Subcutaneous administration of Hepatitis B immunoglobulin: efficacy and adherence Back

Introduction

Treatment with Hepatitis B immunoglobulin (HBIg) has greatly reduced the risk of Hepatitis B (HBV) recurrence after liver transplantation1,2 and, together with antiviral therapy, it is now is considered the standard of care. HBIg was originally available as an intravenous infusion then as an intramuscular injection, and a formulation for subcutaneous injection (Zutectra) was introduced in Europe in 2010. Administered weekly in patients after prophylaxis with intravenous HBIg, beginning at least 6 months after transplantation, this has been shown to maintain antibody titres above the threshold regarded as the minimum for effective prevention of HBV reinfection (100 IU/L) with few adverse events.3-8

Earlier switching from intravenous to subcutaneous administration offers potential advantages for patients and clinicians but until recently there was limited evidence of the efficacy and safety of this approach.9 Now, the Zutectra-Early-Use-Study (ZEUS) has shown that early subcutaneous administration is effective and well tolerated. Specialists attending the 50th International Liver Congress in Vienna met at a Biotest Round Table on April 24th to hear 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.

ZEUS: the efficacy and safety of subcutaneous HBIg

Professor De Simone, Hepatobiliary Surgery and Liver Transplantation, University of Pisa Medical School Hospital, Italy.

Until recently, prophylaxis with HBIg after liver transplantation required intravenous infusion. This was not a ‘home treatment’ – it was inconvenient for patients, who had to travel to a hospital, and it required nurses to administer the dose during a day’s stay in hospital. Intramuscular injection was potentially more convenient but still required nursing assistance. The advent of a subcutaneous formulation (Zutectra) meant that, with appropriate training, patients could administer their treatment at home. However, in accordance with the product’s current marketing authorisation, subcutaneous treatment can at present only be initiated 6 months after transplantation and patients still have to attend hospital regularly during this period. This is a sensitive issue at a time of economic constraint when we need to reduce avoidable hospital attendance.

We believe we can improve quality of life and increase the acceptability of treatment to patients by introducing subcutaneous administration early after transplantation and this was what ZEUS aimed to evaluate. Its design was very simple (see Box): it was a single arm, open label study in which patients were switched from IV infusion to subcutaneous injection 2–3 weeks after transplantation. The treatment paradigm was for the patient to undergo transplantation and then have the possibility of treatment at home, reducing hospital visits as much as possible and ZEUS was designed to be a very close approximation to clinical practice.

ZEUS was conducted in 17 centres in Italy, France, Spain and the UK.  Forty-nine patients were recruited; one patient withdrew from the trial due to graft rejection and one was lost to follow up. The patients were generally representative of the liver transplant population we see in European clinics, with a mean age of 52 and mostly male (84 per cent). The main indications for transplantation were HBV-related liver cirrhosis (92 per cent) and hepatocellular carcinoma (49 per cent). All received concomitant antiviral therapy. Patients were switched to subcutaneous HBIg when, after intravenous administration, they reached an Hepatitis B surface antibody titre of at least 400 IU/L.
Introducing subcutaneous HBIg 2–3 weeks after liver transplantation achieved target titres throughout the 6-month observation period (Figure 1). The final mean antibody titre was 290 IU/L. There were no treatment failures, no unexpected treatment-related adverse events and no dose adjustment was necessary. Patients documented their experiences at every follow-up visit and their records show they rated subcutaneous injection at home as extremely convenient and easy to handle; all were satisfied with their treatment.

We found that the key to successfully switching patients to subcutaneous administration was nurseled education and training. We invested time educating patients when they were on the ward and then periodically when they returned for follow-up visits. The nurses’ role was pivotal to improving treatment and helping patients.

To date, there has been no formal assessment of the cost effectiveness of an early switch to subcutaneous administration compared with traditional models of care but there is little doubt that home treatment with HBIg is likely to be cost effective. This approach to post-transplantation prophylaxis is suitable for all patients. It saves money for the patient by not having to return to hospital or depend on a third person to assist with the injection, and not needing time off work. Self-treatment was also associated with a reduction in doctors’ workload.

Adherence and quality of life

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

Low adherence is common among transplant patients,10 with only 50 – 60 per cent fully adherent with their treatment.11 Factors contributing to low adherence include an increasing number of daily doses and the complexity of prescriptions, and patient-related factors such as negative perceptions about medicines, family support and disease awareness.12-14 However, low adherence is not confined to drug treatment: attendance at clinic appointments and with blood testing is also low in liver transplant patients (Figure 2).11

Our clinical experience has shown us that many patients are aware that failing to have regular HBIg prophylaxis greatly increases their chances of disease recurrence and they are therefore well motivated to attend for treatment. But some groups are at increased risk of low adherence, including patients taking multiple medication, adolescents, people living alone (especially men), individuals who were transplanted at a time when they were well (e.g. for a tumour rather than imminent hepatic failure) and patients who have been receiving  treatment for many years and may have developed memory problems.

Currently, patients are admitted as day patients to receive their monthly HBIg prophylaxis. Asking patients to come to hospital solely for an infusion is a costly use of health resources and disadvantageous for the patient. A switch to self administration of a subcutaneous injection at home is therefore an attractive alternative and, in our experience, patients are very pleased to have this option. In one small study (n=23), patients were quickly able to take over administration of their weekly subcutaneous injections from medical and nursing staff with few missed doses (Figure 3).15 A prospective study of home administration of subcutaneous HBIg in 61 patients showed that physicians assessed compliance with injection dates as good or very good in 91.8 per cent, with none rated as poor.16 Hepatitis B surface antibody levels were above the threshold of 100 IU/L in all patients at the final visit, with mean levels of 248 and 255 IU/L at the first and final visits. In the TWINS 1 study, quality of life assessment using the validated ITaLi-Q tool demonstrated no major differences between intramuscular and intravenous administration of HBIg in liver transplant patients, with intramuscular injection scoring better for flexibility and negative feelings but worse for side effects.16 The TWINS 2 study is now underway, using ITaLi-Q and SF-36 to evaluate quality of life in patients switching from intramuscular to subcutaneous injection over a 6-month period. Interim analysis of outcomes for 78 of the 130 participants shows statistically significant improvements in several domains, and in overall physical and mental component scores, after switching to subcutaneous administration.

Our clinical experience supports what published research has shown. Patients quickly become proficient at self-administering subcutaneous injections – many are already familiar with the technique because they use subcutaneous heparin or insulin. This means that most can learn the task over a two-week period and are able to be independent within two months.

Subcutaneous injection at home is suitable for any patient but may be particularly useful for individuals at greater risk of low adherence. One exception would be the patient who, from the outset, has stated they don’t want to use this technique – this situation might arise in the case of a  long-term patient who, after many years of regularly attending hospital for their infusion, has grown accustomed to this level of care and is reluctant to change.

In summary, the availability of subcutaneous injection of HBIg increases our treatment options. Compared with infusions and intramuscular injection, it requires fewer resources. It is an easy and user-friendly technique and we have found that it is associated with good rates of adherence and improved measures of quality of life.

References

  1. Chen J, Yi L, Jia JD, Ma H, You H. Hepatitis B immunoglobulins and/or lamivudine for preventing Hepatitis B recurrence after liver transplantation: a systematic review. J Gastroenterol Hepatol 2010;25:872-9.
  2. Cholongitas E, Goulis J, Akriviadis E et al. Hepatitis B immunoglobulin and/or nucleos(t)ide analogues for prophylaxis against Hepatitis B virus recurrence after liver transplantation: a systematic review. Liver Transpl 2011;17:1176-90.
  3. Singham J, Greanya ED, Lau K et al. Efficacy of maintenance subcutaneous Hepatitis B immune globulin (HBIG) post-transplant for prophylaxis against Hepatitis B recurrence. Ann Hepatol 2010;9:166-71.
  4. Yahyazadeh A, Beckebaum S, Cicinnati V et al. Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study. Transpl Int 2011;24:441-50.
  5. Di Costanzo GG, Lanza AG, Picciotto FP et al. Safety and efficacy of subcutaneous Hepatitis B immunoglobulin after liver transplantation: an open single-arm prospective study. Am J Transplant 2013;13:348-52.
  6. Committee for Medicinal Products for Human Use. www.ema.europa.eu docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003325.pdf (Accessed 20th February 2015).
  7. Lauchart W, Müller R, Pichlmayr R. Long-term immunoprophylaxis of Hepatitis B virus reinfection in recipients of human liver allografts. Transplant Pro 1987;19:4051-3.
  8. 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.
  9. De Simone P, Carrai P, 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 (Suppl 10):431 (Abstract 912).
  10. Germani G, Lazzaro S, Gnoato F et al. Nonadherent behaviors after solid organ transplantation. Transplant Proc 2011;43:318-23.
  11. Burra P, Germani G, Gnoato F et al. Adherence in liver transplant recipients. Liver Transpl 2011;17:760-70.
  12. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296-310.
  13. 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.
  14. Dharancy S, Giral M, Tetaz R et al. Adherence with immunosuppressive treatment after transplantation: results from the French trial PREDICT. Clin Transplant 2012;26:E293-9.
  15. Yahyazadeh A, Beckebaum S, Cicinnati V et al. Efficacy and safety of subcutaneous human HBV-immunoglobulin (Zutectra) in liver transplantation: an open, prospective, single-arm phase III study. Transpl Int 2011;24:441-50.
  16. Klein CG, Cicinnati V, Schmidt H et al. Compliance and tolerability of subcutaneous Hepatitis B immunoglobulin self-administration in liver transplant patients: a prospective, observational, multicenter study. Ann Transplant 2013;18:677-84.
  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.