COVID-19 Therapeutics: What to Give, What NOT to Give and Why (focus on resource-limited settings) May 28, 2021 Priya Nori, MD Montefiore Health System Albert Einstein College of Medicine Bronx, NY @MontefioreID • Recommendations synthesized from IDSA, NIH and other experts • These guidelines attempt to consider patients being managed at home, requiring oxygen, who should be admitted to the hospital in the best-case Background scenario • Will try my best to acknowledge multiple unique challenges of India • Bottom line slide included 5/28/21 | 3 UMichigan - COV-IND-19 Study Group Massive Challenges • Health infrastructure overwhelmed: shortage of life- saving hospital beds, oxygen, ventilators, and other equipment • 1.366B population, densely crowded cities • Dense air pollution, chronic lung disease and heightened COVID-19 risk • Low health literacy, misinformation, vaccine hesitancy • State media; silencing of opposing views • Low health expenditure despite universal healthcare • Challenges to lockdowns: wage economy, migrant workers • Inadequate testing and reporting of cases • Lack of coordinated response, messaging, treatment protocols • Lack of Antimicrobial Stewardship • Hoarding and price-gouging 5/28/21 | 4 Kumbh Festival, April 12, 2021 • India recorded 168K cases that day • Scientists already warned officials about B.1.617 variant in March • >9M in attendance from all over India • Although outdoors are much lower risk for SARS-CoV-2 transmission (current US policies are based on this fact); this image speaks for itself… 5/28/21 | 5 Source: BBC News 2nd wave started in late February 2021 w/ exponential growth from mid March – mid May 2021 5/28/21 | 6 • Lockdowns vary state- by-state, not mandated by central government of India • Similar to the US (up to states) 5/28/21 | 7 B.1.617 Variant Lineage • 1.617.1, 2, 3 • “Double mutant”: E484Q (related to E484K mutation which resists Ab therapies) and L452R (also found in CA variant, B.1.429) • First detected in India in October 2020 • Dominant virus in India; has emerged in the UK (>1300 cases), Israel, and at least 40 other countries, GISAID database (including NYC) • Most infected in the UK had 0-1 vaccine doses https://www.nature.com/articles/d41586-021-01390-4 https://www1.nyc.gov/assets/doh/downloads/pdf/covid/covid-19-data-variants-052521.pdf 5/28/21 | 8 Rapid Approvals of Investigational Treatments w/ Poor Data by Drug Controller General of India => Polypharmacy & Toxicities Status of Vaccinations in India • 2 primary vaccines: Covishield (ChAd-Ox1) and Covaxin (inactivated whole virion vaccine, Bharat Biotech) • May 16, 2021: Covaxin (BBV152) reportedly effective against strains found in India and the UK (study conducted w/ India Council of Medical Research. • 81% effective in phase 3 trials • "No difference in neutralization between B.1.1.7 (UK) and vaccine strain (D614G) was observed," • Russian Sputnik V approved in April 2021 for use in India (viral vector vaccine); distribution soon Vaccines and Variants • Bottom line: both doses needed for maximal protection against variants 5/28/21 | 11 G20 Countries Agree on Principles to End the Pandemic (w/ focus on vaccines) • “…no export bans, keeping global supply chains open, and working to extend capacity everywhere…” • Supported voluntary licensing and technology transfers but didn't reach a consensus on a pharmaceutical waiver of vaccine patent rights; first suggested By South Africa and India and supported By the US, But the World Trade Organization would need to negotiate the waiver, which could taKe months. • European Commission pledged to secure 1.3 billion vaccine doses for LMICs; includes 1 Billion from the 2 Billion doses announced By Pfizer-BioNTech, 200 million from Johnson & Johnson, and 100 million from Moderna. European officials pledged €1 Billion ($1.218 Billion) to Build vaccine production hubs in Africa. • Pfizer CEO pledged to provide 2 Billion doses to low- and middle-income countries over the next 18 months, according to CNN. • GAVI, the Vaccine Alliance, announced an advance purchase agreement with J&J for 200 million doses for the COVAX program for equitable access • https://podcasts.apple.com/us/podcast/epidemic-with-dr-celine- gounder/id1499394284?i=1000522486912 https://www.cidrap.umn.edu/news-perspective/2021/05/new-pledges-global-summit-target-covid-vaccine-gap 5/28/21 | 12 Treatment Overview • 2 primary phases and strategies: • Antivirals to block viral replication • Anti-inflammatories to limit immune damage occurring in reaction to the virus Ø Introducing steroids too early may delay viral clearance Viral Response Severity of Phase Illness Day 5-8 Time Course Remdesivir – worth it? • Broad-spectrum antiviral; available IV only; good safety profile but watch for hepatitis • ACTT-1 trial: double-blind, randomized, placebo-controlled trial of 1,059 patients; showed that remdesivir was: • Associated with a median time to recovery of 11 days versus 15 days with placebo (RR for recovery 1.32; 95% CI 1.12-1.55, P<0.001) • No mortality benefit • Benefit was highest in patients on oxygen but NOT requiring O2 via HFNC, NIV, mechanical ventilation or ECMO • 9/15/2020: IDSA guidelines ONLY recommend for hospitalized patients with a room air oxygen saturation < 95% Beigel JH et al. NEJM: 5/22/20; https://www.idsociety.org/covid-19-real-time- Slide courtesy of @Dr_MiKe_Stevens learning-networK/clinical-guidelines-and-guidance/clinical-practice-guidelines/ WHO SOLIDARITY trial: • Open-label study of 11,266 hospitalized adult patients with COVID-19 from 405 hospitals in 30 countries; multiple therapies • 2,743 received remdesivir compared to 2,708 controls in intent to treat analysis • No mortality difference between groups • No difference in terms of initiation of ventilation or duration of hospitalization WHO 2020. BMJ 11/19/20. Convalescent Plasma • Plasma containing antibodies from a person who recovered from COVID-19 • 2 RCTs have demonstrated no improvement in clinical status or mortality benefit • 1 RCT showed a reduction in progression to severe respiratory illness if given within 72 hours of symptom onset • 2/4/21 US FDA: only high titer units are authorized and should be used early (prior to respiratory failure requiring intubation and mechanical ventilation). • Convalescent plasma can be given to patients with impaired humoral immunity • 4/14/21: IDSA recommends not using convalescent plasma in hospitalized patients • 5/16/21 National COVID-19 CP Project investigators issued a letter to ICMR and AIIMS recommending high titer CP for patients with early disease not requiring hospitalization or O2; potential benefit especially in patients w/ humoral immune defects (https://ccpp19.org/) • Must be done very safely to avoid other transmissible diseases like malaria Agarwal A et al. BMJ, published 10/22/20; Simonovich VA et al. NEJM, published 11/24/20; https://www.idsociety.org/covid-19-real-time-learning-network/clinical- guidelines-and-guidance/clinical-practice-guidelines/. Libster et al NEJM, published 1/6/21. Inhaled Budesonide Inhaled steroid used for anti-inflammatory effects • Open-label phase 2 STOIC trial comparing inhaled budesonide vs usual care in adults within 7 days of onset of mild COVID-19 • Primary endpoint: composite of eR visits/hospitalization • 73 enrolled in each group • 11 (15%) in usual care group and 2 (3%) in budesonide group required urgent carte • Clinical recovery 1 day shorter in budesonide group (7 vs 8 days, p = 0.007) • Preprint of multicenter open label PRINCIPLe trial: outpatients within 14 days of symptom onset received inhaled budesonide • 4,663 patients; 751 received budesonide, 1,028 usual interventions, 643 “other” • Time to recovery median 3 days shorter in budesonide arm compared to usual care (HR 1.208, 95% CI 1.076-1.3560 • Interim analysis composite COVID-19 related hospitalizations or death 56/692 (8.5%) in budesonide group vs 100/968 (10.3%) in usual care group Ramakrishnan S et al. The Lancet Resp Med 2021. PRINCIPLE Collaborative Group medrxiv.org posted on April 12, 2021. Dexamethasone • RECOVERY trial: • 2,104 patients randomized to dexamethasone (6 mg po or IV once daily x 10 days) vs 4,321 randomized to usual care • Dexamethasone arm with 22.9% 28-day mortality versus 25.7% in usual care arm (RR 0.83, 95% CI: 0.75-0.93, p<0.001) • Maximum benefit in patients requiring mechanical ventilation > O2 supplementation only • There was no benefit in patients who were not requiring oxygen at the time of randomization • IDSA guidelines recommend dexamethasone for patients with a SpO2 of ≤ 94% on room air • 6 mg IV or po for 10 days or until discharge (whichever is earlier!) RECOVERY Collaborative Group. NEJM: 7/17/20; https://www.idsociety.org/Covid-19-real- time-learning-network/CliniCal-guidelines-and-guidanCe/CliniCal-praCtiCe-guidelines/ Tocilizumab • IL-6 inhibitor • UK’s RECOVERY trial: • April 23, 2020 and January 25, 2021, 2,022 patients were randomized to tocilizumab versus 2,094 to usual care; 82% of the patients were receiving steroids. • 596 (29%) of the tocilizumab group died within 28 days compared with 694 (33%) of the usual care group (RR 0.86, 95% CI 0.77-0.96, p = 0.007); the NNT to prevent one death is 25. • Patients not on mechanical ventilation (MV) at the time of trial enrollment: tocilizumab was associated with a reduced chance of progressing to MV or death (33% versus 38%, RR 0.85, 95% CI 0.78-0.93, p = 0.0005). • Tocilizumab still showed a mortality benefit in the subset of patients receiving corticosteroids (27% versus