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Introduction Severe haemophilia A (HA) has a major impact on health‐related quality of life (HRQoL). Aim Assess the impact of emicizumab on HRQoL in persons with severe HA (PwHA) without factor VIII (FVIII) inhibitors in the phase 3 HAVEN 3 and 4 studies. Methods This pooled analysis examines the HRQoL of PwHA aged ≥ 18 years treated with emicizumab prophylaxis via Haemophilia‐Specific Quality of Life Questionnaire for Adults (Haem‐A‐QoL) and EuroQoL 5‐Dimensions 5‐levels (EQ‐5D‐5L). In particular, changes from baseline in Haem‐A‐QoL ‘Physical Health’ (PH) domain and ‘Total Score’ (TS) are evaluated. Results Among 176 evaluable participants, 96 (55%) had received prior episodic treatment and 80 (45%) prophylaxis; 70% had ≥ 1 target joint and 51% had experienced ≥ 9 bleeds in the previous 24 weeks. Mean Haem‐A‐QoL PH and TS improved after emicizumab initiation. Mean (standard deviation) –12.0 (21.26)‐ and –8.6 (12.57)‐point improvements were observed in PH and TS from baseline to Week 73; Week 73 scores were 27.9 (24.54) and 22.0 (14.38), respectively. Fifty‐four percent of participants reported a clinically meaningful improvement in PH scores (≥ 10 points) by Week 73. Subgroups with poorer HRQoL prior to starting emicizumab (i.e. receiving episodic treatment, ≥ 9 bleeds, target joints) had the greatest improvements in PH scores, and corresponding reductions in missed workdays; change was not detected among those previously taking prophylaxis. No change over time was detected by the EQ‐5D‐5L questionnaire. Conclusions Emicizumab prophylaxis in PwHA without FVIII inhibitors resulted in persistent and meaningful improvements in Haem‐A‐QoL PH and less work disruption than previous treatment.

Introduction In 2017, all people with severe haemophilia B (PWSHB) in Ireland switched from standard half-life (SHL) recombinant FIX (rFIX) to rFIX Fc fusion protein (rFIXFc) prophylaxis. Aims To evaluate prophylaxis regimens, bleeding rates and factor usage for two years of rFIXFc prophylaxis in a real-world setting. Methods Data collected retrospectively from electronic diaries and medical records of PWSHB for a two-year period on rFIXFc prophylaxis were compared with paired baseline data on SHL rFIX treatment. Results 28 PWSHB (≥18 years) were enrolled, and at switchover 79% were receiving prophylaxis and 21% episodic treatment with SHL rFIX. At 24 months following switchover, all remained on rFIXFc prophylaxis with reduced infusion frequency; median dose per infusion once weekly (55 IU/kg, 20/28), every 10 days (63 IU/kg, 2/28) or every 14 days (98 IU/kg, 6/28). Median annualised bleed rate improved significantly on rFIXFc prophylaxis (2.0 versus 3.3 on SHL FIX) (p = 0.01). Median FIX trough level with once-weekly infusions was 0.09 IU/ml (0.06-0.14 IU/ml). Management of bleeding episodes was similar with rFIXFc and SHL rFIX; one infusion was sufficient to treat 74% and 77% of bleeds, respectively, with similar total median treatment per bleeding episode. Factor consumption reduced by 28% with rFIXFc prophylaxis (57 IU/kg/week, range 40-86 IU/kg/week) compared with SHL rFIX (79 IU/kg/week, range 44-210 IU/kg/week) (p = 0.002). Conclusion This study provides important insights into real-world experience of switching to rFIXFc prophylaxis in an adult population, demonstrating high rates of prophylaxis, with reduced infusion frequency, bleeding and FIX consumption.

Genital herpes simplex virus infections are among the most prevalent sexually transmitted infections in the United States. It continues to be a public health concern because of its recurrent nature and potential for complications. Treatment is not curative, but rather serves to shorten the duration of symptoms and improve quality of life. Current therapies include episodic treatment and chronic suppressive therapy and are generally well tolerated and effective.

Prophylaxis is the globally accepted standard of care for persons with haemophilia and presents many advantages over episodic treatment. The prophylaxis benefits include bleed reduction, reduction in musculoskeletal complications and improvement in the quality of life. The currently evolving novel therapies for the management of haemophilia has ushered a new era characterized by improved prophylaxis targets and outcomes. These redefined targets and outcomes have necessitated the need to also redefine prophylaxis. In this state-of-the-art review, we redefine prophylaxis in the modern era by revisiting its definition, presenting data to support higher trough levels to achieve with prophylaxis and introducing steady-state haemostasis as a possible new target for prophylaxis.

Scimitar syndrome, or congenital pulmonary venolobar syndrome, is a rare congenital heart defect characterized by the anomalous venous return from the right lung. A number of cases that lack all the features of a typical syndrome have been described as the scimitar variant, but the incidence is rare. These variants may be difficult to diagnose and, if diagnosed, they may not require surgical correction, instead, can be managed through episodic treatment and yearly monitoring for the development of complications. Herein, we report the case of a 9-month-old male baby with an uncommon variant of scimitar syndrome where the aortopulmonary collateral maintaining the blood supply of the right lung aroused from the right subclavian artery and descending thoracic aorta instead of inferior vena cava. Due to this, the management completely changed from catheterization of the heart to just follow-up monitoring of ventricular function and development of severe pulmonary hypertension.

Over the past several years, novel modified clotting factor concentrates (CFCs) have been introduced into practice and are now widely prescribed in the countries where they are licensed. These products allow for less frequent infusions of CFC, thereby providing improved convenience and/or higher trough levels. They have been extensively studied for prophylaxis, episodic treatment of bleeding and for surgical prophylaxis. One issue that has emerged regarding the clinical application of these products revolves around the measurement of infused CFC in the clinical coagulation laboratory. Recent studies have demonstrated significant problems with the measurement of correct FVIII/IX levels following infusion of novel CF VIII/IX concentrates. The source of this problem appears to be related to the tremendous variability of the APTT reagents that are used in the one-stage clotting assay, the most commonly used assay for determining factor levels. More specifically, the issue is related to the type of activator used in the reagents. Depending on the combination of the CFC and the APTT activator, the observed results may be either under- or overestimated to degrees that would be clinically relevant. Recommendations based on a review of published information regarding the potential for incorrect measurements of factor VIII/IX levels following infusion of recently developed, novel factor VIII/IX CFCs are presented for the clinician to use in clinical practice.

Introduction Real-world data on health-related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non-interventional study (NIS; NCT02476942) prospectively collected high-quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice. Aim To report health-related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors. Methods Participants were PwHA without FVIII inhibitors age ≥12 years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) or Haemophilia-Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo-QoL-SF II). Health status was assessed through EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS). Results Ninety-four participants enrolled; median age was 34.0 years (range 12-76). Forty-five received episodic treatment and 49 received prophylaxis for a median time of 27.7 weeks and 30.4 weeks, respectively. Mean (standard deviation) baseline Haem-A-QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ-5D-5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ-VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively). Conclusions Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.

Objective This study aimed to explore real-world evidence on health resource use (HRU) spending on patients with haemophilia and inhibitor. Materials and methods Medical records from 1990 to 2019 of patients with haemophilia and inhibitor from three comprehensive haemophilia treatment centres were retrospectively retrieved. Results In all, 31 patients with haemophilia (A = 30, B = 1) and inhibitor ≥5 BU were included. The mean initial inhibitor of 95.4 BU was detected at the mean age of 6.7 years. The mean number of annual hospitalisations was 3.9. A total of 795 bleeding episodes (major =125, minor =670) were evaluated. The treatment included bypassing agents or plasma exchange before administering high-dose factor VIII concentrate and intervention or surgery. Six patients succumbed to bleeding at the mean age of 17.2 years. Nineteen surviving patients experienced multiple morbidity except six patients with successful and partially successful immune tolerance induction (ITI). The mean (SD) annual total medical consumption for episodic treatment and successful ITI per patient with haemophilia A were 30,804 (81,332) USD and 55,531 (100,566) USD, respectively. Only episodic treatment was paid by the government budget for limited amounts of bypassing agents. Conclusion Management for patients with haemophilia and inhibitor exhibiting severe bleeding is challenging for medical personnel in countries having limited resources over decades. The real-world data will be used to negotiate with the government to increase budget for adequate bypassing agents or nonreplacement therapy and to include ITI in the national haemophilia treatment.

Prophylaxis is the gold standard treatment for haemophilia but requires more amount of clotting factor concentrates, than on demand therapy. Low dose prophylaxis is an alternative for countries with limited resources. There are data of evidence showing the superiority of low-dose prophylaxis than episodic treatment. Studies from China, India, Tunisia, Thailand and Indonesia reported experiences with low dose prophylaxis using outcome assessment. These studies have shown the effectiveness of various protocols regimen with once, twice or thrice injection of 10-15 UI Kg-1 per injection. These protocols allow reduction of joint bleeds and at least delay of joint damages. There is not enough long-term data nowadays, but low dose prophylaxis is certainly better than on demand therapy and should be considered as a first step of prophylaxis in some countries but not the final goal.

During pregnancy several drugs are having contraindication, hence their use is less and dangerous to mother along with fetus .Drugs play an important role in improving the health and promoting well-being. However to produce desired effect, they have to be safe, efficacious and have to be used rationally. During pregnancy medication is less preferred but in some times cannot be escaped to treat the ailments in mother. Avoiding medications may be desirable, it is often not possible and may be dangerous because some women enter pregnancy medical conditions that require continuous and episodic treatment (e.g. asthma, hypertension, epilepsy). So here we discussed the medication that can be used safely during pregnancy along with unsafe and highly contraindicated for both mother and fetus. Certain drugs given during pregnancy may prove harmful to unborn child is one of the classical problem in the medical treatment. The main purpose of this review is to prepare a list of safe medications which can be taken during pregnancy with unsafe and highly contraindicated drugs. And also a quick reference for health care professionals. Keyboard: Current, Pregnancy, Drugs, Fetus

AimFor previously untreated patients (PUPs) with severe haemophilia A in Finland for the past 2 decades, the standard practice has been to start early primary prophylaxis. We evaluated the long-term clinical outcomes and costs of treatment with high-dose prophylaxis in PUPs from birth to adolescence, including immune tolerance induction (ITI). MethodsFrom the medical records of all PUPs born between June 1994 and May 2013 in Finland, we retrospectively extracted data on clinical outcomes and healthcare use. Using linear mixed models, we analysed longitudinal clinical outcome data. To analyse skewed cost data, including zero costs, we applied hurdle regression. ResultsAll 62 patients received early regular prophylaxis; totally, they have had treatment for nearly 700 patient-years. The median age of starting home treatment was 1.1years. The mean (SD) annual treatment costs (Europerkg) were 4391Euro (3852). For ages 1-3, ITI comprised over half of the costs; in other groups, prophylactic FVIII treatment dominated. With these high costs, however, clinical outcomes were desirable; median (IQR) ABR was low at 0.19 (0.07-0.46) and so was AJBR at 0.06 (0-0.24). Thirteen (21%) patients developed a clinically significant inhibitor, 10 (16%) with a high titre. All ITIs were successful. The mean costs for ITI were 383448Euro (259085). The expected ITI payback period was 1.81 (95% CI 0.62-12.12) years. ConclusionsEarly high-dose prophylaxis leads to excellent long-term clinical outcomes, and early childhood ITI therapy seems to turn cost-neutral generally already in 2years.

Introduction: Bleeding phenotypes of severe-type patients with hemophilia A (PwHA) vary greatly, which influence factor consumption and medical cost. Factors affecting bleeding patterns of PwHA include various procoagulant and anticoagulant factors, joint condition and physical activity, etc. We aimed to investigate clinical factors influencing by-nature bleeding frequency of severe-type PwHA during episodic treatment. Methods and materials: There were 19 non-inhibitor, severe-type, previously treated PwHA aged >20 years, who had at least one to five major joints arthropathy, retrospectively enrolled from two hemophilia centers for analysis. They had been refusing prophylaxis therapy with FVIII product due to heavy burden of frequent intravenous FVIII injection and had long-term episodic treatment. Clinical informations were collected from November 2017 to November 2018, including age, body mass index (BMI), body weight, ABO blood grouping, HCV and HIV infection status, baseline VWF:Ag and VWF:activity, mutation of F8 gene. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR), weekly doses and annualized factor consumption costs (calculated by new Taiwan dollars, NTD) were obtained from the patients' medical records. Results: The PwHA with ABR 24.(P-value 13.(P-value 145% had significantly older age (34.9 vs 53.2 years, P-value 28 had significantly lower ABR (58.2 vs 12.2 per year, P-value Conclusion: For severe-type adult PwHA with episodic treatment, baseline VWF:Ag or VWF:activity >145% was associated with lower ABR, AJBR, weekly dose, and annualized factor cost. BMI >28 was associated with lower ABR, AJBR, and weekly dose consumption. Baseline VWF:Ag and BMI were revealed as inverse influencing factors for ABR and AJBR, respectively. The results of our study could be useful for clinicians to have an insight into diversity of bleeding phenotypes of by-nature severe-type PwHA. For developing countries where factor concentrate resources are not enough, these clinical influencing factors might be helpful for the management of therapeutic strategies and resource allocation for severe PwHA. Disclosures No relevant conflicts of interest to declare.

Background: Recurrent joint bleeds leading to arthropathy is the main problem in severe hemophilia children. This study aimed to investigate joint status in severe hemophilia A children receiving episodic treatment in Cipto Mangunkusumo Hospital, Jakarta.Methods: A cross-sectional study was conducted in Cipto Mangunkusumo Hospital as Indonesian National Hemophilia Treatment Center on children (4–18 years) with severe hemophilia A, who previously received episodic treatment, with no history of inhibitor factor VIII. Hemophilia Joint Health Score was evaluated according to HJHS version 2.1 2011. Joint ultrasonography was done for six index joints (bilateral elbows, knees and ankles) using Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) methods. Data of age of first joint bleed, number of target joints and inhibitor factor VIII were obtained from the Pediatric Hemophilia Registry and medical records.Results: There were 59 subjects aged 4 to 18 years. Twenty-nine out of 59 (49.2%) subjects experienced first joint bleed before of 2 years of age. The most common of joint bleeds was a right ankle. Mean total HJHS was 8.71±8.73. Subjects aged 4–10 years showed lower HJHS (4.6±3.7) as compared to subjects aged >10–18 years (12.3±10.3), p10–18 years (28±7.9), p10–18 years, indicating more severe joint destruction in older children and progressivity of joint damage over time. It is important to start prophylactic treatment to prevent progressivity of joint damage.

Introduction Patients with haemophilia on long-acting prophylactic treatment may experience an improvement in health-related quality of life (HRQoL) through reductions in breakthrough bleeds and associated complications, including long-term joint damage, compared with episodic treatment. Aim This analysis examined clinical trial data to understand the psychometric characteristics (reliability, validity and sensitivity to change over time) of the Haem-A-QoL Questionnaire in adult males with haemophilia. Methods Two recent, multinational, Phase 3 clinical trials of new, long-acting factor concentrates (A-LONG: rFVIIIFc; B-LONG: rFIXFc) assessed HRQoL in adolescent and adult males with severe haemophilia A or B respectively. The adults’ baseline assessments, via the 46-item Haem-A-QoL Questionnaire, and change over time at the 6-month assessment were used in the psychometric analyses. Results Internal consistency reliability was adequate (Cronbach's alpha > 0.70) for nine of the 10 Haem-A-QoL domains and for ‘Total Score’ in both trials at baseline (A-LONG, n = 133; B-LONG, n = 73). At baseline, several Haem-A-QoL domains and ‘Total Score’ demonstrated known-groups and convergent validity when compared with other trial measures, including the EQ-5D (items and total scores) and joint impairment. Change score correlations (baseline to 28 weeks) between the EQ-5D and the Haem-A-QoL ‘Total Score’, and ‘Physical Health’ and ‘Feelings’ domains were moderate in magnitude (│r│ ≥ 0.33; P < 0.03), demonstrating sensitivity to change for these outcome measures in A-LONG. Conclusion These psychometric analyses provide evidence of the reliability, validity and ability to detect change of the Haem-A-QoL to assess the HRQoL of adult males with severe haemophilia A and B in longitudinal clinical trials.

Introduction In haemophilia, prophylactic infusion of replacement factor can result in improvements in health-related quality of life (HRQoL) when compared with episodic treatment. The Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire assessed HRQoL in adults with severe haemophilia A or B who received prophylactic or episodic treatment with recombinant factor VIII or IX Fc fusion protein (rFVIIIFc or rFIXFc) in the A-LONG or B-LONG clinical studies. Aims Understand changes in HRQoL during the A-LONG and B-LONG trials. Methods Group-level and individual-level changes over time for the Haem-A-QoL key domains of ‘Physical Health’ and ‘Sports & Leisure,’ and ‘Total Score’ were evaluated in adults through baseline and 6-month HRQoL assessments. Previously determined responder definitions (RDs) were used for evaluating meaningful subject-level HRQoL improvements. Results The analysis included 67 A-LONG and 51 B-LONG subjects who completed the Haem-A-QoL (baseline and 6 months). While HRQoL improvements were observed among all treatment groups, greater improvements in HRQoL were observed among subjects who received episodic treatment pre-study (and prophylaxis on-study) compared to those who received hyphenate prophylaxis. Applying the RDs for interpreting 6-month changes, 47.4%/33.3% (‘Physical Health’), 35.9%/50.0% (‘Sports & Leisure’) and 23.9%/33.3% (‘Total Score’) of A-LONG subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. In B-LONG, 69.2%/57.9% (‘Physical Health’), 44.4%/56.7% (‘Sports & Leisure’) and 41.7%/44.1% (‘Total Score’) of subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. Conclusion Changes in Haem-A-QoL key domains and ‘Total Score’ suggest that prophylaxis with long-acting rFVIIIFc or rFIXFc resulted in meaningful HRQoL improvements.

Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohn's and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees' members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an add-on to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

BACKGROUND & AIMS: In the TAILORIX trial, no benefit could be shown by infliximab dose escalation based on pharmacokinetic (infliximab serum concentrations) and pharmacodynamic (biomarkers and symptoms) monitoring compared with dose escalation based on symptoms alone in patients with Crohn's disease (CD). We investigated whether integration of pharmacokinetic and pharmacodynamic monitoring can be used to evaluate responses to infliximab induction and maintenance therapy, based on findings from endoscopy. METHODS: We performed a post hoc analysis of patients with CD included in a trial to test the effects of infliximab dose escalation, based on biomarkers and serum concentrations of infliximab, on symptoms (the Study Investigating Tailored Treatment With Infliximab for Active Crohn's Disease trial; n = 122). We analyzed data from this study to determine whether concentrations of biomarkers and serum concentrations of infliximab were associated with endoscopic outcomes (n = 116). The primary end points were endoscopic response (CD endoscopic index of severity decrease ≥50% from baseline), endoscopic remission (CD endoscopic index of severity

INTRODUCTION Evaluating treatment success in patients with haemophilia A (HA) remains a vigorous debate, especially concerning the interpretation of results from clinical and observational research. The benefits of short-term prophylaxis are well established, but long-term outcomes, particularly related to humanistic and economic burden, are not as well understood. AIM We conducted a systematic literature review to evaluate the association of episodic or prophylactic bleed control with long-term clinical, humanistic and economic outcomes. METHODS Studies published in English between 1 January 2006 and 15 December 2016 were included. Participants had HA (with or without inhibitors), received prophylactic or episodic treatment and had at least 4 years of treatment or follow-up. Results were analysed qualitatively with descriptive findings. RESULTS A total of 2091 records were screened, resulting in 19 studies from 20 publications for inclusion. Most studies included children (84%), were limited to patients with severe disease (74%) and were conducted in Europe or North America (89%). Ten studies (53%) included patients with inhibitors. Median study follow-up ranged from 5 to 19 years. Long-term bleeding and haemarthrosis outcomes were consistently better for patients receiving prophylaxis, who also required fewer hospitalizations or surgeries. Health-related quality of life, functionality and productivity were generally more favourable in patients receiving prophylaxis. Quantitative comparisons were not feasible due to the lack of consistency in endpoint collection and reporting among studies. CONCLUSION This systematic review confirmed that the benefits of prophylactic treatment on short-term outcomes translate to broader long-term clinical, humanistic and economic benefits. Better harmonization of data collection and outcome assessments across both registries and clinical studies is needed to allow for effective comparisons across studies and across data sources.

We performed a systematic review with the objective of verifying the efficacy of topical use 5% Acyclovir-1% Hydrocortisone cream compared to the placebo group for herpes simplex labialis treatment. We performed a literature search using MEDLINE, Embase, BIOSIS, LILACS, Scopus, Grey literature, the Cochrane Central Register of Controlled Trials, the ISI Web of Science and IBECS from 1990 to June 2014. We reported the outcomes using relative risk (RR) with 95% confidence intervals. The literature search yielded 180 potentially relevant publications. Reviews of the reference lists yielded two further citations. Among these papers, two were considered eligible for inclusion in this review. Both trials included 1,213 patients. A meta-analysis of these studies showed a RR = 0.77, (95% CI 0.70-0.86; p

Background Herpes labialis is characterized by recurrent vesicular eruptions primarily on the lips and perioral skin. The condition is contagious, can cause significant discomfort/pain, and can have an adverse effect on the quality of life. Objective To update the evaluation and treatment of herpes labialis. Methods A PubMed search was completed in Clinical Queries using the key term "herpes labialis". Patents were searched using the key term "herpes labialis" from www.freepatentsonline.com. Results The diagnosis of herpes labialis is mainly clinical based on classic grouped lesions (papules, vesicles, ulcers) on the lip. Antiviral therapy shortens the duration of pain and discomfort, hastens healing, and reduces viral shedding. Thus, episodic treatment is warranted, especially if the patient desires treatment for cosmetic purposes or for relief of pain. Such treatment needs to be initiated promptly, ideally in the prodromal stage and no later than 48 hours from the onset of lesions to achieve optimal results. Chronic suppressive therapy with oral antiviral agents should be considered for patients with severe or frequent (six or more episodes per year) recurrences. Recent patents related to the management of herpes labialis are also discussed. Conclusion For episodic treatment, oral antiviral agents, such as acyclovir (Zovirax), valacyclovir (Valtrex) and famciclovir (Famvir), are superior to topical antiviral therapy. Valacyclovir and famciclovir have greater oral bioavailability and are better absorbed than acyclovir, require less frequent dosing, but are more expensive and are not approved for children. Topical antiviral agents such as 5% acyclovir cream/ointment (Zovirax) ± hydrocortisone (Xerese), 1% penciclovir (Denavir) cream, and 50 mg Buccal Adhesive Tablet (ABT-50 mg) can also be used for episodic treatment of herpes labialis. These topical agents are not effective in the prevention of recurrent herpes labialis. For chronic daily suppressive therapy, oral antivirals are the treatment of choice.

Patients and methods A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate (AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. Results The median age at the beginning of the study was 10 years (IQR 7–12). The median clotting factor concentrate (CFC) usage was 662 IU kg−1 year−1 (IQ range: 280–1437). The median AJBR was 10 (IQ range: 5–17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses (P 3 per year (P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year (P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. Conclusion Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia.

Background: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. Objective: This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII < 1%) over a 10-year time period. Methods: Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factorVIII (25 IU kg-1 3 × week) or episodic therapy with ≥ 25 IU kg-1 every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Results: Twenty-one childrenwere assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plainfilm radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤ 36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. Conclusion: This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life

Introduction: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care in hemophilia A, given its natural mechanism of action, strict homeostatic regulation, and consistent safety profile. Recombinant FVIII Fc fusion protein (rFVIIIFc) is an extended half-life therapy that demonstrated safety and efficacy in previously treated pediatric, adolescent, and adult subjects with severe hemophilia A in the Phase 3 A-LONG and Kids A-LONG trials (NCT01181128 and NCT01458106, respectively) (Young et al, J Thromb Haemostas, 2015; Mahlangu et al, Blood, 2014). Herein, the final results are reported from ASPIRE (NCT01454739), the long-term extension trial of those 2 studies. Methods: This was an open-label, multicenter, long-term trial of previously treated subjects of all ages with severe hemophilia A. Subjects received 1 of the 4 following regimens: individualized prophylaxis (IP; rFVIIIFc 25‒60 IU/kg every 3-5 days, or twice weekly), weekly prophylaxis (WP; rFVIIIFc 65 IU/kg every 7 days), modified prophylaxis (MP; personalized dosing), or episodic treatment (ET; on-demand dosing based on bleeding episodes). Subjects 1 treatment group. The primary endpoint was development of inhibitors. Secondary endpoints included annualized bleeding rates (ABRs), joint ABRs, spontaneous joint ABRs, exposure days (ED), and factor consumption. Descriptive statistics were used for analysis. Analyses were performed separately based on parent study. Results: A total of 211 subjects (150 were from A-LONG and 61 were from Kids A-LONG) enrolled in ASPIRE, and 186 subjects (132 from A-LONG and 54 from Kids A-LONG) completed the study. Subjects from Kids A-LONG had a median (range) age of 6.0 (2-12) years. Of the subjects from the A-LONG study enrolled to ASPIRE, the median (range) age was 31.0 (13-66) years. Most subjects received IP regardless of parent study (Kids A-LONG: IP [n=59], MP [n=3]; A-LONG: IP [n=110], WP [n=27], MP [n=21], ET [n=13]). No inhibitors were observed throughout the study, and the overall safety profile of rFVIIIFc was consistent with the parent studies and prior interim analyses. ABRs remained low throughout the entirety of ASPIRE in subjects prescribed IP (Table 1). For subjects from the Kids A-LONG study, the median (range) number of ED during ASPIRE was 332.0 (18.0-467.0) days. Total median (range) treatment duration was 166.6 (14.4-203.0) weeks. The median (range) number of ED for A-LONG subjects was 267.5 (8.0-660.0) days. Total median treatment duration was 201.4 (5.1-274.6) weeks. Overall, the median (range) duration of treatment with rFVIIIFc was 4.1 (0.4, 5.9) years. From the end of the parent study to the end of ASPIRE, the rFVIIIFc dosing interval increased for 6.6% and 21.1% of subjects from Kids A-LONG and A-LONG, respectively (Table 2). There was no change in median weekly factor consumption from the end of either parent study to the end of ASPIRE. For subjects from Kids A-LONG, the median (IQR) was 0.0 (0.0‒3.2), while the median (IQR) for those from A-LONG was 0.0 (0.0‒0.0). Conclusions: Throughout up to 4 years of treatment with rFVIIIFc in the ASPIRE extension study, no inhibitors were reported, and low ABRs and extended dosing intervals were sustained. These data are consistent with the well-characterized safety profile and durable efficacy of rFVIIIFc prophylaxis in previously treated subjects of all ages with hemophilia A. Disclosures Nolan: Bayer: Research Funding; CSL Behring: Research Funding; Sobi: Research Funding. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Amgen: Consultancy; Biomarin: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Young:Bayer: Consultancy; Bioverativ: Consultancy, Honoraria; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Konkle:Sangamo: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Bioverativ: Research Funding; Pfizer: Research Funding; Shire: Research Funding. Pasi:Shire: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bayer: Speakers Bureau; Octapharma: Honoraria; Pfizer: Speakers Bureau; Biomarin: Honoraria, Research Funding; Sobi: Honoraria; Bioverativ: Honoraria, Research Funding; NovoNordisk: Speakers Bureau; Catalyst Bio: Honoraria; Apcintex: Honoraria. Oldenburg:Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Tripkovic:Sobi: Employment. Rudin:Bioverativ: Employment, Equity Ownership.

L’Infliximab, un anticorps chimerique monoclonal IgG1 dirige contre le TNF constitue le premier traitement biologique approuve dans la maladie de Crohn (MC) et s’est avere efficace dans le traitement de la MC luminale refractaire ou intolerante au traitement standard par les glucocorticosteroides et/ou les immunodepresseurs. La strategie optimale est l’induction therapeutique par 5 mg/kg i.v. aux semaines 0-2-6, suivie d’un traitement systematique d’entretien toutes les 8 semaines. L’infliximab produit une cicatrisation rapide des lesions endoscopiques et histologiques. Le traitement d’entretien par infliximab procure une reduction du nombre de complications, d’hospitalisations, et d’interventions chirurgicales associees a la MC. La reponse a l’infliximab peut etre renforcee par l’administration concomitante d’un traitement immunosuppresseur. Les problemes de securite concernent principalement l’immunogenicite due a la formation d’anticorps anti-infliximab (ATI) qui peuvent conduire a des reactions perfusionnelles, a la perte de reponse et a des reactions serologiques retardees induites par les perfusions. Les mesures destinees a reduire cette immunogenicite comportent au cours du traitement d’entretien, l’administration concomitante d’immunomodulateurs et en phase pretherapeutique, l’utilisation de corticoides. Une tuberculose latente doit etre depistee avant le debut du traitement. D’autres affections opportunistes connaissent un taux legerement superieur, principalement chez les patients traites en meme temps par immunomodulateurs. Les complications malignes chez les patients traites par anti-TNF ne sont pas accrues.

A new measure of treatment satisfaction (GHerpTSQ) for recurrent genital herpes simplex virus (HSV) was validated and used to evaluate two therapeutic strategies widely used for the management of HSV: episodic treatment, where individual herpes outbreaks are treated as they arise; suppressive therapy, where treatment is taken daily to prevent HSV outbreaks. Satisfaction with treatment is important since daily dosing with suppressive therapy is necessary in the absence of symptoms. A 12-item questionnaire was designed using a modified form of the Diabetes treatment satisfaction questionnaire (DTSQ). The psychometric properties of the GHerpTSQ were evaluated within a sample of 125 Canadians with a history of HSV (type 1, 2) infection participating in a 48 week randomised cross-over trial. Factor analysis suggested that the items can be analysed as two separate subscales corresponding to Control/effectiveness, and Convenience/lifestyle; the single item concerning side effects was retained for separate analysis. Forced one-factor analysis showed that the two subscales can be combined to obtain a total score relating to overall treatment satisfaction. The GHerpTSQ has good internal reliability, clear structure with little overlap of subscales and evidence of good sensitivity to changes in treatment.

Valacyclovir given in a 5-day regimen of 500 mg twice per day is effective as short-term treatment of episodes of recurrent genital herpes. This study compared the efficacy of a shorter, 3-day course (for 402 patients) with that of a 5-day course (for 398 patients) of valacyclovir for persons with frequent recurrence of symptoms. No significant differences were detected between the 2 dosing schedules for any of the end points measured. Median times to lesion healing, of pain duration, and of episode length for the 5-day versus 3-day treatment were 4.7 versus 4.4 days, 2.5 days versus 2.9 days, and 4.4 days versus 4.3 days, respectively. The proportions of patients with aborted lesions were 26.6% and 25.4% in the 5-day and 3-day groups, respectively. A 3-day course of 500 mg of valacyclovir administered twice daily as episodic treatment of recurrent genital herpes is equivalent to a 5-day course with regard to key markers of efficacy.

INTRODUCTION The management of Crohn's disease (CD) has changed considerably over the last 20 years. Immunomodulators and biological therapies now play a role in treating patients with CD, but little is known of their influence on surgical rates. AIM To review the surgery rates for CD in an Irish university hospital over a 20-year period and to determine whether newer therapies had an impact on surgical rates. METHOD Seven hundred twenty-two patients attending St Vincent's University Hospital, Dublin, with CD over a 20-year period (January 1986 to December 2005) were identified. The patients were divided into quartiles. Resection rates were determined in all the quartiles, at both 1 and 3 years from diagnosis. RESULTS A decline in surgery, 3 years from diagnosis, was noted between the first quartile (72 patients, 40%) and the second quartile (58 patients, 32%; P=0.03). No significant change in surgical rates at 3 years occurred between the other 3 quartiles (32%, 30%, and 35%, respectively; P=NS). The patients who required a resection within 3 years were diagnosed at a younger age in later years. There was a similar predominance of 60% of female patients requiring surgery in all groups. The patients requiring surgery were twice as likely to be ex-smokers or current smokers in all groups. Use of infliximab, within 3 years from diagnosis, increased from 0, 0, and 16 patients (8.8%) to 40 patients (22.1%) in the last quartile. The majority of patients were treated with infliximab on an "on demand" basis. Use of infliximab earlier within the course of the disease was seen in later quartiles (ie, within 1 y of diagnosis): 0, 0, 6, and 21 patients. CONCLUSION Despite the introduction of infliximab over the past 10 years, no demonstrable difference has been seen in the rates of patients requiring resection surgery within 3 years of diagnosis. The reasons for this are unclear, but may relate to episodic treatment, rather than regular maintenance treatment. Female patients and smokers seem to be particularly at risk of resection surgery.

Severe haemophilia is associated with bleeding into joints and development of arthropathy. Prophylactic treatment with infusion of replacement clotting factor is known to prevent bleeding, preserve joint functioning and result in higher health-related quality of life (HRQoL) than episodic treatment; however, adhering to standard prophylaxis schedules can be difficult, and little is known about the relationship between adherence to prophylactic treatment and outcomes. The aim of this study was to assess the relationship between self-reported adherence to prophylaxis and health outcomes, including HRQoL and bleeding episodes. Adults with haemophilia (n = 55) and caregivers of children with haemophilia (n = 55) in Australia, Canada, and the United States completed an online questionnaire which included measures of HRQoL (SF-12v2 for adults and SF-10 for caregivers of children), self-reported bleeding episodes, and the VERITAS-Pro measure of adherence to prophylaxis in haemophilia. Regression analysis was used to test the association between VERITAS-Pro total score and outcomes. Poorer adherence (higher VERITAS-Pro scores) was associated with a greater number of self-reported bleeding episodes in the past year among adults (p < 0.01), more days of work/school missed among paediatric patients (p < 0.01), and lower physical health status scores among paediatric patients (p < 0.05). This study highlights the benefits of adherence to prophylaxis among those with severe haemophilia and provides evidence for the utility of the VERITAS-Pro by demonstrating a relationship between adherence and outcomes.

SummaryBackground Routine prophylaxis with replacement factor VIII (FVIII) – the standard of care for severe hemophilia A – often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A. Objective In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on-study (rFVIIIFc) regimens. Methods We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n = 80), and prior episodic treatment and on-study weekly prophylaxis (n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimens and annualized bleeding rates (ABRs) in the last 3 months on-study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed. Results As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels of ≥ 1 IU dL−1 (1%) with rFVIIIFc than with equivalent rFVIII regimens. Conclusion These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL−1 than with rFVIII products requiring more frequent dosing regimens.

The treatment of heart failure has evolved during the last thirty years with recognition of neurohormonal activation and the effectiveness of its inhibition in improving quality of life and survival. Over the last twenty years there has been a revolution in the investigation of the mitochondrion with the development of new techniques and the finding that mitochondria are connected in networks and undergo constant division (fission) and fusion, even in cardiac myocytes. This has led to new molecular and cellular discoveries in heart failure, which offer the potential for the development of new molecular-based therapies. Reactive oxygen species (ROS) are an important cause of mitochondrial and cellular injury in heart failure, but there are other abnormalities, such as depressed mitochondrial fusion, that may eventually become targets of at least episodic treatment. The overall need for mitochondrial fission/fusion balance may preclude sustained change in either fission or fusion. In this review we will discuss current heart failure therapy and its impact on the mitochondria. In addition we will review some of the new drug targets under development. There is potential for effective, novel therapies for heart failure to arise from new molecular understanding.

Evaluation of: Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N. Engl. J. Med. 357, 535–544 (2007). There has been significant debate about the potential role of prophylactic treatment for prevention of joint disease in hemophilia. In this study, Manco-Johnson and colleagues report the results of a randomized study that assessed the benefit of recombinant factor VIII for the prophylactic treatment of boys with severe hemophilia A. Prophylaxis, that is, intravenous injection of clotting factor concentrate in anticipation of bleeding, was compared with on-demand, or episodic, treatment, defined as the administration of factor VIII whenever signs of joint bleeding appeared. After a mean follow-up of 49 months, 93% of subjects in the prophylaxis group showed no joint damage on magnetic resonance imaging as compared with 55% in the episodic-therapy group. The number of factor VIII units administered per patient was approximately 350,000 in the prophylaxis group (0.63 joint bleeds per year) and 113,000 in the episodic-therapy group (4.89 joint bleeds per year). This study concludes that prophylaxis with recombinant factor VIII can prevent joint damage and decrease joint bleeds in boys with hemophilia.

Genitourinary medicine physicians have two main treatment options for the management of recurrent genital herpes: patient-initiated episodic or continuous suppressive therapy. As well as effective disease control, important factors in selecting a regimen include patient acceptability and potential improvements in quality of life. Traditionally suppressive therapy has been favoured by many genitourinary physicians who have often been sceptical of the benefits of episodic therapy. This view has been challenged by several recent studies demonstrating the efficacy and the comparable psychological benefits of very short patient-initiated episodic therapy compared with suppressive therapy. In this article, we review the theory and development of episodic therapy, and discuss the recent evidence that suggests the benefits of ultra short episodic therapies for recurrent genital herpes may be much greater than previously demonstrated.

Aims To study the absorption kinetics of sotalol following administration of different formulations. A formulation which results in fast absorption might be useful in the episodic treatment of paroxysmal supraventricular tachycardia (SVT), atrial fibrillation (Afib) or atrial flutter (Afl). Methods In an open randomized crossover study seven healthy male volunteers were given an intravenous infusion of 20 mg sotalol, for assessing the absolute bioavailability, an oral solution containing 80 mg sotalol, an oral solution containing both 80 mg sotalol and 20 mg cisapride and an 80 mg sotalol tablet, which was taken sublingually. Results The addition of cisapride decreased the time at which maximum serum concentrations were reached (t(max)) from 2.79 (1.85-4.34) h to 1.16 (0.68-2.30) h (P=0.009) [95% CI: -2.59, -0.55] and increased the absorption rate constant (k(a)) from 0.49 (0.31-0.69) h(-1) to 1.26 (0.52-5.61) h(-1) (P=0.017). The absolute bioavailability of sotalol was reduced by cisapride from 1.00 +/- 0.15 to 0.70 +/- 0.26 (P=0.006), while maximum serum concentrations of both oral solutions were not significantly different. Compared with the sublingually administered tablet with a median t(max) of 2.12 (0.89-3.28) h, the sotalol/cisapride oral solution gave a smaller t(max) (p=0.009) [95% CI: -1.64, -0.36]. The k(a) of the sotalol/cisapride solution was significanty (P=0.010) larger than the k(a) of 0.56 (0.33-0.75) h(-1) found after sublingual administration of the tablet. Conclusions The sotalol/cisapride oral solution might be suitable for the episodic treatment of SVT, Afib or Afl.

Two distinctly different substitution principles are commonly used in haemophilia: treatment at bleeding episodes only referred to as on-demand treatment, and prophylactic factor administration. The aim of the cross-sectional study which was undertaken in young patients suffering severe haemophilia A was to challenge our hypothesis that on-demand treatment is inferior to prophylactic substitution in prevention of chronic joint disease at young age. The method involved an investigation of 40 patients from Russia (n = 27) and Denmark (n = 13) born between 1975 and 1990 with no history of inhibitors; Russian patients had exclusively received factor VIII on demand, while Danish patients were managed with prophylactic treatment during a mean period of 16 years since median age of 5 years. The study endpoints were clinical joint scores, Quality of Life scores and functional independence scores. Matched by identical age (1 year) 13 Danish and 13 Russian patients were compared, while 14 age similar Russian patients served as controls. Demographic data among all groups were quite comparable. The results are that Russian patients presented with clinical joint scores at 27 8.5 (mean SD) while matched Danish counterparts scored 3.8 5.3 (mean SD), differences being highly significant. The number of joint bleeds in recent 5 years were 199.5 135 (mean SD) vs. 8.1 8.7 (mean SD). Likewise, Quality of Life and functional independence scores were significantly higher in patients on prophylaxis as compared to on-demand treatment. In conclusion, the study outcomes confirmed our hypothesis. Longer term prophylactic factor administration during Two distinctly different substitution principles are commonly used in haemophilia: treatment at bleeding episodes only referred to as on-demand treatment, and prophylactic factor administration. The aim of the cross-sectional study which was undertaken in young patients suffering severe haemophilia A was to challenge our hypothesis that on-demand treatment is inferior to prophylactic substitution in prevention of chronic joint disease at young age. The method involved an investigation of 40 patients from Russia (n = 27) and Denmark (n = 13) born between 1975 and 1990 with no history of inhibitors; Russian patients had exclusively received factor VIII on demand, while Danish patients were managed with prophylactic treatment during a mean period of 16 years since median age of 5 years. The study endpoints were clinical joint scores, Quality of Life scores and functional independence scores. Matched by identical age (±1 year) 13 Danish and 13 Russian patients were compared, while 14 age similar Russian patients served as controls. Demographic data among all groups were quite comparable. The results are that Russian patients presented with clinical joint scores at 27 ± 8.5 (mean ± SD) while matched Danish counterparts scored 3.8 ± 5.3 (mean ± SD), differences being highly significant. The number of joint bleeds in recent 5 years were 199.5 ± 135 (mean ± SD) vs. 8.1 ± 8.7 (mean ± SD). Likewise, Quality of Life and functional independence scores were significantly higher in patients on prophylaxis as compared to on-demand treatment. In conclusion, the study outcomes confirmed our hypothesis. Longer term prophylactic factor administration during childhood and adolescence prevents joint destruction.