Drug repurposing for COVID-19: current evidence from randomized controlled adaptive platform trials and living systematic reviews.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic resulted in a race to develop effective treatments largely through drug repurposing via adaptive platform trials on a global scale. Drug repurposing trials have focused on potential antiviral therapies aimed at preventing viral replication, anti-inflammatory agents, antithrombotic agents and immune modulators through a number of adaptive platform trials. Living systematic reviews have also enabled evidence synthesis and network meta-analysis as clinical trial data emerge globally. SOURCES OF DATA: Recent published literature. AREAS OF AGREEMENT: Corticosteroids and immunomodulators that antagonize the interleukin-6 (IL-6) receptor have been shown to play a critical role in modulating inflammation and improving clinical outcomes in hospitalized patients. Inhaled budesonide reduces the time to recovery in older patients with mild-to-moderate COVID-19 managed in the community. AREAS OF CONTROVERSY: The clinical benefit of remdesivir remains controversial with conflicting evidence from different trials. Remdesivir led to a reduction in time to clinical recovery in the ACTT-1 trial. However, the World Health Organization SOLIDARITY and DISCOVERY trial did not find a significant benefit on 28-day mortality and clinical recovery. GROWING POINTS: Other treatments currently being investigated include antidiabetic drug empagliflozin, antimalarial drug artesunate, tyrosine kinase inhibitor imatinib, immunomodulatory drug infliximab, antiviral drug favipiravir, antiparasitic drug ivermectin and antidepressant drug fluvoxamine. AREAS TIMELY FOR DEVELOPING RESEARCH: The timing of therapeutic interventions based on postulated mechanisms of action and the selection of clinically meaningful primary end points remain important considerations in the design and implementation of COVID-19 therapeutic trials.

Host genetic factors determining COVID-19 susceptibility and severity.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) poses an unprecedented challenge to humanity. SARS-CoV-2 infections range from asymptomatic to severe courses of COVID-19 with acute respiratory distress syndrome (ARDS), multiorgan involvement and death. Risk factors for disease severity include older age, male sex, increased BMI and pre-existing comorbidities. Ethnicity is also relevant to COVID-19 susceptibility and severity. Host genetic predisposition to COVID-19 is now increasingly recognized and whole genome and candidate gene association studies regarding COVID-19 susceptibility have been performed. Several common and rare variants in genes related to inflammation or immune responses have been identified. We summarize research on COVID-19 host genetics and compile genetic variants associated with susceptibility to COVID-19 and disease severity. We discuss candidate genes that should be investigated further to understand such associations and provide insights relevant to pathogenesis, risk classification, therapy response, precision medicine, and drug repurposing.

IgG Seroconversion and Pathophysiology in Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.

Repurposing Antimalarials to Tackle the COVID-19 Pandemic.

Artemisinin-based combination therapies (ACTs) have demonstrated in vitro inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Artemisinins have also shown anti-inflammatory effects, including inhibition of interleukin-6 (IL-6) that plays a key role in the development of severe coronavirus disease 2019 (COVID-19). There is now sufficient evidence for the effectiveness of ACTs, and in particular artesunate/pyronaridine, to support clinical studies for COVID-19 infections.

Health-Related Quality of Life and Experiences of Sarcoma Patients during the COVID-19 Pandemic.

Sarcomas are rare cancers with a spectrum of clinical needs and outcomes. We investigated care experiences and health-related quality of life (HRQoL) in sarcoma patients during the COVID-19 pandemic. Patients with appointments during the first two months of the UK lockdown were invited to complete a survey. Questions included views on care modifications, COVID-19 worry and psychosocial impact, and EORTC-QLQ-C30 items. 350 patients completed the survey; median age 58 (16-92) years. Care modifications included telemedicine (74%) and postponement of appointments (34%), scans (34%) or treatment (10%). Most felt the quality of care was not affected (72%), however, social life (87%) and emotional wellbeing (41%) were affected. Worry about COVID-19 infection was moderately high (mean 5.8/10) and significantly related to higher cancer-related worry; associated with lower emotional functioning irrespective of treatment intent. Curative patients (44%) with low resilient coping scores had significantly higher COVID-19 worry. Patients who did not know their treatment intent (22%) had significantly higher COVID-19 worry and insomnia. In summary, care experiences were generally positive; however, cancer-related worry, low resilient coping and uncertainty about treatment intent were associated with COVID-19 worry. These patients may benefit from additional psychological support during the pandemic and beyond.