Efficacy and safety of stratified versus routine prophylaxis in living kidney transplantation from HBsAg+ donors to HBsAg− recipients: protocol for a multicentre, prospective, observational study

IntroductionIt remains unclear whether kidney transplantation (KT) from hepatitis B surface antigen (HBsAg) +donors to HBsAg− recipients (D(HBsAg+)/R(HBsAg−)) provides comparable transplant outcomes without hepatitis B virus (HBV) transmission compared with D(HBsAg−)/R(HBsAg−) KT. Moreover, no consensus has been reached for standardised prophylaxis regimens to prevent HBV transmission after D(HBsAg+)/R(HBsAg−) KT. We developed stratified prophylaxis regimens, including pretransplant antiviral treatment of donors, and pretransplant hepatitis B vaccination and post-transplant antiviral treatment of recipients, based on donors’ and recipients’ HBV serological characteristics. However, the safety and efficacy of stratified prophylaxis regimens remains unknown.Methods and analysisWe are conducting a prospective, multicentre, observational study. Between September 2020 and December 2023, 100 cases of (D(HBsAg+)/R (HBsAg−)) KT will be recruited from four university-affiliated hospitals with a follow-up at least 2 years. They will naturally receive stratified prophylaxis regimens or routine prophylaxis based on clinical experience to compare the efficacy and safety of these two regimens in (D(HBsAg+)/R(HBsAg−)) KT. The primary outcome will be post-transplant HBV infection to evaluate safety, defined as post-transplant HBsAg−→+or HBV DNA−→+. The composite endpoint of prevention failure will be also an endpoint of safety (any one of HBsAg−→+, HBV DNA−→+, HB e antigen−→+, HB e antibody−→+ and HB c antibody−→+). The efficacy will be evaluated by transplant outcomes, including death-censored graft survival, patient survival, acute rejection, delayed graft function and kidney graft function.Ethics and disseminationThis study will be registered as a clinical audit at each participating hospital and has obtained approval from the Ethics Committee of West China Hospital (reference: 2020-683, 8 September 2020).Trial registration numberNCT04562051.

Longitudinal Efficacy and Safety of N8-GP for Prophylaxis and Bleed Control in US Patients

Introduction: N8-GP is an extended half-life recombinant factor VIII product indicated for use in patients with hemophilia A. The pathfinder trials evaluated routine prophylaxis and bleed control in previously treated patients aged ≥12 years (pathfinder2) and patients aged <12 years (pathfinder5), including an extension trial (pathfinder8). The objective of the present analysis was to compare the efficacy and safety of N8-GP in US vs global (including US) patients. Methods: In the pathfinder2 trial, patients aged ≥12 years with severe hemophilia A were administered N8-GP 50 IU/kg every 4 days (Q4D) as routine prophylaxis or 20 to 70 IU/kg as on-demand treatment. Patients aged <12 years received prophylaxis with N8-GP 60 IU/kg twice weekly in the pathfinder5 trial, and bleeding episodes were treated with 20 to 75 IU/kg. In the pathfinder8 extension trial, the investigator decided on which treatment arm the patient should be allocated based on previous treatment regimen and taking into account bleeding tendency. Results: See Table for efficacy in prophylaxis (median annualized bleeding rates [ABRs]) and bleed treatment (success rate). Median ABRs tended to decrease from 0.84 (global) and 0.86 (US) in pathfinder2 to 0.00 (global) and 0.00 (US) in pathfinder8 in patients aged ≥12 years on the prophylaxis regimen. In addition, in patients aged <12 years, median ABRs decreased from 0.81 (global) and 0.76 (US) in pathfinder5 to 0.00 (global) and 0.49 (US) in pathfinder8. Treatment success rates for US patients were comparable to those for global patients across trials and 100% were rated "excellent" or "good" for patients aged <12 years in pathfinder8. Overall, there were 59 treatment-related adverse events (AEs) in patients on the prophylactic regimen in pathfinder2, 13 of which occurred in US patients, and 11 treatment-related AEs in patients treated on-demand, 3 of which occurred in US patients. In pathfinder5, there were 16 treatment-related AEs, 7 of which occurred in US patients. In pathfinder8, there were 6 treatment-related AEs in patients aged ≥12 years, 3 of which were in US patients. In addition, there was 1 treatment-related AE in a non-US patient aged <12 years. AEs included rash, redness, and injection site reactions. Across trials, 1 previously treated patient (an 18-year-old, from a US site) with an intron 22 inversion developed a low-titer inhibitor at 93 exposure days to N8-GP and was withdrawn when the titer progressed to >5 Bethesda units. The patient returned to their previous FVIII product, and their inhibitor status was negative at follow-up. Conclusions: Efficacy of N8-GP was sustained during the main and extension pathfinder trials in both global and US patients. In addition, a favorable safety profile was maintained throughout the course of the program. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Kearney: Grifols: Research Funding; Daiichi Sankyo: Research Funding; CVS Pharmacy: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Wufsus: Novo Nordisk Inc: Current Employment. Ostrow: Novo Nordisk Inc: Current Employment. Lentz: Novo Nordisk Inc: Consultancy, Honoraria, Research Funding.

Is Routine Prophylaxis Against Pneumocystis jirovecii Needed in Liver Transplantation? A Retrospective Single-Centre Experience and Current Prophylaxis Strategies in Spain

In liver transplant (LT) recipients, Pneumocystis jirovecii pneumonia (PJP) is most frequently reported before 1992 when immunosuppressive regimens were more intense. It is uncertain whether universal PJP prophylaxis is still applicable in the contemporary LT setting. We aimed to examine the incidence of PJP in LT recipients followed at our institution where routine prophylaxis has never been practiced and to define the prophylaxis strategies currently employed among LT units in Spain. All LT performed from 1990 to October 2019 were retrospectively reviewed and Spanish LT units were queried via email to specify their current prophylaxis strategy. During the study period, 662 LT procedures were carried out on 610 patients. Five cases of PJP were identified, with only one occurring within the first 6 months. The cumulative incidence and incidence rate were 0.82% and 0.99 cases per 1000 person transplant years. All LT units responded, the majority of which provide prophylaxis (80%). Duration of prophylaxis, however, varied significantly. The low incidence of PJP in our unprophylaxed cohort, with most cases occurring beyond the usual recommended period of prophylaxis, questions a one-size-fits-all approach to PJP prophylaxis. A significant heterogeneity in prophylaxis strategies exists among Spanish LT centres.

FEIBA® and Novoseven® Neutralize the Anticoagulant Effects of a Novel Small Molecule FXIa Inhibitor BMS-986177/JNJ-70033093 in Human Plasma and Whole Blood in Vitro

Background: FXIa inhibition is a promising antithrombotic drug target. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a novel small molecular inhibitor of FXIa currently in Phase II clinical trials with the potential for reduced bleeding risk as compared to the currently approved oral anticoagulantsHowever, reversal of anticoagulation may still be required in patients who have uncontrolled or life-threatening bleeding or need an urgent surgical procedure. Aim: To evaluate the ability of nonspecific reversal agents (NSRAs) FEIBA®, NovoSeven®, Kcentra®, Profilnine®, BeneFix®, Novoeight®, and Cyklokapron® to neutralize the anticoagulation of BMS-177/JNJ-3093 in the activated partial thromboplastin time (aPTT), thromboelastography (TEG) and thrombin generation assay (TGA) in vitro using human plasma or whole blood. Method: aPTT and TEG were performed in human plasma and whole blood, respectively, using standard assay procedures. TGA was performed in human plasma using diluted kaolin aPTT reagent (1:10,000). JNJ-3093 was evaluated at different concentrations (0.3 -10 µM) to cover the anticipated exposures in the Phase II clinical trials. The NSRAs were evaluated at the anticipated concentrations according to the dosing information in their respective labels. Results: BMS-177/JNJ-3093 produced concentration dependent increases in aPTT (up to 4.4x at 10 μM); prolongations of lag time in TEG (2.6X); prolongations of lag time (3X) as well as reductions in peak thrombin generation (70%) in TGA. FEIBA® effectively neutralized the anticoagulant effects of JNJ-3093 in aPTT, TEG and TGA. NovoSeven® neutralized the BMS-177/JNJ-3093-induced prolongations in aPTT, prolongations in lag time in TEG and TGA assays and partially restored the peak thrombin generation in TGA. In contrast, all other NSRAs tested had negligible effects or did not show neutralization of anticoagulation induced by BMS-177/JNJ-3093 in the referenced assays Conclusion: These results demonstrate that FEIBA® and NovoSeven® can effectively neutralize the anticoagulant effects of BMS-177/JNJ-3093 in vitro. A clinical study is required to determine if these agents can reverse the anticoagulant effects of BMS-177/JNJ-3093 in patients. Table Disclosures Bunce: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Huang Devine:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Chintala:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: FEIBA: hemophilia A and B patients with inhibitors for: control and prevention of bleeding episodes; use around the time of surgery; routine prophylaxis to prevent or reduce the frequency of bleeding episodes NovoSeven: Treatment of bleeding and prevention of bleeding for surgeries and procedures in adults and children with hemophilia A or B with inhibitors, congenital Factor VII (FVII) deficiency, and Glanzmanns thrombasthenia with a decreased or absent response to platelet transfusions; treatment of bleeding and prevention of bleeding for surgeries and procedures in adults with acquired hemophilia Kcentra: urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy in adult patients with need for urgent surgery/invasive procedure or acute major bleeding Profilnine: prevention and control of bleeding in patients with Factor IX deficiency due to hemophilia B BeneFix: control and prevention of bleeding episodes or peri-operative management in adult and pediatric patients with hemophilia B Novoeight: for use in adults and children with hemophilia A for control and prevention of bleeding, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes Cyklokapron: patients with hemophilia for short-term use to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction)

Real-World Persistence with and Adherence to Emicizumab Prophylaxis in Persons with Hemophilia a: A Secondary Claims Database Analysis

Introduction: Emicizumab is a subcutaneously administered, humanized bispecific monoclonal antibody, approved for routine prophylaxis in persons with hemophilia A (PwHA) with or without factor VIII inhibitors. Little is known about patterns of emicizumab use in clinical practice. We aimed to evaluate real-world persistence with and adherence to emicizumab treatment for PwHA on prophylaxis. Methods: This retrospective study used de-duplicated commercial insurance claims data from IBM® MarketScan® Commercial Research and IQVIA PharMetrics® Plus databases from 16 November 2017 to 31 December 2019. Individuals included met the following criteria: 1) evidence of emicizumab use (at least two prescription fills) and 2) continuous enrollment for at least three months pre-emicizumab initiation. Individuals were followed until the end of study period or continuous enrollment. Persistence was defined as the proportion of individuals continuing treatment with emicizumab during the study period. Time to discontinuation and proportion of individuals who restarted emicizumab prophylaxis were reported for patients who discontinued emicizumab. Discontinuation was defined as 60 days without a prescription fill. Adherence was measured over the post-index persistence period using the proportion of days covered (PDC), and the proportion of individuals adherent at ≥80% PDC threshold was reported. Results: We identified 328 unique individuals who met the inclusion criteria. All patients were male (100%); the average age was 23 years (standard deviation [SD] ±16; range=1-64); and the average follow-up post-index was eight months (245±147 days). The vast majority of individuals (92%) were persistent with emicizumab prophylaxis during the study period. Among those who discontinued emicizumab (n=25), the average time to discontinuation was approximately three months (84±124 days); 40% restarted emicizumab prophylaxis after discontinuation, with an average time to restart of approximately four months (126±56 days). During the period for which individuals were persistent to treatment, adherence to emicizumab was high (81%); with 70% individuals meeting the ≥80% PDC threshold. Among those with at least one-year post-index enrollment (n=48), adherence during the first year was also high (85%), with 77% individuals adherent at the ≥80% PDC threshold. Conclusions: In this study, the vast majority of individuals treated with emicizumab had high rates of adherence and persistence to treatment. This is one of the first studies to report real-world persistence with and adherence to emicizumab prophylaxis in PwHA. Future evaluations should examine the association of persistence and adherence with health outcomes in this population. Disclosures Mahajerin: Spark Therapeutics, Alexion, Genentech, Inc.: Speakers Bureau. Khairnar:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Meyer:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Abbass:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Wang:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Acumen, LLC: Ended employment in the past 24 months. Lee:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Tzeng:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Raimundo:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company.

Efficacy and Side Effects of Intracameral Moxifloxacin as Prophylaxis after Cataract Surgery

Purpose: To determine the efficacy of intracameral moxifloxacin at the end of cataract surgery. Methods: Retrospective record based study. Study was based on a consecutive case series of patients who had cataract surgery during 2009 through 2019 in the Department of Ophthalmology at Maharishi Vashishth State Medical College, Basti (India). Intracameral preservative free moxifloxacin injection was given at the conclusion of surgery to most patients. Standardized operating room and sterilization protocols were used. All The medical records were reviewed for the 8 weeks after surgery. Post-operative endophthalmitis rate was computed using the number of cases of postoperative endophthalmitis as the numerator and the number of cataract surgeries as the denominator. Results: Of the 10,108 surgeries performed during study period, 2012 (19.9%) involved intracameral moxifloxacin injection. No adverse drug reactions were reported from administration of intracameral antibiotics during the study period. The post-operative endophthalmitis rate in patient who had not received intracameral antibiotic injection was 0.06%. There was no endophthalmitis case reported in patients who had received intracameral moxifloxacin injection as prophylaxis. Conclusion: The results of this study support the use if intracameral moxifloxacin as a routine prophylaxis for endophthalmitis after cataract surgery. Especially in rural setting as the patients postoperative instruction compliance is poor and many patients are lost to follow-ups sue to different reasons.

Is Group B Streptococcus Colonization Associated with Maternal Peripartum Infection in an Era of Routine Prophylaxis?

Objective This study aimed to assess whether colonization with group B streptococcus (GBS) is associated with maternal peripartum infection in an era of routine prophylaxis. Study Design This study presented a secondary analysis of women delivering ≥37 weeks who underwent a trial of labor from the U.S. Consortium on Safe Labor (CSL) study. The exposure was maternal GBS colonization and the outcome was a diagnosis of chorioamnionitis, and secondarily, analyses were restricted to deliveries not admitted in labor and measures of postpartum infection (postpartum fever, endometritis, and surgical site infection). Logistic regression with generalized estimating equations was used accounting for within-woman correlations. Models adjusted for maternal age, parity, race, prepregnancy body mass index, pregestational diabetes, insurance status, study site/region, year of delivery, number of vaginal exams from admission to delivery, and time (in hours) from admission to delivery. Results Among 170,804 assessed women, 33,877 (19.8%) were colonized with GBS and 5,172 (3.0%) were diagnosed with chorioamnionitis. While the frequency of GBS colonization did not vary by chorioamnionitis status (3.0% in both groups), in multivariable analyses, GBS colonization was associated with slightly lower odds of chorioamnionitis (adjusted odds ratio [AOR]: 0.89; 95% confidence interval [CI]: 0.83–0.96). In secondary analyses, this association held regardless of spontaneous labor on admission; and the odds of postpartum infectious outcomes were not higher with GBS colonization. Conclusion In contrast to historical data, GBS colonization was associated with lower odds of chorioamnionitis in an era of routine GBS screening and prophylaxis. Key Points

Palivizumab Prophylaxis for infants 29 to 32 weeks gestation at birth: A 10-year audit from Vancouver Island using BC Guidelines

Background After initially recommending palivizumab (PVZ), a monoclonal antibody against respiratory syncytial virus (RSV) for all infants 29 to 32 weeks at birth if <6 months age at season start, the American Academy of Pediatrics (AAP) and Canadian Paediatric Society (CPS) guidelines were revised. British Columbia was the only jurisdiction in North America to restrict eligibility for this group to those with additional risk factors, long before the change in national recommendations. Objectives To determine the risk for first season RSV admission for 29 to 32-week gestational age (GA) infants admitted to Victoria Neonatal Intensive Care Unit (NICU) that either received or were denied PVZ prophylaxis. Methods Descriptive cohort study of infants eligible for prophylaxis according to earlier CPS guidelines. Instead, BC guidelines for prophylaxis were applied and data for Vancouver Island infants were collected over 10 consecutive RSV seasons. Results We followed 423 infants. Three hundred and thirty-six (79%) did not receive prophylaxis, of which 10 (3.0%; 95% confidence interval [CI] 1.4% to 5.4%) had an RSV hospitalization before the end of April during their first RSV season versus 3 admissions from 87 (3.5%; 95% CI 0.7% to 10%) infants who received prophylaxis. Conclusions Our risk factor approach to RSV prophylaxis for infants born at 29 to 32 weeks GA resulted in a low (average incidence=3.1%) rate of RSV hospitalization. Our approach would offer considerable cost savings to RSV prophylaxis programs that continue to offer routine prophylaxis beyond 28/29 weeks GA at birth.