Which Factors Influence Decisions to Withdraw from Eculizumab: A Qualitative Study of Patients Diagnosed with aHUS

Abstract

Background

Atypical haemolytic uremic syndrome (aHUS) is a rare life-threatening disease. Lifelong treatment with intravenous eculizumab every 2/3 weeks was recommended, but evidence is emerging that many patients can stop complement inhibition and restart should they relapse. However, little is known about the opinions and needs of patients with aHUS on withdrawal.

Objective

We aimed to understand the factors that affect decisions to withdraw from treatment.

Methods

This was a qualitative study embedded in an eculizumab withdrawal trial. Data were collected through in-depth telephone interviews from January 2019 to June 2022. We conducted a thematic analysis using a constant comparative method. Interviewees included eight adults and the parents of 12 children with aHUS approached to participate in the trial. Follow-up interviews were conducted between January 2021 and June 2024 with those who withdrew from eculizumab.

Results

The onset of aHUS had been traumatic for most. Regarding eculizumab, withdrawal group participants talked of the disruptive treatment regimen and side effects, the time off work/school, and impacts on taking holidays. Decisions to withdraw from eculizumab were driven by the wish to lead more normal lives and concerns about long-term treatment. Drivers for declining withdrawal focused on relapse and its perceived impact. After 2 years, the withdrawal group had regained a semblance of normality, though fears about relapse remained, and they were aware of the need for long-term follow-up. Participants had a greater sense of control over the necessary steps should they/their child relapse.

Conclusion

An understanding of patient/parent experiences should guide discussions about eculizumab withdrawal. Although the availability of an alternative complement inhibitor reduces the frequency of infusions, most of the factors influencing withdrawal decisions remain unchanged. Support to alleviate fears in the early stages of withdrawal would be beneficial. Evidence from the main trial on successful withdrawal, and recovery time where eculizumab was reinstated, may provide reassurance to those who are uncertain about withdrawal.

Key Points for Decision Makers

Lifelong treatment can be burdensome for patients and families and have a substantial negative impact on their lives. This is particularly so when the onset of illness occurs, and treatment is commenced, in babies and young children.

Long-term treatment with eculizumab can be disruptive to work and school because of the fortnightly administration and the side effects experienced. There was a dislike for long-term medication, particularly when there was uncertainty as to whether treatment was still warranted. The opportunity to consider treatment withdrawal was welcomed.

Conversations between clinicians and patients/parents about withdrawal should be guided by an understanding of the experiences at onset and while living on treatment, concerns, and fears. Hearing accounts from parents and adults of the positive impact of withdrawing from eculizumab may provide reassurance to others.

Introduction

Atypical haemolytic uremic syndrome (aHUS) is a rare life-threatening disease most frequently due to excessive activation of the complement system, which leads to thrombus formation in small blood vessels, causing damage to internal organs, particularly the kidneys. The onset of aHUS is attributed to certain genetic, environmental, and immunologic factors. In the UK, the incidence of aHUS is 0.41 per million per year [1], and the prevalence in Europe is approximately 4.9 people per million population [2]. As there is the potential for patients with aHUS to relapse, lifelong treatment is recommended [3]. Until 2011, when eculizumab (a monoclonal antibody) was approved in Europe and the USA [4], plasma therapy and dialysis were the recommended treatments for aHUS, but it had little impact on disease morbidity and mortality, and patients’ quality of life was poor [5]. Eculizumab is an effective treatment and, in a genotype-matched cohort, improved 5-year end-stage kidney disease-free survival from 40% to 86% [1]. As eculizumab inhibits the body’s defence against certain infections, there is a potential risk of a severe meningococcal infection [6–8]. The drug is also costly, at £360,000 per year for an adult in the UK, according to British National Formulary data. Eculizumab is administered by intravenous injection every 2 or 3 weeks. For people with aHUS managed with eculizumab, there is the potential disruption of the onset of the illness, the treatment and its side effects. There is also an expectation of life-long treatment and prophylactic antibiotics. Ravulizumab, which has recently been introduced for the treatment of aHUS, reduces the frequency of dosing required and therefore alleviates some of the burden of treatment. However, other factors, including risk of infection, remain the same.

Evidence is emerging that patients can stop eculizumab [9–11] and—if they relapse—can restart treatment, with no evidence of long-term harm [12]. Patient and caregiver views on medication withdrawal have been explored in juvenile idiopathic arthritis [13] and rheumatoid arthritis [14], but little is known about the views of patients with aHUS about eculizumab withdrawal.

As part of a UK trial to establish whether a safety monitoring protocol could be an alternative management strategy to long-term treatment with eculizumab [15–17], we conducted an embedded qualitative study to explore the views of patients (or the parents of affected children) about treatment, withdrawing from treatment, and the acceptable level of monitoring while off the drug. The findings will help to guide clinicians and patients/parents in their discussions about eculizumab withdrawal in clinical consultations.

Methods

This was a qualitative study employing in-depth semi-structured interviews [18] embedded within a trial assessing the safety of eculizumab withdrawal in patients with aHUS [15]. Given the exploratory nature of the research, a qualitative approach was considered appropriate [19]. As the aHUS population is geographically distributed across the UK, telephone interviews were most feasible and appropriate [20]; our Patient and Public Involvement group agreed on this approach. A topic guide (see the electronic supplementary material [ESM]) was developed with the public contributor who was part of the trial team and research grant co-applicant.

Setting and Recruitment

Adults and children with aHUS on eculizumab were identified from the National aHUS database [21]. The Newcastle clinical team and responsible local clinician assessed their medical records to determine suitability for withdrawal [15]. Site clinical teams discussed the trial with eligible patients/parents when they attended for treatment. All were asked to consider participating in the qualitative study and given information and a reply sheet to complete and return if they wished to discuss this with the researcher. The researcher followed this up with a telephone call/email to answer any questions and schedule an interview if they wished to proceed.

The rarity of aHUS meant that the potential pool of participants was limited (n = 28), so recruiting until data saturation was achieved was not possible.

Data Collection

Telephone interviews were conducted by an experienced qualitative researcher (JL [female]). They were scheduled at a time convenient to the participant. Interviews were digitally recorded and guided by a topic guide that was used flexibly to enable participants to speak freely. Verbal consent was obtained at interview and recorded electronically and on paper. At the end of the interview, withdrawal group participants were asked for permission to be approached again at the end of the 2-year trial period for a second interview.

Analysis

There was no a priori theory, and we took an inductive approach to data collection and analysis [22]. Data were analysed thematically using a constant comparative method [23]. A framework of themes was developed from a small number of transcripts, tested and amended accordingly. The full data set was coded (see the ESM for the codebook) using this thematic framework. A second-level analysis involved a process of comparing and contrasting themes within and across interviews and between the first and follow-up interviews. NVivo (version 14) was used as a data management tool. Throughout the study, findings were shared with the wider team, including lay members with direct experience of aHUS, for comment.

Findings

Site staff approached 26 patients/parents to consider participating in the qualitative study. Of these, 24 returned a reply sheet to the researcher (JL), and four did not respond to calls. Between January 2019 and June 2022, eight adults (four withdrawals, four non-withdrawals) and 12 parents of children with aHUS (10 withdrawals, and two non-withdrawals) were interviewed from 9 of 15 participating hospital sites (Table 1). Follow-up interviews were conducted with 11 of the 14 withdrawal group adults/parents between January 2021 and June 2024. Interview durations ranged from 40 to 60 minutes.

Table 1.

Patient age, sex, potential cause of onset of atypical haemolytic uremic syndrome, and time since starting eculizumab

Study ID	Sex	Age, y	Reported potential cause of onseta	Time since starting eculizumab
Adults
Pt 01	Female	26	Pregnancy	3 y
Pt 05	Male	25	Gallstones	2 y
Pt 10	Female	??	Pregnancy	2.5 y
Pt 21	Female	30	Influenza	3 y
Did not withdraw from eculizumab
Pt 02	Female	25	Limb injury	4 y
Pt 03	Female	70	Unsure	8 y
Pt 06	Female	30	Virus	5 y
Pt 07	Male	60	Swollen limb	5 y
Children
Pt 08	Female	5	Unknown	4 y
Pt 09	Female	9	Infected eye	7.5 y
Pt 11	Female	3.5	Unsure	3 y
Pt 12	Female	3.5	Unsure	2 y
Pt 13	Male	15	Unsure	3 y
Pt 14	Male	3.5	Unsure	3 y
Pt 15	Male	4	Unsure	3 y
Pt 16	Female	4.5	Unsure	4 y
Pt 18	Male	13	Unsure	9 y
Pt 19	Female	8.5	Unsure	5 y
Did not withdraw from eculizumab
Pt 17	Female	2	Virus	9 mo
Pt 20	Male	1.5	Unsure	1 y

mo, months; pt, patient; y, year(s)

^aSelf-reported by adults; reported by parents of children.

Three key themes were elicited from the first-stage interview data: trauma of illness onset; adjusting to lifelong eculizumab; and reasons for eculizumab withdrawal/non-withdrawal. The quotations are labelled ‘Ch’ to indicate it is from a child or ‘Ad’ from an adult and ‘W’ to indicate withdrawn or ‘NW’ for not withdrawn from eculizumab (see Tables 2 and 3 for first- and second-stage participant quotations, respectively).

Table 2.

Themes 1–3: Participant quotations

Theme 1: The onset of symptoms and receiving a diagnosis
“She had to be fed through her nose, and it was just a nightmare basically seeing her like that, and her body actually blew up like a balloon. Her nightdresses and her pyjamas were fitted on her, yeah. She was just totally a different child. She didn’t even look like herself. At that time, I was just so depressed that every day I was crying, and even now it’s making me cry now.” P09-Ch-W “I was laid up in bed for five days with the flu, but then my wee started to get really, really dark almost like dark brown black, and I couldn’t eat and I got so ill, and I thought, ‘Do you know, I think something else is wrong here,’ so I went to hospital and they tested my blood and my urine and everything, and they said, ‘Oh your kidneys have failed. It’s a good thing you’ve came in, basically we’ll have to give you some dialysis.” P21-Ad-W “On Christmas Eve … as soon as I’d finished my lunch, I was in the bathroom being sick and diarrhoea. I was really ill. … and he had to get the emergency in, I thought I was ... well I think I was on my way out, … I got rushed off and put straight on … dialysis. But I didn’t know where I was, I’d gone, I was knocking on the pearly gates I think, and they gave me, I don’t know how many lots of dialysis and plasma.” P03-Ad-NW
Theme 2: Adjusting to a lifetime on eculizumab
“He always knew that something (treatment) was going to happen from him being five or six months old. As he got older, it was more challenging because he was becoming more aware when we were going into hospital, so he would kick and scream and cry. It’s really hard to get a cannula into small hands and then having to hold him down when he was distressed, and they couldn’t get it in the hand. … Then he’d try and pull it off, so we’d have to keep him distracted ... and then towards the age of between one and two, it became even tougher because he would start crying and saying, ‘I don’t want to give you my hand.’” P15–Ch-W “It’s a half day travel to go there and come back, and as I’m working part time, my working day will finish by the time I’m back, so … that flexibility with work I was lucky. That would have been [a] big disruption if my work was more strict, so I would have to use my holidays, which I have done.” P16–Ch-W “I think since [child] had the episode and to this day we haven’t been away just because we didn’t want to chance it. I think it would be scary, and I don’t know what we would do if we were abroad. Even we, if we were only a few hours away, those few hours could be fatal, you know trying to get to a hospital.” P11–Ch-W
Theme 3 – Withdrawing/not withdrawing from eculizumab
Reason for wishing to withdraw	Reason for declining to withdraw
“I didn’t really want to be on that drug for the rest of my life. […] I like that I don’t have to take a drug anymore … The PICC line … restricted me a lot because every time I’d go for a shower, I had to put something on my arm to cover it, and I wasn’t allowed to go swimming. I couldn’t go to the gym as much because there was this thing on my arm.” P05–Adult-W “(the doctor) explained there would be a safe way to take her off medication and if anything happened, she could get the medication, so it was really safe and really sure that everything would be okay, even if she got the illness back. We were happy to take her off the medication, hoping that she continues with a normal life as before.’ P19–Ch-W “I just wanted to stop it so that I can feel like I am a normal person. If you want to go on holiday for 20 days, but every fortnight I need to take the eculizumab so we couldn’t go for 20 days, so that bothers us that I am not a normal person.” P01-Ad-W	“I might end up in hospital again, I hate hospitals, and I was in there for long enough last time, nearly three weeks. I thought that was long enough for me basically being stuck in there, not being able to do anything. That’d probably be the worst thing.” P02–Ad-NW “I’ve told them all I’m frightened to death of coming off. If it happens again, I’m in my 70s, I’m not a young person anymore. My readings are good. They’re up. My kidneys are back working, but they did stop. I had renal failure. I’ve just got this fear, and I don’t think I can make it next time it went like that.” P03-Ad–NW “Obviously, at the time it’s really frightening. I’d never been in hospital before. I’d never had any kidney problems. Nobody in my family had ever had kidney problems or anything like this. I think about how sick I was, and I don’t want to be like that again. It’s the uncertainty that I think is a big thing.” P06-Ad-NW

PICC, peripherally inserted central catheter.

Table 3.

Life after eculizumab: participant quotations

Return to normality?

“The main thing is that I’m more energised than ever before. When I was on eculizumab, I didn’t feel so energised. I don’t have body aches now, and before I used to get like body aches every other day. I can go on holiday, and I’m more relaxed, I feel more normal for me. I feel like I’m no more like having a rare disease, it’s like mentality – my mentality, I’m normal.” P01-Ad-W “I think it did affect her going to hospital and having treatment. She’s obviously a lot happier now she hasn’t got to do that. It’s made her feel a bit more normal, more than anything.” P08-Ch-W

A new normal

“The first few months were a bit worrying, but now we’ve adjusted to it […] (to begin with) I was watching her thinking, ‘Is she having a relapse?’ or, ‘She slept a little bit longer last night …’ you know, like, you start questioning yourself, but I felt like it was more me. I think [child] took to it fine.” P11-Ch-W “The main thing for me is I’ve got the dips, and I know if he’s unwell we’ll dip and if I’ve got a problem, I know I can ring the hospital, and we’ll go straight in. As long as you know you’ve got that backup and you know what to do in the event, then I’m okay.” P18-Ch-W “The last conversation we had with (consultant) … he did highlight when she gets older and she thinks of starting a family of her own it’s something she needs to bear in mind and something that she always needs to bring up at any consultations she goes to that she does suffer with this, and she may obviously pass on to her children or cause complications perhaps during pregnancy as well.” P08–Ch–W

Theme 1: The Onset of Symptoms and Receiving a Diagnosis – “I was so Ill. I Thought I was on My Way Out”

Many participants described the onset of aHUS as traumatic and frightening. Some became emotional when giving their account. At onset, most adults experienced severe and sustained vomiting; for others, it was sudden severe stomach pain, darkened urine, localised limb swelling, or extensive bruising from a minor injury. In babies/children, the symptoms were more varied, though a common feature was extreme lethargy and sleepiness. The rarity of aHUS meant that other potential causes, such as pre-eclampsia and meningitis, were investigated. Adults and children underwent extensive tests, including lumbar puncture and kidney biopsy, and received treatments such as dialysis, blood transfusion, and plasma exchange. A few were transferred to different hospitals, over weeks or even months. Several were diagnosed with aHUS within 24 h; for others, it ranged from 1 to 4 weeks, and the longest was 3 months.

Some expressed fear of another episode, “I think with this condition you are always anxious” (P18-Ch-W). Uncertainties about the triggers meant parents were vigilant if their child had any minor illness. Participants had become expert in, and spoke with confidence about, the routine test results and when there was cause for concern. Being aware of, and able to monitor, any changes gave a sense of control over the situation.

Theme 2: Adjusting to a Lifetime on Eculizumab – “We then Started on the Journey of Regular Infusions”

Participants were relieved to be offered eculizumab. After hospital discharge, eculizumab was administered by infusion (ranging from 30 to 80 minutes) every 2 weeks, and for a smaller number every 3 weeks. Some commented that the 2 weeks came around very quickly: “You felt like you were there every week” (P15–Ch–W). Half had progressed to having a nurse administer the drug at home, which saved a trip to hospital. However, this was not without its problems and on occasions had to be abandoned.

With babies/children, there were initial issues with the cannula, which was also stressful for parents if their child became upset. This became less of a problem over time, but remained difficult for many years for some. Some adults and children were given more permanent vascular access (portacath or peripherally inserted central catheter) to administer eculizumab and take blood without using needles. Two had experienced problems with semi-permanent access; one found that it restricted bathing and leisure activities, and another experienced an infection in the central line.

“Every Time I Wake up, it Takes a Couple of Hours to get Going” – The Physical Impact of Eculizumab

Adults attributed a range of physical symptoms to the eculizumab. Tiredness was most cited; for several, this was constant and for others it lasted 1 or 2 days or passed if they were able to sleep after the infusion. With the fortnightly regimen, one person said they were not tired in only 2 weeks of each month. Other symptoms included leg and back pain, and headaches:

After eculizumab for two to three days it makes me feel very tired, and I have body pain, leg pain, and back pain. The leg pain is the worst. At night, I even couldn’t move my legs in bed. P01–Ad-W

In very young children, lethargy and tiredness after treatment was the main issue. Headaches, dizziness, aches and pains, and slight gastrointestinal upset were also mentioned, all of which resolved relatively quickly.

A few experienced no side effects or described them as not too troublesome. One person reported that, after treatment, “I literally get up and go home” (P07–Ad-NW). For another, tiredness came on a few days preceding the eculizumab infusion, which they considered a sign they needed the drug:

You can almost tell though. I know when I need my treatment. Like, I feel tired and more drained, more lethargic. I get sore legs, so I know when it’s treatment time. P06-Ad-NW

“We Work Around Things” – The Social Impact of Taking Eculizumab

The infusions caused general disruption to school, work, and holidays. Those who experienced post-treatment tiredness felt they led a normal life only 1 in every 2 weeks. The treatment, and any post-infusion tiredness, meant time off work and/or school. A few were self-employed and could more flexibly manage their time, though this meant income loss. There were concerns they may be less desirable to future employers and about the stigma of providing proof for time off work.

Certain participants normalised treatment impact. One described taking an afternoon off work as a “pain” but ultimately “no price to pay” (P02-Ad-NW) and another that “it’s just one of those things” (P17-Ch-W).

Taking longer holidays could be problematic, though a few said that, with sufficient lead-in time, the hospital staff were able to support 2-week holidays by gradually shifting treatment days to accommodate specific travel dates. However, some parents were fearful of being farther away from their care team should their child become ill.

In the non-withdrawal group, holidays were less of an issue. They rarely went away on holiday, which was a preference rather than something imposed by their treatment.

We don’t have many holidays, and I don’t let anything interfere with my treatment every fortnight. They can do it abroad if you want to, but I see it [as] a bit pointless. This drug is more important than a holiday. P03-Ad–NW

Theme 3 – Reasons for Withdrawing/not Withdrawing from Eculizumab

Withdrawing from Eculizumab

Parents made the decision for their child to withdraw from eculizumab, though two slightly older children were part of the discussion. Two adults disclosed that their families disagreed with their decision to withdraw. Most gave more than one reason for wishing to withdraw. The cost of the drug was a concern for many, but other reasons related to wanting a ‘normal’ life and issues with eculizumab.

“I just wanted to stop it so I can feel like I am a normal person” – the wish to lead a normal life

Several participants talked of wanting a normal life for themselves or their child. What constituted a normal life varied between participants and was multifactorial. These factors included being able to travel for longer periods and further afield (an issue for those who had close family abroad), a life without regular medication and treatment side effects, and one where their daily life and leisure time were not impacted.

One parent stated that their child was “fed up with trips to the hospital” (P13-Ch-W). Parents had considered their child’s future with lifelong medication, some of whom were as young as 2 years old. They wanted the chance to explore whether their child could lead a normal life without it. The opportunity to withdraw in the safety of a monitored trial was described as a “no lose” situation with the guarantee of immediate reinstatement of eculizumab (that they know works) should their child relapse. Finally, if regular test results, such as kidney function tests, had been normal for a long time, this reassured participants that now was the optimum time to withdraw from eculizumab: “All signs are good – I want to feel normal.” (P01–Ad–W).

Issues with eculizumab

Concerns about long-term eculizumab

Uncertainty about the long-term effects of eculizumab and the requirement for lifelong treatment was a cause of concern. There were also fears about eculizumab being an immunosuppressant and the higher risk of meningitis and pneumonia. This was a major concern for one parent for the 4 years their child had been on eculizumab and was a reason for withdrawing. They felt that, with the monitoring protocol, detecting an aHUS relapse would be easier than detecting that their child had meningitis.

Is the treatment warranted? “If I don’t have to be on it, I don’t want to be on it”

Participants wanted to know whether eculizumab was needed, particularly long term. This was driven to a large degree by the clinical team’s uncertainty about the aHUS diagnosis. Diagnostic uncertainty as a driver for withdrawal was coupled with a dislike of long-term medication where it is not fully justified, and its impact on their bodies, particularly for young children. One parent thought that even a short break from eculizumab would be beneficial as they could stop prophylactic antibiotics. One parent mentioned uncertainty over the optimum eculizumab dose, and withdrawal was suggested as a viable option because of this. When their kidney function and other related tests had been stable for a long time, adults questioned whether they needed eculizumab.

One participant disliked needles and described the fortnightly cannula insertion as traumatising. Their decision to withdraw was driven primarily by eculizumab-related side effects: “My hair was thinning, and I was getting migraines and all these things, so I heard about this study where you could come off it, and I was like, ‘Yes please!’” (P21–Ad-W).

Reasons for not Withdrawing from Eculizumab

The six non-withdrawal participants all stated that having the opportunity to do so safely was a good idea. Of these, two had hoped to withdraw, but the clinical team advised against it. The first had another condition that caused proteinuria; the second was a child, and there were concerns about the impact of the regular blood tests on their veins. For these reasons, the clinical team decided that monitoring disease activity while off eculizumab would be difficult.

For the remaining four participants, the reasons for not withdrawing varied. The one parent commented that it was a relatively short period since their child had commenced eculizumab, and they had experienced complications following surgery for an unrelated condition. Despite the proposed monitoring plan, they felt that detecting a relapse would be difficult as their child was too young to properly communicate that they were unwell.

The three adult participants were concerned about relapse and being as ill as they were initially. All had adapted to living with eculizumab and did not want this disrupted. The first assumed that withdrawal would lead to kidney failure, time off work, and income loss; the 3 weeks spent in hospital were very difficult. For the second, being on eculizumab gave them peace of mind; if they withdrew, they believed than any minor health issue they experienced would leave them terrified that they were relapsing. They had debilitating comorbid conditions and were much older, so felt that they may not survive a relapse. The third, as a “constant worrier,” was anxious about the uncertainty of when relapse might occur and did not want to live with the constant fear that every time they had a cold the aHUS had returned. They also disliked the idea of having their portacath removed and reinserted elsewhere if treatment was resumed. Lastly, putting themselves at risk of a relapse and being ill would negatively affect their family.

Also, I don’t want to be like, “Okay I‘m going to do this” … because it doesn’t just affect me, it affects all my family. That’s the hardest thing of being ill. At the time when I relapsed, it wasn’t me, it was watching them, watching their reactions. It’s hard to discuss. P06-Ad-NW

A final concern was whether, in the 2-year period, there may be a decision to no longer fund the drug. In that eventuality, they believed participants could be left without an effective treatment.

The adult non-withdrawals were interested in the results of the main trial and would consider eculizumab withdrawal if there was ‘definite’ evidence of its safety. However, this evidence would have to demonstrate that someone with the same genetic mutations had safely withdrawn, “because of all of the factors in play” (P06–Ad-NW).

Life After Eculizumab

Participants interviewed after 2 years had not restarted eculizumab. The trial monitoring protocol had given reassurance and a sense of control over what was happening. Only one adult thought the frequency of the initial monitoring was excessive. Most participants were happy that the number of tests/hospital visits had reduced over time. One parent missed the support from the research nurses during monitoring visits, particularly discussing their anxieties about their child.

Two overarching themes were elicited from the data: “Return to normality?” and “A new normal.”

Return to Normality?

Eculizumab withdrawal had positively impacted on participants’ lives in three main ways. The first related to the side effects attributed to eculizumab. One participant said these had disappeared almost overnight. For another, it was taking time to return to their pre aHUS state, but the extreme fatigue was “improving day by day.” The second was the changes to their lives with no longer having treatment. Though taking the time out of work and/or school had become part of their routine, it was liberating to no longer have to do so.

We’ve just booked to go away because then [child] is going to finish the trial, so we thought we’d do a whole celebratory thing for her to kind of say she’s free now. P11–Ch-W

One parent said that, after stopping prophylactic penicillin, their child now recovers more quickly from minor illnesses. It was also a relief to no longer have the psychological impact of witnessing their child’s distress during treatment, for example, cannulation: “From a sort of mental perspective, it’s done us all a world of good” (P15-Ch-W).

Third, there were many references equating the cessation of treatment to being ‘normal’ because of the lower level of disruption to their daily lives. Also, taking the drug had been a reminder that they had an illness and, particularly for children, were different from others.

A New Normal

Despite the positive impact of withdrawal, one participant said that coming off treatment had triggered a rollercoaster of emotions. Concerns about a relapse while off eculizumab continued: “Now I’m off the drug, I feel like a ticking time bomb, it could happen again at any time” (P21–Ad–W).

Early in the trial, parents admitted to closely observing their child and continually looking for signs of a relapse. Most said this had lessened over the 2-year period, but their anxiety remained in the background, and a few were constantly worried. One parent had noticed a change in their child’s behaviour, being more withdrawn and in a world of their own. They were unsure whether this was related to treatment withdrawal or to changes as they entered adolescence.

Participants had a sense of control and greater resolve that they/their child could confidently withdraw from the treatment and were assured they could deal with a relapse. One participant said they took greater care of themselves to avoid becoming ill and triggering a relapse. Regular testing (bloods), having a hospital contact, knowing the procedure should they/their child relapse, and that eculizumab could immediately be re-started was of major importance.

Participants acknowledged that long-term follow-up was required, and parents thought the current monthly monitoring might be reduced over time. Some said they would be happy if this were once or twice a year, providing they had an immediate route into hospital when needed. The majority were waiting to discuss a care plan with their local consultant, but one participant had agreed theirs: “Every six months and that’s for my lifetime. …, it’s not a bother, and it’s actually quite nice knowing I am being monitored and I’m not just being left” (P21–Ad-W).

Discussion

In this qualitative study, we explored the experiences of adult patients with aHUS (and for children, their parents’ experiences) with the onset of aHUS, of taking eculizumab, and with its withdrawal. Little has been reported from the perspectives of adults and (parents of) children with aHUS.

Decisions to Withdraw from, or Remain on, Eculizumab

Key motivations for withdrawal participants were to attain some normalcy in their lives and concerns about potentially unwarranted long-term medication. Side effects were an issue, particularly for adults, which in other conditions impact on patients’ daily lives [24] and are a key determinant in patients’ health-related quality of life [25]. Adults were concerned about their status as a valued workforce member and the stigma of being considered a malingerer because of work absences for treatment. Parents worried about their child being different from their peers and the questions they faced—or would face in the future—when they took time off school for treatment. Withdrawing from eculizumab was considered an opportunity to be a ‘normal’ person. Similar findings on reasons for withdrawal/non-withdrawal of medication have been reported in studies in patients/caregivers with juvenile idiopathic arthritis [13] and rheumatoid arthritis [14]. With aHUS, monitoring and being able to quickly reinstate eculizumab—and knowing it is effective—should they or their child relapse provided reassurance.

The impact of the onset of aHUS was a key driver for declining eculizumab withdrawal. It had resulted in a changed existence from rarely being ill and no experience of hospital to living with the “ticking time bomb” threat of a potential relapse, constantly watching for anything they feel may act as a trigger, and monitoring any changes in their regular tests. Their thoughts about eculizumab withdrawal focused heavily on a relapse and the subsequent disruption. Adults in this group normalised and reframed the disruption to work and holidays with the eculizumab regimen.

After 2 Years of Withdrawal

After 2 years of withdrawal from treatment, adults and parents had regained some degree of normality, almost to how they were previously. Parents talked positively of the difference that not having the treatment and attending hospital on a fortnightly basis had made to their child and family. Adults no longer experienced the debilitating side effects of the treatment, or these were diminishing over time, which meant they could function normally.

All acknowledged the need to be monitored by the local clinical team for the foreseeable future. Adults/parents had a greater sense of control from knowing what to expect and do should they or their child relapse. Parents were cognisant that their child, as they grow older, would have to understand the condition and be aware of the potential triggers of a relapse. This all constituted a new normal. The fear of relapse may lessen with time after treatment withdrawal, and it is evident that patients and carers gain confidence as the length of time from withdrawal increases [26]. However, the need for monitoring will continue, which, although it may impact on patients, also provides reassurance that is valued by patients and carers.

Limitations

A limitation of the study is the low number of non-withdrawal qualitative study participants (6 of 10 potential recruits). Second, two of the four withdrawal adults were lost to follow-up. Although the data from the 2-year withdrawal period do reflect the views of adult patients, the majority were parents of children. However, as children/parents face a longer time on eculizumab than adults, this is an important group to capture.

The introduction of ravulizumab for the treatment of aHUS in some countries has reduced the required dosing frequency (to every 8 weeks in adults). This will reduce the burden of treatment and the impact of regular intravenous injections, which is an important factor for patients [27] and recognised by clinicians as an important factor in decisions about treatment withdrawal [28]. Nevertheless, many of the considerations identified by patients, including risk of infection, risk of relapse, and need for monitoring, are equally relevant to both eculizumab and ravulizumab.

This study focused on the views of patients and parents of children. We did not explore the views of clinicians but recognise that this aspect may influence discussions about treatment withdrawal and the final decision made by the patient/parent. This is not restricted to anti-complement therapies in aHUS but applies to all informed decision making between patients and healthcare professionals.

Conclusions

Most patients/parents experienced a frightening ordeal at disease onset and were grateful that eculizumab had been prescribed. However, over time, the frequency, route of administration, and side effects of eculizumab had become problematic for some. Discussions about eculizumab withdrawal should be informed by an understanding of their experiences of aHUS onset. Withdrawal generated anxiety, and support to alleviate fears in the early stages would be beneficial. Evidence from the main trial on the optimum monitoring, successful withdrawal, and recovery time where eculizumab was reinstated may provide reassurance to those who are uncertain.

Declarations

Funding

This study was funded by the National Institute for Health and Care Research (NIHR) (Grant 15/130/94) Health Technology Assessment programme. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR.

Conflicts of Interest

The authors have no competing interests.

Ethical Approval

A favourable ethical opinion was obtained from North East-Tyne & Wear South Research Ethics (18/NE/0113).

Availability of Data and Material

It is not possible for the data from this study to be made available.

Author Contributions

JL and NS devised the study design and the topic of exploration for the qualitative component. JL conducted the interviews, analysed the data, and drafted the manuscript. NS reviewed and contributed to the final manuscript.