COVID-19: A need for new rather than repurposed antiviral drugs. (preprint)

BackgroundSARS-CoV-2 infection, the causative agent of COVID-19, has resulted in over 2,500,000 deaths to date1. Although vaccines are becoming available, treatment options remain limited. Repurposing of compounds could reduce the time, cost, and risks associated with the development of new drugs and has been the focus of many clinical studies. Here, we summarise available evidence on 29 FDA-approved compounds, from in vitro results to clinical trials, focussing on remdesivir, galidesivir and favipiravir, and test 29 antiviral compounds activity in vitro. MethodsA comprehensive search strategy was used to retrieve trials and publications related to antiviral compounds with potential efficacy to treat coronaviruses. These data were used to prioritise testing of a panel of antiviral drugs in vitro against patient isolates of SARS-CoV-2. An in vitro screen was carried out to determine the activity of 29 FDA-approved compounds. Results625 clinical trials investigated 16 repurposed antiviral candidate compounds for the treatment of COVID-19. In vitro studies identified ten drug candidates with demonstrable anti-SARS-CoV-2 activity, including favipiravir, remdesivir, and galidesivir. To validate these findings, a drug screen was conducted using two cell lines and wildtype isolates of SARS-CoV-2 isolated from patients in the UK. While eight drugs with anti-SARS-CoV-2 activity were identified in vitro, activity in clinical trials has, as yet failed to demonstrate a strong effect on mortality. ConclusionsSo far, no repurposed antiviral has shown a strong effect on mortality in clinical studies. The urgent need for novel antivirals in this pandemic is clear, despite the costs and time associated with their development. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSRepurposing of existing compounds for the treatment of COVID-19 has been the focus of many in vitro studies and clinical trials, saving time, costs and risks associated with the research and development of new compounds. Added value of this studyWe reviewed the literature for 29 FDA-approved compounds with previously reported (or suspected) anti-SARS-CoV-2 activity and found 625 clinical trials that have been undertaken on 16 different drugs. We determined if repurposed antivirals are suitable for clinical trials based on previously published data, and conducted an additional in vitro screen using locally circulating strains in the UK (PHE2 and GLA1). We report the difference in IC50 from published data using Wuhan1/Wash1 strains with PHE2 and GLA1, including IC50 values below 100M for galidesivir in wild-type virus. Given the limited success of repurposed compounds in the treatment of COVID-19, we comment on the urgent need for new antivirals specifically targeting SARS-CoV-2. Implications of all the available evidenceOur data show that most prospective compounds for repurposing show no anti-SARS-CoV-2 activity, and antiviral activity in vitro does not always translate to clinical benefit. So far, no repurposed compound has shown a strong effect on mortality in clinical studies. Drugs, including monoclonal antibody therapies, that have been developed to target SARS-CoV-2 virus itself have shown most promise.

Quality of life and depressive symptoms among Peruvian university students during the COVID-19 pandemic (preprint)

ObjectivesCharacterize the quality of life and depressive symptoms of university students in Peru during the COVID-19 pandemic and to determine the associated factors. MethodsMulti-centre study in 1634 university students recruited by convenience sampling. Quality of life (QoL) was assessed with the European Quality of Life-5 Dimensions at three levels (EQ-5D-3L) and depressive symptoms with the Patient Health Questionarie-9 (PHQ-9). To evaluate factors associated with QoL and depressive symptoms, linear and adjusted regressions were used, with robust variance reporting coefficients ({beta}). ResultsThe percentage of participants most affected by QoL dimension was: anxiety/depression (47.2%) and pain/discomfort (35.6%). Regarding the Visual Analog Scale (EQ-VAS) of QoL, the score was 76.0 + 25.6. Those who had family economic decline during quarantine ({beta}=-3.4, IC95%=-6.5 to -0.3) or family with chronic diseases ({beta}=-3.7, IC95%=-6.1 to -1.4) presented significantly lower scores in their QoL. Regarding depressive symptomatology, the university students reported a moderate to severe level (28.9%). A higher risk of depressive symptoms was found in residents of Ayacucho ({beta}=0.8, IC95%=0.1 to 1.5), those who were released from quarantine ({beta}=0.7, IC95%=0.2 to 1.2) and those who had a family member with chronic disease ({beta}=1.5, IC95%=1.0 to 2.1). ConclusionsAlmost half and one third of participants reported anxiety/depression, and pain/discomfort in their QoL respectively. Nearly a third presented moderate and severe depressive symptoms. The deterioration of QoL was worse in those who had a decrease in income and a family member with chronic illness. The presence of depressive symptoms was found in students in Ayacucho, those who left home during quarantine and those who had a family member with chronic diseases.

Elevated temperature inhibits SARS-CoV-2 replication in respiratory epithelium independently of the induction of IFN-mediated innate immune defences (preprint)

The pandemic spread of SARS-CoV-2, the etiological agent of COVID-19, represents a significant and ongoing international health crisis. A key symptom of SARS-CoV-2 infection is the onset of fever, with a hyperthermic temperature range of 38 to 41{degrees}C. Fever is an evolutionarily conserved host response to microbial infection and inflammation that can influence the outcome of viral pathogenicity and regulation of host innate and adaptive immune responses. However, it remains to be determined what effect elevated temperature has on SARS-CoV-2 tropism and replication. Utilizing a 3D air-liquid interface (ALI) model that closely mimics the natural tissue physiology and cellular tropism of SARS-CoV-2 infection in the respiratory airway, we identify tissue temperature to play an important role in the regulation of SARS-CoV-2 infection. We show that temperature elevation induces wide-spread transcriptome changes that impact upon the regulation of multiple pathways, including epigenetic regulation and lncRNA expression, without disruption of general cellular transcription or the induction of interferon (IFN)-mediated antiviral immune defences. Respiratory tissue incubated at temperatures >37{degrees}C remained permissive to SARS-CoV-2 infection but severely restricted the initiation of viral transcription, leading to significantly reduced levels of intraepithelial viral RNA accumulation and apical shedding of infectious virus. To our knowledge, we present the first evidence that febrile temperatures associated with COVID-19 inhibit SARS-CoV-2 replication. Our data identify an important role for temperature elevation in the epithelial restriction of SARS-CoV-2 that occurs independently of the induction of canonical IFN-mediated antiviral immune defences and interferon-stimulated gene (ISG) expression.