Cumulative inhibitor incidence in previously untreated patients with severe hemophilia A treated with plasma-derived versus recombinant factor VIII concentrates: A critical systematic review
Introduction
The introduction of coagulation factor replacement therapy over the past half century has greatly contributed to the improvement of the care of people with hemophilia A. Following the epidemics from blood-borne viral transmission in the late 1970s and early 1980s, caused by clotting factor concentrates manufactured using non-virally inactivated pooled plasma, the need for safer hemophilia treatments became crucial to the hemophilia community. The introduction of virus-inactivated plasma-derived coagulation factors first and of recombinant products then has revolutionized the care of people with hemophilia [1], [2]. Indeed, these therapeutic weapons have improved the quality of life of hemophilia patients and their families and have permitted regular infusion of factor concentrate replacement therapy to prevent bleeding and resultant joint damage (i.e. primary prophylaxis), home treatment and ultimately a near normal lifestyle and life-expectancy [3], [4].
Thus, in the era of widespread diffusion, at least in developed countries, of recombinant products and of prophylaxis to prevent arthropathy, the most serious and challenging complication of replacement therapy has become the development of inhibitors against FVIII. Inhibitory alloantibodies developed in approximately 20–30% of patients with severe hemophilia A and render the FVIII replacement treatment ineffective, precluding the affected hemophiliacs a safe and effective standard of care and predisposing them to an unacceptably high risk of morbidity and mortality [5].
The research in this area has been mainly directed toward the identification of possible risk factors contributing to inhibitor development and previously untreated patients (PUPs) have been considered the ideal population for understanding the etiology of this phenomenon [6]. These studies have revealed the importance of both genetic and environmental factors in the development of inhibitors [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]. The role of FVIII replacement therapy (i.e., plasma-derived versus recombinant products) in the likelihood of developing inhibitors has been particularly carefully explored in a number of studies during the last two decades and some investigators have postulated that plasma-derived FVIII concentrates might be associated with a lower incidence inhibitor development thanks to the protective effect of their von Willebrand factor which would mask the epitope sites of inhibitors on the FVIII molecule or would prevent FVIII endocytosis by dendritic cells [19], [20]. However, although two previous systematic reviews have found an increased risk of inhibitor development in hemophiliacs treated with recombinant versus plasma-derived FVIII concentrates [11], [21], a comparison between such trials is very difficult to perform as they differ greatly from each other in terms of design, populations of patients, inhibitor detection and assay sensitivity. In particular, there are some recent reports from external quality assurance suggesting quite large variances in inhibitor detection among laboratories testing identical material that would influence whether patients were identified as being high or low responders [22]. In addition, the scientific value of a number of the studies is questionable as they included retrospective analyses of small populations treated with different types of FVIII products.
Considering these limitations, and with the aim of reducing the most possible potential biases, we have conducted a critical systematic review of the prospective studies evaluating the incidence of replacement therapy-related inhibitors in PUPs with severe hemophilia A.
Section snippets
Search methods
A computer-assisted search of the MEDLINE, EMBASE and SCOPUS electronic databases without temporal limits was conducted using different combinations of the following keywords: “hemophilia”, “FVIII”, “factor VIII”, “RFVIII”, “recombinant factor VIII”, “PDFVIII”, “plasma-derived FVIII”, “concentrates”, “replacement therapy”, “substitutive treatment”, “alloantibodies”, “inhibitors”, “incidence”, and “prospective trials”. Reference lists of all included studies were manually searched for other
Results
Overall we identified 169 references through the electronic and hand searches. After reading the full text of the articles, we excluded 87, because they focusing on other topics (n = 73) or were reviews (n = 14) and retrieved 82 references for further assessment [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67],
Discussion
The issue concerning the impact of factor concentrate (plasma-derived FVIII versus recombinant FVIII) on inhibitor development remains one of the most controversial and challenging subjects of hemophilia management. In this context, PUPs with severe hemophilia, who have the highest risk of inhibitor development during the first 50 days of exposure, represent the ideal population for studying the impact of different FVIII products on inhibitor formation [11]. Since the late 1980s, a number of
Reviewers
Philippe De Moerloose, Professor, University Hospital of Geneva, Division of Angiology and Haemostasis, Dept of Medicine, Geneva, Switzerland.
Emmanuel J. Favaloro, Professor, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Department of Hematology, Westmead, New South Wales, Australia.
Angelika Batorova, National Hemophilia Center, University Hospital, Department of Hematology and Blood Transfusion Medicine, Antolska 11, Bratislava, Slovakia.
Conflict of interest
All authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
Massimo Franchini, MD, graduated from the University of Verona in 1991. He completed his post-graduated speciality in Hematology at the University of Verona in 1995. He was vice-director of the hemophilia center of Verona until 2008. He is currently the Director of the Immunohematology and Transfusion Center at the University Hospital of Parma.
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Identification of aggregates in therapeutic formulations of recombinant full-length factor VIII products by sedimentation velocity analytical ultracentrifugation
2018, Journal of Thrombosis and HaemostasisInhibitors in Hemophilias
2018, Hematology: Basic Principles and PracticeTo serve and protect: The modulatory role of von Willebrand factor on factor VIII immunogenicity
2017, Blood ReviewsCitation Excerpt :SIPPET is the first study suggesting a putative protective role of VWF in inhibitor formation in a randomized controlled design. Before the SIPPET study, several cohort studies investigated the effect of source of FVIII products on immunogenicity [20–25]. In their 2003 systematic review, Wight and Paisley concluded that the incidence of high-responding inhibitors is slightly lower in patients treated with rFVIII compared to pdFVIII [20].
Inhibitors in Hemophilias
2017, Hematology: Basic Principles and PracticePrevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?
2016, Thrombosis ResearchCitation Excerpt :Although many efforts were made in the last years for understanding the underlying pathogenic mechanisms and for identifying genetic and acquired risk factors for inhibitor development in hemophilia A, the knowledge is still inadequate. Although the protective role of prophylaxis is still debated, the results of the SIPPET study not only showed a predictably higher incidence of inhibitors in hemophilia A patients treated with recombinant FVIII products but also an unexpectedly enhanced incidence of alloantibodies in patients treated with plasma-derived FVIII concentrates, approximating data reported for recombinant products in recent meta-analyses [27,28]. The superiority in terms of inhibitor safety of a protocol based on plasma-derived products in all PUPs (or at least in those at higher inhibitor risk) during the first 50 exposure days has hence to be proven so far.
Massimo Franchini, MD, graduated from the University of Verona in 1991. He completed his post-graduated speciality in Hematology at the University of Verona in 1995. He was vice-director of the hemophilia center of Verona until 2008. He is currently the Director of the Immunohematology and Transfusion Center at the University Hospital of Parma.
Annarita Tagliaferri, MD, graduated form the University of Parma in 1980. He completed her post-graduated speciality in Endocrinology and Hematology at the University of Parma in 1983 and 1987, respectively. She is currently the Director of the Regional Reference Center for Inherited Bleeding Disorders of Region of Emilia-Romagna at the University-Hospital of Parma.
Mario Cruciani, MD, is an infectious diseases specialist with more than 20 years of experience in infectious diseases and clinical microbiology. At present he is Consultant in Infectious Diseases at the Center of Comunitary Medicine & HIV Outpatient Clinic in Verona. Among his research interest is meta-analysis of clinical trials and of diagnostic tests.
Carlo Mengoli, MD, is professor of Infectious diseases at the University. At present he works at the Department of Histology, Microbiology and Medical Biotechnology of the University of Padova. Current main research interest is focused in statistical evaluation of evidence in Infectious Diseases and Microbiology.