Search

Heavily treatment-experienced (HTE) people with HIV (PWH) may not achieve virologic suppression (VS) with combination antiretroviral therapy due to multi-drug resistance (MDR), intolerance, and safety concerns. These PWH often receive highly individualized treatment regimens, but these regimens may not enable PWH to achieve VS, thereby halting disease progression. Novel medications are required for treating individuals with MDR HIV. Lenacapavir (LEN), a first-in-class HIV capsid inhibitor, is under investigation for the treatment of HTE individuals with MDR HIV in the Phase 2/3 CAPELLA study.To compare LEN plus optimized background regimen (OBR) with fostemsavir (FTR)+OBR, ibalizumab (IBA)+OBR and OBR alone in terms of VS, CD4 cell count change from baseline (CFB), immunologic recovery, and discontinuation due to adverse events, using indirect treatment comparisons (ITCs).A systematic review identified clinical evidence on HIV-1 treatments in HTE PWH. A feasibility assessment evaluated the identified studies for ITC analyses based on population characteristics, interventions, comparators, and outcomes of interest. Unanchored simulated treatment comparisons (STCs) of LEN+OBR versus comparators were conducted.LEN+OBR had 6.57 times higher odds of VS at Week 24-28 than FTR+OBR (95% CI: 1.34, 32.28), 8.93 times higher odds of VS than IBA+OBR (95% CI: 2.07, 38.46), and 12.74 times higher odds of VS than OBR alone (95% CI: 1.70, 95.37). CFB in CD4 cell count was similar across LEN+OBR, FTR+OBR and IBA+OBR.LEN+OBR has statistically significantly greater odds of VS at Week 24-28 than its comparators and represents a novel treatment for people with MDR HIV.Available evidence on the efficacy and effectiveness of different therapies in HTE PWH is sparse. This is the first analysis that provides comparative treatment estimates which can be used alongside other outcomes to support decisions regarding the care of people with MDR HIV. We have shown that LEN+OBR is favored over key comparators in terms of achieving VS, and therefore has potential to reduce the burden associated with virologic failure in people with MDR HIV.

Aims To identify and synthesize phase 3 and phase 4 randomized controlled trials (RCTs) of sodium-glucose co-transporter (SGLT) inhibitors and metformin as adjuncts to insulin in type 1 diabetes (T1DM) using network meta-analysis (NMA). Materials and methods A systematic literature review (SLR) identified relevant RCTs of ≥12 Weeks duration. MEDLINE, Embase, the Cochrane Library and grey literature were searched through October 2018. NMAs indirectly compared SGLT inhibitors and metformin for change from baseline in HbA1c, weight, total daily insulin dose and systolic blood pressure at Week 24 to 26 and Week 52. Safety outcomes were also explored. Results Nine trials (N = 6780) were included in the SLR. NMAs indicated that all therapies performed better than placebo for the efficacy outcomes at both time points. Compared with metformin at Week 24 to 26, the SGLT inhibitors dapagliflozin (5 mg), sotagliflozin (200 mg) and empagliflozin (10 mg) had larger reductions in HbA1c (mean difference [MD] = -0.24, 95% credible interval [CrI], -0.41 to -0.07, MD = -0.23, 95% CrI, -0.39 to -0.08 and MD = -0.35, 95% CrI, -0.51 to -0.19, respectively) and in weight, which were sustained in sensitivity analyses. There were few differences observed in the results of safety outcomes, such as risk of diabetic ketoacidosis (DKA), which should be interpreted cautiously because of wide CrIs. Conclusions Adjunctive use of SGLT inhibitors in T1DM can improve glycaemic control compared with metformin while enabling weight loss, with consistent efficacy across the class. However, these results are based on indirect evidence so confirmation in a head-to-head study would be valuable.

T1DM is characterized by deficient insulin production, requiring multiple daily insulin doses. However, glycemic control is often suboptimal, and insulin-associated weight gain and hypoglycemia are concerns. Therefore, adjunctive therapy may be beneficial. A SLR with searches conducted to 16 Oct 2018 identified phase III/IV RCTs of MET or SGLT1/2 inhibitors as add-on to insulin in T1DM. MEDLINE, Embase and the Cochrane Library were searched, as well as congresses, reference lists and grey literature. Bayesian NMAs were performed at Week 24/26 (Week 24) and Week 52 (Week 52) for change from baseline in HbA1c and weight, and the proportion of participants experiencing hypoglycemic events and hypoglycemic severe adverse events. Nine placebo (PBO) controlled RCTs of dapagliflozin (DAPA), MET, sotagliflozin (SOTA) or empagliflozin (EMPA) reporting results were included. There was some evidence of heterogeneity in study design and outcomes. Results of the NMAs for MET vs. comparator (Table) found that the SGLT2 and SGLT1/2 inhibitors generally performed better than MET for HbA1c and weight, but there were few significant differences for hypoglycemia at Week 52. Results suggest that adjunctive use of SGLT2 and SGLT1/2 inhibitors including DAPA can improve glycemic control compared to MET while enabling weight loss in T1DM, and demonstrate consistent efficacy for the class. Disclosure B.E. Langford: Employee; Self; Costello Medical. Research Support; Self; AstraZeneca. M. Evans: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sunovion Pharmaceuticals Inc. T. Haskins-Coulter: Employee; Self; Costello Medical. M. O'Connor: Employee; Self; Costello Medical. H.E. Cant: Employee; Self; Costello Medical. L.A. Eddowes: Employee; Self; Costello Medical. C. Edmonds: Employee; Self; AstraZeneca. A. Tank: Employee; Self; AstraZeneca. Funding AstraZeneca; Cambridge University

Alkaptonuria (AKU) is a rare disorder with no licensed treatment; nitisinone may reduce symptoms and progression. The All Alkaptonuria Severity Score Index (AKUSSI) measures disease severity in clinical, joint and spine domains, with 57 subcomponent feature scores. Our primary aim was to assess tools for validating scores such as the AKUSSI by detecting relationships between features both before and during nitisinone treatment.AKUSSI measurements from nitisinone-treated patients visiting the National AKU Centre between 01-Jun-2012 and 31-May-2016 were analysed pre-treatment, at first treatment and annually to Year 3 post-treatment. Principal component analysis (PCA) and redundancy analysis assessed whether any AKUSSI features contributed little information to the overall score.65 AKU patients were included: 17 with a pre-treatment AKUSSI measurement (10 later received nitisinone) and 48 with a first measurement at their first treatment visit. In PCA, the first four principal components (PC1-PC4) explained ≥50% of AKUSSI variance at all visits (54.1-87.3%). Some features regularly dominated their domain's PC1: ears, aortic sclerosis, and nasal/temporal eye scores (clinical), pain-related scores (joint) and cervical, lumbar and thoracic spine scores (spine). Only the right-hand/wrist score was consistently redundant. Right eye (nasal) and left ear scores were redundant pre-treatment, potentially correlating with other dominant clinical PC1 features.PCA and redundancy analysis supported the AKUSSI as a robust AKU disease severity measure, although some AKUSSI features could be removed for simplicity. For small patient populations and rare diseases, PCA and redundancy analysis together can aid validation of disease severity metrics.

Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6–independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-β1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6–dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6–independent, but partially TGF-β–dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.

A lack of decisive evidence on the impact of telemedicine on financial and clinical outcomes has not prohibited significant investment in developing countries. Understanding characteristics that facilitate effective telemedicine programs is required to allow telemedicine to be used to its full potential. This systematic review aimed to identify organizational, technological, and financial features of successful telemedicine programs providing direct clinical care in developing countries.Databases were searched, and the results were reviewed systematically according to predefined inclusion/exclusion criteria. Information on location(s), measure of success, and organizational, technological, and financial characteristics were extracted. This review was impeded by inadequate program reporting, and so a concise checklist was developed to aid improved reporting, enabling future reviews to identify key characteristics of effective programs.This systematic review identified 46 articles reporting 36 programs that fulfilled the inclusion/exclusion criteria. Programs were distributed globally, including regional, national, and international programs. Technological modalities included synchronous technology, real-time teleconsultations, and asynchronous technology. Program integration with existing systems and twinning of international institutions were identified as factors enabling program success. Other factors included simple and easy-to-use technology, ability to reduce the burden on healthcare professionals, and technology able to maintain functionality in challenging environmental circumstances. Reports describing effectiveness and costs were limited.This systematic review identified key factors associated with telemedicine program success. However, inconsistencies in reporting represent an obstacle to establishment of successful programs in developing countries by limiting the application of previous experiences. Adhering to the guidelines suggested here may allow more quantitative assessments of effectiveness and impact for future programs.

Objectives: Hematologic and non-hematologic benefits from iron supplementation are chiefly seen in iron deficient individuals; concerns that iron might promote infection especially in non-iron deficient individuals have complicated global anemia control policies, particularly in malaria-endemic settings. Iron homeostasis, including intestinal absorption, is controlled by hepcidin. Hepcidin is regulated by iron, erythropoietic drive, and inflammation, suggesting its potential utility to appraise iron status and thus guide iron supplementation. Methods: In 1338 African pre-school children we evaluated the Area Under the ROC Curve (AUCROC) for plasma hepcidin concentration as a diagnostic test of iron status, anemia type and erythrocyte incorporation of oral iron, determining and modeling the effects of cutoffs. Results: Hepcidin detected iron deficiency with an AUCROC = 0.85 (optimal sensitivity/ specificity at a cutoff of 5.5 ng/ml); this was not significantly affected by gender, wasting, malaria or carriage of inherited red cell disorders. In anemic children, hepcidin distinguished iron deficiency anemia from anemia of inflammation (AUCROC=0.89, optimal sensitivity/specificity cutoff 5.4 ng/ml). Hepcidin was the best predictor for >20% incorporation into erythrocytes of orally-administered 57Fe (AUCROC=0.90, optimal sensitivity/ specificity cutoff P. falciparum and 86% of children with anemia of inflammation would have avoided iron. Conclusions: In African children, hepcidin ascertains iron status, distinguishes iron deficiency anemia from anemia of inflammation, and hence could guide iron supplementation toward groups in whom it will likely be beneficial and safe.