Impact of timing of prophylaxis commencement,F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A

Introduction

The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA).

Aim

To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL).

Methods

Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively.

Results

The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p < .001), EQ-5D-5L index (0.9647 vs. 0.904, p = .022), EQ VAS (87 vs. 75, p = .01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p = .02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS.

Conclusion

Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.     

Influence of medical insurance schemes and charity assistance projects on regular prophylaxis treatment of the boys with severe haemophilia A in China

Objective

To explore the influence of medical insurance policy and charity assistance projects on the uptake and discontinuation of regular prophylaxis treatment in Chinese severe haemophilia A children.

Methodology

This retrospective study was conducted on children with severe haemophilia A, who received FVIII prophylaxis treatment at 12 haemophilia centres in China from 1 November 2007 to 31 May 2013.

Results

The average duration of prophylaxis treatment received by haemophilia children significantly increased from 16.7 weeks in 2008 to 32.8 weeks in 2012 (P < .001). The main reason for prophylaxis acceptance included dissatisfaction with previous “on‐demand” regimens, availability of improved local medical insurance policies and patient/family awareness of haemophilia. The main reason for subsequent discontinuation of prophylaxis was economic instability. The upper limit of insurance was up to RMB 150 000/y (~USD: 22 000/y) for 80.1% of the insured patients and would be sufficient to cover the continuous low‐dose prophylaxis regimen. However, for many patients the burden of out‐of‐pocket copayment cost represented a risk for poor adherence to regular prophylaxis. In about two third of the patients, the annual out‐of‐pocket copayment cost amounted to >50% of their average annual disposable income. Many patients therefore required assistance from the charity assistance projects, but nonadherence remained prevalent.

Conclusion

Medical insurance policy and charity assistance projects helped haemophilia children to accept and continue prophylaxis regimens. It was the proportion of the out‐of‐pocket copayment cost rather than the upper limit of insurance reimbursement that restricted long‐term regular low‐dose prophylaxis in China.     

Potential preventability of spontaneous bacterial peritonitis

Background  

Antibiotic prophylaxis can reduce the incidence of the first episode and recurrent episodes of spontaneous bacterial peritonitis (SBP) in high-risk cirrhotic patients. However, recent data suggest that SBP prophylaxis may be underused. It is unclear how many cases of cirrhosis that develop SBP might actually be prevented with antibiotic prophylaxis.     

Long-term immunogenicity,efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients

Background

The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq^®) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A.

Methods

Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study.

Results

Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%–88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0–0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0–1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported.

Conclusion

No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.     

Venous Thromboembolism Prophylaxis among Medical Patients at US Hospitals

Background  

Chemoprophylaxis is recommended for medical patients at moderate to high risk of venous thromboembolism (VTE) and is now a requirement of the Joint Commission on Accreditation of Healthcare Organizations. To see who receives prophylaxis and how far hospitals will need to go to meet this requirement, we examined VTE prophylaxis patterns at US hospitals.     

Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy,emicizumab prophylaxis,and FVIII replacement prophylaxis

Introduction

Head-to-head evaluation of valoctocogene roxaparvovec, the first gene therapy approved for haemophilia A, with emicizumab is not available. Therefore, phase 3 trial data were indirectly compared.

Aim

To compare bleeding rates in trials evaluating 6 × 10¹³ vg/kg valoctocogene roxaparvovec (GENEr8-1; NCT03370913), 1.5 mg/kg emicizumab dosed every week (HAVEN 3; NCT02847637), and FVIII prophylaxis (270–902) in participants with severe haemophilia A (FVIII ≤1 IU/dL).

Methods

Valoctocogene roxaparvovec versus emicizumab and FVIII prophylaxis as used in 270–902 versus emicizumab cross-trial comparisons were performed using matching-adjusted indirect comparison (MAIC). Individual participant data from GENEr8-1 and 270–902 were weighted to equalise aggregate participant baseline characteristics from HAVEN 3. After MAIC weighting, annualised bleeding rates (ABR) and proportions of participants without bleeds were compared for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds.

Results

After MAIC weighting, ABR for all bleeds was statistically significantly lower with valoctocogene roxaparvovec than emicizumab (rate ratio [95% CI], .55 [.33–.93]). Additionally, significantly higher proportions of participants had no treated joint bleeds (odds ratio [95% CI], 2.75 [1.20–6.31]) and no treated bleeds (3.25 [1.53–6.90]) with valoctocogene roxaparvovec versus emicizumab. When compared with the mainly standard half-life FVIII prophylaxis regimens in 270–902, mean ABRs (except for all bleeds) were significantly lower, and significantly higher proportions reported 0 bleeds for all outcomes with emicizumab.

Conclusion

Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab. Emicizumab was more effective than FVIII prophylaxis regimens used in 270–902.     

MONITOR‐GCSF DLBCL subanalysis: Treatment patterns/outcomes with biosimilar filgrastim for chemotherapy‐induced/febrile neutropenia prophylaxis

Objective

Prospective data on the use of granulocyte‐colony‐stimulating factor (G‐CSF) in non‐Hodgkin's lymphoma and its aggressive subtypes, including diffuse large B‐cell lymphoma (DLBCL), are limited. MONITOR‐GCSF is a pan‐European, multicenter, prospective, observational study aiming to describe treatment patterns and clinical outcomes in patients receiving biosimilar filgrastim in the prophylaxis of chemotherapy‐induced neutropenia (CIN) and febrile neutropenia (FN).

Methods

This analysis describes patient characteristics, treatment patterns, and outcomes for 245 patients with stage 3 or 4 DLBCL receiving ≤6 chemotherapy cycles as part of MONITOR‐GCSF study, including patients aged ≥65 years and ≥70 years. Outcomes of interest included the incidence of CIN and FN, antibiotic prophylaxis, biosimilar filgrastim prophylaxis, and adverse events (AEs).

Results

MONITOR‐GCSF included 245 patients with DLBCL. Of these patients, 87 (35.5%) experienced one or more CIN (any grade) episode and 24 (9.8%) experienced FN (any grade). The most frequent AE reported was bone pain (n = 7, 2.9%), followed by arthralgia (n = 2, 0.8%) and back pain (n = 2, 0.8%).

Conclusion

In real‐life practice, biosimilar filgrastim demonstrated clinical effectiveness and safety in patients with DLBCL. The large percentage of patients aged ≥65 years adds to the evidence on how to best treat older patients with DLBCL receiving myelosuppressive chemotherapy.     

Long‐term tolerability,immunogenicity and efficacy of Nuwiq® (human‐cl rhFVIII) in children with severe haemophilia A

Introduction

Nuwiq^® (human‐cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line.

Aim/Methods

This study (GENA‐13) was an extension of the GENA‐03 study in which previously treated children aged 2‐12 years with severe haemophilia A received Nuwiq^® prophylaxis for ≥6 months. GENA‐13 examined long‐term tolerability, immunogenicity and efficacy of Nuwiq^® prophylaxis in children.

Results

Of 59 patients enrolled in GENA‐03, 49 continued Nuwiq^® prophylaxis in GENA‐13 for a median (range) of 30.0 (9.5‐52.0) months. No patient withdrew due to drug‐related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2‐5 years) had lower ABRs than children aged 6‐12 years. Annualized bleeding rates were reduced in GENA‐13 vs GENA‐03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 [95% CI: 0.11, 0.74]). Nuwiq^® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq^® was rated as excellent for all 17 assessed procedures.

Conclusion

Long‐term treatment with Nuwiq^® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA‐03.     

Dilemmas on emicizumab in children with haemophilia A: A survey of strategies from PedNet centres

Introduction

Haemophilia A care has changed with the introduction of emicizumab. Experience on the youngest children is still scarce and clinical practice varies between haemophilia treatment centres.

Aim

We aimed to assess the current clinical practice on emicizumab prophylaxis within PedNet, a collaborative research platform for paediatricians treating children with haemophilia.

Methods

An electronic survey was sent to all PedNet members (n = 32) between October 2022 and February 2023. The survey included questions on the availability of emicizumab, on the practice of initiating prophylaxis in previously untreated or minimally treated patients (PUPs or MTPs) and emicizumab use in patients with or without inhibitors.

Results

All but four centres (28/32; 88%) responded. Emicizumab was available in clinical practice in 25/28 centres (89%), and in 3/28 for selected patients only (e.g. with inhibitors). Emicizumab was the preferred choice for prophylaxis in PUPs or MTPs in 20/25 centres; most (85%) started emicizumab prophylaxis before 1 year of age (30% before 6 months of age) and without concomitant FVIII (16/20; 80%). After the loading dose, 13/28 centres administered the recommended dosing, while the others adjusted the interval of injections to give whole vials. In inhibitor patients, the use of emicizumab during ITI was common, with low-dose ITI being the preferred protoco l .

Conclusion

Most centres choose to initiate prophylaxis with emicizumab before 12 months of age and without concomitant FVIII. In inhibitor patients, ITI is mostly given in addition to emicizumab, but there was no common practice on how to proceed after successful ITI.     

Real‐world experience with use of Antihemophilic Factor (Recombinant), PEGylated for prophylaxis in severe haemophilia A

Introduction

Prophylaxis with extended half‐life factor VIII (FVIII) is approved for haemophilia A, but data regarding routine clinical use are limited.

Aim

To assess real‐world experience of ADYNOVATE^® (Antihemophilic Factor (Recombinant), PEGylated prophylaxis in children and adults with haemophilia A.

Methods

A retrospective chart review was conducted in three US haemophilia treatment centres. Records of all patients who began Adynovate prophylaxis in routine clinical practice were identified. Demographic, clinical and patient‐reported information beginning 6 months before initiation of Adynovate until the record review was analysed.

Results

Fifteen patients (aged 9 months to 28 years), with median 9 months’ use of Adynovate (range 1‐15 months), were identified. All had switched from another prophylactic regimen, 13 (87%) from standard half‐life recombinant FVIII. Nine (60%) patients had ≥1 bleed within 6 months preswitch. The most frequent reason for switching was to reduce infusion frequency (14 patients). After switching, infusion frequency reduced for 13 patients, and overall weekly factor consumption decreased by 19%. Eight (53%) patients had no bleeds postswitch, three (20%) had spontaneous joint bleeds (vs four pre‐switch), and three (20%) had only mild traumatic bleeds. Patient/parental satisfaction with Adynovate was documented as positive in 13 of 15 (87%) cases; 2 patients were not satisfied and discontinued Adynovate. No adverse events were considered related to Adynovate.

Conclusion

In patients who switched from a standard half‐life FVIII to Adynovate prophylaxis in routine clinical practice, bleeding control was generally improved or maintained, with a lower infusion frequency and factor consumption in most patients.     

Efficacy of Ivabradine in Combination with Beta-Blocker Versus Uptitration of Beta-Blocker in Patients with Stable Angina

Purpose  

The antianginal and anti-ischemic efficacy of the selective I _f inhibitor ivabradine is established in patients with stable angina in monotherapy and in combination with other antianginals, including beta-blocker. This pilot study compared the antianginal and anti-ischemic efficacy and hemodynamic profile of ivabradine plus 5 mg bisoprolol versus those of 10 mg bisoprolol in patients with stable angina.     

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein

Introduction

Joint arthropathy is the long‐term consequence of joint bleeding in people with severe haemophilia.

Aim

This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis.

Methods

ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25‐65 IU/kg every 3‐5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients.

Results

Forty‐seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A‐LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A‐LONG baseline (23.4), mean improvement at ASPIRE Year 2 was ?4.1 (95% confidence interval [CI], ?6.5, ?1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A‐LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: ?2.4, P = .09; prestudy episodic treatment: ?7.2, P = .003). Benefits were seen in subjects with target joints (?5.6, P = .005) as well as those with severe arthropathy (?8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (?1.4, P = .008), range of motion (?1.1, P = .03) and strength (?0.8, P = .04).

Conclusions

Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.     

No indication of increased infection rates using low‐dose alemtuzumab instead of anti‐thymocyte globulin as graft‐versus‐host disease prophylaxis before allogeneic stem cell transplantation

Background

Alemtuzumab as part of the conditioning protocol is effective in reducing graft‐versus‐host disease (GvHD), but may be associated with increased infection rates, especially when using high doses (ie, 100 mg).

Methods

We performed a retrospective, single‐center, case‐control study analyzing the rates of neutropenic fever, cytomegalovirus (CMV) reactivation, Epstein‐Barr virus (EBV) reactivation, clinical manifest toxoplasmosis, and clinical manifest human herpesvirus‐6 (HHV6) infection using low‐dose alemtuzumab in comparison with anti‐thymocyte globulin (ATG) as GvHD prophylaxis before allogeneic stem cell transplantation. Forty‐four patients transplanted from unrelated donors between 2001 and 2012 were matched by age, diagnosis, and conditioning regimen and treated either with alemtuzumab 10 mg at day ?2 (respectively, 20 mg in case of mismatch transplantation) or ATG. ATG Fresenius (10 mg/kg for 3 days) or Thymoglobulin (2 mg/kg for 3 days) were used.

Results

Rates of CMV reactivation, EBV reactivation, and clinical manifest HHV6 infection or toxoplasmosis did not differ significantly between both groups until 2 years after transplantation. No case of post‐transplant lymphoproliferative disorder was observed. Also, rates of neutropenic fever during inpatient treatment after transplantation did not differ significantly in both groups.

Conclusion

We saw no indication of increased infections rates when using low‐dose alemtuzumab as GvHD prophylaxis before allogeneic stem cell transplantation in this retrospective analysis.     

Risk of pneumocystosis after early discontinuation of prophylaxis among HIV-infected patients receiving highly active antiretroviral therapy

Background  

Risk of pneumocystosis after discontinuation of primary or secondary prophylaxis among HIV-infected patients before CD4 counts increase to ≧200 cells/μL (early discontinuation) after receiving highly active antiretroviral therapy (HAART) is rarely investigated.     

HBIg Discontinuation with Maintenance Oral Anti-viral Therapy and HBV Vaccination in Liver Transplant Recipients

Background  

Hepatitis B (HBV) is an uncommon indication for liver transplantation in the US accounting for approximately 5% of cases. Recurrence prophylaxis is typically long-term hepatitis B immune-globulin (HBIg) and an oral anti-HBV agent. Because of high HBIg costs and improving efficacy of new oral agents, there is increasing interest in HBIg discontinuation.     

High incidence of antimicrobial resistant organisms including extended spectrum beta-lactamase producing Enterobacteriaceae and methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>in nasopharyngeal and blood isolates of HIV-infected children from Cape Town,South Africa

Background  

There is little information on nasopharyngeal (NP) flora or bacteremia in HIV-infected children. Our aim was to describe the organisms and antimicrobial resistance patterns in children enrolled in a prospective study comparing daily and three times weekly trimethoprim-sulfamethoxazole (TMP-SMX) and isoniazid (INH) or placebo prophylaxis.     

Value of prophylaxis vs on‐demand treatment: Application of a value framework in hemophilia

Introduction

Therapeutic advances over the past 30 years have led to longer life expectancy and improved quality of life (QOL) for persons with hemophilia. Access to innovative therapy may be compromised if treatment decisions are driven solely by cost. New strategies are needed to assess true therapeutic values, along with financial cost, as physicians, policymakers, payers and manufacturers work together to improve patient care.

Aim

To provide an evidence‐based assessment of the value of prophylaxis vs on‐demand therapy for hemophilia, based on a widely recognized three‐tiered value framework approach for assessing a range of therapeutic interventions.

Methods

Data from six randomized clinical trials (ESPRIT, Joint Outcomes Study, SPINART, LEOPOLD II, ADVATE and POTTER) and four observational studies comparing primary and secondary prophylaxis vs on‐demand therapy were applied to a hemophilia value framework.

Results

Both primary and secondary prophylaxis showed advantages in Tier 1 “Degree of health/recovery” outcomes, including measures of bleeding, musculoskeletal complications, pain, function/activity and QOL. Tier 2 “Process of Recovery” outcomes, also favoured prophylaxis, including measures of recovery time, return to normal activities, orthopaedic intervention and venous access. In Tier 3 “Sustainability of Health Recovery,” measures of breakthrough bleeds, joint preservation, sustained productivity and QOL showed significant improvement with prophylaxis.

Conclusion

The hemophilia value framework affirmed value of primary and secondary prophylaxis vs on‐demand therapy, with clinical benefit demonstrated in all three tiers. This analysis also demonstrates clinical utility of the value framework process in the determination of optimal and cost‐effective hemophilia care for all stakeholders.     

Adherence to guidelines for antibiotic prophylaxis in surgery patients in German hospitals: a multicentre evaluation involving pharmacy interns

Background and aim  

Surgical site infections (SSIs) are associated with a high morbidity, mortality and healthcare costs. The prevention of SSIs is based on a combination of preoperative preparation, surgical techniques, perioperative antibiotic prophylaxis (PAP) and postoperative wound care. Despite an abundance of evidence demonstrating the effectiveness of antimicrobials to prevent SSIs, the use of antimicrobial prophylaxis in this clinical setting is associated with inappropriate timing and selection and excessive duration of administration. To date, pharmacy interns (PIs) have not been involved in this process. The aim of this study was to evaluate feasibility of involving PIs in monitoring adherence to the guidelines for antibiotic prophylaxis in surgery patients.     

Impact of a Change in Antibiotic Prophylaxis on Total Antibiotic Use in a Surgical Intensive Care Unit

Objective:   

The aim of this study was to evaluate the impactof reducing the length of antibiotic prophylaxis for cerebrospinalshunts on total antibiotic use and key resistantpathogens.