No overall change in the rate of weight gain after switching to an integrase-inhibitor in virologically suppressed adults with HIV

OBJECTIVE: Excessive weight gain has been reported with integrase strand transfer inhibitors (INSTIs). We evaluated weight changes in virologically-suppressed adults with HIV who switched from non-INSTI regimens to raltegravir- or dolutegravir-containing antiretroviral therapy. DESIGN: Retrospective single-centre cohort. METHODS: Adults who switched to raltegravir or dolutegravir before or between January-2015 and October-2017 were identified. Virologically-suppressed, treatment-experienced (≥2 years) individuals, ≥6 months on INSTI, with weight measurements ≤2years pre- and post-switch were included. Our analysis used a random effects model with linear slope pre- and post-INSTI with adjustment for age, gender, ethnicity, pre-switch-regimen (protease inhibitor vs. non-protease inhibitor), and raltegravir vs. dolutegravir use. RESULTS: 378 individuals, 81.2% male, 70.1% white ethnicity, median age of 49 years, median of four weight measurements per participant, and median weight and body mass index (BMI) at switch, of 76.6 kg, and 25.3 kg/m respectively were included. Weight increased by an average of 0.63 kg/year (95% CI 0.17-1.09) pre-switch with no overall change in rate of weight gain post-switch [+0.05 kg/year (-0.61-0.71, p = 0.88)]. In our adjusted model, a transition from minimal weight change to weight gain post-switch was isolated to older individuals though this lacked statistical significance [e.g. +1.59 kg/year (-0.26-3.45) if aged 65 years]. Our findings did not differ by gender, ethnicity, pre-switch regimen, or raltegravir vs. dolutegravir. Similar results were seen for BMI and after adjusting for fixed nucleoside/nucleotide reverse transcriptase inhibitor backbone. CONCLUSION: We found no clear evidence of an overall increase in rate of weight gain following switch to INSTI in virologically-suppressed individuals

Expect the Unexpected in the Medical Treatment of Heart Failure with Reduced Ejection Fraction: between Scientific Evidence and Clinical Wisdom.

Over the past three decades, pharmacological treatment of heart failure (HF) with reduced ejection fraction (HFrEF) has witnessed a significant progress with the introduction of multiple disease-modifying therapies with a proven benefit on morbidity, mortality and quality of life. Recently, several novel medications (sacubitril/valsartan, sodium-glucose contransporter-2 [SGLT2] inhibitors, vericiguat and omecamtiv mecarbil) have shown to provide further improvement in outcomes in patients already receiving standard therapy for HFrEF. Available evidence suggests that sacubitril/valsartan and SGLT2 inhibitors (dapagliflozin and empagliflozin) are beneficial and well-tolerated in the majority inpatients and could be the mainstay treatment of HFrEF. Another group of medications (vericiguat and omecamtiv mecarbil) has shown promising results in reducing the risk of the composite of HF hospitalisation or cardiovascular mortality in patients with the more severe or advanced HF requiring recent hospitalisation. Therefore, these medications may be considered for the treatment of select group of patients with HFrEF with persisting or worsening symptoms despite optimal treatment. In addition, advances in pharmacological management of comorbidities frequently seen in HFrEF patients (diabetes, iron deficiency/anaemia, hyperkalaemia) provide further opportunities to improve outcomes. Given the increasing complexity of evidence-based therapies for HFrEF, there is a growing need to provide a practical perspective to their use. The purpose of this review is to summarise scientific evidence on the efficacy and safety of new and emerging medical therapies in HFrEF, with a focus on the clinical perspective of their use

Cardiometabolic health in people with HIV: expert consensus review

Objectives To develop consensus data statements and clinical recommendations to provide guidance for improving cardiometabolic health outcomes in people with HIV based on the knowledge and experience of an international panel of experts.Methods A targeted literature review including 281 conference presentations, peer-reviewed articles, and background references on cardiometabolic health in adults with HIV published between January 2016 and April 2022 was conducted and used to develop draft consensus data statements. Using a modified Delphi method, an international panel of 16 experts convened in workshops and completed surveys to refine consensus data statements and generate clinical recommendations.Results Overall, 10 data statements, five data gaps and 14 clinical recommendations achieved consensus. In the data statements, the panel describes increased risk of cardiometabolic health concerns in people with HIV compared with the general population, known risk factors, and the potential impact of antiretroviral therapy. The panel also identified data gaps to inform future research in people with HIV. Finally, in the clinical recommendations, the panel emphasizes the need for a holistic approach to comprehensive care that includes regular assessment of cardiometabolic health, access to cardiometabolic health services, counselling on potential changes in weight after initiating or switching antiretroviral therapy and encouraging a healthy lifestyle to lower cardiometabolic health risk.Conclusions On the basis of available data and expert consensus, an international panel developed clinical recommendations to address the increased risk of cardiometabolic disorders in people with HIV to ensure appropriate cardiometabolic health management for this population

Safety and immunogenicity of a self-amplifying RNA vaccine against COVID-19: COVAC1, a phase I, dose-ranging trial

Background: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19. Methods: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20). Findings: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received. Interpretation: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2. Funding: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth

Consensus on the assessment of systemic sclerosis–associated primary heart involvement: World Scleroderma Foundation/Heart Failure Association guidance on screening, diagnosis, and follow-up assessment

INTRODUCTION: Heart involvement is a common problem in systemic sclerosis. Recently, a definition of systemic sclerosis primary heart involvement had been proposed. Our aim was to establish consensus guidance on the screening, diagnosis and follow-up of systemic sclerosis primary heart involvement patients. METHODS: A systematic literature review was performed to investigate the tests used to evaluate heart involvement in systemic sclerosis. The extracted data were categorized into relevant domains (conventional radiology, electrocardiography, echocardiography, cardiac magnetic resonance imaging, laboratory, and others) and presented to experts and one patient research partner, who discussed the data and added their opinion. This led to the formulation of overarching principles and guidance statements, then reviewed and voted on for agreement. Consensus was attained when the mean agreement was ⩾7/10 and of ⩾70% of voters. RESULTS: Among 2650 publications, 168 met eligibility criteria; the data extracted were discussed over three meetings. Seven overarching principles and 10 guidance points were created, revised and voted on. The consensus highlighted the importance of patient counseling, differential diagnosis and multidisciplinary team management, as well as defining screening and diagnostic approaches. The initial core evaluation should integrate history, physical examination, rest electrocardiography, trans-thoracic echocardiography and standard serum cardiac biomarkers. Further investigations should be individually tailored and decided through a multidisciplinary management. The overall mean agreement was 9.1/10, with mean 93% of experts voting above 7/10. CONCLUSION: This consensus-based guidance on screening, diagnosis and follow-up of systemic sclerosis primary heart involvement provides a foundation for standard of care and future feasibility studies that are ongoing to support its application in clinical practice

Primary systemic sclerosis heart involvement: A systematic literature review and preliminary data-driven, consensus-based WSF/HFA definition

Introduction: Primary heart involvement in systemic sclerosis may cause morpho-functional and electrical cardiac abnormalities and is a common cause of death. The absence of a clear definition of primary heart involvement in systemic sclerosis limits our understanding and ability to focus on clinical research. We aimed to create an expert consensus definition for primary heart involvement in systemic sclerosis. Methods: A systematic literature review of cardiac involvement and manifestations in systemic sclerosis was conducted to inform an international and multi-disciplinary task force. In addition, the nominal group technique was used to derive a definition that was then subject to voting. A total of 16 clinical cases were evaluated to test face validity, feasibility, reliability and criterion validity of the newly created definition. Results: In total, 171 publications met eligibility criteria. Using the nominal group technique, experts added their opinion, provided statements to consider and ranked them to create the consensus definition, which received 100% agreement on face validity. A median 60(5–300) seconds was taken for the feasibility on a single case. Inter-rater agreement was moderate (mKappa (95% CI) = 0.56 (0.46–1.00) for the first round and 0.55 (0.44–1.00) for the second round) and intra-rater agreement was good (mKappa (95% CI) = 0.77 (0.47–1.00)). Criterion validity showed a 78 (73–84)% correctness versus gold standard. Conclusion: A preliminary primary heart involvement in systemic sclerosis consensus-based definition was created and partially validated, for use in future clinical research

The heart failure specialists of tomorrow: a network for young cardiovascular scientists and clinicians

The "Heart failure specialists of Tomorrow" (HoT) group gathers young researchers, physicians, basic scientists, nurses and many other professions under the auspices of the Heart Failure Association of the European Society of Cardiology. After its foundation in 2014, it has quickly grown to a large group of currently 925 members. Membership in this growing community offers many advantages during, before, and after the 'Heart Failure and World Congress on Acute Heart Failure'. These include: eligibility to receive travel grants, participation in moderated poster sessions and young researcher and clinical case sessions, the HoT walk, the career cafe, access to the networking opportunities, and interaction with a large and cohesive international community that constantly seeks multinational collaborations.Peer reviewe

Toxicity Associated with Stavudine Dose Reduction from 40 to 30 mg in First-Line Antiretroviral Therapy

To compare the incidence and timing of toxicity associated with the use of a reduced dose of stavudine from 40 to 30 mg in first-line antiretroviral therapy (ART) for HIV treatment and to investigate associated risk factors