2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM

 
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
2020: The Year of the Respiratory
              Viruses
A Primer on Influenza and COVID-19

       Marilyn N. Bulloch PharmD, BCPS, FCCM
            Associate Clinical Professor and
            Director of Strategic Operations
             Harrison School of Pharmacy
                  Auburn University
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
Objectives
• Review the pathophysiology of influenza and COVID-19
• Compare and contrast symptoms of influenza and
  COVID-19
• Describe pharmacologic options for the treatment and
  prevention of influenza
• Identify treatment strategies for patients diagnosed
  with COVID-19
• Discuss pipeline agents being developed for the
  prevention and/or treatment of influenza and/or
  COVID-19
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
Disclosures
• Speaker’s Bureau - Xofluza (Baloxavir)
• Pharmacy Times – contributor
• PowerPak – author (sleep medicine)

 None of these disclosures will impact the
    content of my presentation today
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
Glenn Ridenour MD, Infectious Disease
              Specialist
      Charleston, West Virginia
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
A Brief History of Influenza

                             1st (Documented) Pandemic                                               Advance in Lab Research                       Reason for
                             Earlier pandemics                                                       • 1931 – discovery that influenza can         Pandemics
                             are likely, but were                                                      grow in eggs
                             not recognized or                                                       • 1932 – human influenza isolated             Identified
                             documented for                                                          • 1935 – 1st egg-based vaccine
                             historic purposes                                                         developed                                   Antigenic shift
                                                                                                                                                   studied

1173                     1580                         1700’s                           1930’s                      1940’s                    1950’s

Initial Recognition                                              Term “Influenza”                                              Growth of Knowledge
Influenza as a disease is                                        Coined                                                        • Vaccine given to U.S military
known to be at least 6,000                                                                                                       members during WWII
years old, but was first                                                                                                       • 1946 – discovery of antigenic drift
classified as a disease in
the 12th century

                http://www.medicalecology.org/diseases/influenza/influenza.htm#sect2.1 (Accessed 11 Mar 2015)
                Shope RE. Public Health Reports. 1958;73:165-179
                Potter CW. J Applied Microbiol. 2001;91:572-579
                Kilbourne ED. History of Vaccine Development.
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
How Influenza is
                    Named
          Antigenic Type

          •A, B, or C

          Host of Origin

          •I.E. Swine, Chicken, Equine, ect
          •No host of origin given if human origin

          City of Geographic Origin

          Strain Number

          •Unique

          Year of Isolation

          For Influenza A strains

          •Hemagglutinin and neuraminidase description in parentheses
          •I.E. H3N2

http://www.cdc.gov/flu/about/viruses/types.htm
Source: www.medicalecology.com
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
2019-20 Flu Season Burden

39-56 Million Influenza                                                              410,000-740,000    24,000-62,000 Deaths
                                     18-26 Million Medical Visits
       Illnesses                                                                     Hospitalizations

          https://www.cdc.gov/flu/about/burden/preliminary-in-season-estimates.htm
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
Source: Cruz D. How does the flu change over time? http://spotlight.vitals.com/2015/01/how-does-the-flu-change-over-time/ (Accessed 24 Mar 2015)
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
History of COVID-19

Photo courtesy of Creative Commons CCO: https://www.researchgate.net/figure/Timeline-showing-the-most-important-events-occurred-in-the-world-from-novel-
coronavirus_fig2_342840258
2020: The Year of the Respiratory Viruses A Primer on Influenza and COVID-19 - Marilyn N. Bulloch PharmD, BCPS, FCCM
Which is a symptom of COVID-19,
but not a symptom of Influenza?

 A.   Fever
 B.   Nausea
 C.   Body aches
 D.   Loss of smell
Symptoms of Influenza
                                                                            Symptoms vary WIDELY
                                           Headache                              by patient
                                           Fever (Usually high)
                                           Chills
                                                                            Patients may not have all or even
                                                Congestion or runny nose     most of the known symptoms

                                     Cough (usually non-productive)
                                     Sore throat

                                                                            Symptoms appear 1-4 days after
                                          Shortness of breath or
                                                                                     exposure
                                          difficulty breathing
                                                                              People are contagious ~ 1 day
                                      Fatigue                                   before symptoms appear
                                      Muscle or body aches
                                                                           Most contagious in first 3-4 days, but remain
                                                                             contagious ~ 7 days (up to 2 weeks in
                                                                               children and immunocompromised

                                                                             GI symptoms more common in
                                   Nausea
                                   Vomiting                                   children and with Influenza B
                                   Diarrhea
                                                                            Cough and fatigue may last > 2 weeks

                                Symptoms may have abrupt onset

https://www.cdc.gov/flu/symptoms/symptoms.htm
Symptoms of COVID-19
                                                                Symptoms vary WIDELY by
                   Headache                                            patient
                   Fever (may be low grade)
                   Chills                                 Patients may not have all or even most
                       Loss of smell                             of the known symptoms
                       Congestion or runny nose            Symptoms vary even among those in
                                                                   the same household
             Cough
             Loss of taste
             Sore throat
                                                           Symptoms appear 2-14 days after
                 Shortness of breath or                       exposure (average 5 days)
                 difficulty breathing
                                                            97.5% of people who develop symptoms
                                                           develop them within 11.5 days of exposure
             Fatigue
             Muscle or body aches
                                                         Symptom severity and duration vary widely
                                                                        by patient

                                                             People are contagious ~ 2 days before
            Nausea
                                                           symptoms appear and remain for 10 days
            Vomiting
            Diarrhea

      Some patients never exhibit any signs or symptoms

                   https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
                                                                             Luaer et al. Ann Intern Med. 2020
COVID-19 and Hypercoagulability

                                                                                                Proposed Pathophysiology                      Treatment
 Some patients         Laboratory Abnormalities                    Complications
   develop                                                                                                                                    • Inpatient DVT
                                                                   •   DVT/PE
                                                                                                   • Largely unknown at this time               prophylaxis
hypercoagulable         •   Thrombocytopenia (mild)                •   Microvascular clots in toes
                                                                                                   • May be due to inflammatory               • Unclear if treatment
     state              •   Increased D-dimer****                  •   Catheter clotting
                                                                                                     activation of coagulation                  dose anticoagulation
                        •   Increased ferritin and fibrinogen      •   STEMI
                                                                                                     pathway.                                   should be used.
                        •   Prolonged PT                           •   Large vessel stroke.

                  https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html#clinical-management-treatment%3C
                  https://www.covid19treatmentguidelines.nih.gov/adjunctive-therapy/antithrombotic-therapy/
Patients at High Risk of
                       Complications
                         Influenza                                                                                  COVID-19
                                                                   < 2 weeks post-
Age ≥ 65 years     Age < 2 years              Pregnancy
                                                                       partum                   Increaseing Age               Cancer             CKD

   Diabetes and other                                                Chronic lung
                                 Immunocompromised
   endocrine disorders                                                 disease
                                                                                                      COPD                Immunocompromised    BMI ≥ 30

                                                                      Hematologic
                  Heart Disease               Neurologic              Diseases (I.E.
   Asthma                                                              Sickle Cell
                   and Stroke                 Conditions
                                                                        Disease)                 Serious Heart
                                                                                                                         Sickle Cell Disease   Diabetes
                                                                                                    Disease
                                                                      Children on
Kideny Disease     Liver disease               BMI ≥ 40                long-term
                                                                       salicylates

            American
                              Alaskan Natives            LTC facilities
             Indians

                       https://www.cdc.gov/flu/highrisk/index.htm
                       https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html
Patients Who May Be at Increased
                   Risk for COVID-19 Complications
 Moderate-Severe            Cerebrovascular
                                                             Cystic Fibrosis                Hypertension         Immunocompromised
    Asthma                      Disease

  Steroid or other
                         Neurologic Conditions
immunosuppressive                                            Liver Disease                   Pregnancy            Pulmonary Fibrosis
                           (e.g. dementia)
    medications

                                                                                           Children with
                                                                                            congenital
     Smokers                   Thalassemia                  Type 1 Diabetes               cardiovascular,         Type A Blood Type
                                                                                       neurologic, genetic, or
                                                                                        metabolic conditions

                                                            More to come

               https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/evidence-table.html
Potential Complications of COVID-19

         Pneumonia
                                                Respiratory
           (often                                                           ARDS
                                                  failure
          bilateral)

                                              Cardic events
                                                                        Multiple-organ
               Sepsis                           (e.g. MI,
                                                                           failure
                                                 Stroke)

         Worseing of                                                      Secondary
          chronic                             Inflammation                 bacteria
          disease                                                         infections

https://www.cdc.gov/flu/symptoms/flu-vs-covid19.htm#anchor_1595599580
An ounce of prevention gives a glimmer of hope
Flu Vaccine Effectiveness
             Overall Influenza Vaccine                                                 Vaccine Effectiveness 2019-20
             Effectiveness 2010-2020                                                            Flu Season
80%                                                                           50%       39%                       37%                   42%       37%
60%                        48%              52% 49% 47% 60%                   40%                      33%                    35%
       39%         38% 40%                                                    30%
40%          29%                                                              20%
                                     19%
20%                                                                           10%
 0%                                                                            0%
                                                                                           All        6 mos-8    9-17     18-49        50-64 65 years
                                                                                                       years     years    years        years   and
                                                                                                                                              older

                    Vaccine Effectiveness for Circulating Strains 2019-20 Flu Season
      60%                44%                                                                                    45% 39%
                                               38%                   39%                                                                38% 42%
      40%          31%                                         29%                   28%
                                        22%
      20%                                                                                        4%
      0%
                      All            6 mos - 8 years           9-17 years            18-49 years                50-64 years         65 years and older
                                                                   H1N1       B/Victoria

                   https://www.cdc.gov/flu/vaccines-work/2019-2020.html
                   https://www.cdc.gov/flu/vaccines-work/effectiveness-studies.htm
Vaccine Prevented Burdens
                          2017-18 Flu Season                                                             2016-17 Flu Season
               Averted       Averted Medical      Averted         Averted                  Averted Flu     Averted Medical       Averted         Averted
Age Group                                                                    Age Group
              Flu Cases           Visits       Hospitalizations   Deaths                     Cases              Visits        Hospitalizations   Deaths

All           6,160,213         3,180,360          90,904          5,747     All           5,283,410          2,651,757           72,303          5,217

0-4 years     1,721,215         1,153,214          15,139           68       0-4 years      615,907           412,658              4,294           32

5-17 years    1,151,025         598,533             4,275          110       5-17 years    2,234,364          1,161,869            6,126           43

18-49 years   1,044,837         386,590             6,534          226       18-49 years    528,273           195,461              2,965           78

50-64 years   1,647,176         708,286            16,792          808       50-64 years   1,422,737          611,777             15,088          722

≥ 65 years    595,961           333,738            48,163          4,536     ≥ 65 years     482,130           269,993             43,830          4,341

                          2015-16 Flu Season                                                             2014-15 Flu Season
               Averted       Averted Medical      Averted         Averted                  Averted Flu     Averted Medical       Averted         Averted
Age Group                                                                    Age Group
              Flu Cases           Visits       Hospitalizations   Deaths                     Cases              Visits        Hospitalizations   Deaths

All           5,348,579         2,655,362          69,506          6,413     All           1,408,009          702,400             38,776          3,657
0-4 years     1,059,354         709,767             7,385           87       0-4 years      140,406            94,072               979            17

5-17 years    1,521,776         791,324             4,173           32       5-17 years     357,179           185,733               979            23

18-49 years   1,579,966         584,588             8,868          295       18-49 years    247,680            91,642              1,390           28

50-64 years   733,122           315,243             7,775          362       50-64 years    309,102           132,914              3,278          203

≥ 65 years    454,360           254,442            41,305          5,637     ≥ 65 years     353,641           198,039             32,149          3,386

                  https://www.cdc.gov/flu/vaccines-work/burden-averted.htm
2020-21 Influenza Vaccine
        Components
                     A/Guangdong-
                                                                                   A/Hawaii/70/2019(H1N1)
                Maonan/SWL1536/2019(H1
                                                                                       pdm09-like virus
                   N1)pdm09-like virus
                        A/Hong
                                                                                     A/Hong Kong/45/2019
                Kong/2671/2019(H3N2)-like
                                                                                       (H3N2)-like virus
                          virus

                   B/Washington/02/2019                                              B/Washington/02/2019
                (B/Victoria lineage)-like virus                                   (B/Victoria lineage)-like virus

                  B/Phuket/3073/2013-like                           Cell – or      B/Phuket/3073/2013-like
Egg-Based         (Yamagata lineage) virus                       Recombinant -     (Yamagata lineage) virus
 Vaccines                                                        Based Vaccines

        https://www.cdc.gov/flu/season/faq-flu-season-2020-2021.htm
CDC Recommendations on
  Immunization During COVID19
Patients should continue to receive recommended vaccinations

All essential workers need a flu vaccine

All patients at increased risk for severe COVID-19 need a flu vaccine

All patients at increased risk for influenza complications need a flu vaccine

Defer vaccination in patients with suspected or confirmed COVID19 until out of isolation

Screen all patients for COVID19 symptoms

Wear masks and use other precautions
   • Patient – cloth
   • Immunizer – medical (N-95 not required, even for intranasal vaccine because it is not aerosol-
     generating)
Immunizers in areas of high community transmission (e.g. Alabama) should wear eye protection

Safe distancing
   • Fill paperwork out electronically
   • Ask patients to wait away (e.g. in car) until ready
   • Set a specific time for immunizations

https://www.cdc.gov/vaccines/pandemic-guidance/index.html
Influenza Vaccine Types
             Inactivated Quadrivalent Standard Dose Vaccine
             •Grown in eggs – takes 9 months
             •Egg-adapted changes may induce difference between vaccine and circulating viruses
             •Intradermal IIV has 40% less antigen

             Live Attenuated Influenza Vaccine Quadrivalent
             •For ages 2-49 who are otherwise healthy
             •New H1N1 component since 2017 to address immunity
             •Lower IgG response than IIV but high serum IgA mucosal response
             •Viral shedding can occur for days after vaccination

             High Dose Quadrivalent Vaccine
             •For ages ≥ 65 years
             •Has 4 times standard antigen
             •24.2% more effective vs. IIV and shown to lower risk of hospitalization (esp in LTC patients)

             Adjuvant Quadrivalent Vaccine
             •For ages ≥ 65 years
             •Has MF59 – oil-in-water emulsion of squalene oil
             •Promotes immune response and reduces amount of virus needed to produce vaccine

             Recombinant Quadrivalent Vaccine
             •For ages ≥ 18 years
             •Uses DNA from influenza hemagglutinin that is combined with baculovirus and has 3 times more antigen
             •Production avoids egg-adapted mutations and is produced faster than egg-based vaccines (within 2 months)

             Cell-culture Quadrivalent Vaccine
             •For ages ≥ 4 years
             •Grown in cultured cells of mammalian origin
             •May offer better immunity vs. IIV – more like circulating flu strains

https://www.cdc.gov/flu/prevent/flushot.htm
Which antiviral   A. Zanamivir
only requires 1   B. Baloxavir
dose to treat
                  C. Oseltamivir
uncomplicated
influenza?        D. Peramivir
Influenza Antivirals
Oseltamivir

                                 Oral Capsule
                                   (75 mg)
                                                                                               Major ADRs                                           Pearls

                                                                                                                                                  Only generic flu
          Treatment                                         Prophylaxis                             Nausea/Vomiting
                                                                                                                                                     antiviral

                                                                                                                                                     Available as
        Twice daily X 5                                    Once daily x
                                                                                                       Skin reactions                               capsules and
            days                                            10 days                                                                                  suspension

                                                                                                    Psychiatric effects
                                                                                                                                                      Prodrug
FDA approved      CDC/AAP/IDSA               FDA approved              CDC/AAP/IDSA
                                                                                                       (transient)
 - ≥ 14 days        – Any age                  - ≥ 1 year               - ≥ 3 months

                                                                                                                                                  Drug of choice in
                                                                                                Bad taste (suspension)
                                                                                                                                                     pregnancy

                      Uyeki TM, et al. Clin Infect Dis. 2019;68(6):e1-e47
                      Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
                      Kawai N, et al. J Infect. 2008;56(1):51-57
                      Chairat K, et al. Brit J Clin Pharmacol. 2016;81(6):1103-1112
                      Dutkowski R, et al. Int J Antimicrob Agents. 2010;35(5):461-467.
Zanamivir

        Inhalation                                                          Major ADRS                            Contraindications          Pearls
      (2 inhalations)

                                                                                  Diarrhea

Treatment                  Prophylaxis                                       Bronchospasm                               Reactive lung
                                                                             Naseau (less vs.                             diseases/
                                                                              oseltamivir)                             bronchospasms
                                                                                                                                           Minimal/no
                                                                            Allergic reaction
                                                                                                                                          resistance in
Twice daily                  Once daily                                      Oropharyngeal/                                                  among
 X 5 days                    x 10 days                                        facial edema                                                  influenza
                                                                                 Headache
                                                                                                                                          strains in the
                                                                                                                                                US
                                                                                  Dizziness                             Allergy to milk
                                                                                                                            protein
≥ 7 years                     ≥5 years                                              Cough

                                                                            Nasal congestion

       Uyeki TM, et al. Clin Infect Dis. 2019;68(6):e1-e47;
       Heneghan CJ, et al. BMJ. 2014;348:g2547
       Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
Peramivir

                                 IV
                               Therapy

                                                                         Major ADRS                                             Pearls
                        15-30 minute infusion
                                                                                    Diarrhea                                Approved primarily
                                                                                                                              from studies of
                   Treatment only                                           Skin Reactions                                      Influenza A

                                                                                 Psychiatric                                  Reimbursed as
                      One dose                                                     effects                                  outpatient infusion
                                                                                 (transient)                                     therapy

Indicated for
    those
  ≥ 2 years

Uyeki TM, et al. Clin Infect Dis. 2019;68(6):e1-e47
Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
Endonuclease inhibitor – blocks influenza viral
                                                                      replication

Image reprinted from Noshi T, et al. Antiviral Res. 2018;160:115.
Baloxavir marboxil - Treatment
 Approved for treatment of
 uncomplicated influenza in                                     Only Oral “One and Done” Option
patients ≥ 12 years old – may
    change by flu season                                       40 to < 80 kg                                                    ≥ 80 kg
                                                            (88 lb to < 176 lbs)                                              (≥ 176 lbs)
 Dosage and Administration
      Two tablets = dose
 Tell patients to take at the                    TWO           20-mg                                           TWO            40-mg
            same time                                          Tablets                                                        Tablets
      -------------------------
   Take within 48 hours of
  influenza symptom onset
   --------------------------------
        Dose is based on
        patient’s weight

                                                             Pharmacists should ensure the right dose is selected

                 Compound summary baloxavir marboxil. National Center for Biotechnology Information website. pubchem.ncbi.nlm.nih.gov/compound/124081896.
                 Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
Baloxavir marboxil

                                                                                                                                          Pregnancy and
Major ADRs                               Interactions                                  Administration
                                                                                                                                          Breastfeeding

                                         Live influenza vaccine
    Diarrhea                                                                                                                                        Not studied in
                                                  Laxatives                                    Avoid taking with                                     pregnancy
     Nausea                                                                                          dairy
                                                   Antacids

                                                   Calcium
                                                                                                                                                No harmful effects
   Headache
                                                                                                                                                seen in rat studies
                                                      Iron

   Bronchitis                                   Magnesium
                                                                                            One dose = 2 tablets
                                                  Selenium                                                                                     Excreted into milk of
 Nasopharyngitis                                                                                                                                   lactating rats
                                                      Zinc

              Compound summary baloxavir marboxil. National Center for Biotechnology Information website. pubchem.ncbi.nlm.nih.gov/compound/124081896.
              Influenza antiviral medications: summary for clinicians. www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm.
Baloxavir marboxil Studies

                                                                                                                                     Baloxavir
                               Baloxavir                                                                                             marboxil
                                                                                                                                                           Placebo            P-value
   Median Time To                                         Placebo               P-value
                               marboxil
                                                                                            Median to symptom alleviation           73.2 hours          102.3 hours            24 hours
    median
                   difference 25.6
difference 38.6                                                                           Median duration of viral shedding        48 hours            96 hours
Baloxavir marboxil Studies
                 miniSTONE-2
                 • Otherwise healthy children ages 1-11 years
                 • Treatment of uncomplicated influenza within 48 hours of symptom onset
                 • Treatment groups – 5 day
                             •     Baloxavir – 1 dose then placebo
                                         •     < 20 kg = 2 mg/kg
                                         •     ≥ 20 kg – 40 mg
                             •     Oseltamivir BID per weight dosing for 5 days

ADRS occuring in > 1% of Patients                                                                          Baloxavir    Oseltamivir
                                                                                                            (n=80)        (n=43)
               Baloxavir                     Oseltamivir             Median time to symptom alleviation
                                                                                                          138.1 hours   150 hours
Vomiting       6.1%                          15.5%
                                                                                  Influenza A H3N2        126.9 hours   118.4 hours
Diarrhea       5.2%                          1.7%
                                                                                  Influenza A H1N1        115.8 hours   206.9 hours
Otitis media   2.6%                          6..9%
                                                                     Median fever duration                41.2 hours    46.8 hours
Ear pain       0.9%                          3.4%
                                                                     Median symptom duration              66.4 hours    67.9 hours
URTI           4.3%                          3.4%
                                                                     Median time to normal health         116.5 hours   111.6 hours
Rhinorrhea     3.5%                          1.7%                    Development of flu complication
                                                                                                             7.4%           7%
Cough          2.6%                          1.7%
                                                                     Median duration of viral shedding
Bronchitis     2.6%                          1.7%                                                         24.2 hours    75.8 hours

                                                                     Overall ADR incidence
                                                                                                            46.1%         53.4%

                 Baker et al. Pediatr Infect Dis J.2020;39:700-705
Baloxavir     Placebo       Adjusted Risk Ratio
                                                                (n=374)      (N=375)            (95% CI)
Lab confirmed influenza                                        7 (1.9%)     51 (13.6%)       0.14 (0.06-0.3)
  Negative PCR at baseline but contact with                     5/344        39/337
                                                                                            0.13 (0.05-0.31)
  PCR positive index patient                                    (1.5%)       (11.6%)
                                                                 3/71
  Patients < 12 years                                                      11/71 (15.5%)     0.27 (0.08-0.9)
                                                                (4.2%)
                                                                4/303        40/304
  Patients ≥ 12 years                                                                        0.1 (0.04-0.28)
                                                                (1.3%)       (13.2%)
                                                                 1/46
  Patients with high-risk factors                                          8/52 (15.4%)     0.13 (0.02-0.94)
                                                                (2.2%)
Lab confirmed influenza regardless of fever or                   49
                                                                            114 (30.4%)     0.43 (0.32-0.58)
symotoms                                                       (13.1%)
PCR confirmed illness                                          20 (5.3%)    84 (22.4%)      0.24 (0..15-0.38)

                Ikematsu et al. N Eng J Med.2020;383:309-320
Open-label study of 1,113 adults and children treated in 2006-07 Flu season for
                         uncomplicated Influenza A or B in the outpatient setting

     Duration of Fever
                             No Treatment Oseltamivir      Zanamivir    P-value
Fever Duration After 1st Dose
                                                                          Influenza A             Influenza B
                                                                                                                       P-value for Influenza
                                                              Patients                    Patients    Fever Duration          A vs. B
                                                                (n)                         (n)          (hours)
                      Oseltamivir                               472                         171           52.7
Oseltamivir             Peramivir      Statistic Evaluation
                                                               (n=365)                 (n= 362)
                                                                                                    Hazard ratio (97.5%CI)
Median Time to Symotom Alleviation                             81.8 hours              81 hours       0.97 (0.814-1.157)
                                                                                                           P-value
Patients afebrile 24 hours after 1st dose                     181 (49.7%)             209 (57.7%)          0.0326

Median Time to Normal Activity                                171.3 hours             195.5 hours           > 0.05
Patients developing flu-related
                                                                     10                   12                >0.05
complication
Patients virus-positive on day 2                                  82.1%                  68%               0.0038

Patients virus-positive on day 8                                   0.9%                  1.5%               >0.05

ADRs                                                                288                  293                >0.05

                Kohno S, et al. Antimicrob Agents Chemother. 2011;55(11):5267-5276.
Comparison of Oseltamivir vs.
                  Zanamivir for Household Contact
                  Prophylaxis
                                      Household                                            Oseltamivir +
                                                       Oseltamivir        Zanamivir                                        P-Value
                                       Contacts                                             Zanamivir

                                                                                                                     [Oseltamivir +    [Oseltamivir +
                                            N            n/total (%)      n/total (%)        n/total (%)   Overall   zanamivir\] vs.   zanamivir\] vs.
                                                                                                                       oseltamivir       zanamivir

                                                         23/161            25/164            10/141
All patients                              466                                                              0.0676          --                --
                                                          (14%)             (15%)             (7%)

Index Patients with 1st dose ≤                            14/81             14/95
                                          232                                               2/56 (4%)      0.0499       0.014              0.031
24 hours after symptom onset                              (17%)             (15%)

Index Patients with 1st dose ≤
                                                           9/80             11/69
24 hours after symptom onset              234                                               8/85 (9%)      0.4491          --                --
                                                          (11%)             (16%)

                 Carrat F, et al; BIVIR study group. Antivir Ther. 2012;17(6):1085-1090.
P-Value

                                                                        Oseltamivir +
                                      Oseltamivir          Zanamivir
                                                                         Zanamivir                      [Oseltamivir + [Oseltamivir +
                                       (n=176)              (n=173)                      Oseltamivir
                                                                          (n=192)                        zanamivir\] zanamivir\] vs.
                                                                                        vs. zanamivir
                                                                                                        vs. oseltamivir  zanamivir

Median Time to Symptom
                                            3                     4          3.5           >0.05            0.015           0.78
Alleviation (days)

Day 2 Influenza RT-PCR
                                         62.5%               40.5%         52.6%
Multi-center retrospective study of inpatients treated for Influenza A

                                                                  Oseltamivir       Baloxavir
                                                                                                    P-value
                                                                   (n=431)           (n=359)
                                                                                      224/273
    Patients with resolution of hypoxia [N/total (%)]             152/348 (75.6%)                    0.052
                                                                                       (82%)

    Median time from antiviral administration to
                                                                    71.95 hours     51.717 hours
Single-center, retrospective, observational study of inpatients treated for
                                     Influenza A

                                                                                    Peramivir
                                                                    Combination
                                                                                   monotherapy    P-value
                                                                      (n=431)
                                                                                     (n=359)

  Oxygen requirement on                                                             224/273
                                                                                                  0.082
  admission [N (%)]                                                      4 (40%)     (82%)
  Duration of symptoms prior to                                                     1.9 ± 1.7
                                                                    2 ± 2 days                    0.87
  treatment initiation ± SD                                                           days

  30 day mortality                                                         0        6 (4.5%)        1

                                                                                    2.7 ± 2.9
  Mean time to afebrile                                          2.1± 1.2 days                   0.3 days
                                                                                      days
Yoshimura et al. Eur J Infect Dis. 2020;doi:10.1007/s10096-020-03888-7
Multi-center observational study of 295 outpatients with Influenza A from 50
              Japanese clinics December 1, 2018 to April 30, 2019

Yoshii et al. Intern Med.2020;59:1509-1513
THERAPEUTICS FOR COVID-19

                   Virus Phase          Pulmonary            Severe Phase                                Viral replication                   Antiviral therapy
                                          Phase                                                            and spread
Illness Severity

                                                                                                                                                     Anti-inflammatory,
                                                             Inflammatory                      Increased                                             antithrombotic, and
                                                                                                                       Prothrombot
                                                               Response                   inflammatory state
                                                                                                                          ic state                   anticoagulation approaches
                                                                                           “Cytokine storm”

                                                                                                                                        Cell/organ protection
                                                                                                        Organ and tissue                therapies
                                Time Course of Illness                                                      damage

                                                                      Steroids
                                           Antivirals                                                                                       Organ
                                                                ?Anticoagulation?
                                           Steroids
                                                                  IL-6 Inhibitors                                                           support/replacement
                   Antivirals          ?Anticoagulation?                                                  Organ failure
                                                                  JAK Inhibitors
                                         Convalescent
                                                                  ?Famotidine?
                                            Plasma
                                                                  ?Complement
                                         ?Famotidine?
                                                                    inhibitors?

                                                                                                               Death

                                Adapted from https://rebelem.com/the-recovery-trial-dexamethasone-for-covid-19/                 Adapted Figure 1. Fernandez et al. J Clin Med. 2020;9:2030
Which of the following is recommended in
 the outpatient management of COVID-19

A.   Remdesivir
B.   Hydroxychloroquine
C.   Acetaminophen
D.   Losartan
Outpatient Treatment of COVID-19
• Minimal guidance
• Supportive care
    •   Fever – acetaminophen
    •   Antitussive
    •   Antiemetic
    •   Hydration
• Therapies in studies
 Remdesivir            Telmisartan       Aspirin       Tranexamic acid (UAB)
 Hydroxychloroquine    Imatinib          Rivaroxaban   N-acetylcysteine
 Lopinavir/ritonavir   Colchicine        Vitamin C     Convalescent plasma (UAB)
 Losartan              Interferon-beta   Zinc          Anti-spike (s) SARS-CoV-2
                                                       Monoclonal Antibodies

                                                                      NCT04342728   NCT04365582
                                                                      NCT04338074   NCT04476602
                                                                      NCT04501952   NCT04356495
                                                        NCT04373460   NCT04372628   NCT04324463
                                                        NCT04425629   NCT04419025   NCT04342169
Nucleoside analogue with
                                                               broad-spectrum antiviral activity
                                                           •    Causes pre-mature termination of
                                                                viral RNA transcription
                                                           •    Prodrug – thought to convert to                      For severe COVID-19
              Considerations in times                           active form 2 hours after infusion               •   Oxygen saturation < 94% on room air
                  of short supply
                                                                                                                 •   Supplemental oxygen
      •    Demonstrates most benefit in
                                                                                                                 •   Mechanical ventilation or ECMO
           patients on supplemental oxygen
           rather than mechanical ventilation
           or ECMO

                                                                Remdesivir
Long, complex manufacturing
          process
                                                                (Veklury®)                                             Dose
                                                                                                                       •   200 mg IV day 1 then 100 mg daily
  •       Takes 6-8 months
  •       Inhaled version in development

                                                                                              Duration
                                          Not studied in some
                                                                                              •    Supplemental oxygen – 5 days
                                              populations
                                                                                              •    Ventilator or ECMO – 10 days
                                    •   CrCl < 50 mL/min
                                    •   LFTs > 5 times ULN
                                    •   Pediatrics (studies ongoing)

                Bhimraj et al. IDSA COVID19 guidelines
                Ko WC et al. Int J Antimicrob Agents.2020;doi: 10.1016/j.ijantimicag.2020.105933
                Dong L et al. Drug Discov Ther.2020;14:58-60
Remdesivir Study Summaries
Study           Design                Population                     Groups               Results
Grein et al     Retrospective study   Inpatients with oxygen         200 mg day 1 then    • 36 (68%) patients had improvement in oxygen-
                on compassionate      saturation < 94% on room       100 mg daily for 9     support class
                use                   air                            days                 • 17 or 30 patients requiring ventilation at baseline
                                                                                            were extubated
                53 patients           57% on mechanical                                   • 25 (47%) patients discharged alive
                                      ventilation                                         • 7 (135) patients died
                                      8% on ECMO                                          • ADRs – LFT elevations, diarrhea, rash, kidney
                                                                                            dysfunction, hypotension
Goldman et      Open-label Phase 3    Inpatients with oxygen         Group 1 – 5 days     • Baseline status of patients in 10-day course worse
al.                                   saturation
Hydroxychloroquine

                                Old drug with known immunomodulatory effects – including IL-1 and IL-6

                            Known antiviral activity to other coronaviruses and in vitro activity vs. COVID-19
                            (exact antiviral mechanism unknown – may inhibit endocytosis and viral replication
                            and induce interferon response)

                            Can be safely used – but does have potentially problematic ADRs that need to be
                            monitored for (e.g. QTc prolongation, hypoglycemia)

                            Evidence-base is complicated and difficult to interpret
                            No consistent dosing in clinical trials
                            Conflicting evidence about efficacy

Bhimraj et al. IDSA COVID19 guidelines
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-3
Observational Evaluation of HCQ in
             Hospitalized COVID19 Patients in
             New York
▪ Observational study at New York
                                                                                                  Crude
  Presbyterian Hospital-Columbia University                                  HCQ     No HCQ       Hazard
                                                                                                            Propensity score
  Irving Medical Center                                                                                       Hazard Ratio
                                                                           (N=811)   (n=565)       Ratio
                                                                                                                (95%CI)
▪ March 7 to April 8, 2020                                                                       (95% CI)

▪ Did not enroll patients who were                                                                2.37
                                                              Death or       262
  intubated, died, or transferred within 24                   intubation   (32.3%)
                                                                                   84 (14.9%)    (1.84 –    0.98 (0.73-1.31)
  hours of presentation                                                                           3.02)
                                                                             157
▪ HCQ presented as an option for patients                     Death        (19.36%
                                                                                        75
  with oxygen saturations < 94% on room air                                          (13.27%)
                                                                               )
▪ Dose: 600 mg twice on Day 1 then 400 mg                     Intubated
                                                                             154
                                                                                     26 (4.6%)
  daily for 4 days                                                          (19%)

▪ 85.9% of those in HCQ group received it                     Intubated
                                                                           49 (6%)   17 (3%)
  within 48 hours of presentation                             then died
▪ Use of azithromycin was allowed
                                                              Discharged     552       473
                                                              alive         (68%)    (83.7%)

              Geleris et al. N Eng J Med 2020;382:2411-2418
HCQ for Post-COVID19 Exposure Prophylaxis
•   Household or occupational exposure to COVID-19
       • Distance < 6 feet for > 10 minutes)
       • Without appropriate PPE (eye shield, face mask)
•   Patients in U.S. and Canada
•   Dose
       • HCQ 800 mg x 1
       • HCQ 600 mg 6-8 hours later
       • HCQ 600 mg daily for 4 days
•   Did not meet power - Estimated needed 750 per group
•   Completion of regimen – poor adherence - HCQ (75.4%) vs. Placebo (82.6%); p=0.01
•   Symptom severity of those with symptoms at day 14 did not differ (p=0.34)
•   ADRs higher with HCQ (40.1% vs. 16.8%; p
HCQ ± Azithromycin in Mild-
                            Moderate COVID19
                                       Randomized controlled trial at 55 hospitals in Brazil
                    Adult inpatients with suspected or confirmed COVID-19 within 14 days of symptom onset
     Excluded if on oxygen > 4L/min or >40% by Ventury mask (or more aggressive oxygen requirements) or QTc >480 msec
                                                  Dose – 400 mg BID for 7 days

                                                   HCQ +                                                          Effect Estimate (95% CI)
                                                                   HCQ         Control
                                               Azithromycin
                                                                 (n=159)       (n=173)     [HCQ + A] vs. Control       HCQ vs. Control       [HCQ+A] vs. HCQ
                                                  (n=172)

Mean days free from respiratory support
                                                   11.1            11.2          11.1        0.1 (-0.7 to 0.9)        -0.2 (-1.1 to 0.6)      0.3 (-0.6 to 1.1)
within 15 days

Use of high-flow oxygen or non-invasive
                                                 16 (9.3%)      17 (10.7%)     16 (9.25)     1.1 (0.6 to 2.03)       1.19 (0.65 to 2.21)      0.92 (0.5 to 1.7)
ventilation within 15 days

Use of mechanical ventilation within 15 days     19 (11%)        12 (7.55)     12 (6.9%)    1.77 (0.81 to 3.87)       1.15 (0.49 to 2.7)     1.54 (0.71 to 3.35)

Hospital length of stay (days)                     10.3            9.6            9.5        0.9 (-0.3 to 2.1)          0.2 (-1 to 1.3)       0.7 (-0.6 to 1.9)
In-hospital mortality                            5 (2.9%)        7 (4.4%)      6 (3.5%)     0.64 (0.18 to 2.21)      1.47 (0.48 to 4.53)     0.43 (0.13 to 1.45)

Thromboembolic complications within 15
                                                 2 (1.2%)        3 (1.9%)      2 (1.2%)     0.89 (0.31 to 2.54)      1.39 (0.53 to 3.65)     0.64 (0.24 to 1.68)
days

AKI within 15 days                               6 (3.5%)        4 (2.5%)      5 (2.9%)     1.18 (0.44 to 3.2)       0.88 (0.29 to 2.63)     1.35 (0.47 to 3.84

                         Cavalcanti et al. N Eng J Med.2020;doi:10.1056/NEJMoa2019014
HCQ ± Azithromycin in Mild-
                        Moderate COVID19
                                                 HCQ +                                                          Effect Estimate (95% CI)
                                                                 HCQ         Control
                                             Azithromycin
                                                               (n=159)       (n=173)        [HCQ + A] vs.
                                                (n=172)                                                             HCQ vs. Control        [HCQ+A] vs. HCQ
                                                                                              Control

Median 7-level ordinal score at 15 days        1 (1 to 2)      1 (1 to 2)    1 (1 to 2)   0.99 (0.57 to 1.73)     1.21 (0.69 to 2.11)   0.82 (0.47 to 11.43)

    1. Not hospitalized/no limitations on                        102
                                              118 (68.6%)                   117 (67.6%)
    activities                                                 (64.2%)

    2. Not hospitalized/activities limited    22 (12.8%)       27 (17%)     29 (16.8%)

    3. Hospitalized/ no oxygen                 15 (8.7%)      12 (7.5%)      8 (4.6%)

    4. Hospitalized with oxygen                 5 (2.9%)       6 (3.8%)      5 (2.9%)

    5. Hospitalized with non-invasive
                                                   0           2 (1.3%)      2 (1.2%)
    ventilation or high-flow oxygen

    6. Hospitalized on mechanical
                                                9 (5.2%)       5 (3.1%)       7 (4%)
    ventilation

    7. Death                                    3 (1.7%)       5 (3.1%)      5 (20.9%)

                        Cavalcanti et al. N Eng J Med.2020;doi:10.1056/NEJMoa2019014
OTHER HCQ STUDIES

   Study                                 Hazard Ratio (95% CI)

   Ip et al.                             Adjusted HR 1.02 (0.83 to 1.27)

   Magagnoli et al                       Adjusted HR 0.99 (0.5 to 1.92)

   Mehevas et al.                        Weighted HR 1.2 (0.4 to 3.3)

   Rosenbert et al                       Adjusted HR 1.08 (0.63 to 1.85)

Bhimraj et al. IDSA COVID19 guidelines
HCQ + Azithromycin to Prevent
              Hospitalization or Death
              • Recently completed Phase IIB study
              • HCQ dose – 400 mg BID on day 1 and then 200 mg BID
                for 6 days
              • Stratification based on risk of progression to severe
                COVID-19
                 • High risk – age ≥ 60 years or ≥ 1 specified co-morbidity
              • Symptoms < 10 days
              • Results TBA

NCT04358068
Lopinavir/ritonavir

 Not recommended outside of clinical trial

 ADRs
  • Nausea, anorexia, diarrhea, abdominal discomfort,
    acute gastritis, skin reactions, hepatotoxicity,
    pancreatitis, QTc prolongation

 Many drug interactions
  • CYP3A4 inhibition

Bhimraj et al. IDSA COVID19 guidelines
Lopinavir-ritonavir in hospitalized adults
                         with severe COVID-19
                                          Lopinavir-ritonavir                Standard Care
                                                                                                         Difference (95% CI)                   ▪ Open-label randomized trial
                                                (n=99)                          (n=100)
                                                                                                                                               ▪ Conducted early in pandemic
 Time to clinical improvement                                                                              HR 1.31 (0.95 to
(median days)**§
                                              15 (13 to 17)                   16 (15 to 18)
                                                                                                                 1.8)
                                                                                                                                                 (January 18-February 3, 2020) in
                                                                                                                                                 Wuhan China
28 Day Mortality                                19 (19.2%)                       25 (25%)                   -5.8 (-17 to 5.7)
                                                                                                                                               ▪ Treatment Groups
Clinical improvement
                                                                                                                                                    ▪ Standard care
        Day 7                                           6 (6.1%)                   2 (2%)                   4.1 (-1.4 to 9.5)
                                                                                                                                                    ▪ Lopinavir/ritonavir (400
        Day 14                                        45 (45.5%)                 30 (30%)                  15.5 (2.2 to 28.8)                         mg/100 mg) po BID plus
        Day 28                                        78 (78.8%)                 70 (70%)                  8.8 (-3.3 to 20.9)                         standard care
                                                       14 (12 to                                                                               ▪ Standard care included
Hospital length of stay (days)                                                  16 (13-18)                      1 (0 to 2)
                                                          17)                                                                                    oxygenation, antibiotics, sepsis
ICU length of stay (days)                             6 (2 to 11)              11 (7 to 17)                    -5 (-9 to 0)                      treatment, dialysis, and
Mechanical ventilation
                                                                                                                                                 extracorporeal membrane
                                                       4 (3 to 7)                5 (3 to 9)                    -1 (-4 to 2)                      oxygenation as needed
(median days duration)
Oxygen support (days)                                12 (9 to 16)              13 (6 to 16)                     0 (-2 to 2)
Time to discharge (median                              12 (10 to
                                                                              14 (11 to 16)                     1 (0 to 3)
days)                                                     16)
Time to death (median days)                           9 (6 to 13)              12 (6 to 15)                    -3 (-6 to 2)
                   ** In the modified intention-to-treat analysis that excluded 3 patients with early death, the between-group difference for median time to clinical
                   improvement
                   (15 vs. 16 days) was significant)
                   § Approximately 14% of lopinavir-ritonavir group did not complete full 14-day course; this was primary due to gastrointestinal adverse effects

                                                                                                                                            Cao B et al. N Eng J Med.2020;doi:10.1056/NEJMoa2001282
Image source: https://emcrit.org/pulmcrit/recovery/
RECOVERY Trial
(Randomized Evaluation of Covid-19 Therapy)

    • Large international trial designed to evaluate effects
      of multiple potential COVID-19 treatments
    • Started in March 2020
    • Includes hospitalized adults with suspected or
      confirmed COVID-19 – pregnant and breastfeeding
      women were included
    • Excludes patients with medical histories that in the
      opinion of the physician would put the patients at
      “substantial risk” if they participated
    • Open label
    • Testing – low dose dexamethasone, azithromycin,
      tocilzumamb, convalescent plasma
    • June 2020 - ceased testing of HCQ and
      lopinavir/ritonavir due to lack of benefit
Horby et al. N Eng J Med.2020;doi:10.1056/NEJMoa2021436
https://www.recoverytrial.net/news
Recovery Trial: Dexamethasone

                                      Dexamethasone          Usual Care
                                                                                Rate Ratio          ▪ Dexamethasone 6 mg
                                                                                 (95% CI)
Mean age                              66.9 ± 15.4 years   65.8 ± 15.8 years
                                                                                                      until hospital discharge
Median days since symptom
                                         8 (5 to 13)         9 (5 to 13)
                                                                                                      or for up to 10 days
onset
Median days since hospital
                                                                                                    ▪ Dexamethasone chosen
                                         2 ( 1 to 5)          2 (1 to 5)
admission                                                                                             because it has the least
28-day mortality [n/total (%)         482/2104 (22.9%)
                                                             1,110/4,321
                                                               (25.7%)
                                                                              0.83 (0.75-0.93)
                                                                                 (p 7days) had a
                                      greater mortality benefit with dexamethasone
                                                                                                 Horby et al. N Eng J Med.2020;doi:10.1056/NEJMoa2021436
Use of Steroids
Hospitalized patients with                        • Dexamethasone 6 mg IV/po for up to 10 days
  severe COVID-19 on                              • Alternatives – methylprednisolone 32 mg or
          oxygen                                    prednisone 40 mg

 Patients with COVID-19
                                                  • Steroids are not recommended
  not requiring oxygen

                                                  • Steroids reduced viral clearance and resulted in
         Pearls                                     worse outcomes with SARs and MERS-Co-V
                                                  • May be required to treat ARDS
                                                  • Blood glucose
                                                  • Mental status
 Important Monitoring
                                                  • Adrenal suppression (hemodynamics)
                                                  • Secondary bacterial or fungal infections

         Bhimraj et al. IDSA COVID19 guidelines
Convalescent Plasma
• Emergency Investigational New                                   • Open-label multicenter RCT in Wuhan
  Drug application – March 24,                                      (n=103)
  2020                                                                     • Patients with severe disease
                                                                                   • Time to clinical improvement significantly
• Plasma from COVID-19                                                               shorter with convalescent plasma (13 vs.
                                                                                     19 days; p=0.03)
  survivors into patients                                                          • More patients clinically improved at day
                                                                                     14 [(14 (60.9%) vs. 6 (27.3%); p=0.02]
• Early study in 5 patients                                                        • Shorter time to discharge (13 days vs 19
                                                                                     days; p=0.05)
  showed significant                                                               • More virus negative patients at 72 hours
  improvement in clinical status                                                     [19 (90.5% vs. 7(41.2%); p=0.001]
                                                                           • All patients
                                                                                   • No difference in time to clinical
                                                                                     improvement, amount of clinical
                                                                                     improvement, length of stay, or 28-day
                                                                                     mortality in all patients
                                                                                   • Significantly more patients virus negative
                                                                                     at 24, 48, and 72 hours
                                                                           • Patients with life-threatening disease
                                                                                   • No difference in any outcome

          Li et al. JAMA.2020;324:460-470
          Shen C et al. JAMA.2020;doi:10.1001/jama.2020.4783
          Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-facilitate-
          development-treatments
Tocilizumab (Actemra)
• Disease-modifying anti-rheumatic drug (DMARD) normally used for rheumatoid arthritis and juvenile idiopathic
  arthritis
• Recombinant humanized monoclonal antibody specific for IL-6
• Pathophysiology in severe COVID-19 involves the “cytokine storm” – includes the release of interleukins-6 (IL-6) which
  signals other cells to activate the immune system
• Mechanism – blocks IL-6
• Dose – 4-8 mg/kg (max 800 mg dose) for 1-2 doses (separated by 12 hours)
• Potential indications
     • COVID-19 pneumonia, worsening pulmonary status, Ferritin > 600 mcg/mL, D-dimer > 1 mg/L and mechanical
         ventilation < 24 hours
• Interesting drug-interaction considerations
     • Does not inhibit CYP enzymes, but elevated IL-6 levels do – administering tocilizumab may affect drug
         metabolism by impacting inflammation

                                                                                                                                     Bhimraj et al. IDSA COVID19 guidelines
                                                                                                                     Guarald et al. Lancet Rheumatology.2020;2:E474-484
                                                                                                                                 Crisafulli et al. BioDrugs.2020;34:415-422
                                                  https://www.aphp.fr/contenu/tocilizumab-improves-significantly-clinical-outcomes-patients-moderate-or-severe-covid-19
Tocilizumab (Actemra)

CORIMUNO-TOCI Open label RCT

• 129 patients inpatients with moderate-severe COVID-19 pneumonia not requiring ICU care on
  admission
• Significantly fewer people in tocilizumab group had the composite outcome of need for ventilation
  or death at day 14

Retrospective study of 544 inpatients with severe COVID-19 pneumonia

• Significantly fewer deaths compared to stand care [13 (7%) vs. 73 (20%); p
Famotidine
  • Anecdotal reports from China suggested that patients on famotidine
    prior to COVID-19 infection had improved survival vs. those on PPIs
  • Potential mechanism of benefit still unclear – may bind and inhibit
    COVID-19’s main protease, 3C-like main protease, which processes
    proteins needed for viral replication
  • IDSA recommends against use just for COVID-19 outside of a clinical trial
  • Only one non-randomized study
           • Famotine (n=84) vs. No famotidine (n=1,536)
           • Decrease in composite outcome of death or intubation (HR 0.42; 95% CI 0.21 to
             0.85, p< 0.01)
  • Unpublished anecdotal case studies indicate benefit with 40 mg po TID in
    mild COVID-19
  • Adaptive trial currently recruiting in moderate-severe COVID-19
           • Famotidine IV 360 mg/day for up to 14 days vs. placebo
  • Could be used for stress ulcer prophylaxis in critically ill patients

Bhimraj et al. IDSA COVID19 guidelines
Freedberg et al. Gastroenterology.2020;doi:10.1053/j.gastro.2020.05.053
NCT04370262
The Vitamins and Supplements

 Vitamin C (Ascorbic Acid)                                                       Vitamin D                                                                     Zinc
• Antioxidant – may help with                                • Involved in immunity and                                              • Possible antiviral activity – may
  infection and inflammatory issues                            inflammatory response through                                           inhibit viral RNA polymerase
• Infection may decrease vitamin C in                          multiple pathways                                                       activity and viral replication in
  the body                                                   • No data in COVID-19                                                     COVID-19
• Dose – 1.5-3 grams IV Q 6 hours for                        • Inconsistent data about efficacy                                      • Involved in immunity – antibody
  up to 10 days                                                involving other infections                                              and WBC production, enzyme co-
  • 50 mg/kg IV Q hours for 4 days                           • Multiple guidelines state there is                                      factor, wound healing
    has also been used                                         insufficient evidence to recommend                                    • Dose 220 mg BID for 5 days
  • Oral doses of 1 gram for 7 days                            for or against use.                                                   • Retrospective study of inpatients
    and 4 grams BID are in studies                                                                                                     did not indicate any impact on
• No data in COVID-19 – studies                                                                                                        hospital/ICU length of stay, or
  underway                                                                                                                             duration of mechanical ventilation.
                                                                                                                                       Patients were discharged home
• NIH guidelines recommend use in
                                                                                                                                       more frequently and needed lower
  non-crucially ill patients and say
                                                                                                                                       level of care
  insufficient evidence to recommend
  for/against use in critically ill                                                                                                  • Long term use (> 10 months) may
                                                                                                                                       cause copper deficiency –
                                                                                                                                       hematologic and neurologic effects

                                                                                      Bauer et al. Cleve Clin J Med. 2020;doi:10.3949/ccjm.87a.ccc046
                   Li J. Crit Care.2018;22:258                                        Carlucci et al. Post-ed.2020;doi:10.1101/2020.05.02.20080036
                   Fowler et al. JAMA.2019;322:1261-1270                              Hemila et al. Cochran Database Syst Rev.2013;doi:10.1002/14651858.CD005532.pub3
                   Gruber-Bzura BM. Int J Mol Sci. 2018;doi:10.10.3390/ijms19082419   Marik et al. J Thorac Dis.2020;12:S84-S88
                   Aranow C. J Investig Med.2011;59:881-6                             Erol A. Doi:10.31219/osf.io/p7ex8
                   De Smet et al. MedRxiv.doi:10.1101/202005.01.20079376              Kashiouris et al. Nutrients.2020;12:piie292
What about NSAIDs?
Theory
 • ACE2 is the host cell surface receptor of the SARS-CoV-2 envelope spike protein – COVID-19 causes
   downregulation of ACE2 expression leading to excessive production of angiotensin II which causes
   increased vascular permeability and lung damage
 • NSAIDS (e.g. ibuprofen) upregulate ACE2 allowing COVID-19 more entry into human target cells and
   leading to a more severe infection

 Concern
 • May increase risk of contracting infection and/or cause severe disease

 History of complications in bacterial pneumonia
 • May impair recruitment of polymorphonuclear cells – results in delayed inflammatory response and
   resolution of infection
 • Causal relationship not established

 Study of 403 patients with COVID-19
 • Median age 45 years
 • No difference vs. acetaminophen in mortality or need for respiratory support

 Indomethacin
 • In vitro antiviral activity vs. COVID-19
 • No human studies
                                                                                                             Bhimraj et al. IDSA COVID19 guidelines
                                                                                                              Sridharan et al. Am J Thera.2020;0:1-3
                                                                            Rinott et al. Clin Microbiol Infect. 2020;doi:10.1016/j.cmi.2020.06.003
                                                                                           Sodhi et al. CHEST.2020;doi:10.1016/j.chest.2020.03.040
                                                                                                            Zu et al. doi:10.1101/2020.04.01.017624
Other Repurposed Potential
                   Therapies
     Favipiravir (Avigan)                                                          Colchicine                                                          Heparin
• Anti-influenza antiviral approved in                         • Anti-inflammatory - may be                                                  • Study of 2075 inpatients
  Japan and China                                                helpful in reducing cytokine                                                  associated with lower
• Blocks RNA-dependent RA                                        storm
  polymerase and SARS-Co-V-2 viral                                                                                                             mortality (p=0.003) (data
                                                               • Dose 1.5 mg LD then 0.5 mg in                                                 on route and dose
  replication phase                                              60 mg then 0.5 mg BID for up to
• Dose 1600 mg BID on day 1 then                                 3 weeks                                                                       unavailable)
  600 mg BID for 7-14 days total
                                                               • Study of 105 inpatients in
• ADR of concern – QTc prolongation
                                                                 Greece shown better clinical
• Max dose of APAP/day – 3 grams                                 outcomes (ventilation or death)
• Study of 240 patients with mild                                than standard care (1.8% vs.
  COVID-19 showed better recovery                                14%; p=0.02)
  at day 7 vs. umifenovir (71% vs.
  56%)                                                         • Retrospective review showed no
• Study in 150 patients showed 40%                               difference in protective effect on
  faster time to clinical cure and                               colchicine for RT-PCR (+) or (-)
  28.6% faster viral clearance
  (p
Potential Repurposed Drugs
Being Explored

 Lenzilumab    Losamapimod    Canakinumab    Nitric Oxide

                                Inhaled
  Anakinra      Baricitinib                  Interferons
                              prostacyclin

 Ruxolitinib    Siltuximab     Sirolimus     Ivermectin
Phase II Study in Adult Outpatients with COVID-19 and Symptoms < 5 days
                    Povidone-iodine              Essential oils          Tap water
                                                                                       Control (n=5)
                      gargle (n=5)               gargle (n=5)           gargle (n=5)
Viral clearance
                           5 (100%)                  4 (80%)               1 (20%)        0 (0%)
by day 6
Negative RT-PCR
                           5 (100%)                  4 (80%)               2 (40%)       1 (20%)
at day 12
Progression to
more severe
                             0 (0%)                   0 (0%)                0 (0%)        0 (0%)
disease by day
12

                          10 mL gargle for 30 seconds, three times a day for 7 days

           NCT 04410159
COVID-19 Vaccines
       U.S. government has pledged over $8.2 billion for the development and distribution of various
                                           vaccine candidates
          mRNA

          •Moderna and NIAID – mRNA-1273
           •Encodes pike protein for COVID-19 and uses messenger RNA to tell cells how to make protein to
            make antibodies
           •2 IM doses – 28 days apart
           •The COVE study underway
          •Pfizer developing similar vaccine

          Adenovirus

          •Uses virus that causes common cold with gene from COVID-19 integrated
          •1 IM Dose

          DNA

          •DNA plasmid with electroporation
          •2 intradermal or IM doses depending on vaccine

          Protein subunit

          •Recombinant or native-like trimeric subunit spike protein vaccine
          •1-2 IM doses depending on vaccine

          Inactivated

          •2 IM doses
O’Callaghan KP et al. JAMA.2020;324:437-438
WHO Draft Landscape of COVID-19 candidate vaccines. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
https://www.hhs.gov/about/news/2020/08/07/fact-sheet-explaining-operation-warp-speed.html
7-point Ordinal Scale

 Death                    07                      Not hospitalized,
                                        01        no limitations on
                    06                            activities

 Hospitalized                                02
 On invasive                                      Not hospitalized,
 mechanical         05
                                                  Limitations on activities
 ventilation or
 ECMO
                                     03
                               04
 Hospitalized                                     Hospitalized,
 On non-invasive                                  Not requiring
                         Hospitalized
 ventilation or                                   supplemental oxygen
                         Requiring supplemental
 high-flow oxygen        oxygen

                                                                 NCT04315948
SOLIDARITY Trial
International open-label, randomized adaptive trial

   Coordinated by the World Health Organization
   As of July 1, 2020 – 5,500 patients in 21 countries
   recruited
   Adults hospitalized with confirmed COVID-19                                       Multiple Treatment Groups
                                                                                            •   Remdesivir– ongoing
                                                                                            •   HCQ – stopped
                                                                                            •   Lopinavir/ritonavir - stopped
Primary Endpoint                                                                            •   Lopinavir/ritonavir with IFN-beta – ongoing
                                                                                            •   Standard of care alone. - ongoing
   All-cause hospital mortality at 3 weeks

                                                                                     Key Exclusion Criteria
                                                                                            •   Life expectancy < 3 months
                                                                                            •   LFTs > 5 times ULN
                                                                                            •   Acute co-morbidity within 7 days of screening
                                                                                            •   QTc > 450 ms
Expected Conclusion                                                                         •   Taking medication with known interaction with study
   November 2020                                                                                agents.

                      NCT04321616
                      https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-
                      for-covid-19-treatments
DisCoVeRy Trial
Multi-centered Phase 3, randomized adaptive trial

  European study similar to SOLIDARITY trail

  Adults hospitalized with confirmed COVID-19 and
  oxygen saturation < 94% on room air or requiring     Multiple Treatment Groups
  supplemental oxygen or ventilatory support
                                                            •   Remdesivir (10 days) – ongoing
                                                            •   HCQ – stopped
                                                            •   Lopinavir/ritonavir - stopped
Endpoints                                                   •   Lopinavir/ritonavir with IFN-beta – stopped
  Clinical status on 7-point ordinal scale at day 15        •   Standard of care alone. - ongoing
  Time to improvement
  Time to discharge
  Oxygen requirements                                  Key Exclusion Criteria
  Length of stay
  Mortality                                                 •   Life expectancy < 3 months
  Safety                                                    •   LFTs > 5 times ULN
                                                            •   CrCl < 30 mL/min or on dialysis
Expected Conclusion                                         •   Acute co-morbidity within 7 days of screening
                                                            •   QTc > 450 ms
  March 2023                                                •   Taking medication with known interaction with study
                                                                agents.

                        NCT04315948
REMAP-CAP
Multi-centered embedded randomized adaptive trial

  International study based in UK

                                                    Multiple Treatment Groups
                                                         •   Macrolides for immune function
                                                         •   Alternative steroid strategies
                                                         •   Antivirals
Endpoints                                                •   Immune modulation therapy
                                                         •   Convalescent plasma
  21-day ICU free days                                   •   Therapeutic anticoagulation
  WHO 8 point ordinal scale at day 15                    •   Vitamin C
  All cause mortality - ICU discharge, hospital
  discharge, day 90                                 Key Exclusion Criteria
  Hospital length of stay                                • > 24 hours since ICU admission
  Ventilator free days                                   • > 36 hours treatment with non-trial medications

Expected Conclusion
  Ongoing

                     www.remapcap.org
Other Large COVID-19 Studies

Accelerating COVID-19 Research and Development (ACCORD)

• UK Study of potential drugs
• If medications show promise – they are transitioned into larger studies (i.e.
  RECOVERY)
• Drugs – MEDI3506, zilucoplan, bemcentinib, acalabrutinib

PRINCIPLE Trial

• UK study evaluating potential treatments in patients 50 years and older
• Outpatient study
• Currently evaluating azithromycin and doxycycline

       Wise et al. BMJ.2020;370:m2670
There may or may not be an
         answer
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