Living with an inhibitor: Results from the Study of Haemophilia Experiences, Results and Opportunities in Children and young adults with long-standing inhibitors (the SO-HEROIC study)

Abstract Long-standing inhibitors present many day-today difficulties for the affected individual; the unpredictability of bleeds, bleed management, pain and treatment efficacy all affect quality of life. This study explored these issues through focus groups of affected individuals aged 16-25 in the UK. The data from the focus groups was analysed for recurring themes, which were coded under three umbrella headings: ‘daily impact’, ‘education and future’ and ‘resilience and support’. Participants felt isolated through geography and being extra ‘rare’ within the bleeding disorders community; used pain as a gauge of bleed resolution, often without use of analgesia; described transition to adult care as particularly worrying; and explained the potential impact of living with an inhibitor on future career options. Peer-to-peer networking could provide emotional support for these young adults, who could also be role models for the future. Despite the burden of living with an inhibitor and its treatment, participants described a good quality of life from their own perspectives. With new therapeutic options for these individuals on the horizon, they look forward to a future with fewer bleeds and less pain.

are treated with immune tolerance using recombinant factor VIII/IX in the first instance, with various success rates, followed by additional therapies such as plasma derived factor and immune suppression for those who are deemed resistant to first-line therapy. In those children for whom immune tolerance fails, bypassing agent therapy with rFVIIa (NovoSeven, Novo Nordisk A/S Bagsvaerd, Denmark) or Factor Eight Inhibitor Bypassing Agent (FEIBA) (Shire (formerly Baxalta), Deerfield, Illinois, USA) are used either following bleeding episodes or prophylactically to prevent bleeds. [3] The presence of inhibitors impairs quality of life (QoL) in children with haemophilia and their caregivers [4] and increases caregiver burden. [5,6] Frequent bleeding episodes substantially impact family life, causing pain and worsening health and quality of life scores. [7,8] Arthropathy and restriction of joint movement are worse than in people without inhibitors and, together with pain, occur at an earlier age. This is associated with greater impairment of mobility and absence from work and school. [9] Despite this quantitative evidence of the impact of having and living with an inhibitor, little is known about the impact on daily life of young people. A recent consensus report noted that the instruments used to measure QoL in people with haemophilia and inhibitors are complex, and not designed to deal with the day-today variability associated with erratic bleeding patterns and the differing concerns of children and adults. [10] It is therefore possible that specialist haemophilia services do not fully recognise the needs of patients and families. It is believed that the number of children and young people with long-standing inhibitors reaching adulthood is increasing, [3] and this has important implications for managing the transition to adult services. [11] This study aimed to better understand the impact and concerns of young people living with haemophilia and inhibitors across the UK, and the issues they face, through focus groups and interviews.

Subject identification
We identified all young people aged 16-25 years with inhibitors via the National Haemophilia Database (NHD) by NHD number and centre attended. A questionnaire was sent to all identified young people via their haemophilia centres; the nurses at the centres identified the participants by the NHD number and forwarded the survey to them. The questionnaire was returned by freepost. Respondents were then invited to participate in focus groups.

Focus groups
We ran three focus groups. The first ran alongside a national inhibitor event; however, unfortunately, only one young person attended this meeting. Two others had indicated attendance but had bleeds on the day, which precluded them from travelling. The young man who was at the event suggested that a person with haemophilia facilitating the patient focus group would be more in-keeping with living with haemophilia, as they would have more of an understanding of the dayto-day issues this raises.
The second focus group was facilitated by a patient co-researcher. The focus group of young people from diverse socio-demographic and geographical backgrounds was audio recorded, transcribed verbatim, and coded by hand by the researchers. The third focus group was video recorded. This methodology has recently been used in a video diary research project about living with haemophilia to gain deeper insight into living with haemophilia and proved popular with participants. [12] The participants in the video focus group were of similar socio-demographic backgrounds, and all were studying at, or had achieved degree-level education.
Data from the focus groups were analysed for recurring themes by the study team, using modified grounded theory methodology. [13] Results Twenty-eight young people with long-standing inhibitors were identified from the NHD data. They attended 16 haemophilia centres. The haemophilia nurses reported that six patients were ineligible for the study as they either no longer had an inhibitor (n=2) or they had other health issues (intracranial haemorrhage, autism, developmental delay) that precluded them from participation (n=4). A further four individuals with inhibitors were identified by nurses at the centres, who were also approached and agreed to participate.
Six young men with haemophilia A and a longstanding inhibitor responded to our initial survey. Immune tolerance therapy (ITT) had failed in four of the six; two of the six had not received ITT. All respondents described limitations on physical activity and noted that they had more bleeds that took longer to resolve because of their inhibitor. Four participants agreed to participate in a focus group. A further three participated in the video stories. Demographic data is shown in Table 1.

Data analysis
Data from the focus groups and the video interviews were analysed for recurring themes by the study team.
Fourteen topics were identified, which are listed in Table 2. The themes were coded under three umbrella headings: 'daily impact', 'education and future' and 'resilience and support'. These are discussed further here with direct anonymous quotations to support the analysis and results.

DAILY IMPACT
Living with an inhibitor revealed daily issues mostly related to the unpredictability of bleeding, despite prophylaxis. This served as a daily reminder that haemophilia controlled the person rather than the person controlling haemophilia.

Hospitals/transition/complexity of care
There was a clear recognition that an inhibitor made routine treatment and assessment more complex. This included having to travel long distances to access specialist care, and a realisation that the level of care provided across regions of the UK was variable. This caused concerns that healthcare professional lacked knowledge and skills, and that young people had to be their own experts.
'Yes, it's unpredictability and stigmas around it. So, professionals hearing that you've got haemophilia and understanding what that means, but not really understanding how to deal with an inhibitor patient.' Transition from paediatric to adult care raised concerns about loss of prior knowledge about the person with haemophilia, his inhibitor, his self-management skills and assessment of treatment outcomes, resulting in unnecessary hospital visits.
'Last year, I've just made the switch to the adult clinic. I don't know how it works. I was quite gutted to swap over, to be quite honest. The new consultant is great, but when you've worked with someone for all those years, you kind of … they know you, so you don't really have to explain anything.' Self-management and treatment burden Treatment burden was described. The relentlessness of daily treatment, either for immune tolerance or when on bypassing agent prophylaxis, with little option for new therapies on the horizon, leads to a lack of control.
'It took me an hour and a half to inject that every morning, to mix it … and I had to wait for it to mix, because Fanhdi and FEIBA don't mix very well … So, it's taking half an hour to mix and then you've got to inject, but you can't inject that fast because that amount … I can't remember how much it worked out at, but it's 100-odd ml -you can't just ram that into your veins without doing  Recognising bleeds early and treating them was seen as important; however, there was also a realisation that, despite good treatment, joint disease was already an issue. Some periods with few bleeds were reported, possibly related to age and activity.

'I think at the moment I have one [bleed] a month, like in my target joints and my elbows. But after I'd gotten through being a teenager, I definitely plateaued out, which I think is expected a bit.'
There were times when bleeds occurred spontaneously, leading to questioning treatment response and amending therapy for periods of time. This reveals how people with chronic pain and intermittent acute pain are able to override their pain thresholds, with or without analgesia, to participate in day-to-day activities. While this indicates great strength of character, it also highlights the potential 'risks' that people with inhibitors are prepared to take -or have to take -to maintain a career and income to achieve financial stability.

Inhibitor knowledge and understanding
Most participants had developed inhibitors within a few exposure days as very young children. All had gone through several attempts at immune tolerance, had extended periods of bypassing agent prophylaxis, and exhibited many signs of living with a long-term inhibitor. They had 'learned' their inhibitor knowledge in many differing ways, all coming to an understanding of complex medical knowledge and utilising this to come to terms with their current condition, seemingly without anger or frustration. There was discussion about variation in treatment, dependent on the geographical area where participants lived, or which centre they attended. There was agreement that the number of people with inhibitors in each haemophilia centre was small, with larger centres having more patients and thus, they thought, better access to new therapies and overall better care. It was felt that this inequity was unfair and should be remedied.

RESILIENCE AND SUPPORT
The interviews and focus groups reveal a community of resilient young adults, who are striving to live as near normal lives as possible. They have described their daily lives, and how they cope with bleeds, immobility and pain. They are determined young adults who have reached their current life status due to support from friends and family, who they describe as being key players in their lives.

Importance of family
Family are clearly the most important support mechanism in younger children's lives. In this study, family remained important supporters, even when young adults had left home and moved considerable distances to attend university or work in other cities. There was, however, recognition not only of how important that family support was, but how the inhibitor had affected the whole family and not just the individual with it. Some reflected on amusing and positive aspects of being a friend of someone with an inhibitor.
'My friends are all pretty good; looking after me, making sure I was alright -they were all just thrilled to have a friend in a wheelchair, pretty much.' One young man reflected on not being the only person with health challenges at university, and how sharing health experiences with people with other long-term conditions could also be positive in gaining friendship and support.
'There was one person who lived in my halls; he had a condition… I can't even remember what it was. It was kind of nice that we both… I suppose we probably bonded over the fact that we were both kind of the weird ones with medical conditions.'

Self-esteem
There was discussion of haemophilia making people the people that they are today, with participants expressing that they would not know how to live with a different, 'normal' lifestyle. Despite all the negative things that each person had gone though, there was positivity about how they presented themselves, spoke about their lives and saw their futures. All the participants were vocal, engaged, interesting and self-aware; they portrayed great self-worth, resilience and self-esteem.
'I worry more that other people think … It doesn't bother me, but they're like, "Oh, he's in a wheelchair," you know, like judging what they think it will be like, stuff like that. That can be a bit annoying.'

Inhibitor community
How to seek and obtain support was discussed during the focus groups. For most, support came directly from family and friends. The focus group itself was seen as supportive and was, for some, the first time they had spoken to someone else living with an inhibitor. There was a recognition that they could be role models themselves -showing that life with an inhibitor can be good.

Discussion
This is the first study we know of to engage young adults with long-standing inhibitors in qualitative research that examines, from their perspective, life with an inhibitor. We used mixed methodsinterviews, focus groups and videography -to play to the participants' strengths. This has revealed a small community of resilient young adults who are keen to share personal experiences individually and in a group, to support others in similar situations. We have described how having a long-term inhibitor impacts on daily life, resulting in unpredictability. Bleeds have a significant impact on planning, leading to restrictions in activity and increased reliance on parents and family, compared with young people of similar ages with haemophilia only. Despite being predominantly treated with bypassing agent prophylaxis, most participants described bleeding episodes that were unpredictable and treatment of bleeds as burdensome. Morfini et al [14] described how prophylaxis with bypassing agents improved quality of life for people with inhibitors. Bleed reduction is only possible with repeated injections and full treatment compliance. In an observational study of FEIBA use, only 24.5% of participants on prophylaxis were bleedfree for a year, with a mean of five bleeds per year being experienced [15] . Prophylaxis with NovoSeven reveals only a 45-59% reduction in bleed rate, resulting in repeated bleeds [16] .
Despite a clear understanding of the need for prophylaxis, several participants discussed deliberately skipping doses. They related this to treatment burden, particularly the amount of time needed and the impact this had on their lives. It is well known that adolescents with haemophilia struggle with adherence to prescribed therapy [17,18] . This is in part because of time constraints, which are made worse by the need for ongoing CVAD use, as this demands more care and attention to limit infection risk [19] . Dose-skipping can lead to further bleeds, impacting on mobility and the ability to go to school or work, and causes considerable pain.
We have discovered that pain is a significant issue for this group of young people. They describe putting up with pain ('I just grit my teeth and bear it') because they dislike the side-effects of analgesia, and of opioids in particular. Pain has recently been described in a cohort of younger children with haemophilia in the UK treated with prophylaxis and is poorly understood by haemophilia healthcare professionals [20] . Further work is needed to understand this reluctance to improve pain assessment and to inform the use of non-pharmacological alternatives (e.g. physiotherapy, complementary therapies, exercise) that might improve pain management.
With regard to the future, in terms of education and careers, we found that schools had been less than helpful at coping with reduced mobility, and that managing self-treatment at university presented organisational challenges. More positively, peer relationships were good. Despite the practical challenges, study participants strive to live as normal a lifestyle as possible, adapting and adjusting in 'adhoc' ways to fulfil their dreams. Young describes how difficulties with high school education have an impact on higher education and career choice for those with inhibitors, given their limited mobility due to haemophilic arthropathy [19] . In our study, all participants were studying (or hoping to study) at higher education facilities, and were choosing careers that were feasible, given their physical abilities. Career choices had been made and changed based on perceived limitations (moving from the police force to security, for example), but also as a result of personal experience. One participant had chosen physiotherapy as a career because of his personal involvement with healthcare provision. Achieving a 'position in society' through higher education is recognised as an important step to adulthood for young men with haemophilia [21] .
Growing up 'feeling different', even within one's own family, is another aspect of living with an inhibitor. Palareti et al describe how haemophilia 'plays a role in the individual's growth within the family' and how this impacts on all aspects of daily life [22] . Participants in this study have told us that living with an inhibitor is misunderstood even by their relatives with haemophilia and can lead to isolation. Family support is crucial for children growing up with haemophilia [23] . During adolescence the child develops self-management skills and takes on self-responsibility from his parents [24] . The loss of this support as adolescents move into higher education or away from home is challenging for some [25] , with many having to fully manage care ('self-infusion, ordering supplies, maintaining adherence and navigating the healthcare system') for the first time [26] . Participants in this study described this as a major challenge, particularly for management of 'stock levels' due to the unpredictability of bleeds.
Belonging to this small sub-section of people with haemophilia can be isolating. Those in this study lived in geographically disparate areas of the UK, and for some this was the first time they had met another person with an inhibitor. Peer-to-peer networking for this group could provide emotional support. Due to the logistical difficulties of meeting face-to-face, this could be through online networks for those with haemophilia and/or inhibitors [27,28] .

Conclusion
The number of young adults living with an inhibitor continues to grow as more people live longer with haemophilia in the post-HIV era. We have shown that good QoL can be achieved from the patients' own viewpoint, but requires intensive treatment, good adherence, and regular healthcare provider intervention and attention. Treatment is burdensome, and patients benefit from supportive relationships with family and peers, as well as healthcare providers. These relationships can be 'virtual' as well as face-toface, sharing experiences to benefit others in a similar position. With good treatment, overall outcomes are promising, with participants attending higher education and planning future careers that will enable them to be a valuable part of society.
New therapeutic options (new factor therapies with extended half-lives and non-factor therapies) offer opportunities for this group of individuals. For the first time, they can look forward to a life with less or no bleeds, less treatment (particularly intra-venous) and a lower disease/treatment burden. Access to the new treatments is currently limited. These therapies are still undergoing clinical trials and participation is determined by the motivation of haemophilia centre staff to become involved and by geographical constraints. The participants in this study were acutely aware of these constraints and hoped, very vocally, for a health service that could provide the same standard of care for all people with haemophilia and inhibitors across the UK. This is something we, as healthcare providers, should also strive for.

Limitations
This is an observational study of a small number of young adults from similar socio-demographic backgrounds, with long-standing inhibitors in the UK, describing their personal experiences. The results reported in this study therefore may not be generalisable and may not reflect the views of young people from more financially or socially disadvantaged backgrounds, who did not participate in the focus groups. This requires further study. However, trustworthiness in qualitative research supports the argument that findings are 'worth paying attention to' [29] . We believe that the results in this study add valuable insights for haemophilia healthcare providers.