Making economic evaluations more helpful for treatment choices in haemophilia.

AIM: Poorly conducted economic evaluations have the potential to mislead both clinicians, leading to inappropriate treatment choices, and payers who must decide on the reimbursement of treatment costs. This paper reviews the methods used in economic evaluations in haemophilia and proposes standards for conducting and reporting such evaluations in the future. METHODS: A systematic review of economic evaluations in haemophilia published since 2008 was conducted. The reporting and methods of the studies were assessed using the recently published Consolidated Health Economic Evaluation Reporting Guidelines (CHEERS) checklist. The key methodological deficiencies in the studies were recorded. RESULTS: Twenty-one studies met the inclusion criteria, classified as follows: prophylaxis vs. treatment on-demand (five studies); use of bypassing therapy (six); immune tolerance induction (four); and other topics (six). In general, the quality of reporting was good. However, it was poorest for the CHEERS item of patient heterogeneity, with most studies lacking discussion of heterogeneity in the patient population. The main recurring methodological deficiencies were the evaluation of single episodes of care rather than entire treatment strategies; inadequate control for confounders when comparing treatment options; the frequent use of expert opinion to determine drug doses and treatment patterns; lack of consideration of patient heterogeneity; failure to identify patient subgroups; and the inadequate exploration of uncertainty in estimates. CONCLUSIONS: A set of 12 standards for future reporting and conduct of economic evaluations within haemophilia is proposed, with the objective of making such evaluations more relevant and reliable for those making treatment and reimbursement decisions in the future.

Perioperative management of haemophilia B: A critical appraisal of the evidence and current practices.

BACKGROUND: While there is substantial literature addressing the principles of general management of haemophilia, literature on perioperative management of haemostasis is scarce. OBJECTIVE: The aim of this study was to better understand perioperative management among congenital haemophilia B patients (without inhibitors) and to gain insights into real-world surgical practices. METHOD: A systematic literature review, with an emphasis on haemophilia B, was conducted using EMBASE® , Medline® and the Cochrane Library. Studies from 1974 to June 2015 were accessed, and 132 studies were eligible for the full-study review. An international expert panel with five haematologists and one surgeon reviewed the resulting literature and provided further insights. RESULTS: The literature review revealed that documented experience in the perioperative management of bleeding risk in haemophilia B patients is relatively scarce. Therefore, the review was amended to provide a comprehensive overview of the perioperative management for haemophilia A and B patients; the expert panel applied a particular focus to haemophilia B. Several gaps were identified in the literature including the lack of consensus on defining surgery in terms of bleeding risk, optimal factor levels during surgery and lack of robust evidence on surgical outcomes. The ensuing discussions with the expert panel provided validation of some of the results from the systematic literature review and proposed future directions for perioperative management. Suggestions included collaboration with haemophilia treatment centres (HTCs) to collect real-world data on perioperative management, establishing the need for optimal factor level monitoring practice, and the appropriate adoption of extended half-life products in clinical settings.

Low-factor consumption for major surgery in haemophilia B with long-acting recombinant glycoPEGylated factor IX.

INTRODUCTION: Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long-acting recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery. AIM: To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery. METHODS: This was an open-label, multicentre, non-controlled surgery trial aimed at assessing peri- and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg-1 . Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg-1 , repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events. RESULTS: Intraoperative haemostatic effect was rated 'excellent' or 'good' in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra- or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors. CONCLUSIONS: These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri- and postoperative concentrate consumption and infrequent injections as reported with standard FIX products.

Kreuth IV: European consensus proposals for treatment of haemophilia with coagulation factor concentrates.

INTRODUCTION: This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the 'Kreuth IV' meeting in May 2016. AIM: The objective of the meeting was for experts in the field of haemophilia from across Europe to draft resolutions regarding current issues relating to the treatment of haemophilia. RESULTS: Hospitals providing clinical care for people with haemophilia and related disorders are strongly recommended to seek formal designation as either European Haemophilia Treatment Centres (EHTC) or European Haemophilia Comprehensive Care Centres (EHCCC). There should be agreed national protocols or guidelines on management of the ageing patient with haemophilia. The minimum consumption of factor VIII and IX concentrate in any country should be 4 IU and 0.5 IU per capita of general population respectively. Treatment for hepatitis C with direct-acting antiviral agents should be provided to all people with haemophilia on a priority basis. Genotype analysis should be offered to all patients with severe haemophilia. Genetic counselling, when given, should encompass the recommendation that genetic relatives of the affected person be advised to seek genetic counselling. People with inhibitors should have access to bypassing agents, immune tolerance and elective surgery. National or regional tenders for factor concentrates are encouraged. Outcome data including health related quality of life should be collected. Treatment with extended half-life factors should be individualized and protection against bleeding should be improved by increasing trough levels. Steps should be taken to understand and minimize the risk of inhibitor development. CONCLUSION: It is hoped that these recommendations will help to foster equity of haemophilia care throughout Europe.

Research in haemophilia B--approaching the request for high evidence levels in a rare disease.

Payers in European countries request studies with high levels of evidence for decision making also for rare diseases like haemophilia B (HB). The objective of the study was to determine the status quo of current studies in HB regarding the overall level of evidence generated. The methods used for performing the study were systematic literature research in EMBASE and MEDLINE, search terms 'HB' and 'factor IX' (FIX). The inclusion criteria were journal articles (JA), conference abstracts (CA), English language, published between January 2009 and March 2013, studies only; screening of titles, abstracts, full texts subsequently. ClinicalTrials.gov search: unpublished registered trials (RT) concerning HB or FIX. The analysis was performed on research topic, sponsor, recruitment status and study design. Screening of 1639 hits yielded 31 JA describing 35 studies, and 62 CA. FIX was subject of 21 studies (60.0%) and 29 CA (46.8%). Seven studies focused on various aspects of HB, six on haemophilia studies with separate HB data. Screening of 173 hits from ClinicalTrials.gov yielded 42 RT. Overall, 32 RT (76.2%) related to FIX. Measurement of health-related quality of life (HRQoL) was identified in none of these studies, four CA (6.5%), four RT (9.5%). Randomized study design was found in one study (2.9%), four RT (9.5%). Three studies (8.6%) and seven RT (16.7%) were prospective, observational and comparative. The majority of published clinical studies do not meet payers' expectations for evidence. Therefore, clinical investigation concepts addressing randomization, outcomes research including HRQoL and comparison of therapy options should be discussed. Refined statistical methods and exploitation of complementary real-life data sources may fill current evidence gaps concerning rare diseases.

Kreuth III: European consensus proposals for treatment of haemophilia with coagulation factor concentrates.

This report summarizes recommendations relating to haemophilia therapy arising from discussions among experts from 36 European countries during the Kreuth III meeting in April 2013. To optimize the organization of haemophilia care nationally, it is recommended that a formal body be established in each country to include the relevant clinicians, national haemophilia patient organization, health ministry, paying authority and (if appropriate) regulatory authorities. The minimum factor VIII consumption level in a country should be 3 I.U. per capita. Decisions on whether to adopt a new product should not be based solely on cost. Prophylaxis for children with severe haemophilia is already recognized as the optimum therapy. Ongoing prophylaxis for individual adults should also be provided when required based on clinical decision making by the clinician in consultation with the patient. Children with inhibitors who have failed, or who are not suitable for, immune tolerance therapy should be offered prophylaxis with bypassing agents. Single factor concentrates should be used as therapy wherever possible in patients with rare bleeding disorders. Orphan drug designation for a factor concentrate should not be used to hinder the development, licencing and marketing of other products for the same condition which have demonstrably different protein modification or enhancement.

Haemophilia care in Europe - a survey of 35 countries.

A questionnaire was circulated in 2012 to national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The 35 responses received highlighted major differences in the availability of treatment and care. There was a wide range in factor VIII consumption with usage ranging from 0.20 IU per capita in Armenia to 8.56 IU per capita in Sweden (median: IU per capita). The decrease in health budgets in many countries was not matched by decreases in use of FVIII per capita. In the 19 countries that responded to the previous survey, there was a significant improvement in access to prophylaxis and home treatment.

Musculoskeletal problems in persons with inhibitors: how do we treat?

Inhibitors are a serious complication, considerably increasing the morbidity, mortality and cost of treatment in this patient group. The challenge of treating people with haemophilia (PWH) with inhibitors can be met by a well-coordinated multidisciplinary team specialized in haemophilia. Each treatment centre must run a screening programme to detect inhibitors within their population and develop protocols to treat these patients. The treatment centre in Buenos Aires developed a screening programme that tests all our patients twice a year, ensuring early detection of inhibitors and early treatment of complications. In 2006, we analysed the quality of life (QOL) of non-inhibitor patients and compared it with inhibitor patients detected by this programme and found no differences in QOL measured by the SF36 questionnaire and no differences in school absenteeism. When diagnosis of the inhibitor does not come from a screening programme, its presence is suspected upon a lack of response to conventional replacement therapy for musculoskeletal bleeding, losing the 'golden moment' of treatment. This complication is much more serious when facing a traumatic bleed. In this situation, the lack of early diagnosis can lead to permanent damage or even death. Due to the cost of bypassing factors and the lack of experience of the medical team in the treatment of patients with inhibitors, many treatments that would improve the QOL of patients are instituted in an insufficient manner. Therefore, patients with haemophilia and inhibitors are often untreated or undertreated in their community. Orthopaedic surgeons and physiotherapists play a key role in the treatment of these patients and should be included in therapeutic decision making and most specifically in the postoperative treatment of patients with haemophilia and inhibitors. It is important that these patients have quick access to a trained therapeutic team in order to obtain an early diagnosis and treatment plan to prevent the evolution of the pathological process. Early treatment is cost-effective in maintaining and improving the QOL of patients. Experience in patients with haemophilia and inhibitors is not very extensive. Today, this situation is changing, with several treatment centres beginning to perform surgeries in these most complex patients, giving them a chance to improve their QOL. This article presents the experience of experts from various fields involved in treating patients with inhibitors from a developed and developing world perspective.

Haemophilia care in Europe: the ESCHQoL study.

The aim of this study was to determine the clinical conditions of patients with haemophilia within Europe as recommended by the European Commission. In this multicentre, cross-sectional, ambispective study, conducted within 21 European countries patients' clinical data were collected, amongst others haemophilia type, severity, treatment pattern, use of factor products, bleeding, orthopaedic joint scores and infections. A total of 1400 patients, 84.3% with haemophilia A and 15.7% with haemophilia B were enrolled by 42 centres between 2004 and 2006. Thereof, 417 were children (30.0%) and 983 were adults (70.0%). About 70% of patients had severe factor deficiency (<1%). More than half of the adults were carriers of chronic infections (12.6% HIV, 55.8% HCV), compared to only 3.8% children (no HIV, 2.9% HCV). Patients were grouped according to per capita amount of clotting factor used in patients' region of residence in 2005: region 1: >5 IU; region 2: 2-5 IU; region 3: <2 IU. Paediatric and adult patients in region 3 had median numbers of three and eight joint bleeds, respectively, with worse joint scores compared to region 1 with zero and one bleed. Prophylactic therapy was used in only 31.3% children and 8.9% adults with severe haemophilia in region 3 compared to 93.7% and 54.1%, respectively, in region 1. Statistical analysis revealed that residence in areas with low factor consumption/availability is the most prominent risk factor for joint disease. Access of European patients with haemophilia to optimal care with safe factor VIII concentrates is limited and depends on the region of residence.

Haemophilia care in Europe: a survey of 19 countries.

In 2009, a questionnaire was circulated to 19 national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The responses received highlighted differences in the level of care despite the recent promulgation of consensus guidelines designed to standardize the care of haemophilia throughout the continent of Europe. There was a wide range in factor VIII consumption with usage ranging from 0.38 IU per capita in Romania to 8.7 IU per capita in Sweden (median: 3.6 IU per capita). Despite the specific inclusion of coagulation factor concentrate in the WHO list of essential medications, cryoprecipitate is still used in some eastern European countries.

Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS.

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Patterns of immunodominance in HIV-1-specific cytotoxic T lymphocyte responses in two human histocompatibility leukocyte antigens (HLA)-identical siblings with HLA-A*0201 are influenced by epitope mutation.

Primary human immunodeficiency virus (HIV) infection is controlled principally by HIV-specific cytotoxic T lymphocytes (CTL) to a steady-state level of virus load, which strongly influences the ultimate rate of progression to disease. Epitope selection by CTL may be an important determinant of the degree of immune control over the virus. This report describes the CTL responses of two HLA-identical hemophiliac brothers who were exposed to identical batches of Factor VIII and became seropositive within 10 wk of one another. Both have HLA-A*0201. The CTL responses of the two siblings were very dissimilar, one donor making strong responses to two epitopes within p17 Gag (HLA-A*0201-restricted SLYNTVATL and HLA-A3-restricted RLRPGGKKK). The sibling responded to neither epitope, but made strong responses to two epitopes presented by HLA-B7. This was not the result of differences in presentation of the epitopes. However, mutations in both immunodominant epitopes of the p17 Gag responder were seen in proviral sequences of the nonresponder. We then documented the CTL responses to two HLA-A*0201-restricted epitopes, in Gag (SLYNTVATL) and Pol (ILKEPVHGV) in 22 other HIV-infected donors with HLA-A*0201. The majority (71%) generated responses to the Gag epitope. In the 29% of donors failing to respond to the Gag epitope in standard assays, there was evidence of low frequency memory CTL responses using peptide stimulation of PBMC, and most of these donors also showed mutations in or around the Gag epitope. We concluded that HLA class I genotype determines epitope selection initially but that mutation in immunodominant epitopes can profoundly alter the pattern of CTL response.

Management of difficult-to-treat inhibitor patients.

The workshop looked at seven scenarios based on fictional and real-life cases of difficult-to-treat patients with haemophilia A or haemophilia B and inhibitors with the aim of sharing clinical opinion and experience from around the world. Delegate opinions on the best treatment option for each scenario are described together with actual treatment given in real-life cases and its outcome.

Psychometric evaluation of a patient-reported symptom assessment tool for adults with haemophilia (the HAEMO-SYM).

In patients with haemophilia, repeated bleeding events result in significant comorbid conditions that can degrade health-related quality of life. Clinician-reported symptom measures are available for use in patients with haemophilia A or B; however, there has not been a validated patient-reported symptom evaluation instrument available for haemophilia to date. The objective of this study was to develop and evaluate a self-report instrument, the HAEMO-SYM, for measuring symptom severity in patients with haemophilia. Eighty-four haemophilic subjects from Canada and the USA were enrolled and completed the HAEMO-SYM, SF-36, and Health Assessment Questionnaire-Functional Disability Index (HAQ-FDI). Four-week reproducibility was evaluated in 72 stable subjects. Construct validity was assessed by correlating subscale scores with the SF-36, HAQ-FDI, a coping questionnaire and clinical scores. The final 17-item HAEMO-SYM has two subscales: pain and bleeds. Internal consistency reliability was good (Cronbach's alphas, 0.86-0.94) and test-retest reliability was good (Intraclass Correlation Coefficients, 0.75-0.94). HAEMO-SYM subscale scores were significantly correlated with SF-36 scores (P < 0.05 for all except HAEMO-SYM Pain and SF-36 Mental Health), HAQ-FDI scores (P < 0.05 for all but HAEMO-SYM Bleeds with HAQ-FDI Hygiene and Reach), Gilbert scale (P < 0.01), coping (P < 0.05) and global pain (P < 0.001). Mean HAEMO-SYM scores varied significantly in groups defined by severity, HIV status and treatment regimen. Greater symptom severity was associated with more severe disease, HIV-positive status and prophylaxis treatment. The results of this study suggest that the HAEMO-SYM, a haemophilia-specific symptom severity instrument, has good reliability and provides evidence that supports construct validity in patients with haemophilia.

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven] in elective orthopaedic surgery in haemophilic patients with inhibitors.

Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120-180 microg kg(-1) to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as 'excellent' or 'extremely satisfactory' by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

European principles of inhibitor management in patients with haemophilia.

BACKGROUND: In spite of recent major advances in the understanding and treatment of inhibitor development in patients with haemophilia, multidisciplinary management of many of these patients remains suboptimal and highly heterogenous across Europe. METHODS: Following a series of multidisciplinary meetings and a review of the literature, the European haemophilia community of health professionals and patients jointly defined practical optimum standards for ensuring and harmonizing treatment and care for patients with an inhibitor. RESULTS: Ten complementary principles for the management of inhibitors in haemophilia have been developed, emphasizing the importance and benefits of a centralized, multidisciplinary, expert and holistic approach. CONCLUSIONS: This document will serve as a benchmark to improve the multidisciplinary and practical management of patients with inhibitor. Implementation and adherence to each of these principles should have a major positive impact on the management and outcomes of patients developing an inhibitor.

The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding.

The human progesterone receptor (PR) exists as two functionally distinct isoforms, hPRA and hPRB. hPRB functions as a transcriptional activator in most cell and promoter contexts, while hPRA is transcriptionally inactive and functions as a strong ligand-dependent transdominant repressor of steroid hormone receptor transcriptional activity. Although the precise mechanism of hPRA-mediated transrepression is not fully understood, an inhibitory domain (ID) within human PR, which is necessary for transrepression by hPRA, has been identified. Interestingly, although ID is present within both hPR isoforms, it is functionally active only in the context of hPRA, suggesting that the two receptors adopt distinct conformations within the cell which allow hPRA to interact with a set of cofactors that are different from those recognized by hPRB. In support of this hypothesis, we identified, using phage display technology, hPRA-selective peptides which differentially modulate hPRA and hPRB transcriptional activity. Furthermore, using a combination of in vitro and in vivo methodologies, we demonstrate that the two receptors exhibit different cofactor interactions. Specifically, it was determined that hPRA has a higher affinity for the corepressor SMRT than hPRB and that this interaction is facilitated by ID. Interestingly, inhibition of SMRT activity, by either a dominant negative mutant (C'SMRT) or histone deacetylase inhibitors, reverses hPRA-mediated transrepression but does not convert hPRA to a transcriptional activator. Together, these data indicate that the ability of hPRA to transrepress steroid hormone receptor transcriptional activity and its inability to activate progesterone-responsive promoters occur by distinct mechanisms. To this effect, we observed that hPRA, unlike hPRB, was unable to efficiently recruit the transcriptional coactivators GRIP1 and SRC-1 upon agonist binding. Thus, although both receptors contain sequences within their ligand-binding domains known to be required for coactivator binding, the ability of PR to interact with cofactors in a productive manner is regulated by sequences contained within the amino terminus of the receptors. We propose, therefore, that hPRA is transcriptionally inactive due to its inability to efficiently recruit coactivators. Furthermore, our experiments indicate that hPRA interacts efficiently with the corepressor SMRT and that this activity permits it to function as a transdominant repressor.