Continuous Prophylaxis Research Articles

Інфекції сечової системи: діагностика та лікування, оновлення 2022 року

Urinary tract infections (UTIs) are a common reason for seeking medical care and prescribing antimicrobials. Purpose is to highlight the issues of diagnosis and treatment of UTIs, taking into account the updates of 2022. The diagnostic aspects of UTIs are considered. Antibacterial and non-antibacterial measures for the treatment and prevention of UTIs are highlighted. The priority prescription of phosphomycin in the treatment and prevention of uncomplicated and complicated UTIs is substantiated. The advantages and disadvantages of telemedicine counselling for patients with UTI are shown. To diagnose acute uncomplicated cystitis, a urine test is performed, and if acute pyelonephritis is suspected, a bacteriological urine test is performed. To treat a patient with cystitis, oral nitrofurans (nitrofurantoin) or sulfamethoxazole/trimethoprim are prescribed, and if this is not possible, oral amoxicillin/clavulanic acid or intravenous aminoglycosides (single dose) are used. The introduction of telemedicine into primary care can improve treatment outcomes for urological patients, but doctors prescribe urinalysis and urine bacteriology less frequently during e-visits compared to office visits, and prescribe antibiotics much more frequently. Short-term treatment of symptomatic UTIs, continuous or intermittent low-dose antimicrobial prophylaxis with phosphomycin are recommended by guidelines from leading associations in Europe and the United States as anti-recurrent therapy to reduce the risk of future UTIs and improve the quality of life of women of all ages. No conflict of interests was declared by the authors.

Clinical and Treatment Characteristics of Infants and Toddlers Less Than Two Years of Age with Hemophilia: A Report from the Community Counts Registry

Introduction: Congenital hemophilia is an X-linked bleeding disorder often diagnosed in infants and toddlers (ITs) <2 years of age. Intracranial hemorrhage (ICH) in ITs with hemophilia remains a major complication, with a 7% occurrence, leading to disability and in some cases death. ICH in ITs may be preventable through delivery practices which avoid head trauma, especially when there is a family history (FH) of a bleeding disorder, and by early initiation of prophylaxis. The objective of this study was to examine the role of FH on mode of delivery, delivery practices, and initiation of prophylaxis, all within the context of the new treatment product emicizumab, which is approved for prophylaxis in individuals with hemophilia A (HA) of any age. We hypothesized that a FH of hemophilia would be associated with lower proportion of vaginal deliveries and instrumentation at birth and earlier age of prophylaxis initiation. Methods: We included ITs who were <2 years of age and enrolled in Community Counts, a US based Registry for Bleeding Disorders Surveillance that collects data from individuals who receive care at federally funded hemophilia treatment centers. The analysis was limited to initial surveillance visits through 2021 for ITs born ≥2011 and diagnosed with congenital HA or hemophilia B (HB), with a clotting factor activity level of <50%. Analyzed data included socio-demographics, FH of hemophilia (defined as parent report of one or more blood relative), mode of delivery (including the presence or absence of instrumentation), diagnosis type, age at diagnosis, ICH, treatment product usage, head trauma, and age at prophylaxis initiation. Summary statistics were used to characterize demographic and clinical information by FH. Differences between FH, demographic and clinical information, as well as differences between birth cohorts (2011-2015, 2015-2018, and 2019-2021) and treatment product usage were assessed for statistical significance using chi-square or parametric or non-parametric tests of differences between means as appropriate. Results: Of the 883 ITs in the analysis, most were male (98%), White (73%), non-Hispanic (78%), with HA (78%), severe disease (62%), and a known FH (70%). ITs with a FH had a lower proportion of vaginal deliveries than those with no FH (67% vs. 80%, p = 0.0006) and less instrumentation with vaginal delivery (4% vs. 9%; p = 0.02). ITs with a FH were also diagnosed earlier than those without a FH (p = <0.0001); however, age of prophylaxis initiation was not significantly different between ITs with vs without a FH (10.0 mo ± 6.2 versus 11.2 mo ± 6.0; p = 0.17) [Table 1]. Sixty-eight (8%) ITs had one or more ICH during the first two years of life. ITs with a FH were slightly less likely to have an ICH than those with no FH, but the difference was not statistically significant (7% vs 11%, p=0.08). Among all ITs with an ICH, 8 (12%) were on continuous prophylaxis at the time of ICH and 24 (35%) experienced ICH within the first month of life. Of the 24 with ICH in the first month of life, 17 (71%) had vaginal delivery and 8 (33%) reported head trauma. Regarding prophylaxis, 205 (30%) ITs with HA were on continuous prophylaxis within the first two years of life, 91% with severe HA. Thirty-five (18%) with HB were on continuous prophylaxis, 88% with severe HB. Prophylaxis with extended half-life (EHL) clotting factor and emicizumab increased over the study period for ITs with HB and HA respectively. Additionally, ITs with HA born after 2018 started prophylaxis sooner than those born in earlier years (Table 2). Conclusions: The ICH rate of 8% in ITs in this study is substantial and similar to prior reports. This study showed that a known FH of hemophilia was associated with earlier age of diagnosis and decreased rate of vaginal delivery. Nonetheless, the proportion of ICH was only slightly lower among ITs with a FH than those with no FH, and the difference did not reach statistical significance. EHL clotting factor and emicizumab use for prophylaxis increased across the birth cohorts reflecting the addition of new treatment options. The age of prophylaxis initiation decreased in ITs with HA, perhaps reflecting easier mode of administration and national guidelines supporting early initiation to prevent ICH. In ITs with hemophilia there remains opportunity to further reduce ICH by identifying at risk fetuses, optimizing delivery plans to minimize head trauma, and initiating prophylaxis even within the first month of life. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Durability of Bleeding Protection and Factor IX Activity Levels Are Demonstrated in Individuals with and without Adeno-Associated Virus Serotype 5 Neutralizing Antibodies (Titers

Introduction: Pre-existing adeno-associated virus (AAV) neutralizing antibodies (NAbs) have limited the efficacy of AAV-based gene therapy in prior clinical applications, including in hemophilia. A unique aspect of the Phase 3 HOPE-B clinical trial (NCT03569891) assessing etranacogene dezaparvovec gene therapy, an AAV serotype 5 vector expressing Padua factor IX (FIX), was the enrollment of participants regardless of their baseline AAV5 NAb status. The HOPE-B clinical trial met its primary efficacy endpoint, providing hemostatic protection superior to standard of care FIX prophylaxis over 52 weeks of follow-up after stable FIX Padua expression (defined as Months 7-18). Aim: Assess efficacy and safety of etranacogene dezaparvovec in HOPE-B participants with (NAb+) and without (NAb-) pre-existing AAV5 NAbs over 18 and 24 months of follow-up. Methods: Adult male participants with severe or moderately severe hemophilia B (FIX ≤2%), NAb+ or NAb-, were treated in the Phase 3, open-label, single-arm, HOPE-B trial with a single intravenous infusion of etranacogene dezaparvovec (2x1013 gc/kg), following a ≥6-month lead-in period receiving FIX prophylaxis. FIX activity, annualized bleed rate (ABR), and use of infused replacement FIX concentrates were assessed regularly during the lead-in and the first 12 months after receiving etranacogene dezaparvovec, then every 6 months during the long-term follow-up (Years 2-5). Adverse events were recorded continuously. Although not an exclusion criterion, AAV5 NAbs were assessed on the day of intravenous dosing (baseline), using a custom-developed, cell-based in vitro AAV5 transduction inhibition assay (sensitivity 10 ng/mL antibody, titer 1:7, intra and inter-run coefficient of variation [CV] <30%). Results: Of the 54 participants who received etranacogene dezaparvovec, at baseline 33 participants were NAb- and 21 were NAb+. The median (Q1-Q3) titer among NAb+ participants was 56.9 (23.3-198.9) and 20/21 (95%) NAb+ participants had titers of <1:700. One participant with a markedly high NAb titer of 3212 prior to vector dosing and one participant who only received a partial dose (due to an infusion-related reaction; NAb titer: 198.9), did not express FIX Padua and did not discontinue FIX prophylaxis. All other participants (52/54) discontinued FIX prophylaxis. At 18- and 24-months post-dose, no clinically meaningful correlation between an individual's baseline AAV5 NAb titer and FIX activity levels was identified, up to a NAb titer of <1:700 (24-month Pearson coefficient: -0.29; Spearman coefficient: -0.25; R2: 0.086). Sustained FIX activity levels (median [min-max]) were demonstrated at 18 months post-dose in NAb+ <1:700 (32.0% [10.3-57.9]) and NAb- (35.0% [4.5-122.9]) participants and at 24 months post-dose in NAb+ <1:700 (33.5% [9.1-88.3]) and the NAb- (35.4% [4.7-99.2]) participants (Table 1). At both 18- and 24-months post-dose, NAb+ <1:700 and NAb- participants demonstrated a low ABR (Table 2). The ABR achieved by the NAb+ <1:700 and NAb- subgroups at 18 months was 1.30 and 0.93, and at 24 months was 1.65 and 0.80, respectively. These ABRs were significantly improved compared with the respective ABRs of 4.29 (p=0.0005 and p=0.0065 at 18 and 24 months, respectively) and 3.80 (p<0.0001 at 18 and 24 months) observed during the ≥6-month lead-in period of continuous FIX prophylaxis. The safety profile of etranacogene dezaparvovec was similar between NAb subgroups. At 24 months, corticosteroid-treated transaminase elevations occurred in 6/33 NAb- (18.2%) and 3/21 NAb+ (14.3%) participants. Infusion-related reactions occurred in 2/33 NAb- (6.1%) and 5/21 NAb+ (23.8%) participants. There was no statistically significant association between infusion-related reactions and NAb status (p=0.0956). Conclusions: Throughout 24 months of follow-up, AAV5 NAb- and NAb+ (<700 titer) HOPE-B participants receiving etranacogene dezaparvovec demonstrated significant reductions in ABR, freedom from continuous FIX prophylaxis and a comparable and acceptable safety profile, regardless of NAb status. FIX activity levels were stable, with no association between baseline NAb status (up to titer <1:700) and the long-term durability of FIX expression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Quality of Life in Patients with Clinically Severe Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe Von Willebrand Disease (VWD)

Background: Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, which results from either a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF). Prior studies, largely focused on individuals with mild VWD and bleeding symptoms, have shown significant reductions in quality of life in patients with Von Willebrand disease. Because of the rarity less is known about individuals with severe forms of VWD or those with a severe bleeding phenotype. Aim: To report quality of life measures in participants with clinically severe VWD in the United States (US). Study Design and Methods: ATHN 9 Severe VWD Natural History Study is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at 25 ATHN-affiliated sites across the US. ATHN 9 is an observational study focused on persons with clinically severe VWD treated with VWF factor on demand or for prophylaxis. Participants are identified by site investigators with a projected goal to enroll 130 individuals. Patients with severe VWD defined as type 3 VWD, or a VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 30%, or persons with "clinically severe VWD" defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% and requiring recurrent use of factor concentrates, and prior enrollment in the ATHNdataset national surveillance data collection project are included. Participants with platelet-type or acquired VWD are excluded. Quality of life was assessed using PROMIS measures (PROMIS 25, PROMIS 25 Proxy, PROMIS 29) and the VWIQ at enrollment, annually, and at study exit. PROMIS-29 assesses seven different quality of life domains (physical function, anxiety, depression, fatigue, sleep disturbance, ability to participate in social roles, and pain interference) and has been validated in adult populations. PROMIS measures in the general US population have a mean of 50 and standard deviation of 10. PROMIS-25 is a pediatric questionnaire assessing the same domains (except for sleep disturbance) and an accompanying proxy form for caregivers of participants <8 years of age. Baseline enrollment results are reported here. Results: Enrollment (baseline) PROMIS-29 forms were completed by 43 participants. At baseline, mean physical function was lower than the general population at 45.7 (p=0.005), and fatigue and pain interference were greater than the general population at 53.2 and 53 respectively (p=0.036 and 0.049 respectively). Individuals on continuous VWF factor prophylaxis (n=18) had significantly decreased physical function (p<0.01), and decreased ability to participate in social roles (p<0.01) than individuals on episodic treatment (n=19). Enrollment PROMIS-25 forms were completed for 26 participants, while PROMIS-25 proxy forms were completed for 19 participants. Mean enrollment scores for PROMIS-25 depression symptoms was lower than the general population at 44.4 (p=0.0004) and peer relationships were better than the general population at 54 (p=0.042). Mean enrollment scores for PROMIS-25 Proxy were lower than the general population for depression, fatigue, and pain interference at 41, 42.9, and 45.4 respectively (p<0.0001, p=0.002, and p=0.045 respectively). In contrast to the adult participants, no statistically significant differences were seen between pediatric participants on VWF factor prophylaxis versus episodic treatment. Discussion: Pediatric participants with clinically severe VWD reported less depression and better peer relationships than the general population, and parents of pediatric participants with VWD reported less depression, fatigue, and pain interference in their children compared to the general population. Patient-reported outcomes in adult participants were less encouraging with worse physical function, and more fatigue and pain interference compared to the general population. Adult participants on VWF factor prophylaxis had decreased physical function, and decreased ability to participate in social roles compared to adults treated episodically, perhaps secondary to disease severity and accumulation of bleed-related morbidity. No statistically significant differences were seen in quality of life outcomes between pediatric patients on VWF factor prophylaxis and those on episodic treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adults with Severe or Moderately Severe Hemophilia B Receiving Etranacogene Dezaparvovec in the HOPE-B Phase 3 Clinical Trial Continue to Experience a Stable Increase in Mean Factor IX Activity Levels and Durable Hemostatic Protection after 24 Months’ Follow-up

Introduction: Etranacogene dezaparvovec (formerly AMT-061), an investigational gene therapy for hemophilia B, is an adeno-associated virus serotype 5 (AAV5) vector, containing a codon-optimized, highly active factor IX (FIX) Padua R338L transgene under the control of a liver-specific promoter. The Phase 3 HOPE-B clinical trial (NCT03569891) of etranacogene dezaparvovec met its primary efficacy endpoint, providing hemostatic protection superior to standard of care FIX prophylaxis over 52 weeks of follow-up after stable FIX Padua expression (defined as Months 7-18). However, the potential for liver-directed AAV to sustain long-term clotting factor expression remains unknown, with most human experience derived from early phase clinical trials. Aim: Efficacy and safety data is provided from the pivotal Phase 3 HOPE-B clinical trial over a period of 24 months of gene expression. Methods: In this open-label, single-arm study, adult male participants with severe or moderately severe hemophilia B (FIX≤2%), with or without pre-existing AAV5 neutralizing antibodies (NAbs), were infused with a single dose of etranacogene dezaparvovec (2x1013 gc/kg), following a ≥6-month lead-in period receiving FIX prophylaxis. FIX activity, annualized bleed rate (ABR), and FIX infusions were assessed frequently during the lead-in and first 12 months after receiving etranacogene dezaparvovec, then every 6 months during the long-term follow-up (Years 2-5). Adverse events (AEs) were recorded continuously. Results: Of the 54 participants who received etranacogene dezaparvovec, 53 participants received the full dose and 52 completed 24 months of follow-up. At 464 days (~15 months) following infusion, one 75-year-old participant died from cardiogenic shock, preceded by a urinary tract infection, which was considered unrelated to treatment. Of the 54 participants, 52 (96.3%) discontinued and remained free of continuous FIX prophylaxis from Day 21 to Month 24, including 20 participants with baseline AAV5 NAb titers up to 1:700. One participant with a markedly higher AAV5 NAbs titer (1:3212) and one participant who received only a partial vector dose (due to an infusion-related reaction) did not express FIX Padua or discontinue FIX prophylaxis. Compared with the ≥6-month lead-in period (mean ABR 4.18), mean ABR for all bleeds during Months 7-24 post-treatment was significantly reduced by 64% (mean ABR 1.51; p=0.0002), sustaining the same bleed reduction that satisfied the primary endpoint of the trial during Months 7-18. The mean ABR for all other bleed types was also substantially reduced (Figure 1). The mean FIX activity level of participants was 39.0 IU/dL (standard deviation [SD]: ±18.7; min-max: 8.2-97.1) at Month 6 (n=51) and sustained at 36.7 IU/dL (±19.0; 4.7-99.2) at Month 24 post-treatment (n=50; Figure 2). There was an overall 96% reduction in mean unadjusted annualized FIX consumption from the lead-in period (257,339 IU/year/participant) to Months 19-24 (9751 IU/year/participant; p<0.0001). During the 24 months post-dose, all participants experienced at least one treatment-emergent AE (TEAE); of the 557 events, 424 (76%) were mild, 115 (21%) were moderate, and 18 (3%) were severe. A total of 38 participants (70.4%) experienced 93 treatment-related TEAEs, with only one occurring during Months 18-24. There was an increase in alanine transaminase (with or without increased aspartate transaminase) in eleven participants (20.4%). Nine participants (16.7%) received supportive care with reactive corticosteroids for a mean duration of 79.8 days (SD: 26.6; range: 51-130 days). There were no serious AEs related to treatment; a serious AE of hepatocellular carcinoma was determined by independent molecular genomic and integration analysis to be unrelated to treatment. Conclusions: Demonstrating durability of disease correction with acceptable safety is the next major hurdle for gene therapy in people with hemophilia B. After 24 months’ follow-up, single-dose etranacogene dezaparvovec resulted in stable FIX Padua expression in participants with AAV NAb undetected or <1:700 titer; reduction in ABR remained durable and superior to FIX prophylaxis. This outcome was achieved with limited early reactive corticosteroid exposure in a minority of participants, allowing all participants who discontinued prophylaxis to remain off prophylaxis at Month 24. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Análisis de efectividad y costes sanitarios de la inmunoprofilaxis con autovacuna MV140, vacuna MV140 y tratamiento antibiótico continuado en la prevención de las infecciones urinarias recurrentes

IntroductionThe objective of this study was to compare the results on prevention of uncomplicated recurrent UTI between continuous use of antibiotics, MV140 autovaccine and MV140 polybacterial vaccine from collection strain. Methods377 patients were prospectively analyzed from January 2017 to August 2019 and divided into 3 groups according to the prophylaxis. Group A (126): antibiotics, Group B (126): MV140 autovaccine, Group C (125): MV140 polybacterial vaccine from the collection strain. Variables analyzed were: gender, age, menopause, number of UTI at baseline and 3 and 6 months after the end of prophylaxis, health cost along follow-up at 3 and 6 months. ResultsAt 3 months, group A had 0-1 UTI in 65%, group B had 0-1 UTI in 80.8% and group C in 81.7%. At 6 months, group A had 0-1 UTI in 44.4%, group B had 0-1 UTI in 61.6% and group C in 74.6%. Regarding health cost along follow-up, at 3 months group A had €21,171.87, group B had €20,763.73 and group C €18,866.14. At 6 months, health cost was €32,980.35 in group A, €28,133.42 in group B, and €23,629.19 in group C. ConclusionsMV140 autovaccine and MV140 polybacterial vaccine were more efficient with lower number of UTI at 3 and 6 months and lower health cost along follow-up compared to continued prophylaxis with antibiotics (p <.05). Polybacterial MV140 vaccine from collection strain had higher effect to reduce the number of UTI and less health cost than autovaccine.

Thrombotic Events and Anticoagulation-Related Bleeding Complications in Critically Ill Patients with Coronavirus Disease 2019

Background: Thrombosis (T) is common in coronavirus disease 2019 (COVID-19) patients, and d-dimer concentrations correlate with outcomes. Controversy exists with regards to anticoagulation (AC) for patients. We implemented a full-heparinization AC protocol from the onset of the pandemic and hypothesized that a safety signal would be undetectable. Patients and Methods: Prospective evaluation of 111 patients with COVID-19 critical illness hospitalized from March to June 2020. All patients received therapeutic heparinoid-based AC from admission. Incidences of T, bleeding (B), or both (BT) were noted. The primary outcome was mortality. Kruskal-Wallis test and logistic regression were performed. Results are expressed as n (%), median (interquartile range) and odds ratios with 95% confidence intervals. Alpha was set at 0.05. Results: Thirty-two patients (28%) had T, 23 (20%) had B, and 14 (12%) had BT; 42 (40%) patients were unaffected. Two logistic regression models (outcome = mortality) evaluated BT as T, or BT as B. For BT as T, neither T, B, nor male gender predicted mortality; similarly, for BT as B, neither T, B, nor male gender predicted mortality. Factors associated with higher odds of death included higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; p = 0.0045), higher d-dimer concentration (OR, 1.00; 95% CI, 1.00-1.01; p = 0.043), and higher activated partial thromboplastin time (aPTT; OR, 1.09; 95% CI, 1.02-1.16; p = 0.010). Conclusions: Neither T nor B predicted mortality in this prospective cohort of anticoagulated patients with COVID-19 critical illness. These data support continued full-dose heparinoid prophylaxis.

Effectiveness and health cost analysis between immunoprophylaxis with MV140 autovaccine, MV140 vaccine and continuous treatment with antibiotics to prevent recurrent urinary tract infections

IntroductionThe objective of this study was to compare the results on prevention of uncomplicated recurrent UTI between continuous use of antibiotics, MV140 autovaccine and MV140 polybacterial vaccine from collection strain. Methods377 patients were prospectively analyzed from January 2017 to August 2019 and divided into 3 groups according to the prophylaxis. Group A (126): antibiotics, Group B (126): MV140 autovaccine, Group C (125): MV140 polybacterial vaccine from the collection strain. Variables analyzed were: gender, age, menopause, number of UTI at baseline and 3 and 6 months after the end of prophylaxis, health cost along follow-up at 3 and 6 months. ResultsAt 3 months, group A had 0–1 UTI in 65%, group B had 0–1 UTI in 80.8% and group C in 81.7%. At 6 months, group A had 0–1 UTI in 44.4%, group B had 0–1 UTI in 61.6% and group C in 74.6%. Regarding health cost along follow-up, at 3 months group A had euro21,171.87, group B had euro20,763.73 and group C euro18,866.14. At 6 months, health cost was euro32,980.35 in group A, euro28,133.42 in group B, and euro23,629.19 in group C. ConclusionsMV140 autovaccine and MV140 polybacterial vaccine were more efficient with lower number of UTI at 3 and 6 months and lower health cost along follow-up compared to continued prophylaxis with antibiotics (p < 0.05). Polybacterial MV140 vaccine from collection strain had higher effect to reduce the number of UTI and less health cost than autovaccine.

Extended-duration letermovir prophylaxis for cytomegalovirus infection after cord blood transplantation in adults

AbstractCord blood transplantation (CBT) can be complicated by a high incidence of clinically significant cytomegalovirus infection (csCMVi). We have investigated the efficacy of extended letermovir prophylaxis in seropositive adult CBT recipients. The aim was to continue prophylaxis for ≥6 months (insurance permitting). By day 100, the incidence of csCMVi was 0% in 28 patients who received letermovir prophylaxis. Moreover, of 24 patients alive at day 100, none had csCMVi by day 180, having continued prophylaxis for all (n = 20) or part (n = 4) of that period. Overall, 20 patients stopped letermovir at a median of 354 days (range, 119-455 days) posttransplant, with only 5 requiring 1 (n = 4) or 2 (n = 1) courses of valganciclovir (median total duration, 58 days; range, 12-67 days) for postprophylaxis viremia, with no subsequent csCMVi. There were no toxicities attributable to letermovir. Of the 62 historic control subjects who received acyclovir only, 51 developed csCMVi (median onset, 34 days; range, 5-74 days), for a day 100 incidence of 82% (95% confidence interval, 73-92). Seven patients developed proven/probable CMV disease, and 6 died before day 100 (3 with proven/probable CMV pneumonia). Forty-five patients required extended therapy during the first 6 months for 1 (n = 10), 2 (n = 14), or 3/persistent (n = 21) csCMVi, with 43 (84%) of 51 developing significant treatment toxicities. Letermovir is a highly effective, well-tolerated prophylaxis that mitigates CMV infection, CMV-related mortality, and antiviral therapy toxicities in CBT recipients. Our data support prophylaxis duration of at least 6 months after CBT.

Transplantation of hepatitis D virus patients: Lifelong hepatitis B immunoglobulins?

The introduction of Hepatitis B Immunoglobulins (HBIg) prophylaxis at and after liver transplantation (LT) facilitated excellent long-term survival of transplant patients with chronic hepatitis B virus (HBV) infection. Several studies suggested that only short-term (i.e. 4-8 weeks) HBIg prophylaxis after LT followed by the long-term administration of HBV polymerase inhibitors prevents HBV recurrence. In hepatitis D virus (HDV)/HBV co-infected patients, the need for long-term HBIg prophylaxis on top of HBV polymerase inhibitors is unknown. HDV requires HBV surface antigen (HBsAg) for uptake into hepatocytes to subsequently establish HDV replication. Data on HDV recurrence and its impact on outcomes after LT are limited. In this review, we evaluated the available data on post-LT recurrence of HBV and/or HDV. Overall, HBIg prophylaxis was effective, but 10-13% of patients became HBsAg positive after LT. Only a single study from Turkey reported HDV recurrence, which was not observed in other LT centres. Since all studies administered continuous HBIg prophylaxis, the post-LT recurrence rates without HBIg prophylaxis remain unknown. In a German study, the clinical course and histopathological aspects of liver injury (inflammation, fibrosis and steatosis) were similar in post-LT patients on continuous HBIg and those who stopped HBIg after a median of 72 months. Discontinuation of HBIg in stable patients after LT for HBV/HDV co-infection did not lead to impaired overall survival or a higher recurrence rate in this long-term follow-up. In summary, discontinuation of HBIg after liver transplantation for HBV/HDV liver disease seems safe, but randomized controlled studies are needed before it can be generally recommended.

Efficacy of Intermittent, Oral Famciclovir Prophylaxis for Bortezomib-Induced Herpes Zoster in Multiple Myeloma Patients.

ObjectiveTo explore the efficacy and safety of intermittent, oral famciclovir prophylaxis for bortezomib-induced herpes zoster in multiple myeloma patients.MethodWe retrospectively analyzed the incidence of bortezomib treatment-related varicella-zoster virus reactivation in 719 newly-diagnosed multiple myeloma patients receiving intermittent oral famciclovir prophylaxis, continuous oral acyclovir prophylaxis or no prophylaxis. The definition of intermittent oral famciclovir prophylaxis was oral famciclovir at a dose of 250mg twice daily for 9 days after finishing the last dose of bortezomib therapy every cycle. Age, gender, stage per the International Staging System, type of M protein, baseline of absolute lymphocyte count, absolute neutrophil count, and absolute monocyte count were analyzed to find the potential factors that could predispose to herpes zoster infections.ResultsVaricella-zoster virus infection occurred in 96 patients (13.4%) during bortezomib treatment. The incidence of herpes zoster was significantly higher in the non-prophylaxis group compared with the prophylaxis group (22.9% vs 8.2% P<0.001), while the rate was similar between the intermittent oral famciclovir group and the continuous oral acyclovir group (8.4% vs 7.9% P=0.835). Hepatic and renal toxicity were observed in 12% and 2.8% of the patient respectively in the intermittent famciclovir group, which was similar in the continuous acyclovir group (18.1% and 4.2%). The prophylactic use of antiviral agents is a predictive factor for varicella-zoster virus reactivation.ConclusionIntermittent famciclovir prophylaxis is effective and safe in preventing herpes zoster development and can markedly reduce the duration of oral medicine treatment compared with continuous acyclovir prophylaxis.

Prolonged antibiotic prophylaxis in women with recurrent urinary tract infection

Long term management of women with uncomplicated recurrent urinary tract infection (UTI) is challenging. Although continuous antibiotic prophylaxis is a common form of management, its use is recommended generally for no longer than 12 months. We aimed to evaluate antibiotic resistance and tolerability in women with recurrent UTI treated with “prolonged” continuous antibiotic prophylaxis, defined as longer than 12 months. A retrospective query was performed to identify adult women referred to TTUHSC-EP Urogynecology clinic with uncomplicated recurrent UTI from 1/1/2014-12/31/2018. Recurrent UTI was defined as ≥2 symptomatic UTIs in a 6-month period or ≥3 in a 12-month period. Exclusion criteria included symptomatic prolapse, pelvic malignancy, urinary retention, voiding dysfunction with prior incontinence surgery and active pregnancy. Demographic and clinical data, including strategy and duration of treatment, was recorded for initial and subsequent clinic visits, until present time. "Resistance” was defined as resistance to prophylactic antibiotic as per urine culture in a symptomatic UTI during the prophylaxis course. Descriptive statistics were calculated. Two sample t-tests and Chi square were used for between-group comparisons. Multiple logistic regression was performed to evaluate antibiotic resistance between different duration of antibiotic prophylaxis. One hundred and eighty four women met inclusion criteria. Mean age was 62.1 ± 16. Total follow up time from initial visit was 60.3 ± 59.4 weeks. Initial strategies for prophylaxis included daily or intermittent antibiotics (60.8%), vaginal estrogen (45%), D-mannose (2.6%) and cranberry (1.5%) supplements, alone or in combination. Eventually, most patients were started on continuous antibiotic prophylaxis (84%). Twenty-seven percent (N=42) of those on continuous antibiotic prophylaxis had a “prolonged” duration. Resistance to prophylactic antibiotic occurred in 19.1% of those on "prolonged” courses vs. 5.3% of those on courses of ≦12 months (OR 3.7, 95%CI 1.14-12.18, p=0.03). For those on “prolonged” antibiotic prophylaxis, time to antibiotic resistance was 136.5 ± 92.8 weeks. On regression, factors including age, parity, prior incontinence surgery and prolapse stage did not significantly increase risk for resistance, with exception of thyroid disease (OR 4.8 95%CI 1.43-16.01, p=0.01). There were no cases of discontinuation of continuous prophylaxis due to abnormalities in liver or renal function, or intolerance to antibiotic. In women with recurrent UTI, continuous antibiotic prophylaxis longer than 12 months was associated with an almost four-fold increased risk for resistance to the prophylactic antibiotic. However, the mean time for resistance was ≧2.5 years, and prophylaxis was well tolerated. Prolonged antibiotic prophylaxis seems acceptable with appropriate monitoring and counseling on the risk of resistance.

Association of Child Neurology (AOCN) Consensus Statement on the Diagnosis and Management of Febrile Seizures

Febrile seizures are quite common in children but there are controversies in many aspects of their diagnosis and management. An expert group consisting of pediatric neurologists and pediatricians was constituted. The modified Delphi method was used to develop consensus on the issues of definitions and investigations. The writing group members reviewed the literature and identified the contentious issues under these subheadings. The questions were framed, pruned, and discussed among the writing group members. The final questions were circulated to all experts during the first round of Delphi consensus. The results of the first round were considered to have arrived at a consensus if more than 75% experts agreed. Contentious issues that reached a 50-75% agreement was discussed further in online meetings and subsequently voting was done over an online platform to arrive at a consensus. Three rounds of Delphi were conducted to arrive at final statements. The expert group arrived at a consensus on 52 statements. These statements pertain to definitions of febrile seizures, role of blood investigations, urine investigations, neuroimaging, electroencephalography (EEG), cerebrospinal fluid analysis and screening for micronutrient deficiency. In addition, role of rescue medications, intermittent anti-seizure medication and continuous prophylaxis, antipyretic medication and micronutrient supplementation have been covered. This consensus statement addresses various contentious issues pertaining to the diagnosis and management of febrile seizures. Adoption of these statements in office practice will improve and standardize the care of children with this disorder.

Bleeding in Patients with Clinically Severe Von Willebrand Disease: Interim Analysis of Athn 9: A Natural History Study for People with Severe Von Willebrand Disease (VWD)

Background:Von Willebrand Disease (VWD) is the most common inherited bleeding disorder, occurring in ~0.1% of the population. VWD results from either a quantitative (Type 1 or 3) or qualitative (Type 2) defect in von Willebrand Factor (VWF), a multimeric plasma protein involved in platelet adhesion and aggregation at the vascular injury site. Accurate diagnosis of VWD is complex due to pre-analytical variables, a wide coefficient of variation in testing, and incomplete penetrance. Though individuals with mild VWD and bleeding symptoms are common, less is known regarding persons with VWD and a clinically severe bleeding phenotype.Aims:To characterize the bleeding phenotype and safety of treatment regimens in participants with clinically severe VWD in the United States (US).Study Design and Methods:ATHN 9 is sponsored by the American Thrombosis and Hemostasis Network (ATHN) and is being conducted at 25 ATHN-affiliated sites across the US. Participants are identified by the site investigators with a projected goal to enroll 130 individuals. Patients with severe VWD defined as type 3 VWD, or a VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 30%, or persons with “clinically severe VWD” defined by VWF:RCo, VWF:GPIbM or VWF:Ag ≤ 40% and requiring recurrent use of factor concentrates and prior enrollment in the ATHNdataset national surveillance data collection project are included. Participants with platelet-type or acquired VWD are excluded. Laboratory assessments including a standardized diagnostic battery, VWF genetic analysis (Next-gen sequencing), and inhibitor testing, performed by a central laboratory. Bleeding tendency is assessed by International Society for Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) (abnormal BS is ≥4 in adult males, ≥6 in adult females and ≥3 in children) and the Pictorial Bleeding Assessment Chart (PBAC; heavy menstrual blood loss ≥100) if applicable.Results:Initial data on 81 participants was analyzed. Given that the enrollment occurred during the pandemic, the completion of data varied as follows: Baseline Demographics Forms 81 completed, Baseline History Forms 73 completed, and VWD Diagnostic Testing Results Forms 38 completed. Most were adult (53%), female (58%), Caucasian (82%) and non-Hispanic (82%). Approximately half (38/81, 47%) have undergone central lab diagnostic testing (Table 1) while the remaining had previous diagnostic studies. About half of the patients had Type 1, a quarter have Type 3, and the remaining had Type 2 VWD or unknown. The majority of patients (91%) had VWF:GPIbM activity <30IU/dL and (61%) had a VWF:Ag <30IU/dL. One participant had an inhibitor (1/22, 4%) to VWF. Of the participants with a baseline history form submission (73 in total), more than half (42/73, 57%) had undergone surgery, the most common being nasal cautery (11/42, 26.2%) and dental extraction (11/42, 26.2%); complicated by bleeding most commonly during or following dental extraction (2/11, 18.2%) and endoscopy/colonoscopy (2/4, 50%). Few participants (6/73, 8%) reported the presence of a target joint at enrollment, ankle being most common. The bleeding phenotype was variable with a mean ISTH BAT score of 10 (range 0-39) with the first bleeding event commonly occurring prior to age 10 years (51%), with 20% occurring prior to age 12 months (20%). The PBAC was performed on 6 of the 47 female participants in reference to their last period and was abnormal(mean 247; range 0-754). The majority (70 participants, 96%) utilized factor concentrates for prophylaxis or on-demand treatment; 27 participants (39%) were on continuous prophylaxis, while 8 (11%) were on event-based while less (10%) were on heavy menstrual bleeding (HMB) prophylaxis, and the remainder (40%) received episodic treatment. Participants used plasma derived VWF concentrate most commonly (64.3%) with the remainder using recombinant VWF or DDAVP/antifibrinolytics.Discussion: Initial evaluation of 81 participants with clinically severe VWD were diagnostically determined to be type 1 VWD with a majority having a bleeding phenotype (mean (ISTH BAT 10) and HMB (mean PBAC 247). In contrast to patients with mild disease where antifibrinolytics and desmopressin are frequently used, factor replacement was the most common treatment modality. Future analysis will focus on response to factor replacement therapy, genotype-phenotype correlation and quality of life. DisclosuresWeyand: Novo Nordisk: Research Funding; Genentech: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy. Friedman: Siemens: Consultancy; Bayer: Consultancy; Alexion: Speakers Bureau; Genentech: Consultancy; Instrumentation Laboratories: Consultancy; Sanofi: Consultancy. Haley: American Thrombosis and Hemostasis Network: Research Funding. He: ATHN: Ended employment in the past 24 months. Roberts: Takeda; Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding; Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy. Wynn: Sanofi: Research Funding; Takeda: Research Funding; Genentech: Research Funding. Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. OffLabel Disclosure:Vonvendi (recombinant VWF) does not have a product indication for prophylaxis

Hemophilia Natural History Study (ATHN 7): Safety of Current Therapies for People with Hemophilia A or B

INTRODUCTION: The recent introduction of new therapies for people with hemophilia A and B (HA and HB) mandates careful monitoring of the safety of these treatments. The primary aim of ATHN 7: A Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Hemophilia (NCT03619863) is to monitor the safety of current hemophilia therapies.METHODS: ATHN 7 is a longitudinal, prospective cohort study being conducted at 26 American Thrombosis and Hemostasis Network (ATHN)-affiliated sites. The study is approved by central and local institutional review boards. Any person with a diagnosis of congenital hemophilia A or B (factor VIII or IX activity < 50%) who receives care at a participating site is eligible for inclusion. Participants and/or a parent/guardian sign informed consent and assent prior to participation. Adverse events, including those events designated by the European Haemophilia Safety Surveillance group as well as other adverse events of special interest, are recorded and monitored. Demographic and clinical information are collected at baseline and at least quarterly through participant interview and medical record review. Descriptive statistics of medical history and demographic data as well as longitudinal data are used to characterize the study population.RESULTS: As of June 2021, a total of 391 participants had enrolled in ATHN 7. The median age of participants was 22.5 ± 17.8 years. Males represented 97.7% (382/391) of participants. Eighty-five percent (333/391) were not Hispanic. White participants comprised 82.6% (323/391) of the study population, while 7.9% (31/391) were Black/African American, 3.8% (15/391) were Asian, 1.8% (7/391) were of mixed race, and 3.8% (15/391) were of other or unknown race. The primary diagnosis of participants included 70.1% (274/391) with severe HA, 15.3% (60/391) with moderate HA, 7.2% (28/391) with mild HA, 4.1% (16/391) with severe HB, 2.0% (8/391) with moderate HB, and 1.0% (4/391) with mild HB. Nineteen percent (71/391) of participants had a documented history of an inhibitor at the time of enrollment with a mean peak inhibitor titer of 96.7 ± 214.3 Bethesda Units. Substitution therapy with a non-factor molecule was the primary medication for 43.4% (162/391) participants, while 4.3% (16/391) utilized a plasma-derived clotting factor concentrate, 28.4% (196/391) utilized a standard half-life, recombinant factor concentrate, 18.3% (126/391) utilized an extended half-life recombinant factor concentrate, 4.1% (28/391) utilized a bypassing agent, and 19.3% (133/391) utilized some other hemostatic agent. Continuous prophylaxis was the primary regimen for 79.1% (295/391) participants. The remaining 19.6% (73/391) of participants were on episodic therapy. Within the cohort of 391 participants, a total of 14 adverse events have been reported in 8 participants. No adverse events of special interest were reported. Redness or rash at injection site accounted for 64.2% (9/14) of the reported adverse events, all in participants receiving emicizumab. Two participants experienced bruising or bleeding while on emicizumab. Two participants on emicizumab were diagnosed with malignancy, neither found to be attributed to their therapy. One participant developed an allergic reaction to their standard half-life recombinant factor concentrate.DISCUSSION: Open to enrollment in January 2019, ATHN 7 has now collected 18 months of longitudinal safety data for therapies used to treat HA and HB in 391 participants, an addition of 12 months and 24 participants since our last report. As the study was designed to enhance representation of those utilizing substitution therapy, almost half of the participants were on emicizumab for prophylaxis of bleeding. Adverse events attributable to hemophilia therapy was limited to minor skin reactions. As previously reported, a single participant experienced delayed bleeding after closed head trauma (despite factor replacement and normal intracranial imaging at the time of the event), providing potentially important information on the risk of delayed bleeding from significant trauma in those receiving emicizumab. Over the coming year, participants in ATHN 7 will be transitioned to ATHN's new longitudinal natural history study, ATHN TRANSCENDS (NCT04398628). DisclosuresBuckner: Pfizer: Honoraria; Takeda: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Spark: Honoraria; Genetech: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; uniQure: Consultancy, Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees. Carpenter: Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Kedrion Pharmaceuticals: Honoraria; Genentech: Honoraria; Novo Nordisk: Honoraria. Raffini: Genentech: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; XaTek: Consultancy; Bayer: Consultancy. Zia: Takeda: Consultancy; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees. Recht: Hema Biologics: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; uniQure: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy.

Рецидивирующие инфекции мочевой системы: доказательная база и дискутабельные вопросы мероприятий неантибактериальной профилактики

Рецидивирующая инфекция мочевой системы (ИМС) является распространенным, дорогим и обременительным состоянием, которое касается женщин всех возрастных категорий, рас и этнических групп без учета социально-экономического статуса или образовательного уровня. Современные стратегии, направленные на профилактику рецидивирующих ИМС, как и раньше, не являются оптимальными, о чем свидетельствует относительно высокая распространенность данной нозологии у женщин. Цель данной статьи заключалась в освещении и обсуждении как доказательной базы, так и ряда нерешенных вопросов менеджмента рецидивирующих ИМС. Рассмотрены темы, вызывающие клинический интерес: диагностика, возрастные ассоциации, постоянная и интермиттирующая антимикробная профилактика, эффективность современных мероприятий неантимикробной профилактики, потенциальная роль форинала (комплекс D-маннозы и экстракта плодов клюквы) в профилактике рецидивирующих ИМС.

Erenumab Discontinuation After 12-Month Treatment

To assess migraine outcome after 12-month treatment with erenumab and compare patients who underwent 3-month erenumab discontinuation following the first treatment cycle with those who continued monthly administrations. This is a multicentric observational study in patients with migraine in treatment with erenumab. After a full 12-month treatment cycle (T12), patients could either continue or discontinue erenumab for at least 3 months. Patients who underwent treatment discontinuation were assessed after 3 months (T15) to decide whether to start retreatment. Patients were then assessed following at T16 and T18. Thirty consecutive patients were enrolled. Nineteen patients underwent treatment suspension at T12 up to T15, whereas 11 continued prophylaxis. At T15, patients who discontinued treatment documented significantly more migraine days (17.06 ± 6.5 vs 4.8 ± 2.5; p < 0.0001) and analgesics consumption (14.8 ± 9.2 vs 4.6 ± 2.5; p = 0.002), compared with those who continued treatment. After retreatment, at T16, patients who had previously undergone discontinuation documented a significant improvement in terms of migraine days (9.01 ± 4.4 vs 17.06 ± 6.5; p < 0.0001) and analgesics consumption (9.6 ± 7.3 vs 14.8 ± 9.2; p = 0.004). Such improvement was even greater at T18, comparable with T12. After treatment discontinuation, a rapid migraine worsening was found, despite the high clinical response during treatment and at retreatment, which might be secondary to an untimely interruption of a potentially disease-modifying pharmacologic intervention. Although clinical improvement was documented after retreatment, given the high frequency and degree of worsening during discontinuation, it seems plausible-even ethical-to re-evaluate current timing of discontinuation. This study provides Class III evidence that people with migraine discontinuing erenumab migraine prophylaxis after 12 months were more likely to have an increase in nonresponder status and migraine days than those who continued treatment.

Thrombin Generation in Patients with Severe Hemophilia A May Be Variable but Predictive of Response to Treatment

Introduction: Patients with severe hemophilia A (HA) may have variable bleeding phenotypes despite having equivalently low factor VIII (FVIII) levels of <1%. The basis for this heterogeneity in the clinical expression of severe hemophilia is poorly understood. Recent evidence indicates that global assays of coagulation may be better predictors of the coagulation capacity and hemostasis compared with traditional coagulation tests. Current prophylaxis goals in patients with hemophilia minimize time spent at baseline. Thus, we hypothesized that evaluating endogenous thrombin potential (ETP) at baseline, 10% and 40% FVIII correction levels would better reflect real-world scenarios and the effects of treatment.Our objective was to study thrombin generation (TG) parameters (ETP, peak thrombin and lag time) at baseline, 10% and 40% factor correction levels in patients with severe hemophilia A. Additionally we aimed to determine if the baseline TG parameters were predictive of response at the spiked levels .Methods: Our study was a single institution cross-sectional study. Patients were recruited from 4/28/2011 - 7/31/2014. A total of 123 patients with HA were recruited out of which 55 patients with severe HA without inhibitors were included in our study. Descriptive characteristics of the study population included in our study are described in Table 1. A hemophilia severity score (HSS) was calculated based on adjusted bleeding scores, factor scores and joint scores. Baseline plasma samples at trough FVIII were obtained from patients and thrombin generation was evaluated using a standard calibrated automated thrombogram (CAT). Full-length recombinant FVIII was added to trough patient plasma for final factor concentrations of 0.1 U/dl and 0.4 U/dl. Spearman's rank correlation coefficients were calculated and p values of <0.05 were considered statistically significant.Results: Samples from 55 patients with severe HA without inhibitors were evaluated. CAT mean lag times were 5.04 minutes (SD 1.92), 8.06 minutes (SD 10.0), 5.87 minutes (SD 4.38); mean ETPs were 485.4 nM/minute (SD 296.6), 822.9 nM/minute (SD 372.2), 1038 nM/minute (SD 254); and mean peak thrombin levels were 37.2 nM (SD 37.9), 77.7 nM (SD 45.9), 138.4 nM (SD 58.5) at baseline, 10% correction and 40% factor correction respectively. There were no significant correlations between HSS score and TG parameters at baseline, 10% or 40%. The correlations ranged from -0.15 to .012. Severe versus non-severe genotype and TG was analyzed in 47 participants in whom genotype status was recorded. In the 29 patients with severe genotypes (62%) there were no comparisons that were statistically significant. However, the peak thrombin generation at 40% correction trended towards significance with levels lower in the patients with severe as compared to those with non-severe genotypes (p=0.07). Additionally we evaluated if TG parameters at baseline were predictive of responses at 10% and 40% correction levels. Baseline ETP significantly predicted ETP with both 10% (p<0.001) and 40% correction (p=0.0018) levels. Baseline peak thrombin was a significant predictor of peak thrombin levels with 10% (p<0.001) and 40% correction (p<0.001). Lagtime at baseline was a significant predictor of lag time at 10% correction (p=0.008) but not 40% correction levels (p=0.737). (Figure 1)Conclusion: Our results confirm previous studies indicating variability in thrombin generation among patients with severe HA (FVIII<1%) at baseline as well as at different correction levels. Since phenotypic heterogeneity is observed in patients with severe HA, this may suggest that TG better correlates with bleeding severity as compared to factor levels. Even though the HSS scores do not correlate with TG parameters this may be reflective of the need for a more robust phenotypic score evaluating bleeding severity in patients with hemophilia. Additionally, baseline TG parameters appear to be responsive to treatment at 10% and 40% factor correction levels, suggesting that baseline measurements maybe sufficient to predict response. The introduction of continuous primary prophylaxis has dramatically changed the natural history of the disease as well as orthopedic status. Therefore, new criteria may be warranted to define the degree of clinical severity of hemophilia to improve patient management and healthcare costs. [Display omitted] DisclosuresDunn:World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Other: Unrestricted educational grant, Research Funding; Octapharma: Other: Unrestricted educational grant; NovoNordisk: Other: Unrestricted educational grant; Kedrion: Other: Unrestricted educational grant; Biogen: Other: Unrestricted educational grant, Research Funding; CSL Behring: Consultancy, Other: Unrestricted educational grant; Bayer: Consultancy, Other: Unrestricted educational grant; Alnylam: Other: Unrestricted educational grant.

Cardiometabolic Risk Assessment in Children and Young Adults with Hemophilia

IntroductionA significant challenge in the aging hemophilia population is cardiovascular disease (CVD). It is relevant to study cardiometabolic risk factors in children, because the origins of CVD begin in childhood. Risk factors include obesity, hypertension, abnormal lipid profile, and family history of CVD. The prevalence of cardiometabolic risk factors in children with hemophilia is unknown. The objective of this study was to quantify these risk factors and to evaluate the impact of overweight/obesity on target joints and factor consumption.MethodsMales, 5-20y old, with congenital hemophilia A or B, were enrolled in a cross-sectional study at Rady Children's Hospital San Diego Hemophilia Treatment Center (HTC). Study procedures included standardized measurement of weight, height, waist circumference and blood pressure (BP), and non-fasting laboratory measurement of glucose (<200 mg/dL is normal) and lipid panel (to calculate non-high-density lipoprotein [non-HDL-C]; result was categorized as normal, borderline high, or high per age-based norms). Body mass index (BMI) percentile was determined for children <18 years, and BMI was calculated for adults. Weight category of underweight, normal weight, overweight or obese was assigned based on established norms for BMI percentile and BMI. Waist:height ratio (WHtR) was calculated; >0.5 is considered a cardiometabolic risk factor. (Pre) hypertension was defined as systolic BP (SBP) and/or diastolic BP (DBP) ≥90% for children <18y and SBP >140 or DBP >90 for adults. Parents and adult patients completed questionnaires regarding demographics, personal and family history of CVD, and physical activity. Clinical data were abstracted from the medical record. Descriptive statistics were used to characterize the population. Student's t-test, correlation and chi square test were performed to analyze the data.ResultsForty-three males (mean 12y, range 5-20y, including 6 young adults) were enrolled. The majority were White race (88%) and Hispanic ethnicity (65%). Twenty-three (53.5%) had severe hemophilia A including 2 with high titer inhibitors.No subjects reported congenital heart disease, kidney disease, diabetes mellitus, glucose intolerance, hypercholesterolemia, (pre) hypertension, or cardiovascular events. Two subjects reported a diagnosis of overweight/obesity, and both were referred to a weight and wellness program. A summary of cardiometabolic risk factors is shown in Table 1. Subjects with normal weight had more days of >60 minutes of physical activity compared to those with overweight/obesity (5.2 ± 2.4d v. 3.8 ± 2.5d; p=0.07).Thirty-one (72%) were on continuous prophylaxis including all 21 subjects with severe hemophilia A without inhibitor. The mean prophylactic factor dose in units (IU)/kg/week was 118 IU, range 64 -187. There was no difference between subjects with normal weight (125 IU/kg/week, range 71-187) and subjects with overweight /obesity (111 IU/kg/week, range 64-174); p=0.26, but higher weight was correlated with higher total factor consumption (cor=0.84; p <0.001), up to 12,000 IU per week. There was no difference in history of target joints based on weight category (30% in normal weight v. 25% in overweight/obese, χ2= 0.11, p=0.74).ConclusionsA high proportion of subjects had modifiable risk factors for CVD which were not previously recognized by the patient or parent. Longitudinal follow-up is warranted to define the natural history of CVD in this population. The HTC team, including a genetic counselor, physical therapist and dietician, can identify risk factors for CVD and develop interventions to target cardiovascular risk reduction. Increasing days of physical activity may lead to decreased overweight/obesity, improved outcomes, and less factor consumption. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prophylactic drug management for febrile seizures in children.

Prophylactic drug management for febrile seizures in children.