Hemophilia A and B are rare, X-linked bleeding disorders. My Life, Our Future (MLOF) is a collaborative project established to genotype and study hemophilia. Patients were enrolled at US hemophilia ...treatment centers (HTCs). Genotyping was performed centrally using next-generation sequencing (NGS) with an approach that detected common F8 gene inversions simultaneously with F8 and F9 gene sequencing followed by confirmation using standard genotyping methods. Sixty-nine HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. Of the 924 unique variants found, 285 were novel. Predicted gene-disrupting variants were common in severe disease; missense variants predominated in mild–moderate disease. Novel DNA variants accounted for ∼30% of variants found and were detected continuously throughout the project, indicating that additional variation likely remains undiscovered. The NGS approach detected >1 reportable variants in 36 patients (10 females), a finding with potential clinical implications. NGS also detected incidental variants unlikely to cause disease, including 11 variants previously reported in hemophilia. Although these genes are thought to be conserved, our findings support caution in interpretation of new variants. In summary, MLOF has contributed significantly toward variant annotation in the F8 and F9 genes. In the near future, investigators will be able to access MLOF data and repository samples for research to advance our understanding of hemophilia.
•MLOF used an innovative approach to genotype 3000 hemophilia patients identifying likely causative variants in 98.4% of patients.•Hemophilia genotyping should include structural variation, F8 inversions (for hemophilia A), and consideration of gene-wide approaches.
The treatment of human immunodeficiency virus (HIV) infection has undergone considerable change.
1
–
3
Protease inhibitors and non–nucleoside-analogue reverse-transcriptase inhibitors, when used as ...part of combination drug regimens, can profoundly suppress viral replication, with consequent repletion of CD4+ cell counts.
4
–
7
Multiple clinical trials have shown the virologic and immunologic efficacy of the newer, highly active antiretroviral-drug combinations
7
,
8
by measuring the plasma load of HIV RNA and CD4+ cell counts.
9
–
16
In addition, prophylactic medications are now being used routinely to prevent disseminated
Mycobacterium avium
complex infection.
Several reports have described reductions in mortality and in the rate of hospitalization . . .
Rare coagulation disorders (RCDs) present a considerable and multifaceted public health risk. Although inherited RCDs affect a minor segment of any local healthcare delivery system, their global ...impact is major and highlight the challenges of delivering healthcare services to any rare disease population. These include but are not limited to: (1) a general lack of knowledge about and familiarity with the genetic and clinical implications of the disorder among affected patients, and both urgent and specialty care providers; (2) the potential for preventable morbidity and mortality related to delayed diagnosis and treatment; (3) the lack of safe and effective therapies; and (4) minimal research activity to establish and improve standards of care. A multiagency national partnership has established an approach to address these problems through development of a clinical, genetic, and treatment-related web-based data-collection tool that will: (1) generate a reliable, sufficient knowledge base for these disorders; (2) facilitate new product licensure through subject identification and access to comparative historical treatment data; and (3) serve as an effective tool for outcomes research and post-licensure product surveillance. To maximize impact, this database is being harmonized with a European data-collection effort. Database development and harmonization is in progress. A resource library was completed and disseminated to major national and international bleeding disorder websites to provide state-of-the-art patient and provider education on each RCD. We believe that this model is effective and adaptable to other rare conditions.
Abstract Specialists in rare disorders often face challenges in collecting surveillance and research data. As movement toward more fully realizing the potential of electronic health information gains ...momentum, practitioners who treat individuals with rare disorders are in need of public–private support to tap into the advantages offered by the developing electronic information technologies and the interoperability standards promulgated by the USDHHS. The not-for-profit American Thrombosis and Hemostasis Network (ATHN) was created in 2006 to provide stewardship of a secure, national, web-based database to support federally funded hemophilia treatment centers (HTCs) across the country. In pursuit of its mission to support clinical outcomes analysis, research, advocacy, and public health reporting in the hemostasis and thrombosis community, ATHN has established a spectrum of community-based partnerships. This paper describes the process and public health benefits of creating formal relationships with 127 of the 134 HTCs from 12 regional networks across the U.S., government agencies such as the CDC, Health Resources and Services Administration, and NIH; consumer-based organizations; and industry leaders. This community-based partnership model can be applied to other rare disorders communities with high economic and public health impact.
Knowledge and Therapeutic Gaps Shapiro, Amy D., MD; Soucie, J. Michael, PhD; Peyvandi, Flora, MD ...
American journal of preventive medicine,
2011, Letnik:
41, Številka:
6
Journal Article
Recenzirano
Abstract Rare coagulation disorders (RCDs) present a considerable and multifaceted public health risk. Although inherited RCDs affect a minor segment of any local healthcare delivery system, their ...global impact is major and highlight the challenges of delivering healthcare services to any rare disease population. These include but are not limited to: (1) a general lack of knowledge about and familiarity with the genetic and clinical implications of the disorder among affected patients, and both urgent and specialty care providers; (2) the potential for preventable morbidity and mortality related to delayed diagnosis and treatment; (3) the lack of safe and effective therapies; and (4) minimal research activity to establish and improve standards of care. A multiagency national partnership has established an approach to address these problems through development of a clinical, genetic, and treatment-related web-based data-collection tool that will: (1) generate a reliable, sufficient knowledge base for these disorders; (2) facilitate new product licensure through subject identification and access to comparative historical treatment data; and (3) serve as an effective tool for outcomes research and post-licensure product surveillance. To maximize impact, this database is being harmonized with a European data-collection effort. Database development and harmonization is in progress. A resource library was completed and disseminated to major national and international bleeding disorder websites to provide state-of-the-art patient and provider education on each RCD. We believe that this model is effective and adaptable to other rare conditions.
PURPOSE: Most HIV-infected persons are now treated as ambulatory patients. Obtaining continually updated data about these patients' changing conditions, therapies, and reimbursement is essential to ...health care provision and planning. The systematic tracking of patient medical and laboratory information in an ongoing commercial data collection program (The Health Research Network) allows clinicians to better understand health outcomes, practice patterns, and epidemiologic trends for their patients.
METHODS: To evaluate trends in conditions and therapies of ambulatory HIV-infected patients, we analyzed such data electronically and prospectively collected in the HIV Outpatient Study (HOPS) from 1992 through 1996 from 1876 patients seen in 11,755 clinic visits to ten HIV clinical practices.
RESULTS: Patients were as likely to be diagnosed with
Mycobacterium avium complex (MAC 5.4 cases per 100 person-years) or wasting syndrome (7.8 cases per 100 person-years), as
Pneumocystis carinii pneumonia (PCP; 7.6 cases per 100 person-years) or Kaposi sarcoma (KS; 6.9 cases per 100 person-years). A nested analysis showed that HIV-infected cigarette smokers were at substantially greater risk of pneumonia (relative hazard RH = 2.3), bronchitis (RH = 1.7) and hairy leukoplakia (RH = 1.9) than nonsmokers. By 1996, 35 (56%) of 62 patients with PCP, 9 (30%) of 30 patients with other pneumonias, 28 (90%) of 31 patients with KS, 35 (73%) of 48 patients with MAC, and 24 (63%) of 38 patients with cytomegalovirus retinitis were treated without hospitalization.
CONCLUSIONS: The HOPS provides continually updated information on the changing characteristics, conditions, and therapy of ambulatory HIV-infected patients.
Background: Continuous prophylaxis, or the routine replacement of deficient clotting factor, is the standard of care therapy for individuals with severe hemophilia A and joint bleeding. In the United ...States (US), the majority of eligible patients are prescribed continuous prophylaxis, including approximately 75% of children < 20 years of age. However, up to 30% of severe hemophilia A patients develop neutralizing alloantibodies that render factor replacement ineffective requiring inhibitor eradication through induction of immune tolerance (ITI) therapy. Tolerized patients demonstrate successful elimination of inhibitors and normal response to FVIII concentrates. Non-tolerized patients can also be treated on prophylaxis using bypassing agents.
Aim: This analysis used national surveillance data to compare joint and other outcomes in persons with severe hemophilia A on continuous prophylaxis in three groups: no history of an inhibitor, likely tolerized inhibitor and active (non-tolerized) inhibitor.
Methods: The Community Counts bleeding disorders surveillance project is funded by the Centers for Disease Control and Prevention (CDC) through a cooperative agreement awarded to the American Thrombosis and Hemostasis Network (ATHN) in partnership with the US Hemophilia Treatment Center Network (USHTCN). The Registry for Bleeding Disorders Surveillance component collects detailed medical information on patients with bleeding disorders who receive treatment within the USHTCN. Likely tolerized inhibitors were defined as having a history of a previous inhibitor and currently being treated with FVIII concentrate; active inhibitors were defined as having a history of a previous inhibitor and being treated with bypassing agents. Using the Registry component, the following data elements, stratified by age and inhibitor status, were extracted from the initial visit form: demographics, treatment regimen, mobility, cumulative joint bleeding, invasive joint procedures, pain and opioid use.
Results: Data on 1,300 persons with severe hemophilia A were analyzed including: 739 with a negative inhibitor history; 410 likely tolerized inhibitor patients; and 151 with an active inhibitor. The 410 patients represented 73% of participants with a positive inhibitor history, similar to the North American Inhibitor Registry (DiMichele D, Haemophilia 2009;15:320-8). Participants with likely tolerized inhibitors were treated using continuous prophylaxis in similar proportion to participants with no history of inhibitor (83% vs 78%, respectively), and more often than participants with active inhibitor (83% vs 65%); however outcomes of participants on continuous prophylaxis were similar in all three groups (Table 1). Patients < 20 years of age had less disability, and fewer joint bleeds, invasive procedures, pain and opioid use compared with adult participants.
Conclusions: Improved outcomes on preventive strategies may be best determined prospectively in younger patients due to the lesser degree of established morbidity. Persons with severe hemophilia A on continuous prophylaxis with likely tolerized inhibitors (using FVIII) or with active inhibitors (using bypassing agents) demonstrate outcomes similar to those without inhibitors. However, more age- and treatment regimen- stratified analysis is needed for more precise comparisons. Future findings may contribute to the perspective that prophylaxis should be the standard of care for all hemophilia patients regardless of inhibitor status.
Display omitted
Manco-Johnson:Bayer: Honoraria, Research Funding; Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; CSL Behring: Honoraria. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; BPL: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau. Buckner:Novo Nordisk: Consultancy; Genentech: Consultancy; Baxalta: Consultancy.
Background Hemophilia A and B are rare X-linked bleeding disorders affecting ~1:5000 male births. Hemophilia genotype is important to inform reproductive planning, pregnancy, and neonatal management, ...risk of inhibitor formation and bleeding severity, and basic understanding of mechanisms of disease. In 2012, two separate surveys found only ~20% of patients with hemophilia had a genotype determined. MyLifeOurFuture (MLOF) was formed as a multi-sector collaboration between the American Thrombosis and Hemostasis Network (ATHN), the National Hemophilia Foundation (NHF), BloodworksNW (BWNW), and Biogen to provide hemophilia genotype analysis for patients in the U.S. and to create a Research Repository for future scientific discovery.
Methods Participating hemophilia treatment centers (HTCs) contract through ATHN, enroll patients, obtain samples, and provide clinical results to patients. ATHN offers HTC provider education, a secure infrastructure for clinical data collection, and access for research proposals. NHF educates the bleeding disorders community about the initiative and supports recruitment. Biogen provides scientific collaboration and financial support. BWNW serves as the central sample processing and genotyping laboratory and houses the research sample repository. Genotyping was performed custom molecular inversion probes (MIPs) targeting the F8 and F9 genes and F8 inversions for simultaneous next generation sequencing (NGS) followed by confirmation of variants using standard genotyping methods.. Clinical results were returned to providers, and new variants were submitted to public databases.
Results 69 HTCs enrolled the first 3000 patients in under 3 years. Clinically reportable DNA variants were detected in 98.1% (2357/2401) of hemophilia A and 99.3% (595/599) of hemophilia B patients. 924 unique variants were found; 285 were novel. Predicted gene disrupting variants were common in severe disease, while missense variants predominated in mild-moderate disease. The custom MIP-based NGS inversion screening method successfully detected F8 gene proximal and distal intron 22 inversion and intron 1 inversion variants. Unexpectedly, the NGS approach detected more than one reportable variants in 40 patients (10 females), a finding with potential clinical implications. NGS also detected 108 unique incidental variants unlikely to cause disease; 11 variants were previously reported associated with hemophilia. Interrogation of the ExAC database, which has data from >66,000 individuals without hemophilia, reports DNA variants distributed across the coding regions of both genes.
Conclusions MLOF is the largest hemophilia genetics project performed to date, with plans to genotype over 6000 U.S. hemophilia patients. In the first 3000 patients, clinically reportable DNA variants were identifiedin nearly all patients. Our hemophilia NGS approach accurately identified F8 and F9 gene variants and is, to our knowledge, the first NGS method which can detect F8 inversions. The incidence of discovery of novel variation was high (30%) and novel variants were discovered continuously (per patient) over the course of the study, indicating that additional genetic variation in hemophilia likely remains undiscovered. Although both the F8 and F9 genes are thought to be conserved, we identified incidental variation in both genes, supporting caution in the interpretation of new variants. In summary, MLOF is a successful nationwide collaboration to genotype two rare bleeding disorders at scale which has contributed significantly towards DNA variant identification in the F8 and F9 genes in hemophilia. Through a consented research repository, MLOF data and samples, including phenotypic data from the ATHNdataset, will be accessible to providers and research communities for advancing our understanding of hemophilia and other disorders.
Johnsen:Octapharma: Consultancy; CSL Behring: Consultancy. Meltzer:Biogen: Employment.
▪
Introduction: Cardiovascular disease (CVD) is a disease of aging. While men with hemophilia were initially thought to be protected from CVD, it is now clear that atherothrombotic events do occur. ...The objective of this study is to determine the prevalence of CVD and CV risk factors in older men with moderate and severe hemophilia.
Methods: A U.S. national cross-sectional study began enrollment in 10/2012. Included are men with moderate or severe congenital hemophilia A or B (FVIII or IX level ≤ 5%), age 54-73. Men with an additional bleeding disorder (besides liver dysfunction) were excluded. After informed consent, CV risk factors, medications, and thrombotic event history were obtained from patient interview and chart review. A fasting blood sample was assayed centrally.
Results: As of 7/24/2015, 194 of 200 planned subjects were recruited with enrollment to be completed by 9/2015 and analysis by 12/2015. Planned interim analysis on 165 subjects from 19 U.S. Hemophilia Treatment Centers is presented here. The majority were white (148; 89.7%) or African American (14; 8.5%). Mean age was 61 years (SD: 5; range: 54-73). Most used factor on demand, with only 30.3% (50/165) on prophylaxis, defined as ≥2 doses of FVIII or ≥ 1 dose FIX/week. Eight (4.9%) had a current inhibitor. Viral infection was common; 61.2% had hepatitis C, and 28.5% HIV.
Hypertension (HTN) was reported in 61.2% of subjects, dyslipidemia in 35.1%, and diabetes (DM) in 21.8%; 49.1% had ever smoked, 55.2% denied engaging in at least moderate physical activity and 43.0% had a family history of CVD. Average BMI was 28 kg/m2 (30.3% obese) and waist circumference 96 cm (32.1% enlarged). Fasting blood work showed an abnormally elevated: creatinine in 26.7% subjects (mean, SD) (1.1 mg/dl, 0.5), CRP in 9.7% (5.2 mg/L, 13.7), total cholesterol in 23.0% (174.1 mg/dl, 38.8), triglycerides in 27.9% (129.1 mg/dl, 68.3), LDL in 21.8% (105.1 mg/dl, 34.7); and low HDL in 42.4% (43.2 mg/dl, 11.8).
A minority, 14 subjects (8.5%) reported prior angina or atrial fibrillation/flutter; 5 (3.0%) leg deep venous thrombosis; 4 (2.4%) myocardial infarction (MI) or pulmonary embolism; 3 (1.8%) coronary artery stent placement; 2 (1.2%) transient ischemic event (TIA); and 1 (0.6%) coronary artery angioplasty, CABG, or peripheral arterial disease history.
The prevalence rate of CVD (defined as angina, MI, TIA, or ischemic or embolic stroke) was 9.7% (16 subjects), significantly lower than the 23% prevalence of CVD in similar aged men without hemophilia in the longitudinal Atherosclerosis Risk in Communities (ARIC) cohort (p-value <0.001). None of the men with CVD were on antiplatelet or anticoagulant medications.
Compared to never smokers, ever smokers had a significant odds ratio (OR) of 3.5 (95% CI 1.1-11.3) of CVD. For HTN, dyslipidemia, and DM, the OR (95% CI) of CVD were 2.0 (0.6-6.6), 2.0 (0.7-5.6), and 1.2 (0.4-4.0), respectively. Positive family history (OR 1.4 (0.5-3.8)) and low-level physical activity (1.1 (0.4-3.3)) also suggested some association with increased CVD risk. Higher triglycerides (1.2 (0.4-3.7)) and lower HDL (1.4 (0.5-3.9)) tended to increase CVD risk, but obesity was not a risk factor.
Men using prophylaxis appeared less likely to have CVD (3/50, 6.0%) than men not on prophylaxis (13/115, 11.3%), OR 0.5 (0.1-1.8), although the difference was not statistically significant. HIV+ men (2/47, 4.3%) were also less likely to have CVD compared to non-HIV+ men (14/115, 12.2%), OR 0.3 (0.07-1.5), but not significantly so. Current use of anti-HTN medications (42.4% of all subjects), cholesterol lowering agents (17.6%), and DM medications (13.3%) did not decrease CVD risk. Analysis of cause and effect is limited by the cross-sectional design.
Conclusions: In this interim analysis of an ongoing national cross-sectional study, older men with moderate to severe hemophilia commonly report risk factors for CVD, including HTN (61.2%), dyslipidemia (35.2%) and renal insufficiency (26.7%). Despite this, the prevalence of reported CVD is low at 9.7%, suggesting that men with hemophilia may be protected from forming pathogenic thrombi. Smoking significantly increased the OR of CVD events among men with hemophilia. More data are needed to determine if the approach to prophylaxis or other therapies should be altered in this population. We plan to formally compare the prevalence of CVD and CV risk factors with similarly aged men in the ARIC database once enrollment is complete.
Sood:Bayer: Research Funding. Ragni:Vascular Medicine Institute: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; Biogen: Research Funding; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Genentech Roche: Research Funding; SPARK: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Dimension: Research Funding. Quon:Baxter: Other: Advisory Board, Speakers Bureau; Bayer: Other: Advisory Board; Biogen: Other: Advisory Board, Speakers Bureau; Novo Nordisk: Other: Advisory Board, Speakers Bureau; Grifols: Speakers Bureau. Shapiro:Baxalta, Novo Nordisk, Biogen, ProMetic Life Sciences, and Kedrion Biopharma: Consultancy; Baxalta, Novo Nordisk, Biogen,: Membership on an entity's Board of Directors or advisory committees; Biogen: Speakers Bureau; Bayer Healthcare, Baxalta, Biogen, CSL Behring, Daiichi Sankyo, Kedrion Biopharma, Octapharma, OPKO, ProMetic Life Sciences, PTC Therapeutics, and Selexys: Research Funding. Cuker:Bracco: Consultancy; Genzyme: Consultancy; T2 Biosystems: Research Funding; CSL Behring: Consultancy. von Drygalski:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gill:Baxalta, Bayer, and CSL-Behring: Membership on an entity's Board of Directors or advisory committees. Leissinger:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Konkle:Pfizer: Consultancy; CSL Behring: Consultancy; Octapharma: Research Funding; Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; Novo Nordisk: Consultancy.
PDF
