Stanford COVID-19 Journal Club

May 20, 2020
Student presenter: Maria Filsinger Interrante, MSTP Entering Class of 2016
Faculty moderator: Peter Kim, PhD, Virginia and D.K. Ludwig Professor of Biochemistry
Paper: Amanat, Fatima and Krammer, Florian. "SARS-CoV-2 vaccines: status report." Immunity (2020).
Graphical Guide to SARS-CoV-2 vaccine candidate types: Callaway, Ewen. "The race for coronavirus vaccines: a graphical guide." Nature 580.7805 (2020): 576.

The SARS-CoV-2 vaccine development landscape is an exciting and rapidly developing area. Please see the following guides by the Milken Institute and World Health Organization (WHO) for regularly updated information.

• Milken Institute COVID-19 Treatment and Vaccine Tracker
• WHO draft landscape of COVID-19 candidate vaccines

   

May 6, 2020
Student presenter: Timothy Wu, MD Entering Class of 2018
Faculty moderator: Mark Krasnow, MD, PhD,  Professor of Biochemistry
Paper 1: Carly Ziegler et al. SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 20 April 2020.
Paper 2: Kyle Travaglini et al. A molecular cell atlas of the human lung from single cell RNA sequencing. bioRxiv. 20 March 2020.

April 24, 2020
Student presenter: Jeffrey Kwong, MD Entering Class of 2016; MS Entering Class of 2019
Faculty moderator: Rita Popat, PhD, Clinical Associate Professor of Health Research & Policy 
Paper: Jonathan Grein et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM. 10 April 2020. 

April 16, 2020
Student presenter: Ragini Phansalkar , MSTP Entering Class of 2014
Faculty moderator: Ami Bhatt, MD, PhD, Assistant Professor of Medicine (Hematology) and of Genetics
Paper 1: Alba Grifoni et al. (2020). A Sequence Homology and Bioinformatic Approach Can Predict Candidate Targets for Immune Responses to SARS-CoV-2. Cell host & microbe.
Paper 2: Kristian G. Andersen et al. (2020). The proximal origin of SARS-CoV-2. Nature Medicine.

April 15, 2020
Student presenter: Mollie Friedlander (MSTP Entering Class of 2015) and Caitlin Roake (MSTP Entering Class of 2012) 
Faculty moderator: PJ Utz, MD, Associate Dean for Medical Student Research and Professor of Medicine (Immunology & Rheumatology)
Paper 1: Neeltje van Doremalen et al. (2020). Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. New England Journal of Medicine. 
Paper 2: Sean Wei Xiang Ong et al. (2020). Air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a symptomatic patient. JAMA.

April 9, 2020
Student presenter: Leighton Daigh, MSTP Entering Class of 2014
Faculty moderator: Kevin Grimes, MD, Professor of Chemical and Systems Biology
Paper: Timothy Sheahan et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus. Bioarxiv, 2020.

April 6, 2020
Student presenter: Mollie Friedlander (MSTP Entering Class of 2015) and Caitlin Roake (MSTP Entering Class of 2012) 
Paper 1: Yuanyuan Dong et al. March 2020. Pediatrics. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. 
Paper 2: Xiaoxia Lu et al. March 2020. NEJM. SARS-CoV-2 Infection in Children

April 3, 2020
Student presenter: Gerald Tiu, MSTP Entering Class of 2011
Faculty moderator: Peter Kim, PhD, Virginia and D.K. Ludwig Professor of Biochemistry
Paper: Bin Ju et al. Potent human neutralizing antibodies elicited by SARS-CoV-2 infection. bioRxiv. March 25, 2020.

March 31, 2020
Student presenter: Daniel Berenson, MSTP Entering Class of 2013
Faculty moderator: Jonathan Maltzman, MD, Associate Professor of Medicine (Nephrology)
Paper: Bin Cao et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. NEJM. March 18, 2020.

March 30, 2020
Student presenter: Jamie Brett, MSTP Entering Class of 2010
Faculty moderator: Julia Simard, ScD, Assistant Professor of Epidemiology & Population Health, and, by courtesy, of Medicine in Immunology and Rheumatology
Paper: Philippe Gautret, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. 20 March 2020.

Discussion of the Gautret, et al. study

Abbreviatons:
CCTRL: patients receiving no treatment
HCQ-only: patients receiving hydroxychloroquine, without azithromycin
HCQ-AZM: patients receiving hydroxychloroquine and azithromycin
HCQ: patients receiving hydroxychloroquine, regardless of azithromycin

Why were hydroxychloroquine and azithromycin tested in this trial?
• Hydroxychloroquine is a medication used to treat parasitic infections (such as malaria) and autoimmune diseases (such as lupus). Chloroquine is a related drug also used to treat parasitic infections. Both hydroxychloroquine and chloroquine have been shown to reduce SARS-CoV-2 infection in pre-clinical studies of cells grown in cell-culture dishes.
• Azithromycin is an antibiotic used to treat bacterial infections (such as bacterial pneumonia). Azithromycin has not been tested against SARS-CoV-2; it was added for some patients to prevent bacterial infections.

What was the design of this trial?
This trial enrolled 42 patients with COVID-19 in Southern France: 16 CTRL patients and 26 HCQ patients, which included 20 HCQ-only patients and 6 HCQ-AZM patients. The authors measured the presence of SARS-CoV-2 virus in nose/throat swabs taken 6 days after the start of treatment, or approximately 10 days after the onset of symptoms.

Why shouldn’t the CTRL and HCQ groups be directly compared?
Comparisons between CTRL and HCQ patients cannot be made because of the following:
• In general, the course of COVID-19 illness is highly variable and site-dependent. In some sites, the average patient clears virus within several days after the onset of symptoms; at other sites, it can take multiple weeks.
• The CTRL group and the HCQ group patients were located at different sites. Thus, any differences seen might be due to site differences rather than treatment differences. For example, when examining time from symptom onset to time to testing negative for virus, the HCQ patients do no better than untreated patients in another study (Liu, et al. Lancet Infectious Diseases. DOI https://doi.org/10.1016/S1473-3099(20)30232-2).

What were other design biases in the trial?
In addition to the two main groups (CTRL and HCQ) being located at different sites, the CTRL group included 5 pediatric patients while the HCQ group had no pediatric patients, the CTRL group tended to have more asymptomatic patients than the HCQ group, and 6 patients in the HCQ group (including 3 patients who required intensive care 1 patient who died after treatment began) were removed from the analysis.

Did the HCQ-AZM patients become negative for virus more quickly than the HCQ-only patients?
There was no significant difference at day 6 between the HCQ-AZM group and the HCQ-only group.

What were the adverse effects of using hydroxychloroquine?
0% of the CTRL patients had adverse outcomes. 17% of the HCQ patients had adverse outcomes, which included 3 patients who required intensive care and 1 patient who died. This difference between HCQ and CTRL patients was not statistically significant, but it should be followed in future studies with larger numbers of patients, where the potential for poor outcomes from hydroxychloroquine treatment can be properly assessed.

What conclusions, if any, can be drawn from this trial?
That HCQ patients came from a different site than CTRL patients precludes drawing any conclusions about whether hydroxychloroquine, with or without azithromycin, is more effective than standard-of-care treatment. Patients who received hydroxychloroquine do improve over time, but we don’t know if they would have gotten better just the same without hydroxychloroquine treatment.

How could the trial design have been improved?
• A matched control group (or even better, a randomized control trial design) would allow determination of treatment efficacy compared to standard of care.
• Intention-to-treat analysis would have addressed the design bias introduced by removing patients that had progressively severe disease.
• Additional clinical outcomes could have been analyzed, such as mortality, need for intensive care, need for invasive ventilation, duration of hospital stay, symptoms, and side effects.

Are hydroxychloroquine and chloroquine effective against COVID-19?
To date, there has been no demonstration that chloroquine or hydroxychloroquine treatment benefits patients with COVID-19 disease. It is important to note that for drug development in general, the vast majority of medications that are promising pre-clinically end up failing in large clinical trials. Patients should not receive these medications for COVID-19 outside of a clinical trial. Interested patients and providers should seek opportunities to enroll in these trials. Examples of international trials (currently not enrolling in the U.S.) are the Solidarity trial and the Discovery trial. Examples of U.S. trials are COVID-19 PEP (in Washington and New York) and more on clinicaltrials.gov.

Stanford COVID-19 Journal Club is organized by MSTP students Adele Xu (Entering Class of 2015) and Madeline Cooper (Entering Class of  2017), and is advised by Dr. PJ Utz (Associate Dean for Medical Student Research). Graphic design by Stanford Schor (MSTP Entering Class of  2014), Dana Leonard (SMS Entering Class of  2017), and Richard Liang (SMS Entering Class of  2019).

Dr. PJ Utz
• Gilead Sciences – past consultant and stockholder
• Immunic – holds an NDA to help with biomarkers for COVID-19 trial; daughter was a summer intern

Dr. Jonathan Maltzman
• Spouse is employed by and has equity interest in Genentech/Roche

Dr. Peter Kim
•  Venture Partner, 5AM Ventures