Modeling disability reduction through low-dose prophylaxis versus on-demand therapy in hemophilia A: A meta-analysis and gbd-inspired yld framework for resource-limited settings Free

Low-dose prophylaxis (LDP) is increasingly adopted in low- and middle-income countries (LMICs) as a cost-feasible approach to reduce morbidity in patients with Hemophilia A. While it is known to reduce bleeding rates, there is limited population-level quantification of its long-term disability benefit over on-demand therapy (ODT), especially using burden-of-disease metrics. This study aimed to systematically assess clinical outcomes from existing trials comparing LDP with ODT and model the resulting Years Lived with Disability (YLD), a Global Burden of Disease (GBD)-style disability measure, in LMIC contexts.

A comprehensive search of PubMed, Embase, and Scopus through June 2025 identified twelve eligible studies (6 randomized controlled trials, 6 prospective cohorts) comprising 2,931 participants comparing LDP (≤20 IU/kg, ≤3x/week) to ODT. Extracted outcomes included annual bleeding rate (ABR), incidence of hemarthrosis, and prevalence of target joints. Meta-analysis was conducted using a random-effects model. Disability burden was estimated by modeling YLDs using the formula YLD = prevalence × disability weight × duration. Prevalence of target joint development was used as the disability proxy. Disability weights were adopted from the GBD 2019 dataset for comparable musculoskeletal conditions (DW = 0.079 for moderate limitation). A 10-year disability duration was applied.

The mean ABR was significantly lower in the LDP group (4.2) than in the ODT group (12.5) (p < 0.001). The pooled prevalence of target joint development was 11% in the LDP group compared to 32% in the ODT group (risk ratio: 0.34; 95% CI: 0.26–0.45). Based on these findings, estimated YLDs per 1,000 patients over 10 years were 87 for LDP and 253 for ODT, translating to a 66% relative reduction in long-term disability burden. Sensitivity analyses using a higher DW (0.388, representing severe joint limitation) yielded 427 and 1,242 YLDs per 1,000 patients in the LDP and ODT groups, respectively. The benefit remained robust across different modeling assumptions. Subgroup analyses showed a more pronounced disability reduction in pediatric cohorts and in studies from LMICs.This is the first study to apply a GBD-inspired modeling approach to quantify the disability impact of LDP in Hemophilia A. While LDP is not curative, this analysis reveals that it substantially reduces long-term disability compared to ODT, supporting its adoption as a standard-of-care in resource-limited settings. Beyond traditional clinical metrics, the use of YLDs helps translate treatment decisions into population-level policy implications and supports health-economic justification for early prophylaxis initiation. These findings highlight the value of integrating burden modeling into national hemophilia treatment guidelines and provide a scalable framework for similar rare disease policy evaluation. Future directions include cost-per-YLD-averted analysis and dynamic modeling using national registry data.