during the active treatment phase and HBV reinfection (HBsAg-positivity and clinical symptoms) with serum anti-HBs >100 IU/l. No treatment failures occurred. All patients maintained serum anti-HBs >100 IU/l and remained HBsAg negative to month 6 and all remained HBV DNA negative. Initial doses ranged from 500 IU every 2 weeks (45 %) to 1000 IU once weekly (2 %). The final dose interval was once weekly in 41 per cent of patients, of whom three-quarters required a dose of 500 IU and the remainder required 1000 IU (Table 1). Serum anti-HBs levels are shown in Figure 1. The minimum serum anti-HBs level after the first dose was 115 IU/l and the mean anti-HBs plateaued at approximately 290 IU/l. Safety and tolerability were secondary endpoints. At least one adverse event was reported in 92 per cent of patients but only one event was judged by investigators to be related to treatment (mild haematoma at injection site). There were no serious treatment-related adverse events and no dose adjustment due to adverse events. There were no clinically abnormal levels of IgG, IgA or IgM at the final study visit. Responding to a question from the audience, Professor Romagnoli noted that the prevalence of hepatitis D coinfection in Italy is stable at about 40 – 50 per cent. This is primarily associated with population movement from Eastern Europe and North Africa and is not expected to decline in the near future. He pointed out that patients positive for HBV-D have higher circulating HBsAg and need larger doses of HBIG in the first month after transplantation. There are currently no virostatic drugs effective against HBV-D, Professor Romagnoli added, and patients with HBV-D co-infection require higher levels of immunoglobulin to prevent recurrence.

Practical experience: Switch from IV to s/c HBIG in stable patients

Professor Susanne Beckebaum, Department of Transplant Medicine, University Hospital Münster, Germany

HBIG neutralises HBsAg and has immunomodulatory properties that help to protect the graft against HBsAg-induced inflammation. The rationale for subcutaneous administration of HBIG is that it offers the potential to reduce the severity and frequency of adverse events caused by the high peak and low trough serum anti-HBs levels associated with intravenous administration. In addition, subcutaneous administration can more easily be homebased whereas IV or IM administration is clinic-based. Patients’ satisfaction with treatment may be higher.
There is a growing evidence base to support the use of subcutaneous HBIG.5-9 Among these studies, one describes experience of prophylaxis with subcutaneous HBIG (Zutectra) in a real-world setting.5 This 18-week observational study included 61 patients who were negative for HBV DNA and HBsAg who received prophylactic HBIG at the dose approved at the time (body weight ≥75 kg, 1000 IU; 6. We therefore carried out a prospective study in 43 liver transplant recipients who had switched from 2 – 3 monthly IV HBIG to weekly subcutaneous HBIG to explore the factors that may contribute to this variability.7 Mean age of these patients was 53.6 yr (+/-11.6), 63 per cent were male and 60.4 per cent were also taking antiviral therapy. The median time to switching to subcutaneous administration was 79.2 months (range 8.4 – 211.7). At the time of switching, 56 per cent were treated with 500 IU weekly and the remainder with 1000 IU weekly; the median dose per kg was 9.1 IU (range 6.3 – 13.3). Mean body mass index was 26.2 kg/m2 (+/-4.9). The anti HBs-titers during the course of the study are shown in Figure 2.
Based on our findings, we developed a model that predicts the HBIG dosage needed when administered subcutaneously to achieve stable anti-HBs titers above 100 IU/l. This model has a specificity 86.4 per cent and a sensitivity of 95.2 per cent. It suggests that individuals with a body mass ≥75 kg may, when switching from IV to subcutaneous administration of HBIG, need a lower dose and those with body mass

Impact of subcutaneous HBIG therapy on the quality of life of patients compared to IM or IV treatment regimens

Professor Patrizia Burra, Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Italy

HBV infection accounts for approximately 12 per cent of liver transplants recorded in the European Liver Transplant Registry, and for 15 per cent of surgery for cirrhosis. Patient survival and graft survival is higher than for other indications (deltas virus infection is associated with still higher rates) and disease recurrence has become a significantly less frequent cause of death or graft loss since 1988.10 However, the presence of coinfection with HIV or hepatitis C virus, or alcoholic liver disease, are all associated with worse outcomes after transplantation due to HBV.
There is good evidence from clinical trials that prophylaxis with HBIG combined with antiviral agents is more effective than the component drugs alone2 but, as Bunzel and Laederach-Hofmann have pointed out, ‘the effectiveness of any treatment depends not only on the right choice of therapy but largely also on the active cooperation of patients with the therapeutic regimen’.11 The factors influencing adherence include personality, knowledge of the disorder, family support, the doctor’s characteristics and the complexity of prescribed treatment.12,13 In particular, increasing number of doses per day is associated with a progressive decline in adherence, falling from about 80 per cent with once daily dosing to 50 per cent with a four times daily regimen.14 This is equally true among patients taking immunosuppressants.15 Further, there is no strategy that will improve adherence in all people after transplantation: improvement can be achieved in some whereas in others there is no change or even a worsening.16 Other factors associated with low adherence after solid organ transplantation include living alone, negative general beliefs about medications and longer time since transplantation. After suitable training, most patients are able to switch from monthly IV to weekly subcutaneous administration of HBIG (Figure 3) and maintain anti-HBs titres above the target level.7,9 Adherence to this regimen is high.5 In the recent ZEUS study, all patients said they were satisfied with subcutaneous HBIG; handling of the injection was rated easy by 92 per cent by week 4, increasing to 100 per cent from week 16; and patient diaries indicated complete adherence throughout the study.4 The Immunoglobulin Therapy After Liver Transplantation Questionnaire (ITaLi-Q) was used to record patients’ quality of life; this tool has been validated in patients receiving HBV prophylaxis after liver transplantation. It records patients’ assessments of adverse effects, their positive and negative feelings, the impact of health on daily activities, their perceived need of support and the support they have received, and overall satisfaction. Using this tool, the TWINS I study showed that health-related quality of life scores among patients receiving IM HBIG prophylaxis were superior to those in patients having IV prophylaxis for flexibility and negative feelings but worse for side effects and support received.17 The TWINS II study (unpublished) has now compared quality of life scores before and after switching to subcutaneous administration of HBIG. It has shown that switching to subcutaneous administration is associated with significant improvements across most domains side and in overall satisfaction with therapy. This study also utilised the Short Form-36 tool and the results from this confirmed the ITaLi-Q data.
In summary, the available evidence shows that subcutaneous HBIG is associated with many aspects of superior quality of life scores in patients after liver transplantation, including fewer side effects, improved perception of their autonomy, better feelings about emotions, and improved physical function.

Biotest References

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3. Powell JJ, Apiratpracha W, Partovi N et al. Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence. Clin Transplant 2006;20:524-5.
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8. De Simone R, Carrai R, Leonardi G et al. Early switching to subcutaneous anti-hepatitis B virus immunoglobulins (HBIG) after liver transplantation: 12-month results of a single-center study: 912. Transplantation 2012;94 (10S):912.
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11. Bunzel B, Laederach-Hofmann K. Solid organ transplantation: are there predictors for posttransplant noncompliance? A literature overview. Transplantation 2000;70:711-6.
12. Cherubini P, Rumiati R, Bigoni M et al. Long-term decrease in subjective perceived efficacy of immunosuppressive treatment after heart transplantation. J Heart Lung Transplant 2003;22:1376-80.
13. Washington AW. Cross-cultural issues in transplant compliance. Transplant Proc 1999;31:27S-28S. 14. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296-310.
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17. Franciosi M, Caccamo L, De Simone P et al. Development and validation of a questionnaire evaluating the impact of hepatitis B immune globulin prophylaxis on the quality of life of liver transplant recipients. Liver Transpl 2012;18:332-9.