COVID-19 Therapeutics: What to Give, What NOT to Give and Why (Focus on Resource-Limited Settings)

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 33% in the placebo group, RR: 0.80, 95% CI: 0.70-0.90).

RECOVERY investigators. https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1.full.pdf Baricitinib

• Oral selective Janus kinase 1 & 2 inhibitor with improved outcomes in patients with severe COVID- 19 when combined with remdesivir (ACTT-2 RCT, improved clinical recovery and trend towards mortality benefit) • Combination recommended when corticosteroids are contraindicated: • Both anti-inflammatory and potential antiviral activity • Additional benefit beyond standard corticosteroid use? • Unclear benefit in those already requiring mechanical ventilation in ACTT-2 • COV-BARRIER: 38% relative reduction in mortality and similar safety profile in a phase 3 RCT of baricitinib +SOC (79% on steroids) vs. SOC + placebo (https://www.medrxiv.org/content/10.1101/2021.04.30.21255934v1) • Bottom line as of May 2021: We do not use it much in NYC due to cost and since most can tolerate steroids; awaiting COV-BARRIER publication and update of IDSA/NIH guidelines (if any)

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/

Outpatient Therapeutics: Casirivimab + Imdevimab (Monoclonal Abs) • Recombinant neutralizing human monoclonal antibodies against spike protein of SARS-CoV-2 • Interim analysis of a double-blind, phase 1-3 trial involving 275 outpatients with COVID-19 showed a significant reduction in viral load through day 7 (-0.41 log10 copies per ml, 95% CI -0.71 to -0.10 • A press release from the Phase 3 R10933-10987-COV-2067 study: • COVID-19 related hospitalizations or death from any cause occurred in 18/1,355 casirivimab/imdevimab (1.3%) participants versus 62/1,341 (4.6%) in the placebo arm (P < 0.0001) • In the treatment arm there was one death (vs 5 in the placebo arm). https://www.idsociety.org/covid-19-real-time-learning- network/clinical-guidelines-and-guidance/clinical-practice- guidelines/; NIH COVID-19 Treatment Guidelines; Weinreich DM et al. NEJM, published 12/17/2020. Casirivimab + Imdevimab & Variants

B.1.617 variant contains E484Q and L452R, potentially P614R

https://www.regeneron.com/downloads/treatment-covid19- eua-fact-sheet-for-hcp.pdf • Hydroxychloroquine/chloroquine (+/- azithromycin, +/- zinc) • 6/15/2020: FDA EUA revoked • 5 RCTs + several large cohort studies have shown HCQ without benefit • HIV meds (darunavir/cobicistat OR lopinavir/ritonavir) What NOT to • Oseltamivir, Baloxavir marboxil, Fluvoxamine • Ribavirin, interferon Give • Ivermectin Slide courtesy of @Dr_Mike_Stevens • 2-DG • Famotidine • Colchicine

https://www.idsociety.org/covid-19-real-time-learning-network/clinical- guidelines-and-guidance/clinical-practice-guidelines Why Not Ivermectin?

IDSA & NIH Guideline Panels state that there is currently no high-quality evidence for inpatient/outpatient COVD-19 treatment or post-exposure prophylaxis

In doses used for the treatment of parasitic infections, ivermectin is well-tolerated

Ivermectin does have some in vitro activity against SARS-CoV-2, but concentrations needed to obtain the in vitro IC50 are considerably higher than those achieved in human plasma and lung tissue

Ø“We are unable to exclude the potential for adverse events among hospitalized and non-hospitalized persons with COVID-19 treated with ivermectin rather than no ivermectin” Well-designed, adequately powered, and well-executed clinical trials are needed to inform decisions on treating COVID-19 with ivermectin

https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment- and-management/ https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/ 2-deoxy-d-glucose (2-DG) - hype & desperation

• Approved by Drug Controller General of India for emergency use for moderate to severe COVID-19 • DCGI has track record of emergency approvals based on poor evidence • Based on computer simulations and in-vitro studies from Ministry of Defense showing inhibition of viral growth • Poorly designed trials in process with lack of transparency by Clinical Trial Registry of India (CRTI) • Potential waste of resources • Act of desperation (just like approval of HCQ, ivermectin, and many others)

https://science.thewire.in/the-sciences/dcgi-drdo-2-dg-covid-19-treatment-phase-2-3-trials- shoddy-evidence/ COVID-19 and Bacterial/Fungal Co-infections

ONLY 7% of all hospitalized patients (3.5% at presentation, 15.5% later), ONLY 14% of critically ill patients TAARN www.tarrn.org/COVID

Living rapid review and meta-analysis, 30 studies Updates every 3 months Received

1308 studies screened antibiotics 24 studies eligible >3300 patients 72%

Slide courtesy of Dr. Neil Clancy @ClancyNeil Co-infections: NYC Findings

• Nori et al. ICHE 2020: retrospective study of 5,853 COVID-19 patients admitted to Montefiore from March 1-May 31, 2020, 4130 (71%) received at least one antibiotic dose. • Less than 5% had a bacterial or fungal coinfection. • 56-95% Intubated • Median WBC count 11-30k/uL • Median CRP 19-32mg/dL • 17% received biologics (e.g., tocilizumab) • 29% received corticosteroids

5/28/21 | 28 blaNDM Co-Infection in Community COVID-19 Patients C. albicans (peritoneal fluid and urine - catheter) MSSA MRSA (resp) (resp) S. capitis (blood) C. albicans, E. faecalis, CR E. cloacae CR E. cloacae & MRSA (resp) S. epi (blood) C. koseri (resp) (urine - catheter) CR E. cloacae (blood) CR E. cloacae & MRSA, S. marcescens C. albicans (blood) CR E. cloacae, P. aeruginosa (resp) Micro E. aerogenes x 2* (blood) (resp) C. albicans (blood) CR E. cloacae (respiratory) CR E. cloacae (urine – catheter) CR E. cloacae (Resp) CR E. cloacae & CR K. pneumoniae (blood) CR E. cloacae (resp) CR E. cloacae (blood) CR E. cloacae & VRE (urine – E. cloacae (blood) catheter) CR K. pneumoniae** (blood) Prolonged Intubation & Y Y Y Y Y Invasive Catheters Ceftriaxone Ceftriaxone Azithromycin Ceftriaxone Doxycycline Doxycycline Ceftriaxone Vancomycin Azithromycin Piperacillin-tazobactam Preceding Ampicillin Vancomycin Piperacillin-tazobactam Vancomycin Vancomycin Micafungin Piperacillin-tazobactam Cefepime Cefepime Cefoxitin antibiotics Fluconazole Gentamicin Micafungin Piperacillin-tazobactam Linezolid Piperacillin-tazobactam Fluconazole Tigecycline*** Tigecycline*** Gentamicin Tigecycline*** Tigecycline*** + Gentamicin Ceftazidime-Avibactam Aztreonam Treatment Ceftazidime-Avibactam Aztreonam Aztreonam Ceftazidime-Avibactam

Nori et al. Emerging Co-Pathogens: New Delhi Metallo-beta-lactamase producing Enterobacterales Infections in New York City COVID-19 Patients. J Antimicrob Agents. 2020 Sep 25:106179. doi: 10.1016/j.ijantimicag.2020.106179. Online ahead of print.PMID: 32987104 5/28/21 | 29 • CNS, pulmonary, ocular, sinus infections • Spores are common in moist environment, can contaminate respiratory equipment Mucormycosis • Hyperglycemia is the #1 risk factor • Immunosuppression & hyperglycemia from prolonged, high dose steroids (black fungus) • 20-50% mortality • Needs aggressive surgical debridement and 2-3 antifungal agents • Amphotericin is expensive, in high-demand, and toxic Bottom Line @ Bacterial & Fungal Co-infections

Who gets co-infections and when? • ICU, prolonged intubation, organ failure, central venous catheters • At least several days into hospital admission, not at presentation from the community Bottom line: routine antibiotic use for hospitalized COVID-19 patients is NOT RECOMMENDED • Not recommended for patients outside the hospital and most hospitalized patients • Should NOT be routine part of protocols • NO anti-inflammatory properties • Prophylactic antibiotics and antifungals NOT recommended • ANTIMICROBIAL RESISTANCE ALREADY OUT OF CONTROL IN INDIA!

Source: CDDEP.org So, what treatments should we give? Agent Give it? Monoclonal antibodies If you can get it, give it early, ONLY combination therapy; $$$S

Remdesivir Hard to obtain, low benefit, don’t bother; $$$S

Tocilizimab Hard to obtain, give it in early critically ill patients with high O2 requirement (watch out for co-infections); $$$S

Bottom Dexamethasone Yes, but only per protocol! High O2 requirement, ONLY for 10 days, not Line for for outpatients without O2 needs; MUST control hyperglycemia; $ #COVID INDIA Inhaled Corticosteroids Early promise for outpatient treatment in clinical trials; would prefer this over system steroids for outpatients; await further clinical trial data Crisis and IDSA/NIH updates, $ HQC, Ivermectin, Colchicine NOT RECOMMENDED, NO EVIDENCE Antibiotics (e.g, doxycycline, azithromycin) ONLY give to critically ill inpatients WHEN you suspect & find a co- & Antifungals infection (not for prophylaxis); $-$$$ (amphotericin $$$)

Anticoagulation Yes, for hospitalized patients, $$ Baricitinib Benefit for moderate to severe COVID-19 with remdesivir (when cant give steroids), pre-print RCT with impressive mortality benefit w/ corticosteroids, $$$ Tamil Nadu State Protocol….almost there! Finally! Evidence-based recommendations specifically for India (severely stressed healthcare system)

https://covidindiatreatment.com/clinical-management/ Recommended Sources https://www.idsociety.org/covid-19-real-time- learning-network/ https://www.indiacovidsos.org/home-care Priya Sampathkumar, MD (Mayo Clinic) @PSampathkumarMD

Experts to follow Madhu Pai, MD, PhD (McGill) on Twitter for the @paimadhu most reliable, evidence-based Mike Stevens @Dr_Mike_Stevens information Krutika Kuppalli, MD, (IDSA) @KrutikaKuppalli