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Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections. This Review aims to support clinical decision-making by providing an overview of the evidence for immunotherapy strategies in patients with COVID-19.

Philanthro-capitalism: How charity became big business. The charitable sector is one of the fastest-growing industries in the global economy. Nearly half of the more than 85,000 private foundations in the United States have come into being since the year 2000. Just under 5,000 more were established in 2011 alone. This deluge of philanthropy has helped create a world where billionaires wield more power over education policy, global agriculture, and global health than ever before. Charities link the farmers in Africa to the boardrooms of corporate foundations and the corridors of the World Economic Forum at Davos. Far from being selfless, plutocratic philanthropy may be the ultimate profit-making tool. In this work, author and academic Linsey McGoey puts this new golden age of philanthropy under the microscope--paying particular attention to the Bill and Melinda Gates Foundation. As large charitable organizations replace governments as the providers of social welfare, their largesse becomes suspect. The businesses fronting the money often create the very economic instability and inequality the foundations are purported to solve. We are entering an age when the ideals of social justice are dependent on the strained rectitude and questionable generosity of the mega-rich.

In an open-label, randomized, noninferiority trial, dolutegravir-based antiretroviral therapy was compared with standard care in children and adolescents starting first- or second-line therapy for HIV type 1 infection. Dolutegravir-based ART was superior to standard-care ART.

AbstractObjectiveTo evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis.DesignInvestigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study.SettingTwenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018.ParticipantsPatients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein.InterventionsRandomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab.Main outcome measuresThe primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms.Results812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms.ConclusionsAll four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.Trial registrationEudraCT2011-004720-35, NCT01491815.

In a trial involving 1033 patients hospitalized with Covid-19, the addition of baricitinib to remdesivir was associated with shorter recovery time, particularly among patients receiving high-flow oxygen, and with a 30% higher odds of improvement at day 15 than remdesivir alone. Adverse events were less frequent with the combination therapy.

Abstract Rationale There are no studies on withdrawal of inhaled corticosteroids in patients on long-term triple therapy in the absence of frequent exacerbations. Objectives To evaluate the efficacy and safety of direct de-escalation from long-term triple therapy to indacaterol/glycopyrronium in nonfrequently exacerbating patients with chronic obstructive pulmonary disease (COPD). Methods This 26-week, randomized, double-blind, triple-dummy study assessed the direct change from long-term triple therapy to indacaterol/glycopyrronium (110/50 μg once daily) or continuation of triple therapy (tiotropium [18 μg] once daily plus combination of salmeterol/fluticasone propionate [50/500 μg] twice daily) in nonfrequently exacerbating patients with moderate-to-severe COPD. Primary endpoint was noninferiority on change from baseline in trough FEV1. Moderate or severe exacerbations were predefined secondary endpoints. Measurements and Main Results A total of 527 patients were randomized to indacaterol/glycopyrronium and 526 to triple therapy. Inhaled corticosteroids withdrawal led to a reduction in trough FEV1 of −26 ml (95% confidence interval, −53 to 1 ml) with confidence limits exceeding the noninferiority margin of −50 ml. The annualized rate of moderate or severe COPD exacerbations did not differ between treatments (rate ratio, 1.08; 95% confidence interval, 0.83 to 1.40). Patients with ≥300 blood eosinophils/μl at baseline presented greater lung function loss and higher exacerbation risk. Adverse events were similar in the two groups. Conclusions In patients with COPD without frequent exacerbations on long-term triple therapy, the direct de-escalation to indacaterol/glycopyrronium led to a small decrease in lung function, with no difference in exacerbations. The higher exacerbation risk in patients with ≥300 blood eosinophils/μl suggests that these patients are likely to benefit from triple therapy. Clinical trial registered with www.clinicaltrials.gov (NCT 02603393).