title: Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.
abstract: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival.
  
  
  
  To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation.
  
  
  
  Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost).
  
  
  
  Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.
  
  
  
  Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC.
  
  
  
  The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence.
  
  
  
  TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study.
  
  
  
  This study is registered as PROSPERO CRD42014013544.
  
  
  
  The National Institute for Health Research HTA programme.
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Marcela
authors.initials: M
authors.lastname: Haasova
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Tristan
authors.initials: T
authors.lastname: Snowsill
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Tracey
authors.initials: T
authors.lastname: Jones-Hughes
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Crathorne
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Cooper
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Varley-Campbell
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Ruben
authors.initials: R
authors.lastname: Mujica-Mota
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Coelho
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Huxley
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lowe
authors.affiliation: Department of Paediatric Nephrology, Bristol Royal Hospital for Children (University Hospitals Bristol NHS Foundation Trust), Bristol, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Dudley
authors.affiliation: Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Marks
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Hyde
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Bond
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK.
authors.forename: Rob
authors.initials: R
authors.lastname: Anderson
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000191:economics / Q000627:therapeutic use; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D001379:Azathioprine / Q000191:economics / Q000627:therapeutic use; D000077552:Basiliximab; D002648:Child; D002986:Clinical Trials as Topic; D003362:Cost-Benefit Analysis; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000191:economics* / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D016030:Kidney Transplantation / Q000379:methods*; D018803:Models, Economic; D009173:Mycophenolic Acid / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000191:economics / Q000627:therapeutic use; D020123:Sirolimus / Q000627:therapeutic use; D016559:Tacrolimus / Q000191:economics / Q000627:therapeutic use; D013673:Technology Assessment, Biomedical
chemical_list: D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069594:Abatacept; D000077552:Basiliximab; D000068338:Everolimus; C512542:thymoglobulin; D009173:Mycophenolic Acid; D001379:Azathioprine; D020123:Sirolimus; D016559:Tacrolimus