The potential impact of gene therapy on health-related quality of life (HRQoL) domains in haemophilia

Hypothesised effects of potential gene therapy for haemophilia on domains of the Haemophilia Activities List (HAL)

HAL domain	LYING-DOWN / SITTING / KNEELING / STANDING	FUNCTION OF THE LEGS	FUNCTION OF THE ARMS	USE OF TRANSPORTATION	SELF-CARE	HOUSEHOLD TASKS	LEISURE ACTIVITIES
Hypothesised directionality* and magnitude of domain scores
Score interpretation	Higher/increased scores = Less functional limitationLower/decreased scores = More functional limitation
Hypothesis rationale	Impact of rehabilitative therapy not likely to be seen after 1 month (recall period)	Over time, chance for greater functioning of legs after therapy	Improved function of arms is likely to occur concurrently with improved function of legs	Use of transport is unlikely to change as PWH are not more or less likely to use transport as a result of any treatment regimen	Dated list of self-care activities, thus difficult to accurately measure this HRQoL domain with this instrument	Dated list of household tasks, thus difficult to accurately measure this HRQoL domain with this instrument	Large expected impact of gene therapy after 12 months of therapy
Comments from expert working group	Rehabilitative physiotherapy would have more of an impact on this domain compared with the haemophilia treatment itself	The lower extremities are more commonly affected by this condition, such as the ankles and the knees	The elbows would be the most impacted area in the upper extremitiesThe instrument is not considered to assess function of the upper arms well		Confidence to partake in activities would improve opportunity for self-careImportant to consider that PWH adapt well to their condition as they would have been dealing with it their whole lifeSelf-care improves if pain improves	Important to consider that PWH adapt well to their condition as they would have been dealing with it their whole life	Ability to take part in activities is important to emotional wellbeingDomain name considered misleading and should be more reflective of physical activities; ‘leisure’ is a very broad termIn the longer term more intensive sports activities could be started; weight loss is also possible

Hypothesised effects of potential gene therapy for haemophilia on domains of the Haemophilia-specific Quality of Life Questionnaire for Adults (Haemo-QoL-A)

Haemo-QoL-A domain	PHYSICAL/ROLE FUNCTIONING	WORRY	CONSEQUENCES OF BLEEDING	EMOTIONAL IMPACT	TREATMENT CONCERNS
Hypothesised directionality* and magnitude of domain score
Score interpretation	Higher/increased scores = Better HRQoL or less impairmentLower/decreased scores = Worse HRQoL or less impairment
Hypothesis rationale	Physical functioning expected to improve due to stabilised factor levels and fewer joint bleedsRole functioning expected to disappear or become irrelevant in gene therapy due to nature of the therapy	Worries expected to decrease and HRQoL to increase in the long term as factor levels expected to improve with gene therapy	Consequences of bleeding will decrease (and therefore domain score will improve) with treatment advancement as number of bleeds are likely to decrease	The emotional impact of treatment outcomes may either positively impact a patient (e.g., new sense of freedom, ability to partake in rigorous activities) or negatively impact a patient (e.g., loss of identity, reflection of time lost)	Items within domain were considered dated and not fit for purpose in the context of novel treatment regimens, such as gene therapy
Comments from expert working group	Patients will not need to infuse prior to physical activity	Worry may be engrained and long-lasting, therefore perhaps unlikely to change rapidly in the short termTypes of worries a PWH may have will be largely impacted by their demographics, such as their age, parental status, type of work or school stage	Although bleeding consequences reduce with treatment advancement, PWH will remain aware/conscious of needing to be compliant with treatment in order to reduce consequencesAbility to clot and heal in gene therapy more than any other commonly used existing treatment	There could be a deterioration in emotional wellbeing in the short term on gene therapy, but an improvement in the long term	Advanced or novel treatments can be more costly and are not necessarily covered by insurance or national health service, which could be a potential treatment concernAssumption with gene therapy is patient will only need treatment oncePotential selection bias may occur where patients with fewer treatment concerns are more likely to enrol in clinical studiesSome uncertainties tend to exist around novel regimens, resulting in potential treatment concernsKnown complications or adverse events for commonly used existing therapies may result in treatment concerns

Hypothesised effects of potential gene therapy for haemophilia on domains of the Patient Reported Outcomes, Burdens and Experiences (PROBE)

PROBE domain	DEMOGRAPHIC DATA	PATIENT-REPORTED OUTCOMES – GENERAL HEALTH PROBLEMS	HAEMOPHILIA-RELATED HEALTH	EQ-5D-5L AND EQ-VAS
Hypothesised directionality* and magnitude of domain score
Score interpretation	Higher/increased scores = Better health statusLower/decreased scores = Worse health status
Hypothesis rationale	Gene therapy expected to have strong impact on this domain, such as weight change, education level (ability to stay within education) and relationships	Strong impact expected on this domain assuming treatment will result in normal factor levels (40–50%)	Strong impact expected on this domain as ABR, ‘target’ or damaged joints, range of motion and life-threatening bleeds expected to improve due to higher factor levels	Strong impacts expected on mobility, anxiety and depression, and on EQ-VAS scoresLimitations to relevance of items on self-care, usual activities, and type of pain, and therefore difficult to accurately measure
Comments from expert working group	Improved educational status may only be evident at older ages as gene therapy is not available to children	Large impact expected on acute and chronic pain due to decrease in bleeds, anxiety and depression, activities of daily living and school/workJoint surgery outcomes expected to improve due to more protection (normal factor levels), as well as reduced associated surgery costs as less post-surgery complications expected to occurAnxiety and depression are very important concepts within this domainDefinition of normal factor levels differs between patientsTheoretical increase in risk of heart complications and cancer; however this is not likely to be a major concern for PWH who are more likely to be concerned about efficacy of therapies to increase their ability to partake in activities	Potential for improvement in ABR is dependent upon patient's baseline ABR, which will be different according to geographical location, i.e., PWH in developed countries may report 0–1 ABR (no room for improvement), whereas PWH in developing countries may report 20–30 ABR (room for improvement)	Increased granularity in the detail of the various subdomains is neededImportant to consider that PWH have been shown to report much higher utilities than their health status would suggest due to adaptability and coping mechanisms; improvement in scores might only been seen for patients with lower baseline scores