Davey Smith, MD, MAS Professor of Medicine Chief, Division of Infectious Diseases and Global Public Health Co-Director, San Diego Center for AIDS Research (CFAR) Department of Medicine University of California, San Diego

1. HIV & Global Health Rounds
The UC San Diego AntiViral Research Center sponsors weekly
presentations by infectious disease and global public health clinicians,
physicians, and researchers. The goal of these presentations is to
provide the most current research, clinical practices, and trends in HIV,
HBV, HCV, TB, and other infectious diseases of global significance.
The slides from the HIV & Global Health Rounds presentation that you
are about to view are intended for the educational purposes of our
audience. They may not be used for other purposes without the
presenter’s express permission.

2. Davey Smith, MD
Chief of Infectious Diseases & Global Public Health
Professor of medicine
UC San Diego

3. Smith Disclosures
• Consultant for
• Bayer
• Arena Pharmaceuticals
• Nitto Pharmaceuticals
• Scientific Advisory Board
• Safe Aloha
• FluxErgy

4. Recent Epidemics

5. Where
are we?

6. State of the Epidemic
17 Oct 2020 https://coronavirus.jhu.edu/map.html

7. Natural history
Viral Load
ImmunomodulatorsAntivirals
Antivirals
No Symptoms Mild Moderate Severe
Courtesy of A. Chaillon

8. Natural history
Viral Load
ImmunomodulatorsAntivirals
Antivirals
No Symptoms Mild Moderate Severe
Courtesy of A. Chaillon

9. When to treat and what to use
Viral Load
ImmunomodulatorsAntivirals
Antivirals
No Symptoms Mild Moderate Severe
Courtesy of A. Chaillon

10. Need an Old Drug?

11. Clinical Microbiology and Infection 2020 26988-998DOI: (10.1016/j.cmi.2020.05.019)

12. Clinical Microbiology and Infection 2020 26988-998DOI: (10.1016/j.cmi.2020.05.019)

13. Hydroxychloroquine: in vitro and in vivo
Gautret P, et al. Int J Antimicrob Agents 2020Wang et al. Cell Research 2020
placebo
HCQ
HCQ+Azithro

14. Tragedy of Hydroxychloroquine

15. Something to
think about
https://www.palmerfoundation
.com.au/henry-ford-study-
treatment-with-
hydroxychloroquine-
azithromycin-and-
combination-in-patients-
hospitalized-with-covid-19/

16. Lessons
learned
Don’t fall into the trap: “Something must be
done, this is something, so this must be done.”
Do rigorous science.
Don’t politicize science.

17. Clinical Microbiology and Infection 2020 26988-998DOI: (10.1016/j.cmi.2020.05.019)

18. • Shorter time to recovery in the
remdesivir group vs placebo
• 11 vs 15 days
• Rate ratio for recovery 1.32, 95% CI,
1.13 to 1.55; p<0.001
• Outcomes similar for those with a
duration of symptoms at time of
randomization of < 10 days vs > 10
days
Beigel JH, et al. NEJM 2020

19. Repurposed antiviral drugs: SOLIDARITY trial
• Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon-β1a.
• 10 Endpoint: In-hospital mortality
• Eligibility:
• age ≥18 years,
• hospitalized with a diagnosis of COVID-19,
• not known to have received any study drug, without anticipated transfer elsewhere
within 72 hours, and,
• physician’s view, with no contra-indication to any study drug.
• Participants were randomized in equal proportions between control and
whichever other study drugs were locally available (up to 5 options: these
drugs, and local standard-of-care).
• Placebos were not used.

20. Repurposed antiviral drugs: SOLIDARITY trial
https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1.full.pdf

21. Negative Results
Mortality

22. EIDD 2801
• Orally bioavailable
ribonucleoside analog
• Activity against
various unrelated
RNA viruses influenza,
Ebola, CoV
Venezuelan equine
encephalitis virus
• Lethal mutagenesis
Sheahan et al. https://stm.sciencemag.org/content/12/541/eabb5883

23. Need a new Drug?

24. Clinical Microbiology and Infection 2020 26988-998DOI: (10.1016/j.cmi.2020.05.019)

25. 1st Nobel Prize: Diphtheria
Passive
Antibody
Infusion
Treated
Children
with
Diphtheria
https://medivizor.com/blog/2020/03/29/passive-
antibody-therapy-first-nobel-prize-medicine-

26. Convalescent
plasma

27. Emergent data from clinical trials incomplete
Trial terminated before it
reached its targeted original
sample size of 200 patients;
only 103 were enrolled.
 Thus the study was
underpowered.
Jiling Li et al. JAMA. June 3, 2020.
Convalescent plasma

28. August 23, 2020
Aug 23, 2020

29. Reminder
Don’t fall into the trap: “Something must be
done, this is something, so this must be done.”
Do rigorous science.
Don’t politicize science.

30. Monoclonal
antibodies
Developed from people
who caught the virus
Rogers et. al. Rapid isolation of potent SARS-CoV-2 neutralizing antibodies and protection in a small animal model. Science 2020

31. Monoclonal
antibodies
Purified and
expanded
Developed from people
who caught the virus
Turned into a
treatment

32. Monoclonal
antibodies
>25 Companies have
made MAbs that are in
various stages of clinical
testing
Purified and
expanded
Developed from people
who caught the virus
To then treat other
people with the virus
Turned into a
treatment

33. Cows: polyclonal antibodies
https://www.sciencemag.org/news/2020/06/cow-s-
antibodies-could-be-newest-weapon-against-covid-
19#

34. When to treat and what to use
Viral Load
ImmunomodulatorsAntivirals
Antivirals
No Symptoms Mild Moderate Severe
Courtesy of A. Chaillon

35. When to treat and what to use
Viral Load
ImmunomodulatorsAntivirals
Inflammation
Immunomodulators
No Symptoms Mild Moderate Severe
Courtesy of A. Chaillon

36. Clinical Microbiology and Infection 2020 26988-998DOI: (10.1016/j.cmi.2020.05.019)

37. Clinical Microbiology and Infection 2020 26988-998DOI: (10.1016/j.cmi.2020.05.019)

38. Steroids
https://jamanetwork.com/jo
urnals/jama/fullarticle/2770
278
• a 93% probability of benefit of a fixed-
duration dosing of hydrocortisone
• 80% probability of benefit of a shock-
dependent dosing of hydrocortisone.
• Stopped early did not meet the
prespecified statistical trigger for a
trial conclusion of superiority

39. DATE OF DOWNLOAD: 9/4/2020JAMA. Published online September 02, 2020. doi:10.1001/jama.2020.17023
Association Between Administration of Systemic Corticosteroids and
Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

40. Remdesivir + Baricitinib
• ACTT-2
• >1,000 patients
• Assess the efficacy and safety of a 4-mg dose of baricitinib
(JAK1/JAK2 inhibitor) plus remdesivir versus remdesivir in
hospitalized patients with COVID-19
• Improvement of 1 day reduction in median recovery time.

41. Potus Cocktail
• Regeneron monoclonal antibody cocktail
• Remdesivir
• Dexamethasone
• Zinc
• Vitamin D
• Famotidine
• Melatonin
• Aspirin
https://www.sciencemag.org/news/2020/10/heres-what-
known-about-president-donald-trump-s-covid-19-treatment
Freedberg et al. Gastroenterology. 2020
Sep;159(3).

42. Reminder
Don’t fall into the trap: “Something must be
done, this is something, so this must be done.”
Do rigorous science.
Don’t politicize science.

43. When to treat and what to use
Viral Load
ImmunomodulatorsAntivirals
Inflammation
Immunomodulators
No Symptoms Mild Moderate Severe
Courtesy of A. Chaillon

44. When to treat and what to use
Viral Load
ImmunomodulatorsAntivirals
Inflammation
Hyper-coagulable
Immunomodulators
Anticoagulants
Courtesy of A. Chaillon
No Symptoms Mild Moderate Severe

45. Anticoagulant
drug targets
• Low molecular
weight heparin
• Heparin
• Direct Oral
AntiCoagulants
(DOACs)
https://www.scielo.br/scielo.php?script=sci_arttext&pid=S0066-782X2020000600829&lng=en&nrm=iso&tlng=en

46. HIV

47. • Matched 21 HIV+/CoV+
patients with 42 HIV-/CoV+
patients
• HIV+/CoV+ patients had:
• trend toward increased rates of
ICU admission, mechanical
ventilation, and mortality for
HIV+/CoV+
• higher admission and peak
CRP
Karmen-Tuohy S et al. J Acquir
Immune Defic Syndr. 2020 Sep
Vizcarra P et al. Lancet HIV. 2020 Aug;7(8):e554-e564.

48. Summary
• Studies remain small and short
• PWH should receive the same treatment approach applied to the
general population.

49. Operation Warp
Speed
ACTIV-2
HOW DO WE GET
THERAPIES TESTED
AS QUICKLY AS
POSSIBLE?
every . day . counts

50. ACCELERATING
COVID-19
THERAPEUTIC
INTERVENTIONS
AND VACCINES
(ACTIV)
• April 17, 2020 the NIH started the ACTIV
“public-private partnership to develop a
coordinated research strategy for prioritizing
and speeding development of the most
promising treatments and vaccines”.
• ACTIV 1: Immunomodulatory
• ACTIV 2: Outpatients
• ACTIV 3: Inpatients
• ACTIV 4: Anticoagulants
• ACTIV 5: Inpatients combo stuff
https://www.nih.gov/research-training/medical-research-initiatives/activ

52. A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) and the Accelerating COVID-
19 Therapeutic Interventions and Vaccines (ACTIV) partnership
Adapt Out COVID
ACTIV-2 / A5401
Adaptive Platform Treatment Trial
for Outpatients with COVID-19
(Outpatient monoclonal antibodies
and other therapies)

53. Rapidly and efficiently
evaluate multiple
potential therapeutics for
COVID-19 in an outpatient
setting

54. Randomized, blinded,
controlled platform
that allows agents to
be added and
dropped during the
study

55. Randomized, blinded,
controlled platform
that allows agents to
be added and
dropped during the
study
Begins with phase II
followed by a larger
phase III for
promising agents

56. Randomized, blinded,
controlled platform
that allows agents to
be added and
dropped during the
study
Begins with phase II
followed by a larger
phase III for
promising agents
When two or more
new agents are being
tested concurrently,
the same placebo will
be used, if feasible

57. Prioritized based on:
• Activity against SARS CoV-2
entry or replication
• Phase I pharmacokinetic
and safety data
• Potential to expand to Phase
III if found effective

61. Phase II: 10 Objectives
Determine safety and efficacy of an agent to reduce
the duration of COVID-19 symptoms and
nasopharyngeal SARS-CoV-2 RNA detection through
28 days after study entry.

62. Virology: NP Swabs
• Proportion negative by ≥20%
• Decrease of ≥1 log10 copies/mL
• Reduction in median AUC
Symptoms: Diary
• Relative reduction of ≥20%
Oxygen saturation: Pulse ox
• Proportion oxygen saturation of >=96%
Other considerations:
• Safety
• Dynamics of virology and symptoms
• Viral rebound

63. Phase III: 10 Objectives
Determine if an agent will prevent either
hospitalization or death through 28 days after study
entry.

64. • Ambulatory Adult (≥18 years)
• Active CoV-2 infection ≤7 days prior
to Entry
• At least one COVID-19 symptom for
≤10 days prior to Entry, and at least
one symptom present <48 hours of
entry:
• Tailored per study agent
Sx start
CoV-2 Molecular Test +: < 7 days of study entry
At least 1 symptom still present: < 48 hours of study entry
Eligible Not
Days 0 1 2 3 4 5 6 7 8 9 10

65. • Higher risk of COVID-19 progression:
• Age ≥55 years
• Co-morbidities (HTN, CVD, DM, chronic kidney,
liver or lung disease, obesity (BMI >35)
• Time from symptom onset (≤ or >5 days)

66. • Subjective fever
• Cough
• Shortness of breath or
difficulty breathing at rest or
with activity
• Sore throat
• Body pain or muscle
pain/aches
• Fatigue
• Headache
• Chills
• Nasal obstruction or
congestion
• Nasal discharge
• Nausea
• Vomiting
• Diarrhea

67. Graduation
Based on
symptomatic,
oxygenation, or
virologic endpoints

68. Graduation
Based on
symptomatic,
oxygenation, or
virologic endpoints

69. Graduation
Based on
symptomatic,
oxygenation, or
virologic endpoints
Phase II participants
are evaluable for
Phase III for an agent
that graduates

71. 71
www.riseabovecovid.org

72. Protocol Chair:
Davey Smith, MD
Protocol Vice Chairs:
Rachel Bender, MD
Kara Chew, MD, MS
Eric Daar, MD
Teresa Evering, MD
William Fischer, MD
Babafemi Taiwo, MD
David Wohl, MD
DAIDS Clinical Representative:
Arzhang (Cyrus) Javan, MD
Clinical Trials Specialists:
Jhoanna Roa
Lara Hosey
Community Representative:
Jan Kosmyna, MIS, RN, CCRP
Investigators:
Judith Currier, MD, MSc
Joseph Eron, MD
Statisticians:
Michael Hughes, PhD
Carlee Moser, PhD
Justin Ritz, MS
Pharmacologist:
Courtney Fletcher, PharmD
Virologist:
Jonathan Li, MD
Immunologist:
Scott Sieg, PhD

73. Chasing the dragon: Global
https://coronavirus.jhu.edu/map.html

74. Chasing the dragon: Global
https://coronavirus.jhu.edu/map.html
Sites opening in Brazil, Chile,
Peru, South Africa, India, Thailand,
Kenya, Uganda, Australia,
Argentina, Canada, and
Philippines by the end of the
year

75. Hope
• Antibodies
• Convalescent plasma
• Polyclonal animal sera
• Monoclonal Abs
• Small Molecules
• Camostat
• EIDD 2801
• AT-527
• Fapiravir
• Apilimod
• Antithrombotics
• Unfractionated heparin
• Fractionated heparin
• DOACs
• Immunomodulatory
• Dexamethasone
• Glucocorticoids
• Leronlimab
• Combinations
• Remdesivir+Baricitinitib

76. Parting thoughts
• GOOD
• Science works
• We will likely have a treatment soon that
will help keep people with CoV-2 outside
of the hospital
• Could help with pandemic control
• BAD
• Politics is bad for science
• We are unlikely to have an inexpensive
widely available treatment any time soon

77. Acknowledgements
•Collaborators: Connie Benson, Antoine Chaillon,
Sara Gianella, Steven Hendrickx, Catriona Jamieson,
Susan Little, Sheldon Morris, Stephen Rawlings
•ACTIV-2 Team: Kara Chew, Eric Daar, David Wohl,
Judy Currier, Joe Eron, Javan Azhang, Peter Kim
•Slides: Kevan Akarami, Antoine Chaillon, Chip
Schooley, Lalo Cachay, Judy Currier

78. Thank you
https://www.npr.org/sections/pictureshow/2020/05/06/839406178
/life-interrupted-photos-of-brazil-under-lockdown