Objectives Dolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is now among the most frequently used antiretroviral agents. However, recent reports have raised concerns about potential neurotoxicity. MethodsWe performed a retrospective analysis of a cohort of HIV-infected patients who had initiated an INSTI in two large German out-patient clinics between 2007 and 2016. We compared discontinuation rates because of adverse events (AEs) within 2 years of starting treatment with dolutegravir, raltegravir or elvitegravir/cobicistat. We also evaluated factors associated with dolutegravir discontinuation. ResultsA total of 1950 INSTI-based therapies were initiated in 1704 patients eligible for analysis within the observation period. The estimated rates of any AE and of neuropsychiatric AEs leading to discontinuation within 12 months were 7.6% and 5.6%, respectively, for dolutegravir (n = 985), 7.6% and 0.7%, respectively, for elvitegravir (n = 287), and 3.3% and 1.9%, respectively, for raltegravir (n = 678). Neuropsychiatric AEs leading to dolutegravir discontinuation were observed more frequently in women [hazard ratio (HR) 2.64; 95% confidence interval (CI) 1.23-5.65; P = 0.012], in patients older than 60 years (HR: 2.86; 95% CI: 1.42-5.77; P = 0.003) and in human leucocyte antigen (HLA)-B*5701-negative patients who initiated abacavir at the same time (HR: 2.42; 95% CI: 1.38-4.24; P = 0.002). ConclusionsIn this large cohort, the rate of discontinuation of dolutegravir because of neuropsychiatric adverse events was significantly higher than for other INSTIs, at almost 6% within 12 months. Despite the limitations of this retrospective study, the almost three-fold higher discontinuation rates observed amongst women and older patients underscore the need for further investigation, especially in patient populations usually underrepresented in clinical trials.

A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD). In vitro data demonstrate that nintedanib inhibits several steps in the initiation and progression of lung fibrosis, including the release of pro-inflammatory and pro-fibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of extracellular matrix. Nintedanib also inhibits the proliferation of vascular cells. Studies in animal models with features of fibrosing ILDs such as IPF, SSc-ILD, rheumatoid arthritis-ILD, hypersensitivity pneumonitis and silicosis demonstrate that nintedanib has anti-fibrotic activity irrespective of the trigger for the lung pathology. This suggests that nintedanib inhibits fundamental processes in the pathogenesis of fibrosis. A trial of nintedanib in patients with progressive fibrosing ILDs other than IPF (INBUILD) will report results in 2019.

A proportion of patients with certain types of interstitial lung disease (ILD), including chronic hypersensitivity pneumonitis and ILDs associated with autoimmune diseases, develop a progressive fibrosing phenotype that shows similarities in clinical course to idiopathic pulmonary fibrosis. Irrespective of the clinical diagnosis, these progressive fibrosing ILDs show commonalities in the underlying pathogenetic mechanisms that drive a self-sustaining process of pulmonary fibrosis. The natural history of progressive fibrosing ILDs is characterized by decline in lung function, worsening of symptoms and health-related quality of life, and early mortality. Greater impairment in forced vital capacity or diffusion capacity of the lungs for carbon monoxide, and a greater extent of fibrotic changes on a computed tomography scan, are predictors of mortality in patients with fibrosing ILDs. However, the course of these diseases is heterogenous and cannot accurately be predicted for an individual patient. Data from ongoing clinical trials and patient registries will provide a better understanding of the clinical course and impact of progressive fibrosing ILDs.

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RationaleProgressive fibrosing interstitial lung disease (PF-ILD) is characterised by progressive physiologic, symptomatic, and/or radiographic worsening. The real-world prevalence and characteristics of PF-ILD remain uncertain.MethodsPatients were enrolled from the Canadian Registry for Pulmonary Fibrosis between 2015–2020. PF-ILD was defined as a relative forced vital capacity (FVC) decline ≥10%, death, lung transplantation, or any 2 of: relative FVC decline ≥5 and <10%, worsening respiratory symptoms, or worsening fibrosis on computed tomography of the chest, all within 24 months of diagnosis. Time-to-event analysis compared progression between key diagnostic subgroups. Characteristics associated with progression were determined by multivariable regression.ResultsOf 2746 patients with fibrotic ILD (mean age 65±12 years, 51% female), 1376 (50%) met PF-ILD criteria in the first 24 months of follow-up. PF-ILD occurred in 427 (59%) patients with idiopathic pulmonary fibrosis (IPF), 125 (58%) with fibrotic hypersensitivity pneumonitis (HP), 281 (51%) with unclassifiable ILD (U-ILD), and 402 (45%) with connective tissue disease-associated ILD (CTD-ILD). Compared to IPF, time to progression was similar in patients with HP (hazard ratio [HR] 0.96, 95% confidence interval, CI 0.79–1.17), but was delayed in patients with U-ILD (HR 0.82, 95% CI 0.71–0.96) and CTD-ILD (HR 0.65, 95% CI 0.56–0.74). Background treatment varied across diagnostic subtypes with 66% of IPF patients receiving antifibrotic therapy, while immunomodulatory therapy was utilised in 49%, 61%, and 37% of patients with CHP, CTD-ILD, and U-ILD respectively. Increasing age, male sex, gastroesophageal reflux disease, and lower baseline pulmonary function were independently associated with progression.InterpretationProgression is common in patients with fibrotic ILD, and is similarly prevalent in HP and IPF. Routinely collected variables help identify patients at risk for progression and may guide therapeutic strategies.

Idiopathic pulmonary fibrosis (IPF) is a complex disease of unknown aetiology, which makes drug development challenging. Single administration of bleomycin directly to the lungs of mice is a widely used experimental model for studying pulmonary fibrogenesis and evaluating the effect of therapeutic antifibrotic strategies. The model works by inducing an early inflammatory phase, which transitions into fibrosis after 5–7 days. This initial inflammation makes therapeutic timing crucial. To accurately assess antifibrotic efficacy, the intervention should inhibit fibrosis without impacting early inflammation.Studies published between 2008 and 2019 using the bleomycin model to investigate pulmonary fibrosis were retrieved from PubMed, and study characteristics were analysed. Intervention-based studies were classified as either preventative (starting <7 days after bleomycin installation) or therapeutic (>7 days). In addition, studies were cross-referenced with current major clinical trials to assess the availability of preclinical rationale.A total of 976 publications were evaluated. 726 investigated potential therapies, of which 443 (61.0%) were solely preventative, 166 (22.9%) were solely therapeutic and 105 (14.5%) were both. Of the 443 preventative studies, only 70 (15.8%) characterised inflammation during the model's early inflammatory phase. In the reported 145 IPF clinical trials investigating 93 compounds/combinations, only 25 (26.9%) interventions had any preclinical data on bleomycin available on PubMed.Since 2008, we observed a shift (from <5% to 37.4%) in the number of studies evaluating drugs in the therapeutic setting in the bleomycin model. While this shift is encouraging, further characterisation of early inflammation and appropriate preclinical therapeutic testing are still needed. This will facilitate fruitful drug development in IPF, and more therapeutic strategies for patients with this devastating disease.

one current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ecs) contribute to severe pulmonary arterial hypertension (pAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117 + ecs. Rat lung CD117 + ecs underwent four generations of clonal expansion to enrich hyperproliferative ecs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-β signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. these ec clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe pH. these primitive ec clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-β signaling. Pulmonary arterial hypertension (PAH) remains a devastating disease with dismal prognosis. The pulmonary arteries of PAH patients have lesions of varying severity including formation of neointima, which obstructs the normal blood flow, and complex multicellular plexiform lesions. A current concept suggests that dysregulated programmed cell death, or apoptosis of ECs causes unchecked proliferation of a subset of apoptosis-resistant ECs 1,2. The ECs retain a hyperproliferative and apoptosis-resistant phenotype even in culture 3. These abnormal ECs in the plexiform lesions of PAH patients may originate from primitive endothelial-like stem cells by clonal selection 4. This concept of primitive cells as source of aberrant ECs in PAH is supported by the findings of markers of primitive stem-like cells in the lung vascular lesions 5-7. Likewise, hyperproliferative pulmonary artery smooth muscle cells may also be derived from progenitor cells in PAH 8,9. During vascular development, primitive ECs

The primary analysis of the INBUILD trial showed that in subjects with progressive fibrosing interstitial lung diseases (ILDs), nintedanib slowed the decline in forced vital capacity (FVC) over 52 weeks. We report the effects of nintedanib on ILD progression over the whole trial.Subjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had ILD progression within the 24 months before screening despite management deemed appropriate in clinical practice, were randomised to receive nintedanib or placebo. Subjects continued on blinded randomised treatment until all subjects had completed the trial. Over the whole trial, mean (sd) exposure to trial medication was 15.6 (7.2) and 16.8 (5.8) months in the nintedanib and placebo groups, respectively.In the nintedanib (n=332) and placebo (n=331) groups, respectively, the proportions of subjects who had ILD progression (absolute decline in FVC ≥10% predicted) or died were 40.4% and 54.7% in the overall population (HR 0.66 [95% CI: 0.53, 0.83]; p=0.0003), and 43.7% and 55.8% among subjects with a usual interstitial pneumonia (UIP)-like fibrotic pattern on high-resolution computed tomography (HRCT) (HR 0.69 [0.53, 0.91]; p=0.009). In the nintedanib and placebo groups, respectively, the proportions who had an acute exacerbation of ILD or died were 13.9% and 19.6% in the overall population (HR 0.67 [95% CI: 0.46, 0.98]; p=0.04), and 15.0% and 22.8% among subjects with a UIP-like fibrotic pattern on HRCT (HR 0.62 [0.39, 0.97]; p=0.03).Based on data from the whole INBUILD trial, nintedanib reduced the risk of events indicating ILD progression.