Cost-effectiveness analysis of low-dose prophylaxis versus on-demand treatment for moderate-to-severe hemophilia A in India

ABSTRACT Aim Hemophilia A (HA) is an inherited bleeding disorder caused by a deficiency of clotting factor VIII in the blood. In resource-limited settings like India, affordability is a significant challenge in managing patients with severe HA. This study aims to assess the cost-effectiveness of intermediate-dose prophylaxis versus on-demand factor therapy in adult and pediatric populations with moderate-to-severe congenital HA without inhibitors in India. Method We conducted a prospective cost-effectiveness analysis from a societal perspective, categorizing patients into a base state and a joint disease state (patients with Hemophilia suffering extensive bleeds leading to chronic joint disease). Using targeted literature search and primary market research, we developed a Markov model measuring the total cost of Hemophilia treatment and health outcomes, including life-years (LYs), quality-adjusted life-years (QALYs), incremental cost-utility ratio (ICUR), and incremental cost-effectiveness ratio (ICER). The model extended over a lifetime horizon of 70 years with a one-year cycle length. Sensitivity analyses assessed study robustness. Results Low-dose prophylactic therapy was cost-effective for adults (>18 years) and pediatric populations (<18 years), yielding better health outcomes (adults: 0.15 LYs and 2.43 QALYs gained; pediatric: 0.40 LYs and 3.12 QALYs gained). Intermediate-dose prophylaxis showed positive net monetary benefits in terms of Quality-Adjusted Life Years (QALYs) for both adult and pediatric populations, with dominant ICER and ICUR values in both cases. Conclusion Using intermediate-dose prophylactic factor VIII therapy is a cost-effective approach that improves clinical outcomes compared to on-demand therapy in the Indian adult and pediatric HA populations without inhibitors.


Introduction
Hemophilia A (HA), an X-linked inherited bleeding disorder, is marked by a deficiency of clotting factor VIII in the plasma.In individuals with severe deficiency, it results in spontaneous and/or traumatic bleeding episodes, predominantly affecting joints, soft tissues, muscles, and body cavities.[1].Patients with hemophilia are categorized as mild, moderate, and severedepending on the percent of normal clotting factor present [2].As per the World Federation of Hemophilia annual report, 2020, a total of 347,026 patients globally had bleeding episodes, with 165,379 patients suffering from HA [3].In India, 18,928 patients have been identified with HA, with the majority of patients in the age range of 19-44 years (43%) [3].
Treatment approaches for HA in India include lifestyle modification, physiotherapy, and on-demand or prophylactic treatment of bleeding events using replacement therapy with clotting factor VIII concentrates [2,4].
While prophylaxis has become the standard of care for severe hemophilia, the utilization of prophylactic clotting factor treatment in India remains limited to just 9% of individuals under the age of 18 with severe hemophilia [1,3].In developed countries, the established approach to treating hemophilia involves intermediate-dose prophylaxis (injection of factor VIII at a dose of 15-25 units/kg, administered intravenously two to three times a week).This regimen has demonstrated remarkable joint health benefits when implemented over extended periods.
In India, patients with HA often experience inadequate medical insurance coverage.However, this issue is currently being addressed through government support initiatives.
Presently, approximately 85% of partial or complete financial assistance is provided by the government for on-demand therapy, while prophylaxis support is offered to a limited extent in a few states.The substantial treatment costs continue to pose a significant barrier and source of concern for all stakeholders [21,22].
The guidelines set forth by the Indian Academy of Pediatrics (IAP) also emphasize the potential benefits of low-dose prophylaxis (based on research) commencing at an early age, aiming to enhance the quality of life for patients [23,24].Furthermore, to facilitate hemophilia care, the government has established hemophilia treatment centers that offer free anti-hemophilic factor.However, accessibility to these centers remains limited [25].In an effort to address accessibility issues, a pilot hematology program under the National Rural Health Mission has demonstrated a 21% reduction in out-ofpocket (OOP) expenses [22,26].
The prevalence of inhibitors that neutralize the effects of recombinant clotting factors in India ranges from 8.2% to 13%, further contributing to the overall economic burden [2,27].Direct costs of hemophilia encompass expenses related to medications, laboratory tests, hospitalization, surgical procedures, and consultation fees.Additionally, there are indirect associated costs such as loss of work productivity, inability to attend educational institutions, disability due to illness, and even mortality [5].
Many economic evaluations have been conducted to compare on-demand versus prophylactic treatment in terms of cost-effectiveness (CE) and/or cost-utility [6,15]; however, there is a dearth of such analysis from an Indian perspective.The objective of the current pilot study is to conduct a CE analysis to evaluate prophylaxis versus on-demand factor treatment in people with moderate-to-severe congenital HA without inhibitors in India.

Study population
A CE analysis from the societal perspective was conducted from October 2021-May 2022 among patients with moderate-to-severe HA without inhibitors (adult: 18 years and above; pediatric: 2-18 years of age).The model was conceptualized to evaluate the treatment flow of hemophilia-A patients with the two modes of factor VIII therapy.A virtual cohort was introduced into this model concept with intermediate-dose prophylaxis and on-demand therapy.

Treatment regimens
Treatment regimens were analyzed based on the information provided by various published studies on the accepted prophylactic dosages.For intermediate prophylaxis 15-25 IU/kg twice a week were used for calculations [28].In case of low dose prophylaxis quantity of 10 IU/kg once or twice a week was used for analysis [9] For on demand therapy, treatment regime according to the WFH 2020 guidelines was followed where FVIII is given only after bleeding.Severe bleeds, such as intracranial or psoas bleeds, require a more intensive and extended period of clotting factor replacement (80-100% correction) to ensure effective control and healing.Moderate bleeds are managed with a lower level of correction (50% correction) for a shorter duration with specific amount of clotting factor administered being FVIII 25 IU/kg.

Targeted literature review
A targeted literature review was conducted for the development of the model from the societal perspective.Literature on treatment guidelines; available clinical data (Indian/global)-meta-analysis; published economic data; cost and resource use; and other model inputs (utilities, disutilities, adverse events, morbidity, and mortality) were considered.Inclusion and exclusion criteria were based on Population, Intervention, Comparison, and Outcome criteria.The population included were patients with moderate-to-severe congenital HA without inhibitors across all age groups; the intervention/comparator was intermediate-dose prophylaxis with clotting factor VIII versus on-demand factor therapy; and outcomes were clinical and economic data, QoL, bleed-free model studies, and India-specific budget impact model studies (Table 2).Limited use of secondary data was a key parameter to obtaining directional results.

Model structure and outcomes derived
The Markov model [29] was developed with three discrete health states (base, joint disease, and death) and two transitory health events with a model cycle length of 1 year (Figure 1).The movement of patients from different states was determined by transition probabilities.The model was run with secondary literature inputs to collect primary data.The post collection of primary data, final inputs were used to generate the results for the analysis.Cost-associated outcome from the study is the total direct and indirect cost of prophylactic and on-demand factor, while the health outcomes included life-years (LYs) and quality-adjusted life-years (QALYs).Aggregated outcomes, including ICUR (cost/QALY) and ICER (cost/LY), were also determined.

Model parameters
Model clinical parameters were bifurcated into prophylactic and on-demand therapy, further subdivided into the adult and pediatric populations.The time horizon selected for the study was 70 years (computed based on the life expectancy in India).The minimum age for entering the model was 2 years for the pediatric population and 18 years for the adult population, with male population being 96.7% (based on the available literature).The adult population comprised of pediatric population diagnosed in early stages and were transitioned into adult after attaining 18 years or patients in rare scenario who have been diagnosed at the age of 18 years or above.Based on Key Opinion Leader (KOL) inputs, average doses and frequency values for prophylaxis and on demand treatment were used in the model.Intermediate-dose prophylaxis of 14.6 IU/kg/dose, 2.2 times a week for pediatric population and 14.2 IU/kg/dose, 1.6 times a week for adults was considered for the model.The values for on-demand were 27.5 IU/kg/dose, 2.1 times per bleed event for adults; and 24.6 IU/kg/dose, 1.9 times per bleed event for pediatric population.The cycle length for the model was 1 year, with half-cycle corrections being made.Bleed events within this 1 year were mapped in this morbidity-driven model.Based on KOL inputs, for prophylaxis therapy and on-demand therapy, annualized overall bleed rates of 1.9 and 11.6 bleed/year respectively were used for the model in base case for adult population.The annualized bleed rates of 2.5 and 12.9 bleed/year were used for the pediatric population for prophylaxis therapy and on-demand therapy respectively.The discounting factor considered in the study for costs and effects was 3.5%, as per the National Institute for Health and Clinical Excellence (NICE) standard [30].The cost-effective threshold taken as per gross domestic product (GDP) per capita for India was INR (Indian Rupee) 140,462 [31] and CE was determined at less than or equal to one time the GDP for India.For the baseline set taken in the model, the cost considered was a mix of literature review and public sector cost [32][33][34][35].The direct costs accrued in the model were medication, hospitalization, surgery, physician's visit, and laboratory investigation while the indirect costs were absenteeism from school and work, wage, and productivity loss.
Study gaps were identified based on the dry run and proposed model.These gaps were the baseline to conduct market research to collate the required information on the gaps from physician KOLs treating hemophilia in India.The primary objective of market research conducted was to determine the healthcare resource use and cost in HA.After incorporating the inputs generated in the model, a finalized model was developed to run the CE analysis.

Sensitivity analysis outputs
Sensitivity analysis of the outcomes was performed for any variation in the input parameters and uncertainty in results.It was evaluated using one-way sensitivity analysis illustrated as a Tornado diagram and a probabilistic sensitivity analysis illustrated with an ICER scatter plot compared to a CE plane and a cost-effectiveness acceptability curve (CEAC).Economic model eliminates the use of p-values and significance is found through sensitivity analysis.

Health-associated outcomes
QALY is a standardized measure of disease burden combining both the survival and QoL attributes in a single index [36], while LYs gained represents only the quantity or number of years of life gained with the healthcare intervention [37].Both QALY and LY provide overall wellbeing of the patients, thereby giving a true representation of improvement in patient's life.
Total LYs gained at 'per patient level' in a lifetime horizon after intermediate-dose prophylactic factor VIII was 19.683 years compared to on-demand therapy (19.529 years), with difference gained in LYs being 0.153 in adults.Total QALYs gained after intermediatedose prophylactic factor VIII in adults was 16.644, while for on-demand factor VIII it was 14.213; the difference gained was 2.432.Total LYs gained after intermediate-dose prophylactic factor VIII in pediatric patients was 28.375 years, while for on-demand factor VIII, it was 27.972 years, with the difference being 0.403.The total QALYs gained at 'per patient level' after intermediate-dose prophylactic factor VIII in pediatric patients was 22.845, while for on-demand factor VIII, it was 19.721, with the difference of 3.124.Thus intermediate-dose prophylactic therapy was demonstrated to be superior in terms of QALYs, in both the adult and pediatric populations (Figure 2).

Aggregated outcomes
The intermediate-dose prophylactic factor VIII therapy was found to be cost-effective as compared to ondemand therapy for both the adult and pediatric populations at 'per patient level'.

Sensitivity analysis
A tornado diagram for one-way sensitivity analysis established that the annualized joint bleed rate (adults) and overall annualized overall bleed rate (adults) in on-demand therapy along with the cost of surgery (at 'per patient level') caused the maximum change in the results (Figure 3).In probabilistic sensitivity analysis, the scatter plot indicated that lowdose prophylactic factor was dominant over ondemand factor VIII therapy, both for the adult and pediatric populations (Figure 4).Similarly, CEAC plots showed that prophylactic therapy was cost-effective at any willingness-to-pay level, in both the adult and pediatric populations (Figure 5).

Discussion
Continuous prophylactic therapy is associated with decreased recurrent joint bleed incidence and reduced risk of development of arthropathy in children without preexisting joint damage [18,20], thereby demonstrating to improve the health-related QoL of the patients with HA over time.In this analysis, we have explored the costs and health outcomes of intermediate-dose prophylaxis versus on-demand therapy of factor VIII in the context of Indian adult and pediatric patients with HA.
The key outcomes of the study highlighted the CE of intermediate-dose prophylactic therapy in adult and pediatric populations in comparison to ondemand therapy with factor VIII, which leads to improved clinical and health outcomes, including ICER and ICUR.There was a gain in LYs and QALYs with intermediate-dose prophylaxis as compared to on-demand therapy along with net monetary benefits for both adult and pediatric populations.This was in line with the WFH 2020 and IAP guidelines [38,24].
Previously published literature demonstrated that low-dose prophylaxis therapy significantly reduces bleeding episodes (64.86%-68.99%),improves joint function (18.18% moderate improvement, with 55.76% mild improvement), improves QoL of patients, reduces hospitalization (60.34%), decreases absenteeism from work, and is cost-effective when administered to adult patients with moderate-to-severe hemophilia [1,6,16].For males aged 12-65 years with severe hemophilia A, administering prophylaxis two or three times a week resulted in a 97% reduction in the annualized occurrence of all bleeds compared to   ), decreased bleeding episodes (reduced by 94%), less chronic pain (reduced by 50%), less health care resource utilization (twofold reduction), and improved satisfaction scores (64.3% patients were extremely satisfied with the treatment) [19].
Prophylaxis that is initiated in adulthood (>18 years), primarily when arthropathy is already prevalent is often termed as tertiary prophylaxis.Tertiary prophylaxis is considered an effective treatment strategy in preventing progression of joint damage even though it is initiated after the onset of joint disease.The goal of tertiary prophylaxis is to minimize life threatening bleeds and bleeding frequency, improve QoL of the patients and improve activity/autonomy levels along with reducing worsening of arthropathy [1,42,43].Tertiary prophylaxis reduces the overall bleed episodes (8 vs. 25) and joint bleed episodes (3 vs. 9) and demonstrates improvement in the Hemophilia Joint Health Score (2 vs. 6 in 12 months) in comparison to on-demand therapy in pediatric population [21].Studies conducted in China (patients aged 2-18 years), exhibited decreased bleeding (63.3-68.9%),improved daily activity (60%), superior joint health outcomes (Joint-specific Hemophilia Joint Health Score: prophylaxis, 9.0 ± 10.3; on-demand, 11.9 ± 12.5), and improvement in Canadian Hemophilia Outcomes-Kids' Life Assessment Tool score (57.6-61.9)[7,8,13,14].Quality adjusted life year.The study analyzed certain probable factors that may affect the results of the study model.1000 simulations were run to check the impact of these factors on the comparison between low-dose prophylactic factor and on-demand factor VIII therapy and the incremental scatter plot graph was generated.In majority of the simulations (99.8%), the low-dose prophylactic factor was better than on-demand factor VIII therapy which means that the low-dose prophylactic factor is not only less expensive but also more effective than on-demand factor VIII therapy.Hence, the factors tested had very little effect on the results of our study.
Similarly, in Iran, prophylactic therapy was found to be cost-effective along with having higher effectiveness and utility in patients under 12 years of age (for prophylaxis: costs being $478,963.1 purchasing power parity [PPP], joint health score of 96.67, QALY of 11.98; and for on-demand regime: cost being $521,797.2PPP, joint health score of 93.46, QALY of 10.99).[15].
Secondary prophylaxis or tertiary prophylaxis is favored over on-demand therapy for the pediatric and young adult populations, owing to improvements in school activity participation score, daily activity, reduction in annual bleeds, reduction in hospitalizations, and minimal school absenteeism [11,12,17,20,44].The CE of secondary or tertiary prophylaxis using factor VIII is still an underexplored area in terms of the pediatric population in the Indian context.
The current study includes both adult and pediatric population to give a holistic view regarding clinical decision making.Despite promising CE and clinical outcomes, the study was associated with certain limitations.The utility weights were not specific to India but belonged to countries with similar socioeconomic backgrounds, e.g. the Southeast Asian region was used in the study to be consistent with the study requirements.For age stratified bleed rates and age stratified disease specific mortality, a pooled value has been used for all age groups.Further, inhibitor cost was not considered in the study since the inclusion criteria were only patients without inhibitors.
Thus, based on the outcomes obtained from the study, early low-dose prophylaxis with factor VIII is recommended.The analysis was suggestive of a robust reimbursement system required in an India setting.This system should provide a continued support to the patients in getting rapid reimbursements.Additionally, improved health infrastructure is required, and initiatives might be undertaken to reduce OOP expenditure.Creating awareness regarding the benefits of prophylactic therapy is of paramount importance in the current scenario.

Conclusion
The research found that intermediate-dose prophylactic factor VIII therapy is cost effective and offers better clinical outcomes than on-demand therapy for both adult and pediatric hemophilia-A patients without inhibitors.The study suggests that early prophylaxis could lead to improved pediatric outcomes.In resource-limited contexts like India, personalized prophylaxis tailored to bleeding phenotype and activity level could enhance cost-effectiveness and joint health preservation.

Figure 1 .
Figure 1.Model structure and different states of patients.Abbreviations: PWH: Patients with hemophilia: Base state in which persons with hemophilia A (PWH) are entering and starting therapy; Joint disease state: in which PWH have extensive bleeds leading to joint disease (requiring major surgery).Model flow: Individuals diagnosed with hemophilia initially experience a bleeding incident, which can occur with or without joint involvement.When a bleeding incident transpires without joint involvement, patients may either revert to the base state or advance to the joint disease state.Conversely, when a bleeding incident involves joints, patients may either revert to the joint disease state or show improvement and return to the base state.Both the base state and the joint disease state are associated with the possibility of death.The minimum age for entering the model was 2 years for the pediatric population and 18 years for the adult population.

Figure 2 .
Figure 2. Study outcomes in terms of quality adjusted life years gained and total cost.Abbreviation: QALY: Quality adjusted life year.

Figure 4 .
Figure 4. Probabilistic sensitivity analysis representing the cost-effectiveness cloud.Abbreviations: CE: Cost-effectiveness; QALY:Quality adjusted life year.The study analyzed certain probable factors that may affect the results of the study model.1000 simulations were run to check the impact of these factors on the comparison between low-dose prophylactic factor and on-demand factor VIII therapy and the incremental scatter plot graph was generated.In majority of the simulations (99.8%), the low-dose prophylactic factor was better than on-demand factor VIII therapy which means that the low-dose prophylactic factor is not only less expensive but also more effective than on-demand factor VIII therapy.Hence, the factors tested had very little effect on the results of our study.

Figure 5 .
Figure 5. Probabilistic sensitivity analysis representing cost-effectiveness acceptability curve.Abbreviations: CEAC: Cost-effectiveness acceptability curve; INR: Indian Rupee; QALY: Quality adjusted life year.The PSA results were analyzed using the cost-effectiveness acceptability curve.The curve showed that Low-dose prophylactic factor therapy was below the cost-effectiveness threshold in all the simulations (100%) which indicates a cost-effective medication strategy.The prophylactic therapy was cost-effective for both adults and children, no matter what willingness-to-pay level was considered.

Table 1 .
Breakdown of cost distribution for adult and pediatric patients with hemophilia at 'per patient level'.

Table 2 .
Inclusion parameters for targeted literature review.