Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B.

In Sweden, prophylactic treatment of boys with severe haemophilia has been practised since 1958 in an attempt to convert the disease from a severe to a milder form. The present study population consisted of 60 severe haemophiliacs (52 A, 8 B), aged 3-32 years. Treatment is started when the boys are 1-2 years of age, the regimens used being 24-40 IU F VIII kg-1 three times weekly in haemophilia-A cases (i.e. greater than 2000 IU kg-1 annually) and 25-40 IU F IX kg-1 twice weekly in haemophilia-B cases. The orthopaedic and radiological joint scores (maximum scores of 90 and 78, respectively) are evaluated as recommended by the World Federation of Haemophilia. Of those subjects aged 3-17 years, 29 out of 35 individuals had joint scores of zero. The oldest group had only minor joint defects. The VIII:C and IX:C concentrations had usually not fallen below 1% of normal. All 60 patients are able to lead normal lives. In conclusion, it appears to be possible to prevent haemophilic arthropathy by giving effective continuous prophylaxis from an early age, and preventing the VIII:C or IX:C concentration from falling below 1% of normal.     

Intracranial haemorrhage in haemophilia A and B

In countries with a good standard of health care, intracranial haemorrhage (ICH) during the neonatal period affects 3·5–4·0% of all haemophilia boys, which is considerably (40–80 times) higher than expected in the normal population. ICHs are also frequent after the neonatal period, affecting 3–10% of the haemophilia population who are mainly treated on demand. The risk is higher in inhibitor patients. Spontaneous haemorrhage is reported more frequently than trauma-induced haemorrhage in most studies. The prevalence of ICH in patients treated with a prophylactic regimen is not known. Although more frequent in younger patients, a substantial proportion of ICH occur in adults, suggesting that general risk factors because of age, such as hypertension, are increasingly important as the haemophiliac gets older. Some studies have reported a substantial proportion of ICH affecting patients with milder forms of haemophilia. The risk of ICH has to be considered when discussing treatment strategies for haemophilia patients.     

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on‐demand‐group, 8% (2/24) children with ICH died and 33% had long‐term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non‐frequent or no prophylaxis.     

Social determinants and health‐related dimensions of quality of life in adult patients with haemophilia

The availability of safe and effective factor replacement therapies, in persons with haemophilia (PWH), has in some countries answered the basic need for treatment of these patients. The findings suggest that adult patients who have always been on prophylaxis reported significantly better physical functioning, and thus better quality of life. This study is designed to evaluate the QoL in adult PWH, by focusing on social determinants of QoL and their relationship with health‐related dimensions, in Tabriz, Iran. The survey instrument was a self‐report 36 items questionnaire, ‘A36 Hemofilia – QoL’, which is a disease‐specific questionnaire for the assessment of the health‐related QoL in adults living with haemophilia. A total of 100 haemophilia A and B patients, aged over 17 years participated in this study within 1 year. QoL total score was 71.88 (±26.89 SD). Patients who treat in our Hemophilia Treatment Center, had better QoL score (P = 0.000), and education has a significant impact on the social aspects of QoL (P = 0.18). The QoL was very poor in urban area in contrast to patients who lived in the city (54.45 vs. 74.21 respectively). Single patients have a better QoL than married patients (76.56 vs. 68.50 respectively). Our results showed that low education and lack of awareness of the diseases among PWH lead to reduce of QoL and more disease complications. More and wider treatment and psychological care for improving quality of life of these patients are seriously recommended.     

Cyclosporin A can achieve immune tolerance in a patient with severe haemophilia B and refractory inhibitors

Immune tolerance induction (ITI) is described in a patient with severe haemophilia B complicated by the presence of an inhibitor. A number of ITI regimes were attempted without success and the patient suffered from frequent relapses and bleeding episodes. Successful ITI was achieved with the additional use of cyclosporin A. The patient developed nephrotic syndrome although had a negative Bethesda titre at this time. When cyclosporin A therapy was ceased, the inhibitor titre rose and the patient suffered again from bleeding episodes. Cyclosporin A was reintroduced at a lower dose. The patient has now received cyclosporin A for 10 years, during which time he has relapsed three times for short periods (2 weeks). He is also on prophylaxis with factor IX three times a week with preinfusion levels >1% and without bleeding.     

A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres

Summary.  A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys ≤18 years of age with haemophilia followed in North American treatment centres. Responses were obtained from 4553 cases (74% haemophilia A, 26% haemophilia B). The frequency of prophylaxis, defined as factor infusion greater than or equal to once per week for ≥45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P < 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P < 0.0001). Use of full-dose prophylaxis, defined as the infusion of 25–40 IU kg⁻¹ of factor VIII on alternate days (minimum three times per week) or 25–40 IU kg⁻¹ of factor IX twice weekly, was similar for boys ≤5 years of age in both Canada and the USA (30% and 33% haemophilia A and 35% and 13% haemophilia B). Reasons for initiating prophylaxis included a history of joint bleeding (88%) and age ≤2 years (23%). For prophylaxis triggered by joint bleeding, 38% of haemophilia treatment centres indicated that they would initiate prophylaxis after the first joint bleed and 66% after a history of target joint bleeding, defined most frequently as 2–4 bleeds over a 3–6 consecutive month period. A central venous line was used to ensure easy venous access for full-dose prophylaxis therapy in 80% of boys ≤5 years of age. These data offer a basis for projecting long-term factor concentrate needs for persons with haemophilia living in North America.     

Paediatric care of the child with haemophilia

The paediatric care of children with haemophilia in developed countries should focus on the health of the child, not on the disorder. Gene therapy offers the hope of an ultimate 'cure' for the disorder, but until this is a viable proposition, patients should be given more control over their treatment, and the focus should be on 'self-monitored and self-adjusted' prophylaxis. New instruments for measuring joint function and radiographic changes, and quality of life are valuable tools in improving the treatment of paediatric care for children with haemophilia.     

Persistent factor VIII inhibitors and orthopaedic complications in children with severe haemophilia A

Summary. Persistence of inhibitors against factor VIII (FVIII) may be a risk factor that increases physical disability in haemophilia A (HA) patients. This study aimed to evaluate prevalence of FVIII inhibitors in previously treated children with severe HA and the impact of persistent inhibitors on knee joint status and lumbar bone mineral density (BMD). Fifty children with severe HA, FVIII <1%; aged 5–16 years were enrolled in this study; they received plasma‐derived FVIII on‐demand treatment for 50–250 exposure days (EDs). Inhibitors were checked at basal visit and were followed up for 1 year, using Bethesda assay. Cross‐sectional clinical scoring and radiological evaluation of the knee joint (by Arnold‐Hilgartner staging and Pettersson score), along with lumbar BMD by Dual Energy X‐ray Absorptiometry (DEXA) were performed. Patients with persistent inhibitors for 1 to 5 years, median 2.5 years, were 10 (20%). Six had high titre and none of them had completely normal knees, seven had advanced knee arthropathy and six had low lumbar BMD in comparison to 2 and 8 of the 40 patients without inhibitors respectively (P < 0.05). Persistence of inhibitors for more than 2 years without immuno‐prophylaxis was a risk factor for joint damage. Low lumbar BMD was found in 88.9% of patients with stages four and five knee arthropathy and in 66.7% of patients with positive hepatitis C. Severe HA children in this Egyptian study had a relatively low prevalence of persistent FVIII inhibitors, which, if not treated, may increase the risk of knee arthropathy and lumbar osteopenia.     

The impact of prophylactic treatment on children with severe haemophilia

Twenty-seven children with severe haemophilia receiving regular prophylactic factor concentrate were evaluated to examine the overall effectiveness of prophylaxis in modern haemophilia care. The median age at the start of prophylaxis was 6.2 years (range 1.3–15.9 years) and the cumulative length of follow-up was 808 months (mean 30, range 7–76 months).
Nine patients required a central venous catheter for venous access (age range 1.3–5.2 years), eight boys could cannulate themselves and in 10 the parents performed regular venepuncture. The mean dose of concentrate given at the time of study was 31.8 U/kg three times weekly (range 12.5–52.6U/kg) or 4900 U/kg/year (range 1900–8200). None developed an inhibitor on prophylaxis, though four had previously had an antibody.
The median average annual number of bleeds in the 27 patients prior to prophylaxis was 14.7 (range 3.7–35.4). On prophylaxis this fell to 1.5 (range 0–12.5) ( P  < 0.001) and in the group as a whole the frequency of bleeds diminished in successive years on prophylaxis.
All 20 children with evidence of arthropathy improved on prophylaxis and eight had reversal of chronic damage such that their joints appeared normal at the time of study. There were reductions in the need for walking aids, in hospital admissions, and in numbers of school days lost for bleeding episodes. All families feel that prophylaxis has brought about an improvement in quality of life.     

Comparison of the quality of life between HIV-positive haemophilia patients and HIV-negative haemophilia patients

Summary. In a prospective study, we tested the hypothesis that an already reduced quality of life in haemophilia patients is further diminished in those haemophilia patients who contracted the human immunodeficiency virus (HIV) as a result of transfusion of coagulation factor preparations. From an available pool of 92 males with haemophilia A or B, 18 patients seropositive for HIV infection and 11 seronegative patients were randomly selected for the study. We applied two instruments to measure the quality of life (QOL) in our patients. The first instrument was the quality of well-being (QWB) scale that unifies QOL into a single score based upon an assessment of the patient's symptoms and health-related reductions in mobility, physical activity and social activity. The second instrument was SF-36, the questionnaire from the Medical Outcome Study (MOS) that measures six dimensions of health status (physical functioning, role functioning, social functioning, pain, mental health and health perception). Measurements were obtained with both instruments at three interviews with each patient over a 1-year interval. As expected, HIV disease reduces QOL in haemophiliacs. The number of bleeding episodes within 2 months of interview was increased in the HIV-positive cohort but not within 6 days of interview, indicating that HIV disease independently affects QOL in haemophilia patients. In a typical 30-year-old patient, haemophilia itself has reduced quality of their lives by 9.3 years, and HIV disease additionally from 8.5 to 20 years. On the MOS scales, the two patient groups differed significantly only in the dimensions of health perception and pain magnitude. Although HIV disease led to a decrement in QOL of haemophilia patients, it also appears that haemophilia patients are able to develop coping skills to prevent more drastic effects of HIV disease on their QOL. Future studies will need to explore the nature and mechanisms of this ‘buffering’ effect.     

Aspects of haemophilia prophylaxis in Sweden

Summary.  Prophylactic treatment of haemophilia has been gaining acceptance as the optimal therapeutic option in an increasing number of haemophilia centres in the developed world in recent years. This paper focus on three aspects of prophylactic therapy: when to start treatment, venous access and the dose/dose interval. Evidence is in favour of prophylactic treatment to be started at an early age using either a peripheral vein with 1–2 injections per week and a successive increase in the frequency depending on the child and the veins, or, using a Port-A-Cath which allows a better prophylactic coverage by infusions preferably every second day in haemophilia A and every third day in haemophilia B.     

Adherence to prophylaxis and quality of life in children and adolescents with severe haemophilia A

Treatment adherence in adolescents with chronic diseases is around 50%, and failure is more common in preventive therapy. In haemophilia, contradictory results are reported by the published studies. The objective of this study was to evaluate adherence with factor VIII (FVIII) prophylaxis in Spanish patients with severe haemophilia A between age 6 and 20 years. Data were collected retrosp‐ectively in the previous 2 years. The primary endpoint was the absolute adherence index (AAI), and the endpoints were related to clinical status, age, prophylaxis regimen, responsibility for factor administration and quality of life (QoL), assessed by the Haemo‐QoL questionnaires. A total of 78 patients from 14 Spanish hospitals were recruited. Adherence ranged between ?64.4 and 66.7 (mean ?3.08). No differences were observed between children and adolescents (7.11 vs. 6.39; P = 0.809). A statistically significant association (P < 0.010) between infra adherent group and target joint was found, as was a statistically significant difference (P < 0.010) between the number of bleeding episodes experienced by the adherent group (mean 1.4) and by infra adherents (mean 4.5). There was no significant difference between AAI and prophylactic regimen (6.35 vs. 6.96, P = 0.848), neither between AAI and the person responsible for factor administration (5.57 vs. 8.79, P = 0.326). The Haemo‐QoL scores (8–12 years) were related to adherence level (P < 0.05). Adherence was approximately ideal and patients perceived a high QoL. Because of the repercussions for compliance, it is essential to work during puberty on emotional and self‐acceptance aspects of the disease, as well as coping, and the patient's family, school and health team relationships.     

Reformulated BeneFix®: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B

BeneFix, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6-12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year(-1); and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX.     

Real‐world comparative analysis of bleeding complications and health‐related quality of life in patients with haemophilia A and haemophilia B

Introduction

Clinical severity and impact of haemophilia on quality of life have been generally considered to be lower for haemophilia B (HB) compared with haemophilia A (HA) patients.

Aims

To compare annual bleeding rate (ABR), target joint development and health‐related quality of life (HRQoL) between adult (≥18 years) severe HA and HB patients using recent data from the Cost of Haemophilia in Europe: a Socioeconomic Survey (CHESS) study.

Methods

Multivariate generalized linear models (GLM) were constructed to assess the relationship between haemophilia type, ABR, HRQoL (derived from EQ‐5D index scores) and the presence of target joints while controlling for covariates.

Results

Of the 1225 patients included, 77% (n = 949) had HA and 23% (n = 278) had HB. Of the 514 patients who completed the EQ‐5D, 78% (n = 405) had HA, and 22% (n = 110) had HB. Unadjusted mean ABR was 3.79 in HA and 4.60 in HB. The presence of ≥1 target joint was reported in 59% and 54% of patients with HA and HB, respectively. Unadjusted mean EQ‐5D index score was 0.78 in HA and 0.76 in HB. Haemophilia type was not a significant predictor of ABR, target joints or HRQoL when adjusted for confounding factors such as BMI, age and replacement therapy regimen.

Conclusion

Data suggest comparable ABR, incidence of target joints and HRQoL between patients with HB and HA indicating comparable clinical severity and disease impact on patient quality of life.