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Introduction: Gene therapy is now a reality for individuals with haemophilia, yet little is known regarding the quality‐of‐life impact of factor correction. As few data exist, and recognizing the analogy to liver transplantation (OLTX), we identified OLTX+ and OLTX‐ men in the ATHNdataset to compare post‐OLTX factor VIII and IX on quality of life (QoL) by Haem‐A‐QoL and PROMIS‐29. Methods: OLTX‐ were matched to OLTX+ by age, race, and haemophilia type and severity. Deidentified demographic data, including post‐transplant factor levels, genotype and target joint disease were analysed by descriptive statistics. Haem‐A‐Qol and PROMIS‐29 were compared in OLTX+ and OLTX‐ by student's t‐test and univariate regression models. Results: Of 86 people with haemophilia A (HA) or haemophilia B (HB) cared for at 10 haemophilia treatment centers (HTCs), 21 (24.4%) OLTX+ and 65 (75.6%) OLTX‐ were identified. OLTX+ and OLTX‐ had a similar frequency of target joint disease (p =.806), HA genotypes, null versus non‐null (p =.696), and HIV infection (p =.316). At a median 9.2 years post‐OLTX, median FVIII,.63 IU/mL [IQR 0.52–0.97] and FIX,.91 IU/mL [IQR.63–1.32], Haem‐A‐QoL, PROMIS‐29, and HOT scores were comparable. Severe HA/HB had lower post‐OLTX 'dealing with haemophilia' scores (p =.022) and higher 'sports and leisure' (p =.010) and 'view of yourself' scores (p =.024) than OLTX+ non‐severe participants. Non‐caucasian OLTX+ had significantly lower scores in sports and leisure (p =.042), future expectations (p =.021) and total score (p =.010). Conclusion: Nine years after OLTX, QoL is comparable to OLTX–, but significantly better in OLTX+ with severe than non‐severe disease and in caucasians than non‐caucasians. [ABSTRACT FROM AUTHOR]

Background: Almost half of severe hemophilia A (HA) is caused by an intron 22 inversion mutation (Int22Inv), which disrupts the 26-exon F8 gene. Inverted F8 mRNA exons 1-22 are transcribed, while F8B mRNA, containing F8 exons 23-26, is transcribed from a promoter within intron 22. Neither FVIII activity nor FVIII antigen (cross-reacting material, CRM) are detectable in plasma of patients with an intron-22 inversion. Objectives: To test the hypothesis that (putative) intracellular synthesis of FVIII proteins encoded by inverted F8 and F8B mRNAs confers T-cell tolerance to almost the entire FVIII sequence, and to evaluate the immunogenicity of the region encoded by the F8 exon 22-23 junction sequence. Patients/Methods: Peripheral blood mononuclear cells (PBMCs) from 30 severe or moderate HA subjects (17 with an Int22Inv mutation) were tested by ELISPOT assays to detect cytokine secretion in response to FVIII proteins and peptides and to map immunodominant T-cell epitopes. Potential immunogenicity of FVIII sequences encoded by the F8 exon 22-23 junction region was also tested using peptide-MHCII binding assays. Results: Eight of the Int22Inv subjects showed robust cytokine secretion from PBMCs stimulated with FVIII proteins and/or peptides, consistent with earlier publications from the Conti-Fine group. Peptide ELISPOT assays identified immunogenic regions of FVIII. Specificity for sequences encoded within F8 mRNA exons 1-22 and F8B mRNA was confirmed by staining Int22Inv CD4+ T cells with peptide-loaded HLA-Class II tetramers. FVIII peptides spanning the F8 exon 22-23 junction (encoding M2124-V2125) showed limited binding to MHCII proteins and low immunogenicity, with cytokine secretion from only one Int22Inv subject. Conclusions: PBMCs from multiple subjects with an Int22Inv mutation, with and without a current FVIII inhibitor, responded to FVIII epitopes. Furthermore, the FVIII region encoded by the exon 22-23 junction sequence was not remarkably [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. Among haemophilic (H) men, HCV is the leading cause of liver disease. Direct‐acting antiviral agents (DAA) reduce HCV viral load, but impact on HCC is unknown. Methods: This was a retrospective study of adult H and nonhaemophilic (NH) male discharges, with and without HCC, identified by ICD‐10 codes in the National Inpatient Sample (NIS) database, 2016–2018, with DAA availability. Analyses included discharge‐level weights to reflect national estimates. Categorical variables were assessed by Rao‐Scott chi‐square and continuous variables by weighted simple linear regression. HCC correlates were determined by weighted multivariable logistic regression. Results: Among 7,674,969 adult male discharges, 3730 H (.04%) were identified in 2016–2018, of whom 10.06% had HCV and 1.07% had HCC, significantly higher than NH (1.22% and.27%, respectively) all P <.001. Annual HCC rates were similar during the 3‐year period (2016–2018) in H and NH. Among H, HCC is associated with older age and higher rates of HCV, HBV, NASH, end‐stage liver disease, and Charlson comorbidity (CCI), each P <.001. Among HCC, H were younger and more likely HIV+, each P <.001, but less likely alcoholic (P =.018) or hyperlipidaemic (P =.008) compared to NH. In multivariable regression, risk factors for HCC among H included NASH (OR 21.6), HCV (OR 3.96), CCI (OR1.54), all P <.001, while HIV and hyperlipidaemia were protective. Conclusion: From 2016 to 2018, HCC rates did not change significantly in haemophilia discharges. NASH, HCV, and CCI are significant risks for HCC in haemophilia during the DAA‐era. [ABSTRACT FROM AUTHOR]

Introduction: The B‐Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). Aim: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. Methods: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1–5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5–< 40 IU/dL), age 12.1 years, disease. Twenty‐nine participants had inhibitors or a history of inhibitors. Three versions of the EQ‐5D instrument were used as a measure of QoL: proxy (ages 4–7), youth (ages 8–15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range‐of‐motion (ROM) for elbows, knees and ankles was assessed using a four‐point scale, from which a composite score was calculated. Results: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ‐5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. Conclusion: The B‐Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab is a bispecific monoclonal antibody that mimics factor VIII (FVIII) by binding to factors IXa and X to promote hemostasis in haemophilia A (HA) and HA with inhibitors (HA‐I). As emicizumab differs biochemically from FVIII, there is interest in its real‐world haemostatic efficacy. Aim: To describe real‐world patient experience with emicizumab by retrospective chart review. Methods: We reviewed medical records of patients cared for at the Hemophilia Center of Western PA, who initiated emicizumab following its licensure, and on whom bleeding events and factor use were available. Comparisons between groups were done by Student's t test for continuous data and by chi‐square or Fisher's exact test for discrete data. Results: A total of 42 patients whose charts were reviewed included 18 (42.9%) with HA and 24 (52.1%) with HA‐I. Groups were similar in age, 17 (40.5%) <18 years, race, and haemophilia severity, and initiated weekly subcutaneous emicizumab 1.5 mg/kg, following 4‐week induction. Fourteen (33.3%) experienced at least one breakthrough bleed, of which 11 (44.0%) were joint bleeds, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, P =.251. Surgical procedures were performed in 10 (23.8%), of whom 4 (40.0%) had postoperative bleeding and one developed postoperative thrombosis in association with FEIBA despite emicizumab discontinuation 1 month preoperatively. Local skin reactions occurred in three and headache in one. Overall, 85.0% of those who rated their health indicated it was improved. Discussion: Despite breakthrough bleeds and postoperative thrombosis associated with emicizumab, most HA and HA‐I experienced improved health. [ABSTRACT FROM AUTHOR]

Introduction: Improved life expectancy of persons with hemophilia (PWHs) has led to a greater interest in the role of age-related chronic diseases, such as hypertension, in this cohort. Several observational studies have reported an increased prevalence of hypertension in PWHs; however, this has not been assessed using a large, national database in the United States. Aims: We hypothesized the prevalence of hypertension is increased in PWHs and compared the prevalence of hypertension and associated risk factors among patients with and without hemophilia. Methods: A cross-sectional analysis was performed using discharge data among adult males from the National Inpatient Sample over the 3-year period, 2009 to 2011. Hypertension was compared across groups using Rao-Scott χ2 test. Multivariable logistic regression was used to estimate the odds of hypertension in patients with hemophilia after adjustment for hypertension-associated risk factors. Results: The prevalence of hypertension in patients with hemophilia was less than the prevalence of hypertension in patients without hemophilia (39.5% vs 56.3%, P < .001). Hemophilia was associated with a decreased odds of hypertension after adjusting for associated risk factors (odds ratio: 0.87; 95% confidence interval: 0.81-0.94). Conclusion: In contrast to the findings of several other recent studies, we report a decreased prevalence of hypertension in PWHs. The discrepancy among the reported prevalence of hypertension in our study and several others highlights the potential biases inherent to retrospective and cross-sectional studies and underscores the need for well-designed prospective studies to determine the true incidence of hypertension in PWHs, which may lie somewhere in between our findings and the findings of others. [ABSTRACT FROM AUTHOR]

Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (F.IX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2×1011 vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of F.IX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease. [ABSTRACT FROM AUTHOR]