INTRODUCTION:It remains unclear which cardiovascular disease (CVD) risk scores are optimized for people living with treated HIV with high rates of viral suppression. We evaluated the performance of commonly used CVD risk scores in a population of primarily well-treated HIV patients in England. METHODS:A multi-centre retrospective cohort analysis was performed, including people living with HIV (PLWH) above the age of 40 with no prior major adverse CVD events (MACE), regularly attending 7 HIV clinics in England during 2014. Outcomes were MACE over the following 5 years: myocardial infarction, invasive cardiac procedure e.g. primary angioplasty, cerebrovascular events, new heart failure, and CVD-related death. Clinical outcomes were aligned with the respective risk scores. The following CVD risk models were evaluated: the UK primary-care validated QRISK3, Framingham laboratory and non-laboratory (Office) scores, Data collection on Adverse events of anti-HIV Drugs (D:A:D), Pooled Cohort Equation (PCE), and the World Health Organization (WHO) laboratory and non-laboratory models. Models were scaled for 5-year CVD estimates. We assessed the discrimination and calibration of these 5-year models within our population. Multiple imputation was used to address missing data. RESULTS:Of 2582 people, 94 had at least one MACE documented during follow-up. All seven scores demonstrated moderate discrimination. QRISK3 demonstrated the best calibration in this cohort with an O:E ratio of 1.169, 95% CI 0.950, 1.439, mean calibration-in-the-large (CITL) value of 0.156 (95% CI -0.052, 0.364) and slope of 0.897 (0.682, 1.113). Framingham Office generally overpredicted risk, while WHO scores and D:A:D generally underpredicted risk. Imputing for missing data yielded results similar to the complete case analysis. CONCLUSIONS:CVD risk scores demonstrated moderate performance in a well-treated PLWH cohort. Our findings emphasize the need to calibrate each CVD risk score to the local population to guide prioritization of clinical resources for CVD prevention. EVIDENCE IN CONTEXT:Evidence before this study: We systematically searched Medline, Embase, and Cochrane Library database from January 1995 to August 2023, using the following terms 'HIV/AIDS and Cardiovascular Disease (CVD) outcomes', with an updated search to 2025. The risk of CVD has been reported to be up to two times that of people living without HIV, along with increased rates of heart failure and sudden death. Commonly used CVD risk scores have demonstrated variable performance for PLWH, and only the D:A:D study equation has been specifically validated in an HIV-positive population. Within an era of modern ART regimes and high rates of viral suppression, there have been numerous comparisons of CVD risk across scoring systems, but few studies with observed outcomes of CVD rates to validate the predictions. It remains unclear which CVD risk calculator is the most suitable for PLWH. The use of routinely collected clinical data may also impact the accuracy of results due to the presence of incomplete or missing data fields. In this study, we aimed to evaluate the performance of commonly used CVD risk scores in a population of primarily well-treated HIV patients in England using routinely collected clinical data. Added value of this study: We demonstrate that of the seven CVD risk scores evaluated (QRISK3, Framingham laboratory and non-laboratory (Office) scores, D:A:D, Pooled Cohort Equation (PCE), and the WHO laboratory and non-laboratory models), all showed moderate discrimination compared to observed major adverse cardiovascular events (MACE) rates in an English multicentre cohort of people living with HIV attending clinics. QRISK3, using a large UK primary care database to validate predicted CVD risk, appeared to be most closely calibrated to CVD outcomes in our cohort without the need for additional calibration. Our findings also suggest that the use of non-laboratory scores, which have been suggested for low and middle-income settings where laboratory results may not be available, should be interpreted with caution, and further testing may be required due to their miscalibration in this cohort. Implications of all the available evidence: Using real-world clinical data from people with HIV who are engaged in care in England, these findings emphasize the need to calibrate each CVD risk score to the local population it is used for in order to accurately guide prioritization of clinical resources for primary CVD prevention.

BACKGROUND:Hereditary angioedema is a bradykinin-mediated, rare condition characterised by recurrent and potentially life-threatening attacks of subcutaneous and submucosal swelling. Bradykinin B2 receptor antagonism is a proven mechanism for on-demand treatment of attacks, but no evidence exists on its effects when used prophylactically. Deucrictibant is an investigational orally bioavailable bradykinin B2 receptor antagonist. We aimed to evaluate the efficacy, safety, and tolerability of two dose regimens of oral deucrictibant administered as prophylaxis against hereditary angioedema attacks. METHODS:CHAPTER-1 was a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial conducted in two parts, a double-blind placebo controlled first part and an open-label second part, with only part 1 reported here. Part 1 recruited adults (aged 18-75 years) with hereditary angioedema type 1 or 2 from 37 sites (university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Patients required a documented history of three or more attacks within the last 3 consecutive months before screening or two or more during the screening period (up to 8 weeks) to be eligible. An interactive response technology system randomised eligible patients 1:1:1 to receive oral deucrictibant 20 mg daily, 40 mg daily, or matching placebo for 12 weeks. Randomisation to treatment groups was stratified by the baseline attack rate. Patients, investigators, site personnel, and the sponsor were blinded to treatment assignment. Masking was achieved with identically appearing deucrictibant and placebo capsules. The primary endpoint was the time-normalised number of investigator-confirmed attacks per 4 weeks (monthly attack rate) from weeks 1 to 12 and was assessed using the intention-to-treat set. The endpoint was analysed by comparing each deucrictibant group with the placebo group using a Poisson generalised linear model with a log link function and Pearson's χ2 scaling of SEs to account for potential dispersion. The safety analysis set included all patients who were randomly assigned and who received one or more doses of study drug (deucrictibant or placebo). CHAPTER-1 is registered with ClinicalTrials.gov (NCT05047185) and is now complete. FINDINGS:Between March 9, 2022, and June 19, 2023, 44 patients were screened. Of 34 patients who were randomly assigned, 11 patients received deucrictibant 20 mg, 12 patients received deucrictibant 40 mg, and 11 patients received the placebo, with a median follow-up of 85·0 days (IQR 84·0-86·0). 21 (62%) patients were female, 13 (38%) were male, and 34 (100%) patients were White. The least squares mean monthly attack rate (primary analysis) was 0·40 (95% CI 0·18-0·92) for deucrictibant 20 mg, 0·30 (0·11-0·81) for deucrictibant 40 mg, and 1·93 (1·30-2·88) for placebo; percent reduction in attack rate compared with placebo was 79·2% (95% CI 47·2-91·8) for deucrictibant 20 mg (p=0·0010) and 84·5% (95% CI 53·8-94·8) for deucrictibant 40 mg (p=0·0008). Treatment-related treatment-emergent adverse events were experienced by two (18%) patients receiving deucrictibant 20 mg, one (8%) patient receiving deucrictibant 40 mg, and one (9%) patient receiving the placebo; all were mild in severity (grade 1) and did not require dosing modification of the study drug. There were no serious adverse events or deaths in any treatment group. INTERPRETATION:To the best of our knowledge, this trial provides the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism as a therapeutic approach for the prevention of hereditary angioedema attacks and supports further investigation of oral deucrictibant for bradykinin-mediated angioedema. FUNDING:Pharvaris.

Background Treatment -simplification strategies are important tools for patient -centred management. We evaluated long-term outcomes from a PI monotherapy switch strategy. Methods Eligible participants attending 43 UK treatment centres had a viral load (VL) below 50 copies/ml for at least 24 weeks on combination ART. Participants were randomised to maintain ongoing triple therapy (OT) or switch to a strategy of physician -selected PI monotherapy (PI -mono) with prompt return to combination therapy if VL rebounded. The primary outcome, previously reported, was loss of future drug options after 3 years, defined as new intermediate/high level resistance to at least one drug to which the participant's virus was considered sensitive at trial entry. Here we report resistance and disease outcomes after further extended follow-up in routine care. The study was registered as ISRCTN04857074. Findings We randomised 587 participants to OT (291) or PI -mono (296) between Nov 4, 2008, and July 28, 2010 and followed them for a median of more than 8 years (100 months) until 2018. At the end of this follow-up time, one or more future drug options had been lost in 7 participants in the OT group and 6 in the PI -mono group; estimated cumulative risk by 8 years of 2.7% and 2.1% respectively (difference -0.6%, 95% CI -3.2% to 2.0%). Only one PImono participant developed resistance to the protease inhibitor they were taking (atazanavir). Serious clinical events (death, serious AIDS, and serious non -AIDS) were infrequent; reported in a total of 12 (4.1%) participants in the OT group and 23 (7.8%) in the PI -mono group (P = 0.08) over the entire follow-up period. Interpretation A strategy of PI monotherapy, with regular VL monitoring and prompt reintroduction of combination treatment following rebound, preserved future treatment options. Findings confirm the high genetic barrier to resistance of the PI drug class that makes them well suited for creative, patient -centred, treatment -simplification approaches. The possibility of a small excess risk of serious clinical events with the PI monotherapy strategy cannot be excluded. Funding The National Institute for Health Research Health Technology Assessment programme. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BackgroundCommon Variable Immunodeficiency Disorders (CVID) encompass a spectrum of immunodeficiency characterised by recurrent infections and diverse non-infectious complications (NICs). This study aimed to describe the clinical features and variation in NICs in CVID with and without interstitial lung disease (ILD) from a large UK national registry population.MethodsRetrospective, cross-sectional data from a UK multicentre database (previously known as UKPIN), categorising patients into those with CVID-ILD and those with NICs related to CVID but without pulmonary involvement (CVID-EP; EP= extra-pulmonary involvement only).Results129 patients were included. Chronic lung diseases, especially CVID-ILD, are prominent complications in complex CVID, occurring in 62% of the cohort. Bronchiectasis was common (64% of the cohort) and associated with greater pulmonary function impairment in patients with CVID-ILD compared to those without bronchiectasis. Lymphadenopathy and the absence of gastrointestinal diseases were significant predictors of ILD in complex CVID. Although the presence of liver disease did not differ significantly between the groups, nearly half of the CVID-ILD patients were found to have liver disease. Patients with CVID-ILD were more likely to receive immunosuppressive treatments such as rituximab and mycophenolate mofetil than the CVID-EP group, indicating greater need for treatment and risk of complications.ConclusionThis study highlights the significant burden of CVID-ILD within the CVID population with NICs only. The lungs emerged as the most frequently affected organ, with ILD and bronchiectasis both highly prevalent. These findings emphasise the necessity of a comprehensive and multidisciplinary approach in managing CVID patients, considering their susceptibility to various comorbidities and complications.

Background Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. Methods In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. Results A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P=0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. Conclusions Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.)

Background: Angioedema (AE) manifests with intermittent, localized, self-limiting swelling of the subcutaneous and/or submucosal tissue. AE is heterogeneous, can be hereditary or acquired, may occur only once or be recurrent, may exhibit wheals or not, and may be due to mast cell mediators, bradykinin, or other mechanisms. Several different taxonomic systems are currently used, making it difficult to compare the results of studies, develop multicenter collaboration, and harmonize AE treatment. Objective: We developed a consensus on the definition, acronyms, nomenclature, and classification of AE (DANCE). Methods: The initiative involved 91 experts from 35 countries and was endorsed by 53 scientific and medical societies, and patient organizations. A consensus was reached by online discussion and voting using the Delphi process over a period of 16 months (June 2021 to November 2022). Results: The DANCE initiative resulted in an international consensus on the definition, classification, and terminology of AE. The new consensus classification features 5 types and endotypes of AE and a harmonized vocabulary of abbreviations/acronyms. Conclusion: The DANCE classification complements current clinical guidelines and expert consensus recommendations on the diagnostic assessment and treatment of AE. DANCE does not replace current clinical guidelines, and expert consensus algorithms and should not be misconstrued in a way that affects reimbursement of medicines prescribed by physicians using sound clinical judgment. We anticipate that this new AE taxonomy and nomenclature will harmonize and facilitate AE research and clinical studies, thereby improving patient care.

Hereditary angioedema (HAE) is a rare inherited disorder causing recurrent episodes of swelling that can be potentially life threatening. Treatment of HAE can be divided into on-demand treatment for swelling, and prophylaxis. The last UK consensus on HAE was in 2014 and since then, new medications for prophylaxis have been developed, with more drugs in the pipeline. International guidelines currently recommend the use of long-term prophylaxis (LTP) as the only way of achieving disease control and normalizing patient lives. Modern prophylactic medications are available in the UK, although access is restricted primarily by HAE attack frequency. To establish an updated view of UK clinicians and patients, a Delphi process was used to develop statements regarding LTP as well as other aspects of HAE management. There was consensus that UK access criteria for modern LTP agents based on numerical frequency of attacks alone are too simplistic and potentially disadvantage a cohort of patients who may benefit from LTP. Additionally, there was agreement that patients should be seen in expert centres, remote monitoring of patients is popular post-pandemic, and that the use of patient-reported outcome measures has the potential to improve patient care. Psychological health is an area in which patients may benefit, and recognition of this is important for future research and development.

Introduction Hereditary angioedema (HAE) attacks are caused by excess bradykinin activating bradykinin B2 receptors. Deucrictibant is a selective, orally-administered bradykinin B2 receptor antagonist under development for on-demand and prophylactic treatment of HAE attacks. Methods CHAPTER-1 (NCT05047185) is an ongoing 2-part Phase 2 study evaluating efficacy and safety of deucrictibant for long-term prophylaxis of HAE attacks. In part 1, participants received double-blinded placebo or deucrictibant 20mg/day or 40mg/day (immediate-release capsule formulation) for 12 weeks. Thirty-four participants were enrolled. In the ongoing part 2, participants receive treatment with open-label deucrictibant 40mg/day. Disease control, health-related quality of life (HRQoL), and patient treatment satisfaction were assessed using Angioedema Control Test (AECT); Patient Global Assessment of Change (PGA-Change) and Angioedema QoL Questionnaire (AE-QoL); and Treatment Satisfaction Questionnaire for Medication (TSQM). Results In placebo-controlled part 1, at 12 weeks, 9/10 participants in both deucrictibant 20mg/day and 40mg/day dose-groups had well-controlled disease by AECT vs 3/8 receiving placebo (P=0.0430 both doses). By PGA-Change, 8/10 and 7/9 participants reported feeling “much better” in the deucrictibant 20mg/day and 40mg/day groups vs 1/8 in the placebo group. Mean AE-QoL total score improved from baseline to week 12 by 19.0, 25.9, and 11.9 points in participants receiving deucrictibant 20mg/day, 40mg/day, and placebo. Participants receiving deucrictibant experienced greater treatment satisfaction, with mean TSQM Global Scores of 89.2 and 85.8 with deucrictibant 20mg/day and 40mg/day vs 59.4 with placebo. Conclusion Prophylaxis with oral deucrictibant for 12 weeks resulted in improvement in disease control, HRQoL, and treatment satisfaction vs placebo in people with HAE.

BACKGROUND:Clinical trials investigating drugs for the acute treatment of hereditary angioedema attacks have assessed many different outcomes. This heterogeneity limits the comparability of trial results and may lead to selective outcome reporting bias and a high burden on trial participants. OBJECTIVE:To achieve consensus on a core outcome set composed of key outcomes that ideally should be used in all clinical efficacy trials involving the acute treatment of hereditary angioedema attacks. METHODS:We conducted a Delphi consensus study involving all relevant parties: patients with hereditary angioedema, hereditary angioedema expert clinicians and clinical researchers, pharmaceutical companies, and regulatory bodies. Two Internet-based survey rounds were conducted. In round 1, panelists indicated the importance of individual outcomes used in clinical trials on a 9-point Likert scale. Based on these results, a core outcome set was developed and voted on by panelists in round 2. RESULTS:A total of 58 worldwide panelists completed both rounds. The first round demonstrated high importance scores and substantial agreement among the panelists. In the second round, a consensus of 90% or greater was achieved on a core outcome set consisting of five key outcomes: change in overall symptom severity at one predetermined time point between 15 minutes and 4 hours after treatment, time to end of progression of all symptoms, the need for rescue medication during the entire attack, impairment of daily activities, and treatment satisfaction. CONCLUSIONS:This international study obtained a high level of consensus on a core outcome set for the acute treatment of hereditary angioedema attacks, consisting of five key outcomes.

In hereditary angioedema (HAE), swelling attacks are caused by excessive bradykinin activating the bradykinin B2 receptors. Deucrictibant (PHA121) is a potent, selective, orally administered antagonist of bradykinin B2 receptor under development for on-demand and prophylactic treatment of HAE attacks. CHAPTER-1 is a double-blind, placebo-controlled, 2-part proof-of-concept phase 2 trial of deucrictibant for prophylaxis against angioedema attacks in HAE-1/2. The trial enrolled participants in Canada, Europe, the United Kingdom, and the United States. Eligible participants are aged ≥18 and ≤75 years, diagnosed with HAE type 1 or 2, not receiving other prophylactic treatments at the time of screening, and experienced ≥3 attacks within the last 3 consecutive months prior to screening or ≥2 attacks during screening (up to 8 weeks). Enrollment of target participants was completed (n=34). In part 1 of the trial, participants receive daily treatment with either placebo or one of two dose regimens of deucrictibant (20 or 40 mg/day, capsule formulation). In part 2, participants have the opportunity to continue treatment with open-label deucrictibant 40 mg/day. The primary endpoint is time-normalized number of investigator-confirmed HAE attacks. Secondary endpoints include number of moderate/severe attacks, attacks requiring on-demand treatment, reduction in the attack rate, and number of participants as well as days that are free from attacks. Safety outcome measures include occurrence of treatment-emergent adverse events, clinical laboratory tests, and vital signs. CHAPTER-1 is the first trial evaluating the efficacy and safety of deucrictibant for prophylaxis of HAE attacks. CHAPTER-1 results are anticipated to be presented at the AAAAI conference.

CVID (common variable immunodeficiency) is associated with a variety of gastrointestinal disorders including those mimicking Crohn's disease and ulcerative colitis. At present there is no clear trial data for the treatment of CVID enteropathy. There are no specific recommendations for treatment; however, it is commonly treated in a similar manner to inflammatory bowel disease, with corticosteroids, 5-aminosalicylates (5-ASA), azathioprine and anti-TNF therapy all being used. We describe the case of a 54-year-old with CVID-enteropathy presenting with diarrhoea and evidence of granulomatous inflammation on colonic biopsies. He was successfully treated with ustekinumab following failure/intolerance of prednisolone, 5-ASA and azathioprine. Features of CVID-enteropathy improved both clinically and histologically, with no evidence of serious treatment-related side effects.