ATHENA Study Research Articles

Study protocol: optical coherence tomography angiography for the detection of neovascular age-related macular degeneration: a comprehensive multicentre diagnostic accuracy study in the UK—the ATHENA study

IntroductionThe diagnosis of neovascular age-related macular degeneration (nAMD), the leading cause of visual impairment in the developed world, relies on the interpretation of various imaging tests of the retina. These...

Immune-mediated thrombotic thrombocytopenic purpura landscaping in Gulf countries: a real-world evidence study (ATHENA Study)

Immune-mediated thrombotic thrombocytopenic purpura landscaping in Gulf countries: a real-world evidence study (ATHENA Study)

The Impact of Atherosclerotic Burden on Vascular Outcomes in Patients with Stroke and Atrial Fibrillation: The ATHENA study.

Introduction: Patients with ischemic stroke (IS) and atrial fibrillation (AF) face a higher risk of recurrent vascular events. This study evaluates the impact of atherosclerotic vascular disease burden across different vascular territories on the risk of vascular events in patients with recent ischemic stroke and AF within 90 days. Patients and Methods: We included patients with IS and AF from the International RAF network in a prospective 90-day follow-up. Atherosclerotic vascular disease was identified by at least one of the following: Symptomatic ischemic heart disease, symptomatic peripheral artery disease, internal carotid stenosis ≥50%, or the presence of plaques in the aorta. The primary outcome was a composite of stroke, transient ischemic attack, systemic embolism, cerebral bleeding, and major extracranial bleeding within 90 days postacute stroke. Patients were categorized into 5 groups based on the number of affected atherosclerotic vascular territories, with those with no atherosclerotic vascular disease as the reference. Kaplan-Meier curves were generated and compared using the log-rank test to determine the predictive value of the number of diseased territories for the risk of events. Data analysis was performed with SPSS/PC Win Package 25.0. Results: Of the 2148 patients (mean age 77.59; 53.86% female), 744 (34.60%) had atherosclerosis. Multivariable analysis revealed that involvement of 3 (hazard ratio [HR] 2.80, 95% confidence interval [CI]: 1.20-6.53) or 4 (HR 6.81, 95% CI: 1.02-36.24) vascular territories was significantly associated with the risk of combined events. Conclusions: In patients with recent ischemic stroke and AF, atherosclerosis across multiple territories correlates with a higher risk of future vascular events.

Preliminary Results of a Phase 2a Clinical Trial to Evaluate Safety, Tolerability and Antiviral Activity of Intravenous Brincidofovir (BCV IV) in Immunocompromised Patients with Adenovirus Infection

Background: Adenovirus (AdV) may cause life threatening or fatal infections in immunosuppressed patients including recipients of allogeneic hematopoietic cell transplant (allo-HCT). Brincidofovir (BCV) is a lipid conjugate of cidofovir, that crosses target cell membranes by means of facilitated and passive diffusion and has a long intracellular half-life. The safety, tolerability and antiviral activity of intravenous BCV (BCV IV) were evaluated in a dose ascending Phase 2a study (BCV-PA01: ATHENA study, NCT04706923) in sequential cohorts. Methods: Eligible patients aged 2 months or older who were immunocompromised due to allo-HCT, organ transplant, immunosuppressive medications, or congenital immunodeficiency, and had AdV viremia or disseminated AdV disease were included. AdV viremia was defined as 1) AdV viral load in the blood > 10,000 copies/mL OR 2) two samples greater than 48 hours apart with the second result higher than the first and both greater than 1000 copies/mL, within 7 days prior to initiation of BCV IV treatment. BCV IV was administered intravenously twice weekly for 4 weeks or until resolution of AdV viremia up to 14 weeks, whichever occurred later. The dose escalation was as follows: 0.2 mg/kg (Cohort 1), 0.3 mg/kg (Cohort 2), or 0.4 mg/kg (Cohort 3) for patients weighing < 50 kg and 10 mg/dose, 15 mg/dose, or 20 mg/dose, respectively for patients weighing ≥ 50 kg. The patients were subsequently followed up for 30 days after the last BCV IV dosing. AdV viral loads in blood were monitored weekly by quantitative real-time polymerase chain reaction tests (lower limit of detection (LOD) 25 copies/mL, lower limit of quantification 190 copies/mL, upper limit of quantification 1 x 10 9 copies/mL). Viral clearance was defined as two consecutive plasma viral load test results below the LOD. Results: Of 27 patients treated with BCV IV, 8 were in Cohort 1, 9 in Cohort 2 and 10 in Cohort 3. Baseline characteristics of patients are shown in Table 1. Treatment-related adverse events (TRAE) were observed in 7 patients, as shown in Table 2. No serious TRAEs including gastrointestinal and hepatic toxicities were observed. All TRAEs were reversible and resolved after the completion of the treatment. AE-related discontinuations of treatment were observed in 3 of 8 patients in Cohort 1; 2 of 9 patients in Cohort 2; and 1 of 10 patients in Cohort 3 (Table 2). The reason for discontinuation of treatment beyond 4 weeks of treatment in Cohort 3 was successful clearance of AdV viremia. Antiviral activity was dose-dependent, and viral clearance was achieved in 25% (2/8) in Cohort 1; 56 % (5/9) in Cohort 2; and 100% (10/10) in Cohort 3. The duration of treatment with BCV IV and viral responses are summarized in Table 2. In Cohort 3, it is notable that 90 % of patients achieved AdV viremia clearance in ≤ 4 weeks of treatment with BCV IV. In Cohorts 2 and 3, all patients who achieved AdV viremia clearance maintained undetectable AdV in the blood through the follow-up period. Conclusions: BCV IV was found to be safe and well tolerated in immunocompromised patients. Notably, the potentially serious gastrointestinal and hepatic toxicities described with the oral BCV formulation were not observed. BCV IV was highly effective in a dose-dependent manner, led to rapid clearance of AdV viremia within a short treatment period and provided sustained virologic response. In view of promising results and in the absence of any other approved treatments for AdV infection, our results support the need for further exploration and additional clinical trials of BCV IV as a treatment for AdV infection.

Everolimus plus reduced calcineurin inhibitor prevents de novo anti-HLA antibodies and humoral rejection in kidney transplant recipients: 12-month results from the ATHENA study.

Studies prospectively monitoring de novo donor-specific antibodies (dnDSAs) and their clinical impact are sparse. This substudy of ATHENA was initiated to evaluate the effect of everolimus (EVR) or mycophenolic acid (MPA) in combination with reduced calcineurin inhibitor (CNI, tacrolimus [TAC] or cyclosporine [CsA]) on the formation of human leukocyte antibodies (HLA), including dnDSA, and the impact on clinical outcomes in kidney transplant (KTx) recipients. All eligible patients were randomized 1:1:1 to receive either EVR + TAC, EVR + CsA or MPA + TAC, with basiliximab induction plus steroids after transplantation up to Month 12. The incidence of dnDSA by treatment group and the association with clinical events were evaluated descriptively as an exploratory objective in the intent-to-treat (ITT) and per-protocol (PP) populations with at least one antibody assessment. Overall, none of the patients in the EVR + TAC group had either dnDSA or antibody mediated rejection (PP or ITT population) and only one patient with dnDSA in the TAC + MPA group had antibody mediated rejection. The EVR regimen was comparable to MPA regimen with an extremely low incidence of dnDSA over 1 year of treatment.

PB0334 Immune-Mediated Thrombotic Thrombocytopenic Purpura Landscaping in Gulf Countries: A Real-World Evidence Study (ATHENA Study)

PB0334 Immune-Mediated Thrombotic Thrombocytopenic Purpura Landscaping in Gulf Countries: A Real-World Evidence Study (ATHENA Study)

Efficacy and safety of dronedarone across age and sex subgroups: a post hoc analysis of the ATHENA study among patients with non-permanent atrial fibrillation/flutter.

Age and sex may impact the efficacy of antiarrhythmic drugs on cardiovascular outcomes and arrhythmia recurrences in patients with atrial fibrillation (AF). We report on a post hoc analysis of the ATHENA study (NCT00174785), which examined cardiovascular outcomes in patients with non-permanent AF treated with dronedarone vs. placebo. Efficacy and safety of dronedarone were assessed in patients according to age and sex. Baseline characteristics were comparable across subgroups, except for cardiovascular comorbidities, which were more frequent with increasing age. Dronedarone significantly reduced the risk of cardiovascular hospitalization or death due to any cause among patients 65-74 [n = 1830; hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.60-0.83; P < 0.0001] and ≥75 (n = 1925; HR 0.75, 95% CI 0.65-0.88; P = 0.0002) years old and among males (n = 2459; HR 0.74, 95% CI 0.64-0.84; P < 0.00001) and females (n = 2169; HR 0.77, 95% CI 0.67-0.89; P = 0.0002); outcomes were similar for time to AF/AFL recurrence. Among patients aged <65 years (n = 873), cardiovascular hospitalization or death due to any cause with dronedarone vs. placebo was associated with an HR of 0.89 (95% CI 0.71-1.11; P = 0.3). The incidence of all treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation was comparable among males and females, and increased with increasing age. These results support the use of dronedarone for the improvement of clinical outcomes among patients aged ≥65 years and regardless of sex.

Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer.

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

Abstract 13392: Efficacy and Safety of Dronedarone vs Placebo Across Age and Sex Subgroups: A Post Hoc Analysis of the Athena Study Among Patients With Nonpermanent Atrial Fibrillation/flutter

Introduction: Dronedarone reduced the risk of cardiovascular (CV) hospitalization or death compared with placebo among patients with nonpermanent atrial fibrillation/flutter (AF/AFL) in the ATHENA study (primary endpoint). Prior work suggests a differential response to AF/AFL management based on age and sex. This post hoc analysis assessed response to dronedarone in these important subgroups. Methods: Efficacy and safety of dronedarone vs placebo were analyzed by age (&lt;65y, 65-74y, ≥75y) and sex. Results: Median duration of follow-up was 22 months overall in the ATHENA study. Of 4628 patients, 873 (19%), 1830 (40%), and 1925 (42%) were &lt;65y, 65-74y, ≥75y old, respectively; 2459 (53%) were men. Older patients had a higher prevalence of structural heart disease and higher CHA 2 DS 2 -VASc scores. Dronedarone significantly reduced the risk of first CV hospitalization or death in the 65-74y and ≥75y subgroups, with a similar trend among patients &lt;65y (Table). The same pattern was observed for first CV hospitalization and first AF/AFL recurrence. Dronedarone significantly reduced the risk of first CV hospitalization or death in both men (hazard ratio [HR]: 0.74 [95% confidence interval: 0.64, 0.84]; P &lt; 0.0001) and women (HR: 0.77 [0.67, 0.89]; P = 0.0002). Dronedarone also significantly reduced the risk of first AF/AFL recurrence in men (HR: 0.85 [0.77, 0.94]; P = 0.0017) and women (HR: 0.71 [0.64, 0.80]; P &lt; 0.0001). Treatment-emergent adverse events (TEAEs) led to treatment discontinuation in 8% [6%], 13% [6%], and 15% [11%] of patients with dronedarone [placebo] in the &lt;65y, 65-74y, and ≥75y subgroups, respectively, without sex-based differences. Conclusions: In the ATHENA study, dronedarone decreased the risk of CV hospitalization or death and decreased AF/AFL recurrence regardless of patient sex as well as in patients 65y and older. A similar trend was observed in patients &lt;65y. No new drug-related safety signals were identified across age and sex subgroups.

An open-label, randomized trial indicates that everolimus with tacrolimus or cyclosporine is comparable to standard immunosuppression in de novo kidney transplant patients

This is a randomized trial (ATHENA study) in de novo kidney transplant patients to compare everolimus versus mycophenolic acid (MPA) with similar tacrolimus exposure in both groups, or everolimus with concomitant tacrolimus or cyclosporine (CsA), in an unselected population. In this 12-month, multicenter, open-label study, de novo kidney transplant recipients were randomized to everolimus with tacrolimus (EVR/TAC), everolimus with CsA (EVR/CsA) or MPA with tacrolimus (MPA/TAC), with similar tacrolimus exposure in both groups. Non-inferiority of the primary end point (estimated glomerular filtration rate [eGFR] at month 12), assessed in the per-protocol population of 338 patients, was not shown for EVR/TAC or EVR/CsA versus MPA/TAC. In 123 patients with TAC levels within the protocol-specified range, eGFR outcomes were comparable between groups. The mean increase in eGFR during months 1 to 12 post-transplant, analyzed post hoc, was similar with EVR/TAC or EVR/CsA versus MPA/TAC. The incidence of treatment failure (biopsy proven acute rejection, graft loss or death) was not significant for EVR/TAC but significant for EVR/CsA versus MPA/TAC. Most biopsy-proven acute rejection events in this study were graded mild (BANFF IA). There were no differences in proteinuria between groups. Cytomegalovirus and BK virus infection were significantly more frequent with MPA/TAC. Thus, everolimus with TAC or CsA showed comparable efficacy to MPA/TAC in de novo kidney transplant patients. Non-inferiority of renal function, when pre-specified, was not shown, but the mean increase in eGFR from month 1 to 12 was comparable to MPA/TAC.

Efficacy of different photoprotection strategies in preventing actinic keratosis new lesions after photodynamic therapy. The ATHENA study: a two-center, randomized, prospective, assessor-blinded pragmatic trial

Background: Treatment of actinic keratosis (AK) and field cancerization with photodynamic therapy (PDT) is an effective therapeutic approach with a significant reduction in the number of AK lesions (–75% or more) associated with a significant cosmetic improvement of the photodamaged skin. Recently, also, the daylight PDT (DL-PDT) has proven to be as effective as the conventional PDT (C-PDT), but with a better tolerability. After C-PDT and DL-PDT it is advised to use photoprotection strategies to improve the clinical evolution and prevent the appearance of new AK lesions that usually appear 3–6 months after the last phototherapy session. However, there are no robust clinical data regarding the type of photoprotection to be used (SPF level, duration of treatment, etc.) after successful PDT.Study aim: The present study (ATHENA trial) evaluated the efficacy and tolerability of a topical product based on 0.8% piroxicam and 50+ solar filters (ACTX), applied twice a day as sequential therapy after C-PDT or DL-PDT on the evolution of AK lesions number compared to the use of very high photoprotection products commonly used in this clinical setting (SPF50+ or SPF100+ associated with photolyase) (Standard Sunscreens: SS group). Subjects and methods: This was a multicenter, randomized, two-arm, prospective controlled, assessor-masked outcome evaluation, parallel group (1:1), pragmatic study of 6 months duration in patients with multiple AK lesions suitable for photodynamic therapy. The objectives of the study were the evaluation of the evolution of the number of AK lesions during the period of treatment/application of the study products, and the Investigator global clinical assessment score (IGA score; 4: marked improvement, 3: good, 2: moderate; 1 no improvement; 0: worsening) 2, 3, and 6 months after the last PDT session. A total of 68 subjects (50 men, 18 women; mean age 70 years), 34 assigned to treatment with ACTX and 34 to treatment with SS (17 treated with a SPF50+ and 17 with a photolyase-containing SPF100+ products), were enrolled in the study.Results: The number of AK lesions present before C-PDT/DL-PDT was 11.8 ± 5.8 in the ACTX group and 12.4 ± 6.9 in the SS group. In both groups, there was a progressive reduction of AK lesions observed at baseline (–86% and –87% after 2 months and –88% and –83% at month 3 in ACTX and in the SS group, respectively). At month 6, AK mean lesion number was 1.8 ± 1.6 in the ACTX and 3.2 ± 2.3 in the SS group; this difference was statistically significant (p = 0.03). The IGA score at the end of the study was 3.2 in the ACTX and 2.7 in the SS group (p = 0.05). The percentage of subjects with an IGA score of 4/3 (very good or good) was 81% in the ACTX and 55% in the SS group (p = 0.06).Conclusion: In subjects with AK treated with C-PDT or DL-PDT, a “medicalized” photoprotection treatment is associated with a favorable clinical outcome with progressive reduction of lesions. In contrast to a very high photoprotection (SPF50+ or SPF100+/photolyase), the use of piroxicam 0.8%/SPF 50+ is associated with a significantly greater improvement in clinical evolution of AK lesions.

Effects of dronedarone on all-cause mortality and on cardiovascular events in patients treated for atrial fibrillation: a meta-analysis of RCTs.

The efficacy and safety profiles of the dronedarone were rather praised when the molecule was placed on the market (2009). However, there are today some safety concerns (in particular, risk of liver toxicity) that have led to limit the use of this drug to paroxysmal or persistent atrial fibrillation, and to exclude it from therapy protocols for ventricular tachyarrhythmias. The aim of the present study was to explore some efficacy and safety endpoints concerning dronedarone, by analyzing the evidence derived from quantitative evaluation (meta-analysis) of literature data. We comprised in the meta-analysis exclusively randomized controlled trials (RCTs) that reported relevant clinical outcomes with dronedarone. In addition, eligible RCTs had to have randomized 100 patients at least in order to have adequate statistical power, and they had to have clearly reported the outcomes of interest. Primary efficacy outcomes were a) all-cause mortality,b) major acute cardiovascular events and c) worsening heart failure. Secondary outcomes of interest were ventricular tachyarrhythmias, stroke and systemic embolism. We performed a number of sensitivity analyses to better ascertain the sources of heterogeneity. We also performed a number of subgroup analyses. At the end of the selection process, the studies regarded suitable for meta-analysis were seven. Dronedarone use was not associated with any significant advantage as regards all-cause mortality(pooled odds ratio =1.31; 95% CI: 0.78 to 2.18; P= 0.31) and major cardiovascular events (pooled odds ratio=1.45; 95% CI: 0.7 to 3.01; P=0.28), as well as regarding the endpoint" worsening heart failure" (pooled odds ratio =1.32; 95% CI: 0.87 to 2.01; P= 0.20). Moreover, using subgroup analyses, in patients with permanent AF, dronedarone use was associated with increased all-cause mortality compared to placebo(P=0.03),as well as with higher risk of major acute cardiovascular events (P=0.04) and episodes of worsening heart failure(P=0.02). In addition, when data from ATHENA study were excluded, dronedarone use was associated with increased all-cause mortality (post exclusion pooled odds ratio=1.77; 95% CI: 1.15 to 2.72; P=0.0089), increased risk of major cardiovascular events (post exclusion pooled odds ratio=2.16; 95% CI: 1.34 to 3.47; P= 0.0014) and increased risk of worsening heart failure(post exclusion pooled odds ratio= 1.618; 95% CI: 1.14 to 2.3; P=0.006). In our meta-analysis, dronedarone did not provide any significant benefit with regard to all-cause mortality and major cardiovascular events, as well as regarding the risk of worsening heart failure. Sensitivity analyses then showed that the exclusion of a study, namely ATHENA study, caused a shift in the overall odds ratio, so as to convert the dronedarone use to the ominous role of predictor of higher mortality, worse cardiovascular morbidity and increased risk of worsening heart failure. Thus, dronedarone should be used with caution as second-line medication and exclusively for the secondary prevention of paroxysmal or persistent atrial fibrillation, in patients without signs or symptoms of cardiac decompensation, preferably for limited periods of time and under assiduous clinical and laboratory surveillance.

The Athena Study

Athena Study Group. Background The ATHENA study was set up to compare efficacy and safety of everolimus [EVR] combined with tacrolimus [TAC] or cyclosporine A [CyA] vs. a mycophenolic acid [MPA] with TAC standard regimen in de novo kidney transplant [KTx] recipients. Methods In this 12 months [M] prospective, open-label, multi-center study 612 patients [pts] were randomized 1:1:1 at time of Tx to either EVR (target trough: 3-8ng/ml M1-M12) + TAC (target trough: 4-8ng/ml M1-M3; and 3-5ng/ml M3-M12), or EVR (3-8ng/ml M1-M12) + CyA (target trough: 75-125ng/ml M1-M3; and 50-100ng/ml M3-M12) or TAC (target trough: 4-8ng/ml M1-M3; and 3-5ng/ml M3-M12) + MPA, all with steroids. Here we report M12 efficacy and safety data from 208 EVR+TAC, 199 EVR+CyA and 205 TAC+MPA treated pts. Results Treated BPAR events occurred in 6.7% of EVR+TAC pts vs 17.6% of EVR+CyA and 3.9% of TAC+MPA pts. Most of these events were graded mild, classified as BANFF IA: 1.9% vs 9% vs 1.5%, respectively; only few BANFF IIB/III occurred with 1.5% vs 2% vs 0.5% per group, respectively. Only few patients died during study period: 5 pts in EVR+TAC, 5 in EVR+CyA and 6 in TAC+MPA group. Incidence of graft loss was overall small: 4.8% (10 pts) in EVR+TAC vs 6.5% (13pts) in EVR+CyA and 2.9% (6pts) in TAC+MPA group - including 5 primary non-functioning grafts in each EVR-group and 1 in TAC+MPA group. Safety profiles of the three regimen were comparable: the incidence of AEs or infections leading to study drug discontinuation or dose adjustment/interruption were 56.7% in EVR+TAC, 55.5% in EVR+CyA vs 61.3% in TAC+MPA arm. These discontinuations or pausing [d/p] of study drug application were driven mainly by infections (as reasons for d/p: 15.2%EVR+TAC, 10.1%EVR+CyA, 31.3%TAC+MPA) and leukopenia (as reasons for d/p: 1.9%EVR+TAC, 3.0%EVR+CyA vs.10.8%TAC+MPA; p<0.01). Total incidence of leukopenia under treatment was 8.6% in EVR+TAC, 6.6% in EVR+CyA vs 19.1% for TAC+MPA (p<0.01). There were no differences on wound healing seen from incidences of AEs on wound complications, such as wound dehiscence, wound complications or impaired healing, with summed up incidences as follows: 41.9% EVR+TAC, 38.9% EVR+CyA, 43.2% TAC+MPA. No difference in proteinuria was seen, incidence of nephrotic proteinuria was 1.3% in EVR+TAC vs 0.7% in EVR+CyA and 3.7% in TAC+MPA treated patients. Conclusion ATHENA as to date largest prospective randomized European KTx study confirmed good efficacy and event rates within international standards for all 3 groups. There were no unexpected safety events for the patient population studied herein. Of note, there were no differences in reported AEs on wound healing, no differences in proteinuria but less leukopenia and fewer infections with EVR-based regimens.

Significant Anti-CMV/BKV Effect of a Modern Everolimus-Based Regimen Comparted to Standard Tacrolimus-MPA Regimen in de Novo Kidney Transplant Recipients

Athena Study Group. Background The ATHENA trial was designed to compare everolimus [EVR] in combination with tacrolimus [TAC] or cyclosporine A [CyA] vs. a standard regimen of mycophenolic acid [MPA] and TAC in de novo kidney transplant [Tx] recipients. Of specific interest was monitoring of infections with main focus on CMV and BKV. Methods In this randomized 12 months [M] prospective, open-label study with 15 German and 12 French study sites, in total 612 patients [pts] were randomized 1:1:1 at time of Tx to either EVR (target trough: 3-8ng/ml M1-M12) +TAC (target trough: 4-8ng/ml M1-M3; 3-5ng/ml M3-M12), or EVR (3-8ng/ml M1-M12) + CyA (target trough: 75-125 ng/ml M1-M3; 50-100 ng/ml M3-M12) or to control TAC regimen (target trough: 4-8ng/ml M1-M3; 3-5ng/ml M3-M12) with MPA. All pts received ongoing steroids. Here we present M12 data on infections within ITT population with 208 EVR+TAC pts, 199 EVR+CyA pts and 205 TAC+MPA pts. Results From randomization to M12 total incidence of infections was significantly higher in TAC+MPA group with 82% compared to 73% in EVR+TAC and 72% in EVR+CyA treated pts (p<0.05 for both EVR groups). In general, most frequent evet was urinary tract infection with similar incidences across groups: 41% vs 41% vs 40%, respectively. Major differences were seen for viral infections with an incidence of 41% in TAC+MPA vs 26% in EVR+TAC and 12% in EVR+CyA treatment groups (p<0.01). Of specific interest was incidence of BKV and CMV infections: BKV events were reported with 23% in TAC+MPA vs 17% in EVR+TAC vs 9% in EVR+CyA treatment groups (p<0.01) and CMV infections - as well significantly less under EVR treatment - with 21% in TAC+MPA vs 6% in EVR+TAC and 3% in EVR+CyA group (p<0.01). In addition to this more than three-fold difference for CMV infections between TAC+MPA and EVR-treatment, patients with CMV disease and/or recurrent CMV events occurred only in TAC+MPA group, not under EVR-treatment. Matching of CMV-donor/recipient status at baseline was balanced across groups for all risk-constellations and, of note: 3 months CMV-prophylaxis with valganciclovir for D+/R- and D+/R+ pts was requested per protocol. Conclusion ATHENA as largest European KTx study confirmed comparable efficacy and safety of all 3 regimens together with beneficial outcomes on viral infections: significantly less viral infections for EVR-based treatment groups compared to TAC+MPA group and a significant, protective effect of EVR-based regimens vs CMV/BKV events was robustly demonstrated.

Primary HPV testing verification: A retrospective ad-hoc analysis of screening algorithms on women doubly tested for cytology and HPV.

To evaluate human papillomavirus (HPV) testing as a primary screening tool, we retrospectively analyzed data comparing (1) HPV testing to the algorithms of the ATHENA Study: (2) cytology alone, (3) cytology with ASCUS triage in women 25-29 and (4) cotesting ≥ 30 or (5) cotesting ≥ 25. We retrospectively analyzed data from women tested with both cytology and HPV testing from 2010 to 2013. Cumulative risk (CR) for CIN3+ was calculated. Crude and verification bias adjusted (VBA) sensitivity, specificity, predictive values, likelihood ratios, colposcopy rate, and screening test numbers were compared. About 15,173 women (25-95, 7.1% <30) had both HPV and cytological testing. Nearly 1,184 (8.4%) had biopsies. About 19.4% had positive cytology, 14.5% had positive HPV. HPV testing unassociated with ASCUS was requested in 40% of women <30, versus 84% ≥30, with similar HPV16/18 genotyping results (68% vs. 70%). 84 CIN3+ were detected with the following 3-year cumulative risk (CR) (95% confidence interval): HPV+/ASCUS+, 46% (32-66%), HPV+/NILM 30% (15-58%), HPV-/ASCUS+ 12% (6-23%), and HPV-/NILM 0.8% (0.2-3.6%). HPV had higher specificity 57% (54-60%) than cotesting ≥30 52% (49-55%). HPV sensitivity 78% (69-87%), positive 12.3% (9.8-15.3%), negative 97 (96-98%) predictive values, positive 1.8 (1.6-2.1) and negative likelihood ratios 0.6 (0.5-0.6), were not significantly different. Cotesting increased colposcopy rate and doubled testing per CIN3+ diagnosed. While HPV-/NILM cotesting results are associated with low CIN3+ risk, HPV testing had similar screening performance to cotesting and to cytology alone. Additionally, HPV testing and cytology incur false negatives in nonoverlapping subsets of patients. Diagn. Cytopathol. 2017;45:580-586. © 2017 Wiley Periodicals, Inc.

Knowledge of Patients' Human Papillomavirus Status at the Time of Cytologic Review Significantly Affects the Performance of Cervical Cytology in the ATHENA Study.

With human papillomavirus (HPV) testing, patients' HPV status may be known when reviewing cytology specimens. 41,955 women 25 years or older had cytology and HPV screening. Originally, cytology was reviewed blinded to HPV status. We re-reviewed unblinded to HPV status a subset of 428 cytology slides from women with cervical intraepithelial neoplasia grade 2 + (CIN2+) and 1,287 from women without CIN2+. Of the original interpretations of atypical squamous cells of undetermined significance(ASC-US), 33.7% were downgraded to negative after unblinded review, and 8.7% were upgraded to atypical squamous cells, cannot rule out a high-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion. Of the original interpretations of ASC-US, 66.7% were downgraded on unblinded review in HPV-negative women and 30.2% were upgraded in HPV 16+/HPV 18+ women. Unblinding increases the sensitivity for cervical intraepithelial neoplasia grade 3+ of cotesting from 54.1% to 62.4% (P = .0015) and the sensitivity of HPV primary screening from 72.2% to 77.1% (P = .0029). With cotesting, specificity with unblinding is improved, whereas with HPV primary screening, there would be a small decrease in specificity. Unblinded cytology increases overall sensitivity with either cotesting or HPV primary screening; specificity is either slightly improved or is not affected by unblinding.

Abstract 2623: Common genetic variants associated with breast cancer risk used in the Athena study to enhance models identifying women for breast cancer chemoprevention

Abstract Background: The U.S. Preventive Services Task Force recommends that women with a &amp;gt;3% five-year risk of developing breast cancer consider taking selective estrogen receptor modifiers (SERMs) or aromatase inhibitors (AIs) to reduce their risk. Polygenic risk score (PRS), calculated by adding the individual breast cancer risk association for each common genetic variant (SNP), has been found to predict women at low- to high-risk of breast cancer. We analyze associations between SNP risk alleles and known breast cancer risk factors (ethnicity, family history of breast cancer and number of biopsies); furthermore, we quantify the likely impact on chemoprevention recommendations by adding the PRS to known risk models in a subset of women participating in the University of California 100,000 women Athena Breast Health Network. Methods: Our research cohort included 838 women with no previous diagnosis of breast cancer from the University of California, San Francisco, and was enriched for women determined to be at elevated risk for developing breast cancer by the Gail model. A panel of 75 breast cancer risk SNPs were evaluated on saliva and blood samples (Akesogen Inc; COGS oncochip array). The PRS for each patient was calculated by converting the odds ratio for each SNP into a likelihood ratio (LR) and combining LR's across SNPs. Breast Cancer Surveillance Consortium (BCSC), Gail, BCSC-PRS and Gail-PRS scores (risk models incorporating PRS within a Bayesian framework), were evaluated for each patient. Associations between variables were assessed using t-test or ANOVA. A threshold of p&amp;lt;0.05 was used to assess significance. Results: Women in this study carry an average of 65 risk allele SNPs (of 150, 2 per locus). By ANOVA, there is a statistically significant association between the SNPs risk allele count and ethnicity (p = 0.014), with a trend towards association with a family history of a first-degree relative with breast cancer (p = 0.053). PRS is significantly associated with a family history breast cancer (p = 0.031); neither SNP allele count nor PRS associates with previous biopsy status. We found by adding PRS that 12% (86/707) and 13% (104/776) of patients with a prior BCSC or Gail score &amp;lt;3% five-year risk, respectively, changed classifications and would be eligible for chemoprevention. Conversely, 37% (36/98) and 36% (22/62) of patients with a BCSC or Gail score of &amp;gt;3% five-year risk, respectively, changed classifications by adding PRS and would no longer be eligible for chemoprevention. Conclusion: The addition of SNP based PRS to BCSC and Gail models significantly changes how women are classified and as a result changes whether risk reducing agents are recommended. PRS will be combined with BCSC and genetic test results for 9 breast cancer genes to calculate a women's breast cancer risk in the PCORI-funded Athena WISDOM study of 100,000 women, comparing risk-based vs. annual mammography screening. Citation Format: Sarah Theiner, Sarah D. Sawyer, Paige Kendall, Alexandra S. Perry, Denise Wolf, Scott Huntsman, Bo Pan, Jeffery A. Tice, David A. Pearce, Thomas Cink, Laura Esserman, Elad Ziv, Laura van ‘t Veer. Common genetic variants associated with breast cancer risk used in the Athena study to enhance models identifying women for breast cancer chemoprevention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2623.

Evaluating HPV-negative CIN2+ in the ATHENA trial.

A post hoc analysis of the ATHENA study was performed to determine whether true HPV‐negative cervical lesions occur and whether they have clinical relevance. The ATHENA database was searched for all CIN2 or worse (CIN2+) cases with cobas HPV‐negative results and comparison was made with Linear Array (LA) and Amplicor to detect true false‐negative HPV results. Immunostaining with p16 was performed on these cases to identify false‐positive histology results. H&E slides were re‐reviewed by the study pathologists with knowledge of patient age, HPV test results and p16 immunostaining. Those with positive p16 immunostaining and/or a positive histopathology review underwent whole tissue section HPV PCR by the SPF10/LiPA/RHA system. Among 46,887 eligible women, 497 cases of CIN2+ were detected, 55 of which tested negative by the cobas® HPV Test (32 CIN2, 23 CIN3/ACIS). By LA and/or Amplicor, 32 CIN2+ (20 CIN2, 12 CIN3/ACIS) were HPV positive and categorized as false‐negatives by cobas HPV; nine of 12 false‐negative CIN3/ACIS cases were p16+. There were 23 cases (12 CIN2, 11 CIN3/ACIS) negative by all HPV tests; seven of 11 CIN3/ACIS cases were p16+. H&E slides were available for six cases for re‐review and all were confirmed as CIN3/ACIS. Tissue PCR was performed on the six confirmed CIN3/ACIS cases (and one without confirmation): four were positive for HPV types not considered oncogenic, two were positive for oncogenic genotypes and one was indeterminate. In summary, subanalysis of a large cervical cancer screening study did not identify any true CIN3/ACIS not attributable to HPV.

Design and rationale of the ATHENA study--A 12-month, multicentre, prospective study evaluating the outcomes of a de novo everolimus-based regimen in combination with reduced cyclosporine or tacrolimus versus a standard regimen in kidney transplant patients: study protocol for a randomised controlled trial.

BackgroundImmunosuppression with calcineurin inhibitors remains the mainstay of treatment after kidney transplantation; however, long-term use of these drugs may be associated with nephrotoxicity. In this regard, the current approach is to optimise available immunosuppressive regimens to reduce the calcineurin inhibitor dose while protecting renal function without affecting the efficacy. The ATHENA study is designed to evaluate renal function in two regimens: an everolimus and reduced calcineurin inhibitor-based regimen versus a standard treatment protocol with mycophenolic acid and tacrolimus in de novo kidney transplant recipients.Method/DesignATHENA is a 12-month, multicentre, open-label, prospective, randomised, parallel-group study in de novo kidney transplant recipients (aged 18 years or older) receiving renal allografts from deceased or living donors. Eligible patients are randomised (1:1:1) prior to transplantation to one of the following three treatment arms: everolimus (starting dose 1.5 mg/day; C0 3–8 ng/mL) with cyclosporine or everolimus (starting dose 3 mg/day; C0 3–8 ng/mL) with tacrolimus or mycophenolic acid (enteric-coated mycophenolate sodium at 1.44 g/day or mycophenolate mofetil at 2 g/day) with tacrolimus; in combination with corticosteroids. All patients receive induction therapy with basiliximab. The primary objective is to demonstrate non-inferiority of renal function (eGFR by the Nankivell formula) in one of the everolimus arms compared with the standard group at month 12 post transplantation. The key secondary objective is to assess the incidence of treatment failure, defined as biopsy-proven acute rejection, graft loss, or death, among the treatment groups. Other objectives include assessment of the individual components of treatment failure, incidence and severity of viral infections, incidence and duration of delayed graft function, incidence of indication biopsies, slow graft function and wound healing complications, and overall safety and tolerability. Exploratory objectives include evaluation of left ventricular hypertrophy assessed by the left ventricular mass index, evolution of human leukocyte antigen and non-human leukocyte antigen antibodies, and a cytomegalovirus substudy.DiscussionAs one of the largest European multicentre kidney transplant studies, ATHENA will determine whether a de novo everolimus-based regimen can preserve renal function versus the standard of care. This study further assesses a number of clinical issues which impact long-term outcomes post transplantation; hence, its results will have a major clinical impact.Trial registrationClinicaltrials.gov: NCT01843348, date of registration – 18 April 2013; EUDRACT number: 2011-005238-21, date of registration – 20 March 2012Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1220-9) contains supplementary material, which is available to authorized users.

Risks and resilience in immigrant youth adaptation: Who succeeds in the Greek school context and why?

Positive immigrant youth adaptation in the school context is a sign that development and acculturation are proceeding well. It is also a predictor of positive adult outcomes. Significant diversity has been observed in the adaptive success of immigrant youth, revealing a mixture of risk and paradox. In this article, I draw on data from a three-wave longitudinal project, the Athena Study of Resilient Adaptation, to examine the question of who among immigrant youth succeeds in the Greek school context and why. The study focused on immigrants from Albania and ethnic Greeks from the former Soviet Union. Findings from this study do not support the well-known immigrant paradox, where immigrant youth adaptation is positive and at times better than that of their non-immigrant peers. Instead, immigrant youth adaptation in the school context was worse than that of their Greek peers, both concurrently and over time, and especially with respect to core developmental tasks. Moreover, neither immigrant generation nor ethnic group significantly differentiated these results. Immigrant youth's personal and social capital contributed to individual differences in their adaptation. It is argued that these results may reflect societal-level influences, such as the low tolerance for diversity in Greek society and the almost complete lack of institutionalized educational support.