Today we're focusing on a hot topic – the use of chloroquine and hydroxychloroquine for treatment of COVID-19. This drug had a lot of buzz early on, but recent data has been lukewarm at best.

Background: why chloroquine?

• Chloroquine and hydroxychloroquine are old medications generally used for the treatment of malaria, amebiasis, and certain inflammatory conditions like rheumatoid arthritis.
• These medications have anti-viral activity in vitro, but there is no demonstrated clinical efficacy in treatment of viral illness
• There are several proposed mechanisms including immunomodulatory/immunosuppressive effects – which, it should be noted, may potentially be harmful in the setting of viral disease
• Chloroquine isn't available in Canada. Hydroxycholorquine is, but due to the recent media frenzy, the supply is unstable and there are very real concerns that patients who need these drugs for legitimate indications may have difficulty accessing them

In-vitro and animal data

• There is some in-vitro data of chloroquine and hydroxychloroquine activity against COVID-19; and some data informing potentially effective doses1,2
• Animal data is not supportive – one study of chloroquine in mice with SARS was negative3

Human data

• There was a lot of buzz about this drug early on and hype from some very small/low-quality studies
  • Gautret (2020)4: this was a much-discussed very small French trial of 26 patients hospitalized with COVID-19 (though note that some of them were actually asymptomatic!)
    • They all received hydroxycholorquine; 6 also received azithromycin
    • Non-randomized; control group was patients who refused treatment
    • Their primary endpoint was negative viral PCR on day 6
    • This was lauded as a positive study as all patients who received both drugs had viral clearance at 6 days; vs 57% of the patients who had hydroxychloroquine only; and 12% of controls
    • HOWEVER – a lot of caveats here: high loss to follow up, high potential for bias, non-clinical endpoint
  • Gao (2020)5: this was a publication stating that "chloroquine use in 100 patient is superior to the control treatment for inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting virus negative conversion, and shortening the disease course" – but no patient data was published
  • Chen (2020)6: randomized trial of hydroxychloroquine use in patients with mild illness
    • 62 patients in a Wuhan hospital with mild illness only
    • Patient were randomized to 200mg BID of hydroxychloroquine vs control
    • Their primary outcome as a time to clinical improvement
    • They reported improved numbers in the treatment group BUT v small numbers, no mention of statistical significance, arguably relevant clinical endpoint
  • Higher-quality data has now emerged showing no benefit to HCQ, and potential harm
    • Magagnoli (2020)7
      • Retrospective cohort analysis of patients admitted to VA hospitals in the US with exposure to hydroxychloroquine, hydroxychloroquine and azithromycin, or neither drug
      • Adjusted risk of death was higher in the HCQ group (HR 2.61)
      • Unadjusted mortality was higher in both HCQ and HCQ + AZA groups compared to no Tx (27.8% vs 22.1% vs 11.4% respectively)
    • Borba (2020)8
      • Randomized clinical trial of low vs high-dose hydroxychloroquine for severe COVID
        • 450mg BID on day 1, then daily x 4d vs 600mg BID x 10d
      • Interim analysis recommended early termination of the trial after enrollment of 81 of a pre-planned 440 patients due to increased mortality in the high-dose group (39% vs 15%)
        • More QTc prolongation in high-dose group
      • Tang (2020)9
        • Open-label RCT for hydroxychloroquine in mild-to-moderate COVID
        • 151 patients
        • Intervention: 1200mg PO daily x 3d load, then 800mg PO daily for 2-3 weeks
        • Primary outcome of viral clearance by 28 days, defined by 2 consecutive negative PCR tests
        • Outcome: no difference (85% vs 81%); increase in adverse events in HCQ group (30% vs 7%)

Side effects

• Have not been investigated in the setting of COVID-19
• From experience with malaria and rheumatologic illnesses, hydroxychloroquine is generally well-tolerated
  • Dose of 400mg/d max (generally)
• Common side effect: GI upset
• Less common but more potentially worrisome: hypoglycemia, skin reactions, QTc prolongation (especially in combination with other QT-prolonging agents like azithromycin!), hepatotoxicity, bone marrow suppression, and retinal toxicity (related to long-term cumulative use)

Bottom line

• While it's tempting to jump at any and all possible therapies right now, we need to first do no harm
• Despite initial promising pre-clinical data and anecdotal reports, more recent evidence on hydroxychloroquine fails to demonstrate a clinical benefit; and suggests the potential for harm, especially at high doses

Sources

1. Wang, M., Cao, R., Zhang, L. et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res30, 269–271 (2020). doi: 10.1038/s41422-020-0282-0

1. Yao X, Ye F, Zhang M et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clinical Infectious Diseases, ciaa237, doi: 10.1093/cid/ciaa237

1. Barnard D, Day C, Bailey K et al. Evaluation of immunomodulators, interferons and known in vitro SARS-CoV inhibitors for inhibition of SARS-CoV replication in BALB/c mice. Antiviral Chemistry & Chemotherapy, 2006, 17:275–284. doi: 10.1177/095632020601700505

1. Gautret P, Lagier JC, Parola P et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrobial Agents, 2020. doi: 10.1016/j.ijantimicag.2020.105949

1. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends, 2020. doi:10.5582/bst.2020.01047

1. Chen J, Liu L, Liu D et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). J Zhejiang Univ (Med Sci), 2020;49(1). doi:10.3785/j.issn.1008-9292.2020.03.03

1. Magagnoli J, Narendran S, Pereira P et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. MedRxiv pre-print, 2020. doi:10.1101/2020.04.16.20065920

1. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open.2020;3(4):e208857. doi:10.1001/jamanetworkopen.2020.8857

1. Tang W, Cao Z, Han M. Hydroxychloroquine in patients mainly with mild to moderate COVID-19: an open-label, randomized, controlled trial. MedRxiv pre-print, 2020. doi: 10.1101/2020.04.10.20060558

Hot topic alert! We're unpacking the latest evidence around remdesivir – miracle drug, or overblown hype?

What is remdesivir?

• Anti-viral that has been studied in vitro and in pre-clinical/animal models showing promising effects for COVID-19:
  • Preventing symptoms occurrence if given early
  • Improving symptoms during infection
  • Decreasing viral load
• Acts as an adenosine nucleotide triphosphate analogue interfering with viral replication
• Many ongoing phase II and III trials are exploring the use of remdesivir compared to other anti-virals and/or standard of care
• Despite this early promise: the history of medicine is littered with therapies that looked promising in vitro/in preclinical models/in small non-randomized trials; only to end up having no benefit (or even causing harm!) when studied in robust RCTs

RCT: Wang et al1

• Methods
  • Double-blinded, placebo-controlled RCT at 10 hospitals in Wuhan, China
  • Population
    • 236 pts randomized in 2:1 fashion (158 REM, 78 placebo)
    • Inclusion - all of: age > 18, COVID-19 confirmed with PCR, imaging evidence of pulmonary disease, hypoxemia (SpO2 < 94% on RA or P/F < 300), within 12d of Sx onset
    • Exclusion: pregnancy/breastfeeding, severe CKD (GFR < 30), hepatic disease (transaminases > 5x ULN), transfer to non-study hospital, other clinical trial participation
  • Treatment protocol
    • REM: 200mg IV on day 1; followed by 100mg daily
    • 10 day protocol (REM vs placebo infusions)
  • Outcomes
    • Primary outcome: time to clinical improvement up to day 28 OR hospital discharge (whichever came first)
      • Defined as an improvement by 2 points on a 6 points scale (from 1= discharge to 6=death)
    • Secondary outcomes: many; including 28d mortality, frequency of mechanical ventilation, duration of oxygen therapy, hospital LOS, etc.
    • Also looked at viral load and viral PCR clearance
  • Statistical analysis
    • Intention to treat
    • Power calculated with an estimated treatment effect of 1.4 for REM
    • *trial stopped early due to low enrollment: only recruited 58% of their intended cohort (low numbers in China as virus was contained)
  • Results
    • Patient characteristics
      • Median time from symptom onset was 10 days (IQR 9-12)
      • REM groups appears slightly more comorbid/sicker (slightly higher incidence CAD, DM,HTN; higher RR)
      • No difference in other treatments received
        • About 30% got lopinavir-ritonavir; about 60% got steroids; about 90% got antibiotics
      • *Most patients were not that sick: over 80% required only low-flow oxygen
        • Question of the necessity of treatment for this group in the first place?
      • Primary outcome
        • No statistically significant difference
          • Time to clinical improvement: median 21.0 days [IQR 13.0–28.0] in the REM group vs 23.0 days [15.0–28.0]; HR 1.23 [95% CI 0.87–1.75]
          • Trend (not statistically significant) towards faster improvement in subgroup that received remdesivir within 10d of Sx onset (18d vs 23d)
        • Secondary outcomes
          • No difference in: 28d mortality (14% vs 13%), length of hospital stay, length of oxygen therapy
          • Small difference in one secondary endpoint (time to clinical improvement by 6-point scale) à questionable significance
          • *No difference in viral load
            • Given that this is purported mechanism of action, this casts serious doubt on the in-vivo efficacy of this drug
          • Adverse events
            • Similar between groups (constipation, hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, transaminitis and hyperbilirubinemia)
              • Reported in about 2/3 of patients
            • Overall no difference
          • Major caveats
            • Generally a well-done study
            • Risk type 2 error?
              • Underpowered to detect time to clinical improvement (under-recruitment)
                • Definitely underpowered for outcomes like illness severity, mortality
              • Not given early enough? About half of pts got drug 10d after Sx onset
                • Previous animal models all involve drug administration within 24h of Sx onset
                • Practically, administering the drug early would likely be challenging as most patients don't present to hospital until 5-10d into their disease course
              • Funding: Chinese Academy of Medicine Science, Beijing Science and Technology Project, National Key Research and Development Program of China
                • NOT Gilead
              • Bottom line
                • NO statistically significant difference in time to clinical improvement for moderately ill patients treated with remdesivir vs placebo
                • Remdesivir appears safe: no apparent increase in SEA

NIH study: prelim results

• The US NIH (National Institute of Health) put out a press release on April 29 about promising preliminary data results from the ACTT trial (Adaptive COVID-19 Treatment Trial)2
  • Run at the University of Nebraska, sponsored by the NIAID
  • Details of the study not reported other than in a media release3
    • Participants with confirmed SARS-CoV-2 with "evidence of lung involvement"
    • Outcome: improvement on a 7 point scale?
  • Interim analysis: reported a 31% faster recovery with REM vs placebo (11d vs 15d)
    • "Results also suggested a mortality benefit" that didn't reach significance
  • Questionable validity: interim analysis, no details available, not peer-reviewed; also contrary to above well-conducted RCT

Coming down the pipeline

• Two phase 3 randomized parallel group trial are underway, sponsored by Gilead sciences (NCT04292899 and NCT04292730) that seek to enroll 6000 patients with severe COVID-19, and 1600 patients with moderate COVID-19 respectively
• NCT04292730 aims to be completed in May of 2020 and the preliminary results should be available shortly.

Sources

1. Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, April 2020. doi: 10.1016/S0140-6736(20)31022-9

1. NIH press release, Apr 29 2020. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19

1. NIH press release, Feb 25 2020. https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivir-treat-covid-19-begins

Today we're going back to some critical public health basics: self-monitoring, self-isolation (and the key difference between them), and how to care for someone with COVID-19. 

 Sources

All the information in today's podcast was taken from the attached BC CDC graphics:

• How to Self-Monitor
• How to Self-Isolate
• Guide for caregivers and household contacts of patients with COVID-19

Welcome to Viruswatch! Your source for short and sweet updates about all things COVID-19. Today we're starting off with the basics and covering a broad overview of what you NEED to know about this novel coronavirus; with a particular focus on virus transmission. Note that many topics will be explored in more depth in later episodes – stay tuned!

What is COVID-19?

• COVID-19 is the name that has been given to the disease caused by the novel coronavirus (aka SARS-CoV-2)
• It is a 30kbp, +ssRNA virus suspected to have originated in bats1
• Coronaviruses are a family of viruses
  • Found predominantly in animals
  • In humans: most often cause the common cold
  • Can cause severe disease like SARS (Severe Acute Respiratory Syndrome – aka SARS-CoV-1) or MERS (Middle Eastern Respiratory Syndrome)
• SARS-CoV-2 binds the ACEII receptor (alveolar cells, vascular/intestinal endothelium)2

Virus transmission

• Controversial area!
• Known spread via droplet transmission: large droplets expelled from the respiratory tract during close contact
  • The WHO and CDC suggest this is the primary mode of spread3,4
• Fomite spread
  • Evidence that the virus remains active on environmental surfaces for prolonged periods, suggesting the potential for spread via fomites. Regular cleaning and disinfecting protocols kill these viruses5
  • Half-life is longest on plastic and stainless steel (virus detected up to 72h)5
• Airborne spread?
  • Aerosolized spread is possible during aerosol-generating procedures such as intubation, bronchoscopy, non-invasive positive-pressure ventilation, etc.
  • An old study showing that aerosolized coronavirus (in lab conditions) may survive in ambient air up to 6 hours6
  • One group took surface environmental samples from the airborne isolation rooms of several COVID patients à found that all air samples were negative, but air duct samples as well as one shoe sample from a HCW was positive7
  • Inconclusive evidence about the impact of airborne spread8
• Questions remain about spread via stool, blood, other modes
• Important caveats about mode of transmission! Many studies to date:
  • Use artificial set-ups to simulate real world conditions (ie putting virus into a nebulizer)
  • Look for the presence of viral RNA on various surfaces à don't know that actual implications of this would be for infectivity!
• Asymptomatic spread
  • Asymptomatic, pre-symptomatic, and minimally symptomatic spread are now believed to be possible9
  • In many studies, significant percentage of patients testing positive were asymptomatic or minimally symptomatic at the time of the positive test
  • This has significant infection control implications, and also raises the question of the efficacy of various workplace screening protocols
• The R0 (parameter of infectivity) is thought to be between 2 to 3, though this will vary significantly depending on environment and human behavior

Clinical Presentations

• There appear to be three primary phenotypes for COVID 19
  • Asymptomatic/presymptomatic/minimally symptomatic carriers
  • Febrile respiratory illness (ILI: influenza-like illness)
  • GI illness (small minority of patients have only GI symptoms)10
• Symptoms to look out for include fever, cough, shortness of breath, upper respiratory tract symptoms, malaise, fatigue, nausea, vomiting, diarrhea, abdominal pain
• As case numbers have skyrocketed, more people are presenting with atypical features: failure to thrive, electrolyte abnormalities, chest pain, neurologic deficits/stroke, etc
• Investigations
  • Most common lab abnormality is lymphopenia
  • Inflammatory markers such as CRP, D-dimer, ferritin may help determine phase of illness and identify those at higher risk of deterioration
    • Cardiac enzymes (troponin, BNP) and liver enzymes (AST/ALT) may also be elevated
    • Coagulation parameters often abnormal
  • Imaging
    • CXR typically reveals patchy bilateral infiltrates
      • May be normal in early/mild disease
    • POCUS: inflammatory B-line pattern (patchy B-lines with irregular/thickened pleura)
    • CT scan: typical findings include bilateral ground-glass opacities with a lower lobe predominance11
  • Biphasic disease course: late hyperinflammatory phase
    • It's been recognized that some patients experience abrupt clinical deterioration late in their disease course, attributed to an HLH-like immune hyperactivation12
  • Hypercoagulability seems to be important: high indigence of abnormal coagulation parameters and clinical VTE13

 Testing

• Testing is currently done via RT-PCR assay of NP swab
• Reported test characteristics vary; sensitivities range from 60-80% in informal reports
  • Suboptimal NP swab technique
  • Primarily lower respiratory/GI tract burden of virus
  • Phase of illness: v early disease OR past the viral replicative phase
• Who gets tested?
  • Check with your local health authority/regional guidelines

Disease severity

• Most patients have mild illness and do not require hospitalization
  • Initial figures were about 80%; this may be higher as we recognize that large numbers of people may be asymptomatic and unaware of their infection
• Of those requiring hospitalization: about 5% seem to have critical illness14
  • This number varies significantly in different cohorts and as the pandemic evolves

Treatment

• Treatment for COVID-19 is supportive
  • Treat hypoxemia with supplemental O2
  • Treat symptoms: analgesia, antipyretics, anti-emetics, etc
• There are no proven therapies at this point though several are under investigation
• In particular, at this point:
  • Steroids are not routinely* recommended for all COVID-19
    • Recommended in a subset of critically ill patients
  • Hydroxychloroquine is not routinely recommended for COVID-19
  • Anti-virals and antibiotics are not routinely recommended for COVID-19
  • Full-dose anticoagulation for patients without clinical evidence of VTE is not routinely recommended for COVID-19
• Use of these therapies should occur:
  • Within the context of clinical trials
  • As directed by your unit/hospital/health authority
• See future podcasts for all the nitty gritty details about therapies!

Sources

1. Guo, Y., Cao, Q., Hong, Z. et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Military Med Res 7, 11 (2020). doi: 10.1186/s40779-020-00240-0

1. Hamming I, Timens W, Bulthuis ML et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol, 2004 Jun;203(2):631-7. doi: 10.1002/path.1570

1. Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations. WHO scientific brief, March 29 2020. https://www.who.int/news-room/commentaries/detail/modes-of-transmission-of-virus-causing-covid-19-implications-for-ipc-precaution-recommendations

1. CDC Interim Infection Prevention and Control Recommendations for Patients with Suspected or Confirmed Coronavirus Disease 2019 (COVID-19) in Healthcare Settings. April 13 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-recommendations.html

1. Doremalen N, Morris D, Holbrook M et al. Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med, 2020; 382:1564-1567. doi: 10.1056/NEJMc20049733

1. Pyankov O, Bodnev S, Pyankova O et al. Survival of aerosolized coronavirus in ambient air. Journal of Aerosol Science, 2018,115:158-163. doi: 10.1016/j.jaerosci.2017.09.009

1. Ong SWX, Tan YK, Chia PY, et al. Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient. JAMA. 2020;323(16):1610–1612. doi: 10.1001/jama.2020.3227

1. Rubens J, Karakousis P, Jain S et al. Stability and viability of SARS-CoV-2. New Eng J Med, April 2020. doi: 10.1056/NEJMc2007942

1. Ganhdi M, Yokoe D, Havlir D. Asymptomatic Transmission, the Achilles' Heel of Current Strategies to Control Covid-19. New Eng J Med, April 2020. doi: 10.1056/NEJMe2009758

1. Pan L, Mu M, Yang P et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol. 2020 May;115(5):766-773. doi: 10.14309/ajg.0000000000000620

1. Karimian, M and Azami, M. Computed Tomography Scan Findings in Patients with COVID-19: A Systematic Review and Meta-Analysis (4/4/2020). Lancet pre-prints. Available at SSRN: https://ssrn.com/abstract=3571539
2. Siddiqi S and Mera M. COVID-19 Illness in Native and Immunosuppressed States: A Clinical-Therapeutic Staging Proposal. J Hear Lung Transplant, 2020,29(5):405-407. doi: 10.1016/j.healun.2020.03.012

1. Thachil J, Tang N, Gando S et al. ISTH interim guidance on recognition and management of coagulopathy in COVID‐19. J Thromb Haemost, 2020. doi: 10.1111/jth.14810

1. Wu Z, and McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA.2020;323(13):1239–1242. doi:10.1001/jama.2020.2648