Searching for the role of primary prophylaxis in preventing inhibitor development in hemophilia A

Abstract

Approximately 30% of individuals with severe hemophilia A generate antibodies (inhibitors) against therapeutically administered factor VIII (FVIII), typically during the first 20 exposure days [1Wight J. Paisley S. The epidemiology of inhibitors in haemophilia A. A systematic review.Haemophilia. 2003; 9: 418-35Crossref PubMed Scopus (511) Google Scholar]. Inhibitor development remains the most serious complication of treatment of hemophilia, as the safe and effective standard of care, particularly prophylaxis in children, is precluded. Despite improvements in treatment of bleeding with by‐passing agents [2Mehta R. Parameswaran R. Shapiro A.D. An overview of the history, clinical practice concerns, comparative studies and strategies to optimize therapy of bypassing agents.Haemophilia. 2006; 12: 54-61Crossref PubMed Scopus (21) Google Scholar] and recent implementation of prophylactic regimens [3Carcao M. Lambert T. Prophylaxis in haemophilia with inhibitors: update from international experience.Haemophilia. 2010; 16: 16-23Crossref PubMed Scopus (31) Google Scholar], patients with inhibitors experience higher morbidity and a poorer quality of life than non‐inhibitor patients, mainly related to their orthopedic status [4Gringeri A. Mantovani L.G. Scalone L. Mannucci P.M. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group.Blood. 2003; 102: 2358-63Crossref PubMed Scopus (311) Google Scholar]. Inhibitors develop as a result of a complex process in which many genetic and environmental factors interplay [5Coppola A. Santoro C. Franchini M. Tagliaferri A. Di Minno G. Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies.Haemophilia. 2010; 16: 13-9Crossref PubMed Scopus (48) Google Scholar]. Some recent data emphasize the contribution of treatment‐related factors. In keeping with the ‘danger model’ of the immune response, the immune system is activated by alarm signals arising from the injured tissues to a greater extent than by the recognition of non‐self. Thus, the presentation of the exogenous. FVIII may be not sufficient for initiating an immune response [6Matzinger P. The danger model: a renewed sense of self.Science. 2002; 8: 76-82Google Scholar]. In the presence of danger conditions (i.e. severe bleeds, trauma or surgery with major tissue injury), the foreign protein is intensively presented in association with signals that up‐regulate the cellular T and B lymphocyte response. Conversely, regular exposure to lower doses of antigen, in the absence of danger signals, as occurs in regular prophylaxis, may induce the tolerization of the foreign protein. Consistently, recent studies [7Gouw S.C. van der Bom J.G. van den Berg H.M. Treatment‐related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study.Blood. 2007; 109: 4648-54Crossref PubMed Scopus (418) Google Scholar, 8Gouw S.C. van den Berg H.M. le Cessie S. van der Bom J.G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.J Thromb Haemost. 2007; 5: 1383-90Crossref PubMed Scopus (129) Google Scholar, 9Maclean P.S. Richards M. Williams M. Collins P. Liesner R. Keeling D.M. Yee T. Will A.M. Young D. Chalmers E.A. Paediatric Working Party of the UKHCDOTreatment related factors and inhibitor development in children with severe haemophilia A.Haemophilia. 2011; 17: 282-7Crossref PubMed Scopus (56) Google Scholar] have reported an increased inhibitor risk for patients receiving initial intensive treatments (surgery or severe bleeds requiring high‐dose and/or prolonged treatment). In parallel, after some indirect data or non‐controlled studies [10Yee T.T. Beeton K. Griffioen A. Harrington C. Miners A. Lee C.A. Brown S.A. Experience of prophylaxis treatment in children with severe haemophilia.Haemophilia. 2002; 8: 76-82Crossref PubMed Scopus (64) Google Scholar, 11Knobe K.E. Sjörin E. Tengborn L.I. Petrini P. Ljung R.C. Inhibitors in the Swedish population with severe haemophilia A and B: a 20‐year survey.Acta Paediatr. 2002; 91: 910-4Crossref PubMed Google Scholar, 12Morado M. Villar A. Jiménez Yuste V. Quintana M. Hernandez Navarro F. Prophylactic treatment effects on inhibitor risk: experience in one centre.Haemophilia. 2005; 11: 79-83Crossref PubMed Scopus (70) Google Scholar], a protective effect of prophylaxis against the development of inhibitors was shown at multivariate analysis in a case‐control Italian study [13Santagostino E. Mancuso M.E. Rocino A. Mancuso G. Mazzucconi M.G. Tagliaferri A. Messina M. Mannucci P.M. Environmental risk factors for inhibitor development in children with haemophilia A: a case‐control study.Br J Haematol. 2005; 130: 422-7Crossref PubMed Scopus (179) Google Scholar], showing a 70% reduction of inhibitor risk in children starting prophylaxis at a median age of 35 months, compared with children receiving on‐demand treatment. Similar findings came from the large multinational CANAL (Concerted Action on Neutralizing Antibodies in severe haemophiLia A) study, in which early regular prophylaxis (introduced at a median age of 20 months) was an independent predictor associated with a 60% reduction of risk of inhibitor development [7Gouw S.C. van der Bom J.G. van den Berg H.M. Treatment‐related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study.Blood. 2007; 109: 4648-54Crossref PubMed Scopus (418) Google Scholar]. Starting from this pathophysiological and clinical background, Kurnik et al. [14Kurnik K. Bidlingmaier C. Engl W. Chehadeh H. Reipert B. Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development.Haemophilia. 2010; 16: 256-62Crossref PubMed Scopus (151) Google Scholar] implemented a new prophylaxis regimen started very early (over the first 50 exposure days, when the risk of implemented inhibitor is the highest), specifically designed to induce tolerance to the administered FVIII by avoiding immunological danger signals. Interestingly, only one of 14 patients receiving such a new regimen developed inhibitors compared with 14 of 30 children retrospectively analyzed who were treated with standard prophylaxis, resulting in a > 90% reduction of risk. With the aim of further addressing the potential role of prophylaxis in inhibitor development in hemophilia patients, we have performed a systematic review of all the published experiences. A computer‐assisted search of the MEDLINE and SCOPUS electronic databases without time limits was conducted using different combinations of the following keywords: ‘hemophilia’, ‘prophylaxis’, ‘primary prophylaxis’, ‘inhibitor’, ‘alloantibody’. In addition, the reference lists of all included studies were manually searched for other potentially eligible studies. Overall, 272 studies were initially retrieved and 221 were excluded as they focused on other topics or because they were review articles. Thus, 51 potentially relevant clinical reports were identified and examined in detail. Of them, 24 were further excluded because the relevant data were unavailable or because analyzed patients were included in other published studies or because the study design did not permit a pooled analysis of the data. Finally, 27 studies with usable information (15 prospective, 11 retrospective and one retrospective/prospective), published between 1996 and 2011, were included in this systematic review [8Gouw S.C. van den Berg H.M. le Cessie S. van der Bom J.G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.J Thromb Haemost. 2007; 5: 1383-90Crossref PubMed Scopus (129) Google Scholar, 10Yee T.T. Beeton K. Griffioen A. Harrington C. Miners A. Lee C.A. Brown S.A. Experience of prophylaxis treatment in children with severe haemophilia.Haemophilia. 2002; 8: 76-82Crossref PubMed Scopus (64) Google Scholar, 12Morado M. Villar A. Jiménez Yuste V. Quintana M. Hernandez Navarro F. Prophylactic treatment effects on inhibitor risk: experience in one centre.Haemophilia. 2005; 11: 79-83Crossref PubMed Scopus (70) Google Scholar, 14Kurnik K. Bidlingmaier C. Engl W. Chehadeh H. Reipert B. Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development.Haemophilia. 2010; 16: 256-62Crossref PubMed Scopus (151) Google Scholar, 15Klukowska A. Komrska V. Jansen M. Laguna P. Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on‐demand treatment and surgical procedures, with Octanate: interim report from an ongoing prospective clinical study.Haemophilia. 2011; 17: 399-406Crossref PubMed Scopus (22) Google Scholar, 16Strauss T. Lubetsky A. Ravid B. Bashari D. Luboshitz J. Lalezari S. Misgav M. Martinowitz U. Kenet G. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study.Haemophilia. 2011; 17: 625-9Crossref PubMed Scopus (26) Google Scholar, 17Shirahata A. Fukutake K. Higasa S. Mimaya J. Oka T. Shima M. Takamatsu J. Taki M. Taneichi M. Yoshioka A. Study Group on Factors involved in formation of inhibitors to factor VIII and IX preparationsAn analysis of factors affecting the incidence of inhibitor formation in patients with congenital haemophilia in Japan.Haemophilia. 2011; 17: 771-6PubMed Google Scholar, 18Celkan T. Ozdemir N. Reduced early prophylaxis of children with haemophilia in a developing country, Turkey.Haemophilia. 2011; 17: e840-1PubMed Google Scholar, 19Liesner R. Khair K. Hann I.M. The impact of prophylactic treatment on children with severe haemophilia.Br J Haematol. 1996; 92: 973-8Crossref PubMed Scopus (167) Google Scholar, 20Panicker J. Warrier I. Thomas R. Lusher J.M. The overall effectiveness of prophylaxis in severe haemophilia.Haemophilia. 2003; 9: 272-8Crossref PubMed Scopus (82) Google Scholar, 21Tarantino M.D. Collins P.W. Hay C.R. Shapiro A.D. Gruppo R.A. Berntorp E. Bray G.L. Tonetta S.A. Schroth P.C. Retzios A.D. Rogy S.S. Sensel M.G. Ewenstein B.M. RAHF‐PFM Clinical Study GroupClinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin‐free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A.Haemophilia. 2004; 10: 428-37Crossref PubMed Scopus (137) Google Scholar, 22Smith M.P. Giangrande P. Pollman H. Littlewood R. Kollmer C. Feingold J. The ReFacto St. Louis Study GroupA postmarketing surveillance study of the safety and efficacy of ReFacto (St Louis‐derived active substance) in patients with haemophilia A.Haemophilia. 2005; 11: 444-51Crossref PubMed Scopus (30) Google Scholar, 23Kempton C.L. Soucie J.M. Abshire T.C. Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates.J Thromb Haemost. 2006; 4: 2576-81Crossref PubMed Scopus (55) Google Scholar, 24Feldman B.M. Pai M. Rivard G.E. Israels S. Poon M.C. Demers C. Robinson S. Luke K.H. Wu J.K. Gill K. Lillicrap D. Babyn P. McLimont M. Blanchette V.S. Association of Hemophilia Clinic Directors of Canada Prophylaxis Study GroupTailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian hemophilia primary prophylaxis study.J Thromb Haemost. 2006; 4: 1228-36Crossref PubMed Scopus (205) Google Scholar, 25Singleton E. Smith J. Kavanagh M. Nolan B. White B. Low risk of inhibitor formation in haemophilia patients after a change in treatment from Chinese hamster ovary cell‐produced to baby hamster kidney cell‐produced recombinant factor VIII.Thromb Haemost. 2007; 98: 1188-92Crossref PubMed Scopus (20) Google Scholar, 26Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. DiMichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1471) Google Scholar, 27Blanchette V.S. Shapiro A.D. Liesner R.J. Hernandez Navarro F. Warrier I. Schroth P.C. Spotts G. Ewenstein B.M. for the rAHF‐PFM Clinical Study GroupPlasma and albumin‐free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.J Thromb Haemost. 2008; 6: 1319-26Crossref PubMed Scopus (139) Google Scholar, 28den Uijl I. Mauser‐Bunschoten E.P. Roosendaal G. Schutgens R. Fischer K. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment.Haemophilia. 2009; 15: 1215-8Crossref PubMed Scopus (15) Google Scholar, 29Petrini P. Rylander C. Clinical safety surveillance study of the safety and efficacy of long‐term home treatment with ReFacto utilizing a computer‐aided diary: a Nordic multicentre study.Haemophilia. 2009; 15: 175-83Crossref PubMed Scopus (9) Google Scholar, 30Young J.H. Liu H.C. Hsueh E.J. Huang M.L. Peng C.T. Chen R.L. Maas‐Enriquez M. Achilles K. Efficacy and safety evaluation of sucrose‐formulated recombinant factor VIII for Taiwanese patients with haemophilia A.Haemophilia. 2009; 15: 968-70Crossref PubMed Scopus (12) Google Scholar, 31Recht M. Nemes L. Matysiak M. Manco‐Johnson M. Lusher J. Smith M. Mannucci P. Hay C. Abshire T. O’Brien A. Hayward B. Udata C. Roth D.A. Arkin S. Clinical evaluation of moroctocog alfa (AF‐CC), a new generation of B‐domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full‐length recombinant factor VIII.Haemophilia. 2009; 15: 869-80Crossref PubMed Scopus (79) Google Scholar, 32Collins P. Faradji A. Morfini M. Enriquez M.M. Schwartz L. Efficacy and safety of secondary prophylactic vs. on‐demand sucrose‐formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13‐month crossover study.J Thromb Haemost. 2010; 8: 83-9Crossref PubMed Scopus (120) Google Scholar, 33Oldenburg J. Goudemand J. Valentino L. Richards M. Luu H. Kriukov A. Gajek H. Spotts G. Ewenstein B. Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method] demonstrates efficacy, safety and low‐risk for immunogenicity in routine clinical practice.Haemophilia. 2010; 16: 866-77Crossref PubMed Scopus (36) Google Scholar, 34Bacon C.L. Singleton E. Brady B. White B. Nolan B. Gilmore R.M. Ryan C. Keohane C. Vince Jenkins P. O’Donnell J.S. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin‐free recombinant factor VIII product (ADVATE).Haemophilia. 2011; 17: 407-11Crossref PubMed Scopus (28) Google Scholar, 35Dmoszynska A. Kuliczkowski K. Hellmann A. Trelinski J. Kloczko J. Baglin T. Hay C. O’Shaughnessy D. Zawilska K. Makris M. Shaikh‐Zaidi R. Gascoigne E. Dash C. Clinical assessment of Optivate, a high‐purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A.Haemophilia. 2011; 17: 456-62Crossref PubMed Scopus (12) Google Scholar, 36Gringeri A. Lundin B. von Mackensen S. Mantovani L. Mannucci P.M. ESPRIT Study GroupA randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).J Thromb Haemost. 2011; 9: 700-10Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar, 37Matysiak M. Bobrowska H. Balwierz W. Chybicka A. Kowalczyk J.R. Shaikh‐Zaidi R. Gillanders K. Dash C.H. Clinical experience with Optivate, high‐purity factor VIII (FVIII) product with von Willebrand factor (VWF) in young children with haemophilia A.Haemophilia. 2011; 17: 737-42PubMed Google Scholar], as reported in Table 1. Statistical analysis was performed using the chi‐square test. A P value < 0.05 was considered statistically significant.Table 1Characteristics and results of studies included in the systematic reviewAuthor, year [Ref] Study designSevere hemophilia FVIII:CFVIII ProductPatientsInhibitorsTotal NOn demand n (%)ProphylaxisTotal n (%)On demandProphylaxis n (%)Regimen (IU Kg−1)Start, Age/EDTotal n (%)HR n (%)LR n (%)Trans. n (%)Total n (%)HR n (%)LR n (%)Trans. n (%) (A) PUP/MTP StudiesMorado, 2005 [12Morado M. Villar A. Jiménez Yuste V. Quintana M. Hernandez Navarro F. Prophylactic treatment effects on inhibitor risk: experience in one centre.Haemophilia. 2005; 11: 79-83Crossref PubMed Scopus (70) Google Scholar] RetrNot reported10 PDFVIII, 38 RFVIII 2 both5019/50(38.0)31/50 (62.0)Not reportedMean 34 months (1 month–8 years)15/50 (30.0)15/19 (78.9)12/15 (80.0)3/15 (20.0)NI0/31–––Gouw, 2007 [8Gouw S.C. van den Berg H.M. le Cessie S. van der Bom J.G. Treatment characteristics and the risk of inhibitor development: a multicenter cohort study among previously untreated patients with severe hemophilia A.J Thromb Haemost. 2007; 5: 1383-90Crossref PubMed Scopus (129) Google Scholar] Pros*< 2RFVIII (Kogenate, Kogenate FS, Recombinate, ReFacto)236169/236 (71.6)67/236 (28.4)At least once weekly within 50 EDMedian 21 month/22 ED67/236 (28.4)63/169 (37.3)40/169 (23.7)23/169 (13.6)NI4/67 (6.0)4/67 (6.0)0/67NIKurnik, 2010 [14Kurnik K. Bidlingmaier C. Engl W. Chehadeh H. Reipert B. Auerswald G. New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development.Haemophilia. 2010; 16: 256-62Crossref PubMed Scopus (151) Google Scholar] Pros< 111 PDFVIII, 15 RFVIII260/2626/26 (100)‘early’ 25 once i.w. then 25 twice and thrice i.w. according to bleeding patternMedian 10.7 months (0.5–24.5)/1 ED1/26 (3.8)––––1/26 (3.8)0/261/26 (3.8)NIKurnik, 2010 [14] Retr14 PDFVIII, 16 RFVIII300/3030/30 (100)40–50 thrice i.w.Median 19 months (0.8–87)/30 ED14/30 (46.7)––––14/30 (46.7)8/30 (26.7)6/30 (20.0)NIKlukowska, 2011 [15Klukowska A. Komrska V. Jansen M. Laguna P. Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on‐demand treatment and surgical procedures, with Octanate: interim report from an ongoing prospective clinical study.Haemophilia. 2011; 17: 399-406Crossref PubMed Scopus (22) Google Scholar] Pros< 2PDFVIII (Octanate)3920/39 (51.3)19/39 (48.7)28.5 ± 6.5 per EDNot reported4/39 (10.3)4/20 (25.0)3/20 (15.0)0/201/20 (5.0)0/19–––Strauss, 2011 [16Strauss T. Lubetsky A. Ravid B. Bashari D. Luboshitz J. Lalezari S. Misgav M. Martinowitz U. Kenet G. Recombinant factor concentrates may increase inhibitor development: a single centre cohort study.Haemophilia. 2011; 17: 625-9Crossref PubMed Scopus (26) Google Scholar] Retr‐Pros< 161 PDFVIII, 43 RFVIII104104/104 (100)0/104Not reportedNA17/104 (16.4)17/104 (16.4)NININI––––Shirikata, 2011 [17Shirahata A. Fukutake K. Higasa S. Mimaya J. Oka T. Shima M. Takamatsu J. Taki M. Taneichi M. Yoshioka A. Study Group on Factors involved in formation of inhibitors to factor VIII and IX preparationsAn analysis of factors affecting the incidence of inhibitor formation in patients with congenital haemophilia in Japan.Haemophilia. 2011; 17: 771-6PubMed Google Scholar] RetrNot reportedPD FVIII, RFVIII119†76/119 (68.4)43/119 (36.1)Not reportedNot reported37/119 (31.1)27/76 (35.5)NININI10/43 (23.3)NININICelkan and Özdemir 2011 [18Celkan T. Ozdemir N. Reduced early prophylaxis of children with haemophilia in a developing country, Turkey.Haemophilia. 2011; 17: e840-1PubMed Google Scholar] RetrNot reported9 RFVIII, 1 PDFVIII100/1010/10 (100)25–30 once or twice i. w.4.45–48 months (> 12 months only in 1 patient)3/10 (30.0)––––3/10 (30.0)2/10 (20.0)1/10 (10)0/10 (B) PTP StudiesLiesner, 1996 [19Liesner R. Khair K. Hann I.M. The impact of prophylactic treatment on children with severe haemophilia.Br J Haematol. 1996; 92: 973-8Crossref PubMed Scopus (167) Google Scholar] Retr< 1PDFVIII260/2626/2615–25 thrice i.w.Median 6.2 years (1.3–15.9)0/26––––0/26–––Yee, 2002 [11Knobe K.E. Sjörin E. Tengborn L.I. Petrini P. Ljung R.C. Inhibitors in the Swedish population with severe haemophilia A and B: a 20‐year survey.Acta Paediatr. 2002; 91: 910-4Crossref PubMed Google Scholar] Retr< 1PDFVIII, RFVIII320/3232/32 (100)25–40 thrice i.w.0.4–12.7 years1/32 (3.1)––––1/32 (3.1)0/321/32 (3.1)1/32 (3.1)Panicker 2003 [20Panicker J. Warrier I. Thomas R. Lusher J.M. The overall effectiveness of prophylaxis in severe haemophilia.Haemophilia. 2003; 9: 272-8Crossref PubMed Scopus (82) Google Scholar] Retr< 1RFVIII220/2222/22 (100)20–30 thrice i.w.Median 4.5 years (0.3–16)0/22––––0/22–––Tarantino 2004 [21Tarantino M.D. Collins P.W. Hay C.R. Shapiro A.D. Gruppo R.A. Berntorp E. Bray G.L. Tonetta S.A. Schroth P.C. Retzios A.D. Rogy S.S. Sensel M.G. Ewenstein B.M. RAHF‐PFM Clinical Study GroupClinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin‐free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A.Haemophilia. 2004; 10: 428-37Crossref PubMed Scopus (137) Google Scholar] Retr< 2RFVIII (Advate)1070/107107/107 (100)25–40 IU Kg−1 thrice i.w. or e.o.d.Not reported1/107 (0.9)––––1/107 (0.9)0/1071/107 (0.9)0/107Smith, 2005 [22Smith M.P. Giangrande P. Pollman H. Littlewood R. Kollmer C. Feingold J. The ReFacto St. Louis Study GroupA postmarketing surveillance study of the safety and efficacy of ReFacto (St Louis‐derived active substance) in patients with haemophilia A.Haemophilia. 2005; 11: 444-51Crossref PubMed Scopus (30) Google Scholar] Retr< 2RFVIII (ReFacto StLouis)47‡22/47 (46.8)25/47 (53.2)Not reported. Mean dose 29.3 ± 8.1Not reported1/47 (2.1)1/22 (4.5)1/22 (4.5)0/220/220/25–––Kempton, 2006 [23Kempton C.L. Soucie J.M. Abshire T.C. Incidence of inhibitors in a cohort of 838 males with hemophilia A previously treated with factor VIII concentrates.J Thromb Haemost. 2006; 4: 2576-81Crossref PubMed Scopus (55) Google Scholar] Retr< 1203 PDFVIII, 554 RFVIII 81 both565†369/565 (65.3)196/565 (34.7)Not reportedNot reported5/565 (0.9)4/369 (1.1)NININI1/196 (0.5)NININIFeldman, 2006 [24Feldman B.M. Pai M. Rivard G.E. Israels S. Poon M.C. Demers C. Robinson S. Luke K.H. Wu J.K. Gill K. Lillicrap D. Babyn P. McLimont M. Blanchette V.S. Association of Hemophilia Clinic Directors of Canada Prophylaxis Study GroupTailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian hemophilia primary prophylaxis study.J Thromb Haemost. 2006; 4: 1228-36Crossref PubMed Scopus (205) Google Scholar] Pros< 2RFVIII250/2525/25 (100)Canadian escalating dose regimen§Mean age at study entry 1.6 ± 0.5 years1/25 (4.0)––––1/25 (4.0)0/251/25 (4.0)0/25Singleton, 2007 [25Singleton E. Smith J. Kavanagh M. Nolan B. White B. Low risk of inhibitor formation in haemophilia patients after a change in treatment from Chinese hamster ovary cell‐produced to baby hamster kidney cell‐produced recombinant factor VIII.Thromb Haemost. 2007; 98: 1188-92Crossref PubMed Scopus (20) Google Scholar] Retr< 1RFVIII (Kogenate FS)84†36/84 (42.9)48/84 (57.1)Not reportedNot reported. 37% pts < 12 years2/84 (2.4)2/36 (5.6)0/362/36 (5.6)0/360/48–––Manco‐Johnson, 2007 [26Manco‐Johnson M.J. Abshire T.C. Shapiro A.D. Riske B. Hacker M.R. Kilcoyne R. Ingram J.D. Manco‐Johnson M.L. Funk S. Jacobson L. Valentino L.A. Hoots W.K. Buchanan G.R. DiMichele D. Recht M. Brown D. Leissinger C. Bleak S. Cohen A. Mathew P. et al.Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia.N Engl J Med. 2007; 357: 535-44Crossref PubMed Scopus (1471) Google Scholar] Pros< 2RFVIII (Kogenate, Kogenate FS)6533/65 (50.8)32/65 (49.2)25 e.o.d. vs. episodic treatment¶Mean age at study entry 1.6 years2/65 (3.1)0/33–––2/32 (6.2)2/32 (6.2)0/320/32Blanchette, 2008 [27Blanchette V.S. Shapiro A.D. Liesner R.J. Hernandez Navarro F. Warrier I. Schroth P.C. Spotts G. Ewenstein B.M. for the rAHF‐PFM Clinical Study GroupPlasma and albumin‐free recombinant factor VIII: pharmacokinetics, efficacy and safety in previously treated pediatric patients.J Thromb Haemost. 2008; 6: 1319-26Crossref PubMed Scopus (139) Google Scholar] Pros< 2RFVIII (Advate)50**2/50 (4.0)48/50 (960)Standard (median 34) x 3 or 4 or modified (46) 1 or 2 i.w.Mean 3.1 ± 0.5 years0/500/2–––0/48–––Den Uijl, 2009 [28den Uijl I. Mauser‐Bunschoten E.P. Roosendaal G. Schutgens R. Fischer K. Efficacy assessment of a new clotting factor concentrate in haemophilia A patients, including prophylactic treatment.Haemophilia. 2009; 15: 1215-8Crossref PubMed Scopus (15) Google Scholar] RetrNot reportedRFVIII (Advate)71††18/71 (25.4)53/71 (74.6)Median 41 i.w., 3 (1–7) infusionsNot reported. Median patient age on proph. 21 years0/710/18–––0/53–––Petrini & Rylander 2009 [29Petrini P. Rylander C. Clinical safety surveillance study of the safety and efficacy of long‐term home treatment with ReFacto utilizing a computer‐aided diary: a Nordic multicentre study.Haemophilia. 2009; 15: 175-83Crossref PubMed Scopus (9) Google Scholar] Retr< 1RFVIII (ReFacto)54††9a/54 (16.7)45/54 (83.3)Swedish regimen‡‡Not reported. Median patient age 17.5 months (0.4–57)3/54 (5.6)0/9–––3/45§§ (6.7)1/45 (2.2)2/45 (4.4)NIYoung 2009 [30Young J.H. Liu H.C. Hsueh E.J. Huang M.L. Peng C.T. Chen R.L. Maas‐Enriquez M. Achilles K. Efficacy and safety evaluation of sucrose‐formulated recombinant factor VIII for Taiwanese patients with haemophilia A.Haemophilia. 2009; 15: 968-70Crossref PubMed Scopus (12) Google Scholar] Pros< 1RFVIII (Kogenate FS)38††29/389/38≥ 2 infusion per week (mean 24 ± 8)Not reported. 6% of pts < 2 years, 50% 2–18 years0/380/29–––0/9–––Recht 2009 [31Recht M. Nemes L. Matysiak M. Manco‐Johnson M. Lusher J. Smith M. Mannucci P. Hay C. Abshire T. O’Brien A. Hayward B. Udata C. Roth D.A. Arkin S. Clinical evaluation of moroctocog alfa (AF‐CC), a new generation of B‐domain deleted recombinant factor VIII (BDDrFVIII) for treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic equivalence to full‐length recombinant factor VIII.Haemophilia. 2009; 15: 869-80Crossref PubMed Scopus (79) Google Scholar] Pros< 2RFVIII (Xyntha)2040/204 (0)204/20430 twice or thrice i.w.Not reported. patient age 7–70 years5/204¶¶ (2.45)–––5/204 (2.45)0/2045/204 (2.45)0/204Collins, 2010 [32Collins P. Faradji A. Morfini M. Enriquez M.M. Schwartz L. Efficacy and safety of secondary prophylactic vs. on‐demand sucrose‐formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13‐month crossover study.J Thromb Haemost. 2010; 8: 83-9Crossref PubMed Scopus (120) Google Scholar] Pros< 1RFVIII (Kogenate FS)1919/19 (100)19/19 (100)20–40 thrice i.w.Adults0/190/19–––0/19–––Oldenburg, 2010 [33Oldenburg J. Goudemand J. Valentino L. Richards M. Luu H. Kriukov A. Gajek H. Spotts G. Ewenstein B. Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method] demonstrates efficacy, safety and low‐risk for immunogenicity in routine clinical practice.Haemophilia. 2010; 16: 866-77Crossref PubMed Scopus (36) Google Scholar] Pros< 2RFVIII (Advate)402***167/402 (41.5)235/402 (58.5)Not reportedNot reported. 30% pts < 12 years3/402††† (0.7)2/167 (1.2)0/1671/167 (0.6)1/167 (0.6)1/235 (0.4)0/2351/235 (0.4)0/235Bacon, 2011 [34Bacon C.L. Singleton E. Brady B. White B. Nolan B. Gilmore R.M. Ryan C. Keohane C. Vince Jenkins P. O’Donnell J.S. Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin‐free recombinant factor VIII product (ADVATE).Haemophilia. 2011; 17: 407-11Crossref PubMed Scopus (28) Google Scholar] RetrNot reportedRFVIII (Advate)101†30/101 (29.7)71/101 (70.3)Not reportedNot reported. 33% pts < 18 years1/101‡‡‡ (1.0)1/30 (3.3)0/301/30 (3.3)0/300/71–––Dmoszynska, 2011 [35Dmoszynska A. Kuliczkowski K. Hellmann A. Trelinski J. Kloczko J. Baglin T. Hay C. O’Shaughnessy D. Zawilska K. Makris M. Shaikh‐Zaidi R. Gascoigne E. Dash C. Clinical assessment of Optivate, a high‐purity concentrate of factor VIII with von Willebrand factor, in the management of patients with haemophilia A.Haemophilia. 2011; 17: 456-62Crossref PubMed Scopus (12) Google Scholar] Pros< 2PDFVIII (Optivate)7059/70 (84.3)11/70 (15.7)Mean 17.6 twice or thrice i.w.Not reported. Mean patient age 33.5 years0/700/59–––0/11–––Gringeri, 2011 [36Gringeri A. Lundin B. von Mackensen S. Mantovani L. Mannucci P.M. ESPRIT Study GroupA randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study).J Thromb Haemost. 2011; 9: 700-10Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar] Pros< 1RFVIII (Recombinate, then Advate)40§§§19/40(47.5)21/40 (52.5)∼25 per Kg thrice i.w. (target trough FVIII level > 1%)¶¶¶Not reported. Median age at study entry 50 months (10–84)5/40 (12.5)2/19 (10.5)NININI3/21 (14.3)NININIMatysiak, 2011 [37Matysiak M. Bobrowska H. Balwierz W. Chybicka A. Kowalczyk J.R. Shaikh‐Zaidi R. Gillanders K. Dash C.H. Clinical experience with Optivate, high‐purity factor VIII (FVIII) product with von Willebrand factor (VWF) in young children with haemophilia A.Haemophilia. 2011; 17: 737-42PubMed Google Scholar] Pros< 1PDFVIII (Optivate)25****20/25 (80.0)5/25 (20.0)At least 1.5 regular doses per week (mean 30.5 IU Kg−1)Not reported. Mean patient age 4.67 ± 0.970/250/20–––0/5–––PUP, previously untreated patients; MTP, minimally treated patients; PTP, previously treated patients; Retr, retrospective; Pros, prospective; BDD, B‐domain deleted; PDFVIII, plasma‐derived factor VIII concentrate; RFVIII, recombinant factor VIII concentrate; ED, exposure days; NI, not indicated; HR, high responders; LR, low responders; Trans, transient. *Combination of four RFVIII registration prospective studies. †Only se