COVID-19 TELE-EDUCATION SERIES FOR HEALTHCARE PROVIDERS IN LMICS
PROJECT ECHO ETIQUETTE v Foundation of love and respect (Respond kindly rather than react if you disagree) v It is everybody’s responsibility to keep ECHO a safe space v Test your equipment ahead of time (both audio and video) v Introduce yourself before speaking v Avoid making noise (i.e. potato chips, shuffling papers, whispering, cell phones, loud bags, etc.) v For questions during Q&A session use the chat box v Mute microphone when not speaking (Left bottom corner of your screen) v If you are to speak, speak remember to unmute before speaking and speak close to the microphone v Position webcam effectively to show your face if alone or to capture the whole group v Have a light source from the front (Avoid being backlit) v IT issues? Send a message through chat/email
COVID-19 TELE-EDUCATION SERIES FOR HEALTHCARE PROVIDERS IN LMICS What’s New in COVID-19? Treatment and Research Updates Yuri van der Heijden, MD, MPH Vanderbilt University Medical Center The Aurum Institute May 12 & 13, 2020
DISCLOSURES • I have no significant financial conflicts of interest to disclose • I receive support from the National Institutes of Health to Vanderbilt University Medical Center for research activities • Off-label therapies will be discussed but not recommended
LEARNING OBJECTIVES • General SARS-CoV-2 updates • Remdesivir • Treatment candidates • Additional research
GLOBAL PANDEMIC We Think We Know We Don’t Know 2 major types (L & S) Further evolution Epidemiology Sex differences Clinical significance Respiratory droplets Natural aerosols Transmission Lingers on surfaces Viability post-infection & type of specimen Immunity Antibodies are induced Relationship of antibody detection & risk of reinfection Tang X, et al. National Science Review. 3 March 2020 van Doremalen N, et al. NEJM. 16 April 2020 Wölfel R, et al. Nature. 1 April 2020 Wu F, et al. medRxiv (PREPRINT - NOT IN PEER-REVIEWED PUBLICATION). 20 April 2020
GLOBAL PANDEMIC Disruption to programs and service delivery • • Other infectious diseases • Non-communicable diseases • Disease prevention efforts • COVID-19 impact on tuberculosis - model • 3-month lockdown, 10-month restoration • Additional 6.3 million TB cases 2020-2025 • Additional 1.4 million TB deaths • Setback of 5-8 years in global TB fight https://informationisbeautiful.net/visualizations/covid-19-coronavirus-infographic- datapack/ http://www.stoptb.org/assets/documents/news/Modeling%20Report_1%20May%2 02020_FINAL.pdf
NO APPROVED SPECIFIC TREATMENT Don’t forget basics Public health messaging • Infection control & prevention in healthcare settings • Do not abandon principles of evidence-based care Example: ICU • Low tidal volume ventilation • Conservative fluid management after shock • Daily awakening & spontaneous breathing trials • Care bundles and checklists • Rice T, Janz D. Annals ATS. 22 April 2020
TREATMENT TARGETS Sanders J, et al. JAMA. 13 April 2020
Siddiqi H, et al. Journal Heart Lung Transplant. 20 March 2020
REMDESIVIR, GS-5734 • Prodrug, metabolized to adenosine nucleotide analogue • Inhibits viral RNA-dependent RNA polymerase • Efficacy against SARS-CoV-1, MERS-CoV, and Ebola virus in vitro & animal studies • Efficacy against SARS-CoV-2 in vitro Wang M, et al. Cell Research. 4 February 2020
REMDESIVIR • Randomized, double-blind, placebo-controlled, 10 hospitals in Hubei Province, China • 200mg IV day 1, 100mg daily days 2-10 • Outcome: time to clinical improvement • Symptom duration ≤ 10 days before remdesivir • HR 1.52 (0.95-2.43) • Stopped early (control of outbreak in Wuhan) • Pointed to need for larger studies Wang Y, et al. Lancet. 29 April 2020
REMDESIVIR • Gilead announcement 29 April 2020 • SIMPLE trial • Phase 3, open-label • Compared 5-day & 10-day dosing • Hospitalized, severe disease https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir- in-patients-with-severe-covid-19 (NOT IN PEER-REVIEWED PUBLICATION)
REMDESIVIR 29 April 2020 NIH NIAID press release • Interim analysis of Adaptive COVID-19 Treatment Trial (ACTT) sponsored by NIAID • Randomized, placebo-controlled trial, began February 21, 2020 • 1063 patients, 68 sites (47 U.S.; 21 countries in Europe & Asia) • Median time to recovery 11 days remdesivir vs 15 days placebo (p<0.001) • Mortality rate 8.0% remdesivir vs 11.6% placebo (p=0.059) https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19 (NOT IN PEER-REVIEWED PUBLICATION)
REMDESIVIR EUA FDA Emergency Use Authorization (EUA) 1 May 2020 • Treatment of suspected or lab confirmed COVID-19 • Adults and children hospitalized with severe disease (any of the following): • Oxygen saturation ≤ 94% on room air • Require supplemental oxygen • Require mechanical ventilation • Require extracorporeal menbrane oxygenation (ECMO) https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment https://www.fda.gov/media/137566/download
TREATMENT CONSIDERATIONS Caution in pregnancy (assess risk/benefit) • • Not recommended eGFR < 30 mL/min Caution with hepatic impairment • Aseptic technique in preparation • No preservative or bacteriostatic agent • • Lyophilized powder + sterile water + saline Store prepared solution • • Up to 4 hours 20ºC - 25ºC Up to 24 hours 2ºC - 8ºC • • Must review & provide “Fact Sheet for Patients and Parents/Caregivers” https://www.fda.gov/media/137566/download
REMDESIVIR ADVERSE EFFECTS • Infusion reaction (hypotension, nausea, vomiting, diaphoresis, shivering) • Liver enzyme elevation (Also noted in COVID-19 patients) • ↑ ALT observed in majority of healthy volunteers during clinical development • Check liver tests before starting & daily while receiving remdesivir • Do not start remdesivir if ALT ≥ 5 times upper limit of normal ( x ULN) • Stop if ALT ≥ 5 x ULN during treatment, may restart when ALT < 5 x ULN • Stop if ↑ ALT with signs/symptoms liver inflammation or ↑ bilirubin, alk phos, INR • Mandatory reporting of adverse events or medication errors https://www.fda.gov/media/137566/download
HYDROXYCHLOROQUINE & CHLOROQUINE • 4-aminoquinolines • Treatment of malaria, lupus, rheumatoid arthritis • Possible antiviral mechanisms • Alkalanize endosome & inhibit autophagosome-lysosome fusion • Inactivate enzymes needed for viral replication • Alter glycosylation of angiotensin converting enzyme-2 Ferner R, Aronson J. BMJ. 8 April 2020 Devaux C, et al. IJAA. 12 March 2020
HYDROXYCHLOROQUINE & CHLOROQUINE 28 March 2020 Reference Study Description Comment Gautret P . IJAA. Open-label, non-randomized clinical trial n=36, day 6 viral load • FDA Emergency Use 20 March 2020 hydroxychloroquine ± azithromycin reduction Authorization Borba M. JAMA. Phase IIb randomized clinical trial high vs n=81, higher dose group with 24 April 2020 low dose chloroquine (azithromycin for ↑ mortality & QTc interval 24 April 2020 all) – stopped at interval analysis prolongation • FDA cautions Geleris J. NEJM. Observational comparing n=1376, no difference against use 7 May 2020 hydroxychloroquine to none intubation or death https://www.fda.gov/media/136534/download https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or
HIV PROTEASE INHIBITORS Randomized, controlled, open-label trial • • Hospitalized, low oxygen • Lopinavir-ritonavir x 14 days vs standard care • Primary outcome • Time to clinical improvement HR 1.31; 95% CI 0.95,1.80 • • Letters to Editor: • Underpowered • Randomized late into course (13 days) Secondary signals • Cao B, et al. NEJM. 7 May 2020 https://www.nejm.org/doi/pdf/10.1056/NEJMc2008043?listPDF=true
• Patients randomized (2:1) to 14-day combination of 14-days • • lopinavir 400 mg / ritonavir 100 mg every 12 h vs lopinavir/ritonavir • ribavirin 400 mg every 12 h alone (n=41) • interferon beta-1b 8 million IUs, alternate days x 3 days (n=86) • Combination group shorter median time from treatment to negative NP swab • 7 days (IQR 5,11) vs 12 days (IQR 8,15); HR 4.37; 95% CI 1.86, 10.24; p=0.001 • Note that subgroup (n=34) of combination group omitted interferon beta-1b • Implications: Early treatment with triple antiviral may shorten duration of virus shedding, alleviate symptoms, and facilitate discharge of patients with mild to moderate COVID-19 Hung I, et al. Lancet. 8 May 2020
IMMUNE MODULATORS • May reduce cytokine impact (“cytokine storm”) triggered by viral infection • Interleukin (IL)-1, IL-6, TNF, interferon 𝛅 , and JAK inhibition proposed as potential targets • Anecdotal reports of use with good outcomes • Trials studying tocilizumab, sarilumab, siltuximab, baracitinib, and ruxolitinib all proposed or currently in trials • COLCORONA – colchicine phase 3, multi-center, randomized, double-blind, placebo-controlled trial Feldmann M, et al. Lancet. 2 May 2020 https://www.smartpatients.com/trials/NCT04322682
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