Efficacy and Safety of Recombinant Factor VIII in Previously Untreated and Previously Treated Children with Hemophilia A: A Systematic Review

Abstract

Introduction

Inhibitor development is a primary concern for pediatric patients with hemophilia A (HA) undergoing recombinant factor VIII (rFVIII) therapy, yet relevant research is lacking. We aimed to compare the efficacy and safety of standard (SHL) and extended half-life (EHL) rFVIII products in previously treated (PTPs) and untreated (PUPs) pediatric patients with HA.

Methods

Following PRISMA guidelines, we searched clinical studies from PubMed, Embase, and Cochrane Library. Data were extracted and a single-arm meta-analysis was performed.

Results

This systematic review included 16 studies involving 1145 patients. Three studies reported changes in annual bleeding rate (ABR); their results displayed no statistically significant difference in ABR changes in pediatric patients with HA after rFVIII treatment. Ten studies reported inhibitor development, nine focused on PUPs. Here, EHL rFVIII showed a proportion of inhibitors at 27.5% (95% confidence interval [CI] 22.6%; 32.6%), and third-generation SHL rFVIII showed a proportion of inhibitors at 36.4% (27.2%; 46.2%), with a high-titer proportion of 20.9% (12.9%; 30.3%) for the latter. Both SHL rFVIII (octocog alfa) and EHL rFVIII (rurioctocog alfa pegol) presented low proportions of inhibitor development. Octocog alfa exhibited the lowest high-titer inhibitor incidence, marked at 12.7% (5.3%; 24.5%). Eleven studies addressed adverse events (AEs), with octocog alfa showing low reported treatment-related AEs at a proportion of 14.5% (6.5%; 26.7%).

Conclusion

Our analysis revealed that both octocog alfa and rurioctocog alfa pegol showed low inhibitor development, with octocog alfa having few treatment-related AEs. Regular monitoring for inhibitors during rFVIII therapy is important.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12325-025-03110-0.

Key Summary Points

Hemophilia A (HA) in pediatrics poses significant challenges, particularly inhibitor development during recombinant factor VIII (rFVIII) therapy, highlighting an unmet research need.

This systematic review compared the efficacy and safety of standard half-life (SHL) and extended half-life (EHL) rFVIII products in previously treated and untreated patients with HA.

The results of this systematic review showed that both SHL rFVIII product octocog alfa and EHL rFVIII product rurioctocog alfa pegol had low inhibitor development.

These findings emphasize the importance of regular inhibitor monitoring and suggest octocog alfa may have low treatment-related adverse events.

Introduction

Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by genetic mutations in the factor VIII (FVIII) gene [1]. The latest global report from the World Federation of Hemophilia showed that the current prevalence of HA per 100,000 live male births is 23.2 [2]. HA is categorized according to the degree of FVIII deficiency, including severe (FVIII activity < 1%), moderate (FVIII activity of 1–5%), or mild (FVIII activity of 6–30%). Patients with severe HA commonly experience internal bleeding, primarily affecting their joints and soft tissues. These episodes of joint and soft tissue bleeding, characterized by accompanying pain, could impose substantial limitations on these patients’ daily activities by reducing their mobility [3]. Without prompt and effective treatment to address the bleeding, individuals with HA are at risk of developing more severe complications such as hemophilic joint disease [4]. FVIII replacement therapy has consistently been the standard of care for individuals with HA, with the treatment goal of controlling bleeding, particularly in surgical patients, and maintaining patients’ FVIII levels above the minimal threshold of 0.01 IU/mL (or 1%) [5, 6].

FVIII replacement therapy has been the primary choice for preventing and treating bleeding in patients with HA for a long time. The development of factor concentrates marked a major era in improving the outcomes of pediatric and adult patients [7]. Currently, new therapies such as emicizumab, concizumab, and emerging new extended half-life (EHL) recombinant FVIII (rFVIII) concentrates have become available. However, standard half-life (SHL) rFVIII concentrates like octocog alfa remain the cornerstone of treatment for many patients with HA, especially in regions where access to new therapies is limited by economic, regulatory, or other factors [8]. Therefore, understanding the characteristics, efficacy, and safety of these established products still holds significant clinical importance. SHL rFVIII concentrates have a relatively short drug half-life of approximately 8–12 h, often requiring frequent intravenous infusions. In pediatric and older patients with hemophilia, the burden of regular and frequent intravenous treatment may lead to poor treatment adherence [9]. This situation highlights the need for EHL rFVIII concentrates to address this issue. The covalent binding of polyethylene glycol and fusion with the fragmented crystallizable region of the immunoglobulin G1 molecule have been used to enhance the half-life of rFVIII [10]. As a result of this modification, the half-life of rFVIII is extended by approximately 1.4–1.5 times that of the original rFVIII, leading to a reduced dosing frequency and better hemostatic outcomes in patients with hemophilia [11]. To date, EHL rFVIII therapy has demonstrated a good safety profile consistent with SHL rFVIII therapy in some major trials [12, 13].

Nonetheless, rFVIII therapy still presents several limitations affecting safety and efficacy. The primary concern is the immunogenicity of rFVIII concentrates, which leads to an inhibitor formation rate of approximately 30% following treatment in previously untreated patients (PUPs) [14]. The potential association between certain rFVIII concentrates and an increased risk of inhibitor development in PUPs with severe HA remains a subject of ongoing debate and controversy [15]. Furthermore, the development of inhibitors in children could have a profound effect on their treatment and overall well-being. Currently, there is a lack of comprehensive evaluations of the efficacy and safety of rFVIII concentrate treatment in pediatric patients with HA. Therefore, with the publication of numerous clinical studies in recent years, we performed a comprehensive systematic review to assess the effectiveness and safety of rFVIII in pediatric PUPs and previously treated patients (PTPs) with HA.

Methods

Search Strategy

This systematic review is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. A computerized and systematic data searching of relevant studies was conducted in PubMed, EMBASE, and Cochrane databases from inception to 22 November 2024, with no constraints on provenance or language. Key words (MeSH in PubMed, Emtree in Embase) and free words were used to search for the following: (1) hemophilia A, factor VIII deficiency; (2) children, child, pediatrics, childhood; (3) factor VIII, coagulation factor VIII, recombinant factor VIII; and (4) randomized controlled trials, randomized, placebo, open label, clinical trial, real world research. The title words and free words among above groups were combined with “or” and the aforementioned four groups were combined with “and.” The search strategy is shown in Table S1.

Inclusion and Exclusion Criteria

Studies meeting the following criteria were included: (1) the research design of a clinical trial; (2) the study population consisted of pediatric PTPs or PUPs with HA, with or without healthy subjects as controls; (3) the treatment measure was recombinant hemophilia factor VIII, not limited to the product; and (4) the reported results were related to the treatment of hemophilia with rFVIII (annual bleeding rate [ABR], adverse events [AEs], and progression to FVIII inhibitors and/or binding antibodies).

Studies that included one of the following criteria were excluded: (1) irrelevant research content; (2) types of studies that were a review, systematic review, meta-analysis, case report, case series, conference abstract, and letter to the editor; (3) the study was not in English; (4) inability to obtain or extract available data; and (5) the patient’s age was over 12 years or the number of patients was less than 10.

Data Extraction

Data extracted from the included studies included authors, publication year, study location, type of study design, total number of patients, treatment regimen, total ABR, inhibitor development, and outcomes related to safety (number of patients with AEs, total number of AEs, AEs considered treatment-related, and serious AEs). The Risk of Bias In Non-randomized Studies-of Interventions (ROBINS-I) tool was used for quality assessment of nonrandomized controlled and nonrandomized noncontrolled clinical trials [16]. Data extraction and quality assessment were performed collaboratively by three reviewers through group discussions, and final decisions were made after their agreement.

Sensitivity Analysis

To verify the robustness of the results to methodological variations, we conducted a sensitivity analysis on the incidence of inhibitors and AEs in the included studies. In the sensitivity analysis, we restricted our primary analysis to studies with a patient population greater than 50. It is reported that prior treatment experience with rFVIII products in patients with HA may exert an influence on the incidence of inhibitors [15]. Therefore, in the sensitivity analysis (Table S2) and the pooled proportion of inhibitor incidence (Table 2), minimally treated patients (MTPs) were excluded from the population of PUPs.

Table 2.

Pooled proportion of inhibitor development by product type

Variable	N	Events/total	Pooled inhibitor development proportion (95% CI)	Between-study variance (τ2)
Overall study	10	217/762	27.8% (18.3%; 38.3%)	0.027
PTPs	1	1/69	NA	NA
PUPs	9	216/693	31.7% (26.2%; 37.5%)	0.004
Third-generation SHL	5	129/378	36.4% (27.2%; 46.2%)	0.008
rFVIII length
Full-length rFVIII	3	69/217	35.7% (19.3%; 53.9%)	0.019
B-domain deleted rFVIII	2	60/161	37.5% (29.0%; 46.4%)	0.001
EHL	4	87/315	27.5% (22.6%; 32.6%)	< 0.001

SHL standard half-life, EHL extended half-life, PUPs previously untreated patients, PTPs previously treated patients, FVIII factor VIII, rFVIII recombinant FVIII, CI confidence interval, τ² Tau² between-study heterogeneity, N number of studies included in the analysis, NA not available

Data Analysis

The current systematic review was performed by following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) recommendations [17]. The approach displayed in our systematic review was achieved using the metaprop function from the meta package in R 4.2.1 software. The proportion was used as the effect size, the arcsine square root transformation method (PFT) was used as the statistical effect measure, and the 95% confidence interval (CI) was computed. Considering the observational nature of the included studies, a random-effects model was utilized to account for the presumed heterogeneity. Inhibitor development and AEs were assessed for each study. All results were visualized using forest plots. The sensitivity analyses were informed using the metainf function from the meta package in R software.

Results

Study Selection

We identified 867 studies through an initial search. After removing 73 duplicate studies, we conducted title and/or abstract screening of 794 publications. During the initial screening, 677 publications were excluded because they did not align with the scope of this study. Subsequently, the full text of 117 studies was reviewed, and 16 studies met the inclusion criteria for the systematic review, including 1145 patients. The study selection process is shown in Fig. 1.

Fig. 1.

Flowchart of literature screening. n number of studies

Characteristics

Sixteen studies were included into this systematic review: one nonrandomized, noncontrolled, clinical trial; one nonrandomized, clinical trial; four noncontrolled, clinical trials; and ten clinical trials. Notably, most of the studies showed similar levels of quality, obviating the need for sensitivity analyses predicated on methodological quality. Table 1 provides a concise overview of the studies, including fundamental patient details (e.g., prior treatment and inclusion criteria), product types, follow-up durations, and outcomes. Within the intervention treatments, nine studies reported EHL rFVIII, while another seven studies reported SHL rFVIII. Among the included studies, six studies included PTPs, and nine studies included PUPs, and two of these studies involved a subset of MTPs.

Table 1.

Characteristics of the included studies

Study	Type of study	Sample size (intervention)	Previously treated/untreated patients (PTPs/PUPs)	Inclusion criteria	Product (name/type/source)	Follow-up	Outcomes
Blanchette VS 2008 [18]	Clinical trial	53 (prophylaxis)	PTPs	FVIII ≤ 2%/ ≥ 50 Eds	Octocog alfa/SHL, full-length, third-generation rFVIII/Takeda	141–933 days	AE
Auerswald G 2012 [19]	Clinical trial	55 (prophylaxis and on demand)	PUPs, n = 18; MTPs, n = 37	FVIII < 2%/ ≤ 20 Eds	Octocog alfa/SHL, full-length, third-generation rFVIII/Takeda	75 EDs or 3 years	Inhibitor development; ABR; AE; immunogenicity
Young G 2015 [20]	Clinical trial	71 (prophylaxis)	PTPs	FVIII < 1%/ ≥ 50 Eds	Efmoroctocog alfa/EHL, BDD-rFVIIIFc, fourth-generation rFVIII/ Sanofi Genzyme​	28 weeks	ABR; duration of bleed
Stasyshyn O 2017 [21]	Clinical trial	84 (prophylaxis and on demand)	PTPs	FVIII < 1%/ ≥ 50 Eds	Lonoctocog alfa/EHL, B-domain truncated, rFVIII-SingleChain, third-generation rFVIII/CSL Behring	Median 5.6 months	Efficacy rating; ABR; spontaneous ABR; joint ABR; AE
Chowdary P 2018 [22]	Clinical trial	68 (prophylaxis)	NA	FVIII < 1%	Turoctocog alfa pegol /EHL, full-length-PEGylated, third-generation rFVIII/ Novo Nordisk	NA	ABR; spontaneous ABR; traumatic ABR; joint ABR; muscle ABR
Mathias MC 2018 [23]	Clinical trial	103	PUPs	FVIII < 1%/ ≥ 50 Eds	Moroctocog alfa/SHL, B-domain deleted, third-generation rFVIII/ Pfizer	Median (IQR) 431 (257–816) days	Inhibitor development
Jonker CJ 2020 [24]	Clinical trial	168 (prophylaxis)	PUPs	FVIII < 2%/96% patients ≥ 50 Eds	Octocog alfa/SHL, full-length, third-generation rFVIII/ Takeda	NA	Inhibitor development
Šaulytė Trakymienė S 2020 [25]	Nonrandomized, noncontrolled clinical trial	68 (prophylaxis)	PTPs	FVIII ≤ 1%/ ≥ 50 Eds	Turoctocog alfa pegol/EHL, full-length-PEGylated, third-generation rFVIII/Novo Nordisk	5 years	AE; duration of bleed; ABR; spontaneous ABR; traumatic ABR; hemostasis efficacy
Yaish H 2020 [26]	Nonrandomized clinical trial	60 (prophylaxis)	PUPs	FVIII < 1%/ ≥ 50 Eds	Turoctocog alfa/SHL, B-domain truncated, third-generation rFVIII/ Novo Nordisk	≤ 24 months	ABR; inhibitor development; hemostatic efficacy; AE
Sidonio Jr RF 2023 [27]	Uncontrolled clinical trial	59 (prophylaxis and on demand)	PUPs	FVIII < 1%/ ≥ 50 Eds	Rurioctocog alfa pegol/EHL, full-length-PEGylated, third-generation rFVIII/ Takeda	NA	Inhibitor development; ABR; spontaneous ABR; traumatic ABR; joint ABR; hemostatic efficacy; AE
Königs C 2022 [13]	Clinical trial	103 (prophylaxis and on demand)	PUPs	FVIII < 1%/ ≥ 50 Eds	Efmoroctocog alfa/EHL, BDD-rFVIIIFc, fourth-generation rFVIII/ Sanofi Genzyme​	12 weeks	ABR; inhibitor development; AE
Wu R 2022 [28]	Uncontrolled clinical trial	69 (prophylaxis and on demand)	PTPs	FVIII < 1%/ ≥ 50 Eds	Omfiloctocog alfa/SHL, B-domain truncated, third-generation rFVIII/ Novo Nordisk	24 weeks	ABR; inhibitor development; hemostatic efficacy; hemophilia joint health score
Ljung R 2023 [29]	Uncontrolled clinical trial	43 (prophylaxis)	PUPs, n = 37; MTPs, n = 6	FVIII < 1%/ ≥ 50 Eds	Octocog alfa (BAY 81-8973)/ SHL, full-length, third-generation rFVIII/ Bayer	50 days	ABR; inhibitor development; immunogenicity; AE
Kenet G 2023 [30]	Uncontrolled clinical trial	81 (prophylaxis)	PUPs	NA	Turoctocog alfa pegol/EHL, full-length-PEGylated, third-generation rFVIII/ Novo Nordisk	Median (range) 2.9 (0.1–7.2) years	ABR; inhibitor development; hemostatic efficacy; AE
Chowdary P 2020 [31]	Clinical trial	65 (prophylaxis)	PTPs	FVIII < 1%/ ≥ 50 Eds	Rurioctocog alfa pegol/EHL, full-length-PEGylated, third-generation rFVIII/ Takeda	2.2 years	ABR; hemostatic efficacy; AE; health-related quality of life
Carcao M 2024 [32]	Clinical trial	103 (prophylaxis and on demand)	PUPs	FVIII < 1%/ ≥ 50 Eds	Efmoroctocog alfa/EHL, BDD-rFVIIIFc, fourth-generation rFVIII/ Sanofi Genzyme​	58 weeks	Inhibitor development

The core coagulation function of both B-domain deleted rFVIII products and B-domain truncated rFVIII products is primarily controlled by the A and C domains. When analyzing the development of inhibitors and the incidence of AEs, these two types are collectively referred to as rFVIII products with B-domain deleted

SHL standard half-life, EHL extended half-life, FVIII factor VIII, rFVIII recombinant FVIII, PEGylated polyethylene glycol-ylated, BDD-rFVIIIFc B-domain-deleted recombinant factor VIII Fc fusion protein, ABR annual bleeding rate, AE adverse event, PUPs previously untreated patients, PTPs previously treated patients, MTPs minimally treated patients, Eds exposure days, n number of patients with non-missing data, NA not available, SD standard deviation, IQR interquartile range

The primary focus of this systematic review was a single-arm meta-analysis on the proportion of inhibitor development (including ten studies) and the incidence of AEs (including 12 studies), with calculation of pooled effect estimates and 95% CIs.

Total ABR

Three studies [20, 29, 31] reported changes in the ABR from baseline to post-treatment in patients who received rFVIII therapy. Young et al. [20] found that patients who received prophylactic treatment with the EHL rFVIII product turoctocog alfa pegol showed a non-significant change in the mean ABR (standard deviation, SD) from baseline to post-treatment (2 [13.33] vs 1.96 [10.07], P > 0.05). Ljung et al.’s study [29] included 43 patients with a baseline mean (SD) ABR of 1.1 (1.6). They reported that after treatment with the third-generation SHL rFVIII product octocog alfa (BAY 81-8973), the ABR in the no inhibitors subgroup (n = 20) was 0.9 (1.4), P > 0.05, that in the low titer subgroup (n = 6) was 3.1 (5.4), P > 0.05, and that in the high-titer subgroup (n = 17) was 2.8 (3.7), P > 0.05. Chowdary et al. [31] reported that after patients received prophylactic treatment with rurioctocog alfa pegol, the average spontaneous ABR increased compared to baseline in both the subgroup of patients younger than 6 years old (n = 32, mean [SD], 0.66 [1.24] vs 0.1 [0.52], P = 0.02) and the subgroup aged 6–12 years (n = 33, 0.76 [1.67] vs 0.2 [1.47], P > 0.05). However, the average spontaneous ABR decreased compared to baseline in both the adolescent subgroup (n = 30, 1.77 [3.05] vs 2.5 [5.73], P > 0.05) and the adult subgroup (n = 121, 1.26 [3.09] vs 2.3 [5.72], P > 0.05). Overall, these findings suggested that the impact of rFVIII therapy on ABR varies across studies and patient subgroups, with some indicating no significant changes while others show trends toward increased or decreased ABR in specific age groups. Further research is needed to better understand the factors influencing the effectiveness of rFVIII products in different patient populations.

Inhibitor Development

Ten studies [13, 19, 23, 24, 26–30, 32] involving 844 patients described the incidence of inhibitors. Among these, one study [28] included PTPs, while the remaining nine studies [13, 19, 23, 24, 26, 27, 29, 30, 32] included PUPs. The proportion of inhibitor development was 31.7% (95% CI 26.2%; 37.5%) for the PUPs (Table 2). Among the PUPs, the proportion of inhibitor development in those treated with EHL rFVIII was 27.5% (95% CI 22.6%; 32.6%) and that in those treated with third-generation SHL rFVIII was 36.4% (95% CI 27.2%; 46.2%) (Fig. 2a, b). Among the third-generation SHL rFVIII subgroup, the proportion of high-titer inhibitors was 20.9% (95% CI 12.9%; 30.3%) (Fig. 2c). In the subgroup of PUPs who received third-generation SHL rFVIII, the proportion of inhibitor development for full-length rFVIII products was 35.7% (95% CI 19.3%; 53.9%) and that of high-titer inhibitors was 21.7% (95% CI 8.9%; 38.1%) (Fig. 2d, e). The proportion of inhibitor development for B-domain deleted rFVIII products was 37.5% (29.0%; 46.4%) (Table 2). The product octocog alfa showed the lowest incidence of high-titer inhibitors at 12.7% (95% CI 5.3%; 24.5%) (Fig. 2e).

Fig. 2.

Inhibitor development in PUPs. a patients treated with EHL rFVIII; b patients treated with third-generation SHL rFVIII; c incidence proportion of high-titer inhibitors in PUPs treated with third-generation SHL rFVIII; d incidence proportion of inhibitors in PUPs treated with full-length third-generation SHL rFVIII; e incidence proportion of high-titer inhibitors in PUPs treated with full-length third-generation SHL rFVIII. The study by Auerswald et al. (2012) [19] included 55 patients, of whom 18 were PUPs and 37 were MTPs. The study by Ljung et al. (2023) [29] enrolled 43 patients, of whom 37 were PUPs and 6 were MTPs. Both studies did not separately calculate the high-titer inhibitor incidence proportions for PUPs and MTPs. Therefore, the high-titer inhibitor incidence proportions in c and e combine the PUP and MTP data from these two studies. SHL standard half-life, EHL extended half-life, FVIII factor VIII, rFVIII recombinant FVIII, PUPs previously untreated patients, PTPs previously treated patients, MTPs minimally treated patients, CI confidence interval, Tau² between-study heterogeneity, I² between-study heterogeneity, Chi² chi-square test, P P value

Safety Outcomes

Twelve studies [13, 18–21, 25–31] involving 811 patients documented the occurrence of AEs, treatment-related AEs, or serious AEs (SAEs). Among these, six studies [18, 20, 21, 25, 28, 31] included PTPs, while six studies [13, 19, 26, 27, 29, 30] included PUPs. A summary of AEs in patients is shown in Table 3. Among the 12 studies, 4658 AEs were reported, including 1126 treatment-related AEs and 370 SAEs. Of these, only 65 SAEs (mostly related to inhibitor development) were considered treatment-related to rFVIII. None of the studies reported treatment-related deaths, and most of SAEs were resolved. The incidence proportion of treatment-related AEs in PUPs was 51.6% (95% CI 28.6%; 74.3%), and it was 46.2% (95% CI 13.5%; 80.7%) in the third-generation SHL rFVIII group and 56.8% (95% CI 21.9%; 88.4%) in the EHL rFVIII group (Table 4). Among the subgroup of PUPs who received third-generation SHL rFVIII, the incidence proportion of treatment-related AEs for full-length rFVIII products was 32.3% (95% CI 2.9%; 73.0%) (Table 4). Notably, among the third-generation SHL rFVIII products, octocog alfa had the lowest reported proportion of treatment-related AEs at 14.5% (95% CI 6.5%; 26.7%) (Fig. 3).

Table 3.

AE occurrence

Study	AE [events, n (N), %]a	Treatment-related AE [events, n (N), %]a	SAE [events, n (N), %]a	Description of SAE
Blanchette VS 2008 [18]	537, 52 (53), 98.1%	6, 2 (53), 3.8%	15, NA	One patient experienced laryngitis, eye inflammation, and influenza. The other developed memory impairment, tremor, and pallor
Auerswald G 2012 [19]	931, 53 (55), 96.4%	14, 8 (55), 14.5%	46, 28 (55), 50.9%	Sixteen product-related SAEs in 16 subjects were all cases of inhibitor development. Eleven complications/infections in six subjects potentially associated with the placement of a port/venous access device. Six of these complications were SAEs, (five catheter-related infections and one catheter site hematoma)
Young G 2015 [20]	213, 59 (69), 85.5%	2, NA	7, 5 (69), 7.3%	Head injury in two subjects, and the remaining SAEs (fall, Bacillus infection, Escherichia infection, croup infectious, and metapneumovirus infection) in one subject each
Stasyshyn O 2017 [21]	NA	183, 64 (84), 76.2%	11, 9 (84), 10.7%	Hand fracture, laceration, traumatic rupture of the spleen, device occlusion, systemic inflammatory response syndrome, bacteremia, pneumonia, anemia, and dyspepsia. No SAEs were considered by the investigator as related to treatment
Šaulytė Trakymienė S 2020 [25]	838, 66 (68), 97.1%	16, 11 (68), 16.2%	18, 16 (68), 23.5%	The two SAEs (cases of hypersensitivity and hemorrhage) considered to be possibly or probably related to N8-GP treatment occurred in the main phase
Yaish H 2020 [26]	721, 60 (60), 100.0%	NA	49, 44 (60), 73.3%	FVIII inhibition (n = 25), device-related infection (n = 5), traumatic hemorrhage (n = 4), pyrexia (n = 4), anemia (n = 3), head injury (n = 3)
Sidonio Jr RF 2023 [27]	283, 54 (54), 100.0%	14, 13 (54), 24.1%	32, 24 (54), 44.4%	SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development
Königs C 2022 [13]	NA	683, 75 (89),84.3%	71, 34 (89), 38.2%	21 (24%) subjects receiving rFVIIIFc as prophylaxis experienced FVIII inhibitor development. Other related SAEs included 1 event of deep vein thrombosis, 1 event of soft tissue hemorrhage (occurred in the context of high-titer inhibitor development), and 1 event of a central venous access device related thrombosis
Wu R 2022 [28]	182, 53 (69), 76.8%	182, 53 (69), 76.8%	2, 2 (69), 2.9%	Two (2.9%) SAEs (bronchitis and FVIII inhibitor) were recorded in 2 patients
Ljung R 2023 [29]	NA	NA, 23 (43), 42.6%	NA, 26 (43), 60.5%	22 patients with an SAE of “anti-factor VIII antibody positive” and one patient with an SAE of “factor VIII inhibition”
Kenet G 2023 [30]	760, 78 (81), 96.3%	NA	80, 48 (81), 59.3%	Four SAEs categorized as “injury, poisoning and procedural complications”, three categorized as “infections and infestations”, two cases of “FVIII inhibition”, and one categorized as “surgical and medical procedures”
Chowdary P 2020 [31]	193, 55 (65), 84.6%	3, 2 (65), 3.1%	13, 7 (65), 10.8%	All treatment-related AEs were mild or moderate in severity; all SAEs were considered not related to study drug

SHL standard half-life, EHL extended half-life, AE adverse event, SAE serious adverse event, PUPs previously untreated patients, PTPs previously treated patients, FVIII factor VIII, rFVIII recombinant FVIII, rFVIIIFc recombinant factor VIII Fc fusion protein, N total number of patients included in the study, n number of patients with non-missing data, NA not available

^aPercentage was calculated as n/N × 100%

Table 4.

Pooled proportion of treatment-related AEs

Variable	N	Events/total	Pooled adverse event proportion (95% CI)	Between-study variance (τ2)
Overall study	12	345/790	37.6% (18.4%; 59.1%)	0.138
PTPs	6	134/408	24.7% (2.7%; 58.0%)	0.177
Third-generation SHL	2	55/122	35.5% (0.0%; 99.7%)	0.356
EHL	4	79/286	19.8% (0.0%; 58.3%)	0.164
PUPs	6	211/382	51.6% (28.6%; 74.3%)	0.081
Third-generation SHL	3	75/158	46.2% (13.5%; 80.7%)	0.097
rFVIII length
Full-length rFVIII	2	31/98	32.3% (2.9%; 73.0%)	0.083
B-domain deleted rFVIII	1	44/60	NA	NA
EHL	3	136/224	56.8% (21.9%; 88.4%)	0.099

SHL standard half-life, EHL extended half-life, PUPs previously untreated patients, PTPs previously treated patients, FVIII factor VIII, rFVIII recombinant FVIII, CI confidence interval, τ² Tau² between-study heterogeneity, N number of studies included in the analysis, NA not available

Fig. 3.

Treatment-related incidence of AEs in PUPs treated with third-generation SHL rFVIII. SHL standard half-life, FVIII factor VIII, rFVIII recombinant FVIII, PUPs previously untreated patients, AEs adverse events, CI confidence interval, Tau² between-study heterogeneity, I² between-study heterogeneity, Chi² chi-square test, P P value

Sensitivity Analysis

The sensitivity analysis indicated that the results for different types of rFVIII products varied with changes in methodology (Tables S2 and S3). The results of the sensitivity analysis were generally consistent with those of the primary analysis, suggesting that the methodology of this study is robust.

Discussion

rFVIII products represent a pivotal treatment modality for HA, primarily serving to replenish the deficient coagulation factor VIII within patients' bodies, thus facilitating normal blood clotting and reducing incidences of bleeding [33]. With the progressive advancements in biotechnology in recent years, the development and utilization of recombinant FVIII products have offered patients with HA a safer and more effective therapeutic option. Compared to the historical reliance on plasma-derived treatments, recombinant products have significantly mitigated the risk of transmissible diseases, thereby enhancing the overall safety of the treatment regimen [34]. This systematic review comprehensively analyzed the published data on the efficacy and safety of rFVIII products in both previously treated and untreated pediatric patients with HA. Sixteen studies were included in this review, involving 1145 patients. Among them, 15 studies focused on patients with severe HA, three reported ABR, ten reported inhibitor development, and 12 described AEs.

ABR quantifies the average number of bleeding episodes a patient experiences per year, providing a standardized measure to assess the severity of the disease and the efficacy of therapeutic interventions [35]. Research indicated that prophylactic treatment with recombinant factor VIII significantly reduces ABR in patients with HA, thereby improving their quality of life and preventing long-term joint damage associated with recurrent bleeding episodes [36]. Studies examined rurioctocog alfa pegol, an EHL rFVIII product, regarding its effectiveness in PTPs with severe HA. This previous study showed improvement in the patients’ ABR and hemostatic efficacy following treatment [37, 38]. A systematic review assessed the effectiveness of prophylactic treatment with octocog alfa in previously treated or untreated patients with HA, and showed that nearly all (1953 out of 1956) patients responded positively to the treatment, and prophylactic therapy significantly reduced the incidence of bleeding events and non-traumatic joint bleeding events [39]. This systematic review yielded analogous findings, incorporating three studies that reported changes in the ABR from baseline to post-treatment. Overall, these findings indicated that the impact of rFVIII therapy on ABR in pediatric patients with HA has no obvious statistical difference, highlighting the need for further research to elucidate the factors influencing treatment effectiveness in this population.

The development of FVIII inhibitory antibodies is a severe complication in patients with HA following FVIII replacement therapy. Inhibitor development renders conventional prophylaxis ineffective and increases the risk of morbidity and mortality [33, 40]. In patients with HA, inhibitor development is affected by genetic factors, mainly mutations in the F8 gene, and non-genetic factors, and the latter is largely associated with FVIII treatment [41]. Studies have indicated that PUPs with severe HA have an increased risk of developing FVIII inhibitors, particularly in the case of high-titer inhibitor development in pediatric patients with HA [26, 42]. Our systematic review established that, among EHL rFVIII products, patients who used rurioctocog alfa pegol had a low proportion of inhibitor development than those who used efmoroctocog alfa and turoctocog alfa pegol. Regarding third-generation SHL rFVIII products, patients who used octocog alfa showed lower proportions of inhibitor development and high-titer inhibitor development than patients who used moroctocog alfa, turoctocog alfa, and octocog alfa (BAY 81-8973). PTPs with severe HA have a low risk of developing inhibitors when re-treated with rFVIII products [43]. A systematic review included 41 independent cohorts comprising 19,157 PTPs with severe HA who were re-treated with rFVIII. This previous review reported an overall inhibitor occurrence proportion of 2.06 cases per 1000 person-years. Interestingly, patients who received octocog alfa treatment showed a lower overall inhibitor occurrence proportion of 0.99 cases per 1000 person-years, suggesting a potential association between the immunogenicity of patients and different rFVIII products [44]. Regardless of the prior treatment history, the risk of inhibitor development in pediatric patients with HA is consistently higher than that in their adult counterparts. Younger patients have a greater risk of inhibitor occurrence than adult patients [45]. Surprisingly, there is a lack of research specifically focusing on inhibitor occurrence in pediatric patients with HA following rFVIII treatment. This systematic review identified only one study that described inhibitor occurrence in PTPs, so our findings lack robust reference value. The comparison of inhibitor development across different rFVIII concentrates is limited by the predominantly single-arm study designs in the available evidence. Further randomized controlled trials are needed to better understand the immunogenicity of these products.

Moreover, the overall incidence of treatment-related AEs in PTPs was slightly lower than that in PUPs, which is consistent with previous research. There is currently a lack of a comprehensive systematic review that specifically focused on PUPs with HA receiving rFVIII treatment. In this systematic review, patients reported 1126 treatment-related AEs and 370 SAEs, of which 65 (17.6%) were considered treatment-related, predominantly involving inhibitor development, all of which were effectively managed. Among the third-generation SHL rFVIII products, octocog alfa had the lowest reported proportion of treatment-related AEs.

The number of studies including the outcome of the ABR in this systematic review was limited and it lacked control groups. Furthermore, baseline data only was used for comparison, resulting in substantial heterogeneity. Most of the SAEs related to treatment are primarily associated with inhibitor development. Therefore, this systematic review used inhibitor development as the main outcome measure. The cumulative inhibitor occurrence proportion was not selected as the primary outcome because of varying study durations in the included studies. Additionally, because most studies do not report the follow-up times of non-inhibitor patients, hazard ratios were not chosen as the primary outcome. In contrast to previous systematic reviews [38, 39, 44, 45], this review included pediatric patients with HA and directly compared the inhibitor occurrence proportion of all rFVIII products. However, this systematic review has certain limitations. The comparison of single-arm trials in our analysis, based on the product type, may be misleading owing to differences in the distribution of genetic/treatment-related risk factors because no comparative studies were identified. Many studies also include patients with moderate-severe disease, which could potentially confound the results if these patients have a significantly lower risk of inhibitor formation. Furthermore, some studies [13, 19, 21, 27, 28] in this systematic review included patients who received on-demand treatment, while the majority focused on patients who underwent prophylactic treatment. Additionally, two PUP studies [19, 29] included in this systematic review contained data from patients receiving minimal treatment. While these data were excluded in the analysis of the proportion of inhibitor development, they could not be removed in the analysis of the proportion of high-titer inhibitor development because of the limited number of cases.

Limitations

This systematic review has a moderate risk of bias, primarily due to variables that might affect physicians’ selection of rFVIII products. These variables include F8 gene mutation and a family history of inhibitors, as well as variations in the severity of patients’ conditions and treatment approaches. Furthermore, this systematic review identified potential associations between certain products and increased immunogenicity, but these findings should be interpreted cautiously. This caution is necessary because the safety profiles of different rFVIII products vary among pediatric patients at high risk of inhibitor development, and variations in study designs may lead to significant differences in risk assessment. Additionally, this study relies on the comparison of inhibitor development across different individual studies of various FVIII concentrates. Future crossover randomized studies are needed to better understand the immunogenicity of each product. Overall, the overall quality of evidence was low, primarily due to a high risk of bias and confounding, a lack of control groups in most studies, and limited research for each product. Therefore, these findings should be interpreted cautiously.

Conclusion

Despite the limited number of studies included in this systematic review, it was also found that among EHL rFVIII products, pediatric patients with HA who used rurioctocog alfa pegol had a low proportion of inhibitor development. Regarding third-generation SHL rFVIII products, patients who used octocog alfa had low proportions of inhibitor development and high-titer inhibitor development, as well as the lowest reported proportion of treatment-related adverse events AEs.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

All authors (Xiaoqin Feng, Xuan Zhou, Jing Sun, and Zhenguo Wang) had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Xiaoqin Feng, Xuan Zhou, and Jing Sun contributed to the study concept and design, data acquisition, analysis, and interpretation. Xiaoqin Feng and Xuan Zhou performed the systematic literature review. Xiaoqin Feng and Xuan Zhou drafted the manuscript. Jing Sun and Zhenguo Wang critically revised the manuscript. Zhenguo Wang provided technical support for this research, mainly including conception, study design and interpretation of data.

Funding

The Rapid Service Fee and the Open Access fee of the article were funded by Takeda (China) International Trading Company.

Data Availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Declarations

Conflict of Interest

Xiaoqin Feng, Xuan Zhou, Jing Sun have received no compensation or remuneration for their contribution to the writing of this manuscript or its appendices. Zhenguo Wang is currently employed by Takeda (China) International Trade Co., Ltd.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.