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Pharmacology/Background: - mRNA vaccines: encodes for viral proteins; uses host machinery to produce solitary viral proteins to induce immune response; does not produce whole virus
- recombinant vector-based vaccines: virus vectors genetically modified to include select proteins from pathogen of interest to induce immune response
- inactivated vaccines: pathogenic agent killed by chemicals, heat, or radiation; antigens from inactivated virus induce immune response
- subunit vaccines: contain virus components rather than entire pathogen to minimize side effects; often require adjuvant to elicit stronger immune response for long-term immunity
- virus-like particle vaccines: self-assembling multiprotein structures mimicking authentic native virus but lacking viral genome; nonreplicative, nonpathogenic
U.S. vaccines under investigation:
Pharmacology/Background: - Proposed mechanism: induces nonspecific immune effects
- Vaccines under investigation: BCG, MMR, zoster vaccine (recombinant), polio vaccines
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Drugs w/ antiviral activity (eg, remdesivir, hydroxycholoroquine)
Pharmacology/Background: - Proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase; circumvents proofreading activity by exonucleases
- FDA MedWatch: Remdesivir by Gilead Sciences: FDA Warns of Newly Discovered Potential Drug Interaction That May Reduce Effectiveness of Treatment; see FDA alert
Emergency Use Authorization: Remdesivir for the Treatment of Covid-19 – Final Report - KEY FINDINGS: RDV, esp if given early, shortened recovery time vs placebo
- Study considerations: primary outcome changed mid-study, but incl as secondary outcome; varied protocols for other COVID-19 tx; remote monitoring
- Multinational, double-blind, RCT; 1,062 hospitalized pts (mean age 58.9y, 89% severe dz) received RDV 200 mg IV x1, then 100 mg daily (n=541) or placebo (n=521) for up to 10 days total; supportive care and other COVID-19 tx per protocol; median 9 days btwn sx onset and tx
- Primary outcome of time to recovery: RDV 10 days vs placebo 15 days (rate ratio 1.29, 95% CI 1.12-1.49); in pts w/ severe dz, RDV 11 days vs placebo 18 days (rate ratio 1.31, 95% CI 1.12-1.52); no difference if mech vent or ECMO (rate ratio 0.98, 95% CI 0.76-1.57); significantly faster time to recovery w/ RDV vs placebo if randomized during 1st 10 days
- Secondary outcome of improvement odds at day 15 higher w/ RDV vs placebo (OR 1.5, 95% CI 1.2-1.9); lower mortality by day 15 w/ RDV (6.7% vs 11.9%) but no significant difference by day 29; no difference in ADR incidence
- Access N Engl J Med article
Remdesivir for 5 or 10 Days in Patients With Severe Covid-19 (SIMPLE-Severe) - KEY FINDINGS no significant difference between 5- or 10-day RDV in pts not requiring mech vent
- Study considerations: no placebo control; randomization not stratified; protocol amended mid-study to lower age eligibility limit; 10-day group sicker at baseline; not all pts completed full course of assigned RDV; viral load not evaluated; extension phase added to evaluate mech vent, ECMO, and multiorgan failure pts
- Randomized, multicenter, multinational, open-label study: 397 hospitalized pts w/ confirmed SARS-CoV-2, pneumonia, and O2 sat ≤94% on RA or receiving supplemental O2, randomized 1:1 to receive RDV 200 mg IV x1, then 100 mg IV q24h x5 days total (n=200, median age 61y) or 10 days total (n=197, median age 62y); 10-day group sicker at baseline
- Unadjusted analysis of 14-day clinical status improvement rate: 5-day 64%, 10-day 54%, w/ no difference after adjusted analysis; ADRs incl acute resp failure (5-day 5%, 10-day 9%), resp failure (5-day 2%, 10-day 5%), grade 4 CrCl reduction (5-day 3%, 10-day 12%); elevated LFTs (5-day 2.5%, 10-day 3.6%)
- Access N Engl J Med article
Remdesivir in Adults With Severe COVID-19: A Randomised, Double-blind, Placebo-controlled, Multicentre Trial - KEY FINDINGS: RDV not assoc w/ significant clinical benefits; early tx may reduce time to clinical improvement
- Study considerations: underpowered due to low enrollment; imbalanced baseline characteristics despite randomization; possible delay in tx start; questionable utility of subgroup analyses
- Double-blind RCT; 237 pts (median age, 65y) received RDV 200 mg x1, then 100 mg daily x9 days (n=158) or placebo (n=78); incl pts w/ SaO2 <94% on RA, <12 days after sx; pts also received LPV/r (18%), IFN (19%), and steroids (38%); more RDV pts w/ late tx start (>10 days after sx) and RDV group had higher rates of HTN, DM and CAD
- Terminated early due to low enrollment and control of epidemic in China; no difference in time to clinical improvement (RDV 21 days, placebo 23 days) or 28-day mortality (RDV 14%, placebo 13%); in pts w/ ≤10 days from sx, non-significant difference in time to clinical improvement (RDV 18 days, placebo 23 days) and 28-day mortality (RDV 11%, placebo 15%)
- Viral loads decreased at similar rates in both groups; ADRs similar btwn groups (RDV 66%, placebo 64%); higher D/C rates in RDV (12%) vs placebo (5%)
- Access Lancet article
Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial (SIMPLE-Moderate) - KEY FINDINGS: improved clinical status w/ 5 days RDV vs SOC, but not w/ 10 days RDV
- Study considerations: open-label; randomization not stratified; protocol amended mid-study for inclusion criteria and primary endpoint; discharge rates may have been influenced by RDV duration; SARS-CoV-2 viral load and other relevant labs not assessed; results w/ uncertain clinical importance; nonrandomized extension phase ongoing
- Randomized, multicenter, multinational, open-label study: 584 hospitalized pts (median age 57y) w/ moderate COVID-19, randomized to receive RDV 200 mg IV x1 then 100 mg IV q24h or SOC x5 or x10 days; SOC pts more likely to receive other antivirals incl HCQ, CQ, AZ, and LPV/r
- Clinical status 11 days after RDV 5-day tx better than SOC (OR 1.65, 95% CI 1.09-2.48); no statistical difference in clinical status on day 11 between RDV 10-day tx vs SOC; overall ADR rates similar between RDV 5-day tx and SOC but higher in RDV 10-day tx vs SOC (59% vs 47%) w/ nausea, hypokalemia, HA more frequent in RDV 10-day group vs SOC
- Access JAMA article
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: RDV had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access N Engl J Med article
Note: For published studies on combo tx w/ baricitinib, refer to JAK inhibitors
Treatment trials: Inpatient Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Emergency Use Authorization revoked June 15, 2020: Effect of Hydroxychloroquine With or Without Azithromycin on the Mortality of COVID-19 Patients: A Systematic Review and Meta-analysis - KEY FINDINGS: HCQ alone not assoc w/ reduced mortality in hospitalized pts, but HCQ+AZ significantly increased mortality
- Study considerations: varying dz severity; HCQ admin (dosing, timing, duration) highly heterogeneous; aggregate analysis not w/ original pt data; mostly incl observational studies
- Meta-analysis incl 3 RCTs, 1 interventional non-randomized study (w/ critical bias risk), 25 observational studies (15 studies w/ mod or serious bias risk, 10 w/ critical bias risk); study quality lowered by lack of info for tx assignment, time to intervention, unbalance co-interventions, and confounder imbalance btwn groups
- HCQ not significantly assoc w/ mortality (pooled RR 0.83, 95% CI 0.65-1.06 for all studies, I2=84%; pooled RR 1.09, 95% CI 0.97-1.24 for RCTs, I2=0%); HCQ+AZ assoc w/ incr mortality (RR 1.27, 95% CI 1.04-1.54, I2=38%)
- Access Clin Microbiol Infect article
Effect of Hydroxychloroquine in Hospitalized Patients With Covid-19 (RECOVERY) - KEY FINDINGS: HCQ did not lower 28-day mortality vs SOC
- Study considerations: randomized but open label; HCQ dose based on PK modeling; limited number of intubated pts; no children enrolled; no collection of virological or laboratory parameters
- Randomized, controlled, open-label, adaptive platform study; current analysis incl HCQ vs SOC only, results for other tx arms published or forthcoming
- Hospitalized pts (mean age 65.4y) w/ suspected or confirmed COVID-19 randomized to HCQ 800 mg q6h x2, then 400 mg q12h plus SOC for up to 10 days (n=1,561) vs SOC only (n=3,155); at randomization 17% invasive mech vent, 60% O2 only
- 28-day all-cause mortality higher w/ HCQ vs SOC only (RR 1.09, 95% CI 0.97 to 1.23), similarly across subgroups; HCQ group less likely to be discharged alive w/in 28 days vs SOC (rate ratio 0.9, 95% CI 0.83-0.98); among pts not mech vent baseline, HCQ group w/ higher frequency of mech vent or death (risk ratio 1.14, 95% CI 1.03-1.27)
- Access N Engl J Med article
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: HCQ had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: not peer-reviewed; randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access New Engl J Med article
Observational Study of Hydroxychloroquine in Hospitalized Patients With COVID-19 - KEY FINDINGS: HCQ not assoc. w/ change in composite endpoint (intubation or death)
- Study considerations: non-randomized; weighted propensity score model; treatment bias, HCQ pts were generally sicker; missing data and inaccuracies in EHR
- Observational cohort study w/ propensity score matching; 1,376 consecutive hospitalized pts (60% pts >60y) w/ confirmed mod-severe COVID-19; 811 pts treated w/ HCQ 600 mg bid x2, then 400 mg daily x4 days, 565 pts did not receive HCQ; 45% pts also treated w/ AZ 500 mg x1, then 250 mg daily x4 days; pts eligible for tx w/ other investigational COVID-19 tx; HCQ pts generally older, sicker, and received more concurrent tx; 86% HCQ pts received tx w/in 48h of presenting to ED
- Primary composite endpoint (intubation or death) rates higher w/ HCQ (32%) vs no HCQ (15%) in unadjusted analysis (HR 2.37, 95% CI 1.84 to 3.02); adjusted analysis showed no significant association btwn HCQ use and composite endpoint (HR 1.04, 95% CI 0.82 to 1.32)
- Access N Engl J Med article
Hydroxychloroquine With or Without Azithromycin in Mild-to-Moderate Covid-19 - KEY FINDINGS: HCQ or HCQ+AZ did not improve clinical status at 15 days vs SOC
- Study considerations: randomized but open-label; pts had mild-mod. dz; primary outcome assessment changed mid-study to be more granular; observer bias
- Multicenter, open-label, RCT; 667 hospitalized pts (mean age 50y) w/ mild-mod COVID-19 (58% pts required no O2) and <15 days since sx onset, randomized to receive SOC alone (n=229), SOC plus HCQ 400 mg bid x7 days (n=221), or SOC plus HCQ 400 mg bid and AZ 500 mg daily x7 days (n=217); use of CS (19.8%), other immunodulators, abx, and antivirals allowed; median time from admission to randomization 1 day, median time from sx onset to randomization 7 days
- No significant difference in clinical status at day 15 w/ HCQ vs SOC alone (OR 1.21, 95% CI 0.69 to 2.11), or HCQ+AZ vs SOC alone (OR 0.99, 95% CI 0.57 to 1.73); no significant difference in secondary outcomes such as intubation w/in 15 days, O2 requirement, LOS; QT prolongation more frequent in HCQ groups; elevated LFTs more frequent in HCQ+AZ group vs SOC alone
- Access N Engl J Med article
Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial (ORCHID) - KEY FINDINGS: HCQ did not significantly improve clinical status at day 14 vs placebo
- Study considerations: terminated early due to low enrollment; included pts w/ respiratory sx for up to 10 days; f/u limited to 28 days; no eval for viral shedding, inflammatory biomarkers, effect of other tx
- Multicenter, blinded, RCT; 479 hospitalized pts (median age 57y) w/ severe dz received HCQ 400 mg bid x1 day, then 200 mg bid x4 days (n=242) vs placebo (n=237); median sx duration 5 days; pts also received RDV (21.7%), AZ (19%), CS (18.4%)
- No significant difference in clinical status at 14 days (adjusted OR 1.02, 95% CI 0.73-1.42); no significant difference in death rate at 28 days (adjust OR 1.07, 95% CI 0.54-2.09)
- Access JAMA article
Other studies: - Hydroxychloroquine in Patients With Mainly Mild to Moderate Coronavirus Disease 2019: An Open-label, Randomised, Controlled Trial; full-text BMJ article
- Azithromycin in Addition to Standard of Care Versus Standard of Care Alone in the Treatment of Patients Admitted to the Hospital With Severe COVID-19 in Brazil (COALITION II): A Randomised Clinical Trial; full-text Lancet article
- Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State; full-text JAMA article
- Treatment With Hydroxychloroquine, Azithromycin, and Combination in Patients Hospitalized With COVID-19; full-text Int J Infect Dis article
- Clinical Efficacy of Hydroxychloroquine in Patients With COVID-19 Pneumonia Who Require Oxygen: Observational Comparative Study Using Routine Care Data; full-text BMJ article
- Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-randomized Clinical Trial; full-text Int J Antimicrob Agents article
- Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized With Covid-19; full-text Med article
Treatment trials: Outpatient Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Emergency Use Authorization revoked Jun 15, 2020: Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 - KEY FINDINGS: HCQ did not substantially reduce sx severity in early, mild infxn
- Study considerations: internet-based surveys in younger pts w/ mild sx; limited testing due to shortage; primary endpoint and sample size modified mid-study; study halted before secondary endpoints; medication adherence; loss to f/u
- Double-blind, multisite RCT; 423 non-hospitalized pts (median age 40y) w/ lab-confirmed or probable COVID-19 and <5 days of sx, randomly assigned 1:1 to receive HCQ 800 mg x1, then 600 mg in 6-8h, then 600 mg daily x4 more days (n=212) or placebo (n=211); 81% had lab-confirmed infxn or epidemiologic link to a person w/ lab-confirmed infxn, 58% received SARS-CoV-2 testing; 56% enrolled w/in 1 day of sx onset; comorbid conditions incl asthma (11%), HTN (11%), DM (4%); 68% w/o comorbid conditions
- No significant difference in overall sx severity over 14 days or incidence of hospitalization between groups; higher rate of ADRs w/ HCQ (43% vs 22%)
- Access Ann Intern Med article
Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial - KEY FINDINGS: no benefit of HCQ vs SOC
- Study considerations: randomized but open-label and not placebo-controlled; study protocol amended to remove DRV/c tx option and to incl. additional specimen collection at day 7; most pts were HCWs; self-reported compliance
- Multicenter, open-label, RCT; 293 non-hospitalized pts (mean age 41.6y) w/ confirmed SARS-CoV-2 infxn, mild dz, and <5 days of sx, received HCQ 800 mg PO x1, then 400 mg PO daily x6 days (n=136) or no antiviral tx (n=157); median time from sx onset to randomization 3 days; 53.2% w/ chronic health conditions; f/u 28 days
- No significant difference in mean viral load reduction at day 3 or day 7 b/w groups; no significant reduction in hospitalization or time to sx resolution b/w groups; no pts required mech vent or died during study period; no relevant tx-assoc ADRs reported
- Access Clin Infect Dis article
Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial - KEY FINDINGS: no clinical benefit of HCQ as pre-exposure prophylaxis
- Study considerations: terminated early for futility before reaching enrollment of 200 participants; small sample size; did not quantify exposures or timing of exposures
- Double-blinded RCT; 125 hospital-based HCWs (median age 33y) w/ confirmed negative SARS-CoV-2 received HCQ 600 mg daily (n=64) or placebo (n=61) x8wk
- No significant difference in SARS-CoV-2 infxn rate at 8wk; mild adverse effects in HCQ group; no difference in median QTc change; 6 of 8 participants w/ positive SARS-CoV-2 developed sx, no hospitalization, and all clinically recovered
- Access JAMA Intern Med article
A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 - KEY FINDINGS: no benefit of HCQ used as prophylaxis w/in 4 days postexposure
- Study considerations: recruitment through social and traditional media platforms w/ enrollment via internet-based survey; f/u via email surveys, 10% didn’t complete day 14 survey; access to testing limited; sample-size adjusted mid-study; delay btwn SARS-CoV-2 exposure and HCQ start; medication adherence varied
- Double-blinded RCT; 821 asymptomatic pts (median age 40y) w/ mod-high COVID-19 exposure risk (66.4% HCWs, 29.8% household contacts, 3.8% other occupations) given HCQ 800 mg PO x1, then 600 mg 6-8h later, then 600 mg PO daily x4 days (n=414) or placebo (n=407) w/in 4 days after exposure; adherence HCQ 75.4%, placebo 82.6%
- No difference in lab-confirmed COVID-19 incidence or COVID-19 illness w/in 14 days (HCQ 11.8%, placebo 14.3%); 1 hospitalization per group, no deaths or arrhythmias; ADRs more common w/ HCQ
- Access N Engl J Med article
Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
The QT Interval in Patients With COVID-19 Treated With Hydroxychloroquine and Azithromycin - KEY FINDINGS: QTc prolongation observed w/ HCQ+AZ
- Study considerations: non-comparative; small sample size; pts had other risk factors for QT prolongation besides HCQ plus AZ tx; HCQ and AZ dosing not provided
- Retrospective, observational study; 84 hospitalized pts (mean age, 63y) w/ confirmed SARS-CoV-2 treated w/ HCQ plus AZ; comorbidities incl CAD (11%), HTN (65%), CKD (7%), DM (20%), COPD (8%), CHF (2%); 7% on amiodarone tx
- Mean QTc interval increased from 435 msec at baseline to 463 msec; 30% pts had QTc prolonged by >40 msec; 11% pts developed QTc interval of >500 msec; no cases of torsade de pointes; acute renal failure only predictor of maximal QTc >500 msec on multivariate analysis
- Access Nat Med article
Other studies: - Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19); access JAMA Cardiol article
- Assessment of QT Intervals in a Case Series of Patients With Coronavirus Disease 2019 (COVID-19) Infection Treated With Hydroxychloroquine Alone or in Combination With Azithromycin in an Intensive Care Unit; access JAMA Cardiol article
Pharmacology/Background - Proposed mechanism: inhibits viral entry and replication via intracellular alkalinization, interferes w/ maturation of viral particles through impaired glycosylation; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ AZ; monitor ECG
- FDA MedWatch: Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Emergency Use Authorization revoked June 15, 2020: 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 - KEY FINDINGS: higher CQ doses not recommended for critically ill pts due to safety concerns
- Study considerations: small sample size; interim safety data, limited efficacy analysis; high-dose CQ arm had older pts w/ more comorbidities; no contemporaneous control group
- Double-blind RCT; 81 hospitalized pts (mean age 51y; 77% w/ confirmed COVID-19 at enrollment) randomized 1:1 to high-dose CQ (600 mg bid x10 days) or low-dose CQ (450 mg bid x1 day, then 450 mg daily x4 days); all pts received AZ 500 mg daily x5 days, 90% received oseltamivir for suspected influenza infxn
- High-dose CQ group halted early due to safety concerns and all pts converted to low-dose CQ; small sample size in low-dose CQ group limits efficacy analysis, but resp secretions negative at day 4 in 6 of 27 tested pts
- 27% pts died (39% w/ high-dose CQ, 15% w/ low-dose CQ); 15% pts developed QTc interval >500 msec (19% w/ high-dose CQ, 11% w/ low-dose CQ), 2 pts had ventricular tachycardia w/ 2 deaths
Preliminary Evidence From a Multicenter Prospective Observational Study of the Safety and Efficacy of Chloroquine for the Treatment of COVID-19 - KEY FINDINGS: CQ incr viral clearance and shortened duration of sx
- Study considerations: non-randomized; historical controls treated w/ various antivirals; demographics and tx differed across time and btwn sites, incl dosing and timing of tx start; mostly moderate dz; incomplete clinical and lab data collection
- Multicenter prospective observational study; 197 hospitalized pts (mean age 44y, 91% moderate dz) w/ confirmed SARS-CoV-2 received CQ (500 mg qd or bid for up to 10 days); 176 historical controls (mean age 46y) received other antiviral tx; time btwn sx onset and tx start longer in CQ by 4 days
- Primary endpoint of time to viral suppression shorter w/ CQ (difference, 6 days); higher rate of viral clearance w/ CQ vs controls by day 10 (96% vs 91%) and by day 14 (80% vs 57%); duration of fever shorter w/ CQ; no difference in LOS; similar rates of ADRs in both groups (CQ 27%, control 32%) w/ no serious ADRs in CQ group
- Access Natl Sci Rev article
HIV protease inhibitors (eg, lopinavir, darunavir) Pharmacology/Background: - Proposed mechanism: interferes w/ maturation of viral particles by inhibiting protease enzymes
- Drugs under investigation: lopinavir/ritonavir, darunavir w/ ritonavir, darunavir/cobicistat
A Trial of Lopinavir–Ritonavir in Adults Hospitalized With Severe Covid-19 - KEY FINDINGS: no benefit w/ LPV/r tx vs SOC
- Study considerations: randomized but open-label; delayed tx initiation from sx onset; viral kinetics showed possible lack of antiviral effect (LPV/r exposure at normal doses lower vs concentrations needed for anti-SARS-CoV-2 activity)
- Open-label RCT; 199 hospitalized pts (mean age, 58y) w/ confirmed SARS-CoV-2 and O2 sat ≤94% on RA randomized 1:1 to LPV/r 400 mg/100 mg bid x14 days plus SOC, or SOC alone; 13 days median time btwn sx onset and randomization; SOC group had higher rates of vasopressor use (27% vs 17%), noninvasive mech vent (19% vs 10%), and invasive mech vent (18% vs 14%)
- No difference in median time to clinical improvement (LPV/r 16 days vs SOC 16 days) or 28-day mortality (LPV/r 19% vs SOC 25%); rate of detectable viral load similar between groups at all sampling timepoints; similar rates of ADRs (LPV/r 48% vs SOC 50%), 14% of LPV/r pts D/C due to ADRs
- Access the free full-text N Engl J Med article
Lopinavir–Ritonavir in Patients Admitted to Hospital With COVID-19 (RECOVERY): A Randomised, Controlled, Open-Label, Platform Trial - KEY FINDINGS: compared w/ SOC, LPV/r did not lower 28-day mortality, length of stay, need for mech vent, or risk of death
- Study considerations: randomized but open-label; unclear if adequate dose used; limited number of intubated pts; no collection of virological or laboratory parameters
- Randomized, controlled, open-label, adaptive platform study; current analysis incl LPV/r vs SOC only, results for other tx arms published or forthcoming
- Hospitalized pts (mean age 66.2y) w/ suspected or confirmed COVID-19 randomized to LPV/r 400 mg/100 mg bid plus SOC for up to 10 days (n=1616) vs SOC only (n=3424); 25% pts w/ no ventilatory support, most pts needed O2 only, small proportion needed mech vent
- No significant difference in 28-day all-cause mortality (RR 1.03, 95% CI 0.91 to 1.17), incl across subgroups; no significant difference in time to discharge or proportion of pts discharged
- Access full-text Lancet article
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: LPV regimens had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: not peer-reviewed; randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access New Engl J Med article
Other studies: - Arbidol Monotherapy Is Superior to Lopinavir/Ritonavir in Treating COVID-19; access J Infect article
- Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients With Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial; access Med article
- Treating COVID-19 With Chloroquine [vs LPV/r]; access J Mol Cell Biol article
- Triple Combination of Interferon Beta-1b, Lopinavir-Ritonavir, and Ribavirin in the Treatment of Patients Admitted to Hospital With COVID-19: An Open-label, Randomized, Phase 2 Trial; access Lancet article
- Antiviral Activity and Safety of Darunavir/Cobicistat for the Treatment of COVID-19; access Open Forum Infect Dis article
ACEIs/ARBs (eg, losartan, ramipril) Pharmacology/Background: - Proposed mechanism: blocks viral entry by inhibiting ACE2 receptors
Pharmacology/Background: - Proposed mechanism: activity against RNA-dependent RNA polymerases; in vitro activity against arboviruses (eg, Zika)
Pharmacology/Background: - Proposed mechanism: inhibits viral polymerase acidic protein endonuclease activity, inhibiting viral replication; reported in vitro activity against SARS-CoV-2
Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial; access pre-print medRxiv article
Pharmacology/Background: - Proposed mechanism: inhibits coronavirus proteases; reduces inflammatory cytokine release by blocking pyroptosis pathway
DPP-4 inhibitors (eg, linagliptin) Pharmacology/Background: - Proposed mechanism: blocks viral entry; reportedly blocks MERS-CoV entry receptor (DPP-4)
Pharmacology/Background: - Proposed mechanism: binds to protease implicated in viral replication
Published studies: - Famotidine Use Is Not Associated With 30-day Mortality; A Coarsened Exact Match Study in 7185 Hospitalized COVID-19 Patients from a Large Healthcare System; full-text Gastroenterology article
- Famotidine Use is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study; full-text Gastroenterology article
- Famotidine Use and Quantitative Symptom Tracking for COVID-19 in Hon-hospitalized Patients: A Case Series: full-text Gut article
Pharmacology/Background: - Proposed mechanism: terminates viral replication by binding to RNA-dependent RNA polymerase
- Not currently available in the U.S. Used in Japan for tx of influenza. First approved drug in China for tx of COVID-19
- Also known as avifavir, favilavir, fapilavir, Avigan
Favipiravir vs Arbidol for COVID-19: A Randomized Controlled Trial - KEY FINDINGS: FPV did not significantly improve clinical recovery at day 7 vs umifenovir but did decr time to no fever and cough
- Study considerations: not peer-reviewed; active control; more severe/critical pts in FPV group; pts received other antivirals and traditional Chinese medicine; limited observation time frame
- Prospective, open-label, multicenter RCT; 240 adult pts (71% age <65y; 42% pts w/ positive PCR for SARS-CoV-2; 96% w/ CT findings suggestive of COVID-19 pneumonia) received either umifenovir (Arbidol) 200 mg tid x7-10 days (n=120) or FPV 1,600 mg bid x1 on day 1, then 600 mg bid x7-10 days total (n=116); all pts received SOC
- No significant difference in primary endpoint of clinical recovery rate on day 7 (61% FPV, 51% umifenovir); quicker defervescence and sx relief w/ FPV in pts w/ moderate dz; no difference in rate of auxiliary O2 tx or noninvasive mechanical ventilation; higher serum uric acid in FPV group
- Access pre-print medRxiv article
Experimental Treatment With Favipiravir for COVID-19: An Open-Label Control Study - KEY FINDINGS: FPV decr dz progression and incr viral clearance vs LPV/r
- Study considerations: non-randomized, open-label study; excl older and severe pts; possible historical bias; relationship btwn viral titer and clinical prognosis not well defined
- Open-label, non-randomized, before-after controlled study; 80 pts (median age, 47y) w/ confirmed COVID-19 received either FPV 1,600 mg bid x2 doses, then 600 mg bid (n=35) or LPV/r 400 mg/100 mg bid (n=45) for up to 14 days or until viral clearance; pts excl if >7 days from sx onset, >75 yo, or severe clinical status, incl SaO2 <93%; all pts received inhaled IFN, and SOC
- Median time to viral clearance shorter in FPV pts (4 days vs 11 days); no difference in chest CT improvement rates on day 4 and 8, but higher rates seen in FPV pts on day 14 (91% vs 62%); higher CT improvement rates also assoc w/ pts w/ <7-day viral clearance time; more adverse events in LPV/r group (56% vs 11%)
- Access Engineering article
Pharmacology/Background: - Proposed mechanism: COVID-19 assoc w/ abnormal lipid and carbohydrate metabolism leading to lipid deposits; fenofibrate increases breakdown, reducing viral replication and dz severity
Pharmacology/Background: - Proposed mechanism: inhibits kinases which may play role in viral entry, replication, and egress; prevents viral/cell fusion via lysosomal alkalinization; anti-inflammatory activity in animal models attenuates acute lung injury
Pharmacology/Background: - Proposed mechanism: reduces inhibition of host antiviral response by blocking transport of viral proteins into nucleus
- Pharmacokinetic studies show that doses up to 10x the usual human dose result in concentrations that are substantially lower than those assoc w/ in vitro antiviral activity
Published studies: - Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With Coronavirus Disease 2019; access Chest article
- ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin Is Associated With Lower Mortality in Hospitalized Patients With COVID19; access pre-print medRxiv article
Pharmacology/Background: - Proposed mechanism: activates protein kinases leading to structural changes in ACE2 receptor and subsequent reduced SARS-CoV-2 binding affinity
Pharmacology/Background: - Proposed mechanism: interferes w/ host-regulated pathways involved in viral replication rather than a virus-targeted mechanism; broad-spectrum in vitro activity against various viruses, including coronaviruses
- Pharmacokinetic studies show that higher doses (at least 3x usual dose) may be needed to achieve adequate concentrations for antiviral activity
Pharmacology/Background: - Proposed mechanism: targets mTOR complex involved in replication of various viruses, including coronaviruses
Pharmacology/Background:
- Proposed mechanism: interferes w/ virus replication
Pharmacology/Background: - Proposed mechanism: reduces infectivity and virulence by inhibiting conversion of plasminogen to plasmin (plasmin interacts w/ viral surface proteins to increase binding to cellular receptors)
Pharmacology/Background: - Proposed mechanism: inhibits fusion of viral and cellular membranes by intercalating into membrane lipids
- Not currently available in the U.S. Used in Russia and China for tx of influenza
- Also known as Arbidol
Favipiravir vs Arbidol for COVID-19: A Randomized Controlled Trial - KEY FINDINGS: FPV did not significantly improve clinical recovery at day 7 vs umifenovir but did decr time to no fever and cough
- Study considerations: not peer-reviewed; active control; more severe/critical pts in FPV group; pts received other antivirals and traditional Chinese medicine; limited observation time frame
- Prospective, open-label, multicenter RCT; 240 adult pts (71% age <65y; 42% pts w/ positive PCR for SARS-CoV-2; 96% w/ CT findings suggestive of COVID-19 pneumonia) received either umifenovir (Arbidol) 200 mg tid x7-10 days (n=120) or FPV 1,600 mg bid x1 on day 1, then 600 mg bid x7-10 days total (n=116); all pts received SOC
- No significant difference in primary endpoint of clinical recovery rate on day 7 (61% FPV, 51% umifenovir); quicker defervescence and sx relief w/ FPV in pts w/ moderate dz; no difference in rate of auxiliary O2 tx or noninvasive mechanical ventilation; higher serum uric acid in FPV group
- Access pre-print medRxiv article
Other trials: - Arbidol Combined With LPV/r vs LPV/r Alone Against Corona Virus Disease 2019: A Retrospective Cohort Study; access J Infect article
- Arbidol Monotherapy Is Superior to Lopinavir/Ritonavir in Treating COVID-19; access J Infect article
- Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients With Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial; access Med article
- Lopinavir-Ritonavir Alone or Combined With Arbidol in the Treatment of 73 Hospitalized Patients With COVID-19: A Pilot Retrospective Study; access pre-print medRxiv article
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Immunomodulating drugs (eg, corticosteroids, tocilizumab)
corticosteroids (eg, dexamethasone) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response via inhibition of multiple cytokines
- Drugs under investigation: dexamethasone, methylprednisolone, inhaled budesonide, inhaled ciclesonide
Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 - KEY FINDINGS: CS use assoc w/ lower 28-day mortality in critically ill pts
- Study considerations: prospective meta-analysis of original pt data, only incl adults; heterogeneous definitions for mortality timeframe and critical illness; significant weight (57%) from RECOVERY trial based on preliminary data; meta-analysis of serious AEs not done, inconsistent definitions and not reported by RECOVERY; optimal CS dose/duration not assessed
- Prospective meta-analysis incl. 7 RCTs (6 studies w/ low bias risk, 1 study w/ “some concerns” of bias); 1,703 hospitalized, critically ill pts (mean age 60y) w/ COVID-19 treated w/ CS (dexamethasone, hydrocortisone, or methylprednisolone) (n=678) or SOC/placebo (n=1,025)
- 28-day all-cause mortality: CS 33% vs SOC/placebo 41% (summary OR 0.66, 95% CI 0.53-0.82 based on fixed-effect analysis; summary OR 0.7, 95% CI 0.48-1.01; I2=15.6% based on random-effects
- Access full-text JAMA article
Dexamethasone in Hospitalized Patients With COVID-19 — Preliminary Report (RECOVERY) - KEY FINDINGS: DEX reduced 28-day mortality in hospitalized pts receiving O2 or mech vent but not in pts not needing respiratory support
- Study considerations: randomized but open-label; incl limited numbers of peds, pregnant, and breastfeeding pts; excl pts w/ contraindication or definitive indication for dexamethasone
- Randomized, controlled, open-label, adaptive platform study; current analysis incl DEX vs SOC only, results for other tx arms forthcoming
- Hospitalized pts (mean age 66.1y) w/ suspected or confirmed COVID-19 (89% pts positive) randomized to DEX 6 mg PO/IV qd for up to 10 days (n=2,104) vs SOC only (n=4,321); other tx incl AZ (22%), HCQ (<1%), and IL-6 antagonist (1.9%); 16% pts needed mech vent or ECMO, 60% needed O2 only; median tx duration: 7 days; median sx duration before tx: 8-9 days
- 28-day all-cause mortality lower in DEX vs SOC group (RR 0.83, 95% CI 0.74 to 0.93); pre-specified subgroup analysis showed greater benefit in mech vent pts (36% RR reduction) and non-intubated pts on O2 (18% RR reduction) but no benefit in pts not needing resp support
- Hospital stay shorter w/ DEX vs SOC (12 vs 13 days) w/ greater probability of discharge w/in 28 days (RR 1.10, 95% CI 1.03-1.17) and lower risk of progression to invasive mech vent (RR 0.77, 95% CI 0.62-0.95)
- Access full-text N Engl J Med article
Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With Coronavirus Disease 2019 (COVID-19; Metcovid): A Randomized, Double-blind, Phase IIb, Placebo-controlled Trial - KEY FINDINGS: short-course methylprednisolone did not reduce mortality in hospitalized pts
- Study considerations: randomized; small sample size; high overall mortality compared w/ other settings; late methylprednisolone admin. in some pts
- Randomized, double-blind, controlled study; 393 hospitalized pts (mean age 55-57y) w/ COVID-19 received methylprednisolone 0.5 mg/kg IV bid x5 days (n=194) or placebo (n=199); 81.3% pts w/ lab-confirmed dz
- No significant difference in 28-day mortality; possible lower mortality rate in pts ≥60 yo w/ methylprednisolone in subgroup analysis
- Access full-text Clin Infect Dis article
Early Short Course Corticosteroids in Hospitalized Patients With COVID-19 - KEY FINDINGS: early CS in mod-severe dz decr care escalation, improved clinical outcomes
- Study considerations: quasi-experimental design; varied antiviral tx and timing; guideline adherence in post-protocol group not universal; limited f/u
- Multicenter, quasi-experimental study; institutional protocol modified to incl early CS initiation; outcomes compared before and after protocol implementation; post group pts received early methylprednisolone 0.5-1 mg/kg/day IV divided in 2 doses x3 days (up to 7 days if ICU care); 57% pre-protocol and 68% post-protocol pts received CS
- 213 hospitalized pts (median 62y; 81 pre-protocol, 132 post-protocol) w/ confirmed mod-severe COVID-19 tx w/ SOC + antivirals; CS dose and duration similar btwn groups but earlier initiation in post group (2 vs 5 days); COPD more frequent in pre-protocol group
- Lower rate of composite endpoint (ICU transfer, mech vent, death) in post-protocol (35%) vs pre-protocol (54%); median LOS reduced by 3 days w/ CS use
- Access full-text Clin Infect Dis article
Other published studies: - Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19; access JAMA article
- Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19; access JAMA article
- Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19; access JAMA article
- Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial; access Clin Infect Dis article
- Historically Controlled Comparison of Glucocorticoids With or Without Tocilizumab versus Supportive Care Only in Patients With COVID-19-Associated Cytokine Storm Syndrome: Results of the CHIC Study; access Ann Rheum Dis article
- Effect of Systemic Glucocorticoids on Mortality or Mechanical Ventilation in Patients With COVID-19; access J Hosp Med article
- Risk of COVID-19-Related Death Among Patients With Chronic Obstructive Pulmonary Disease or Asthma Prescribed Inhaled Corticosteroids: An Observational Cohort Study Using the OpenSAFELY Platform; access Lancet Respir Med article
IL-6 inhibitors (eg, tocilizumab) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia A Randomized Clinical Trial - KEY FINDINGS: compared w/ usual care, TCZ did not decr dz progression at day 4 or death at day 28, but may reduce risk of ventilation/death at day 14
- Study considerations: randomized, but open-label; primary outcome amended mid-study; small sample size; usual care not standardized; earlier TCZ admin not evaluated; CS used more in usual care group
- Multicenter, open-label, randomized study; 130 hospitalized non-ICU pts (mean 64y) w/ mod-severe COVID-19 pneumonia received TCZ 8 mg/kg + usual care on day 1 and if clinically indicated on day 3 (n=64) vs usual care alone (n=67); usual care incl. abx, antivirals, CS, vasopressors, and anticoagulants
- No significant difference in death or vent needs on day 4; cumulative incidence of ventilation or death, TCZ 24% vs usual care 36% (HR 0.58; 90% CI, 0.33-1); no significant difference in mortality over 28 days between groups
- Access JAMA Intern Med article
Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia A Randomized Clinical Trial - KEY FINDINGS: TCZ did not reduce clinical worsening vs SOC
- Study considerations: randomized, but open-label; small sample size, study interrupted due to low enrollment; excluded pts at risk for ICU admission; significant imbalances btwn groups, incl antiviral use and baseline labs
- Prospective, open-label, randomized study; 126 hospitalized pts (median age 60y) w/ COVID-19 pneumonia received TCZ 8 mg/kg (max 800 mg) w/in 8h of randomization w/ 2nd dose 12h later (n=60) or SOC only (n=66)
- No statistical difference in clinical worsening w/in 14 days (TCZ 28.3% vs SOC 27%, RR 1.05, 95% CI 0.59-1.86)
- Access JAMA Intern Med article
Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19 - KEY FINDINGS: early TCZ use assoc. w/ lower in-hospital mortality in critically ill
- Study considerations: non-randomized; inverse probability weighting; significant imbalances btwn groups; number of TCZ doses not recorded; CS duration not recorded; missing data for some key variables
- Multicenter cohort study; 3,924 hospitalized pts (median age 62y) received TCZ w/in 2 days of ICU admission (n=433) vs no TCZ; TCZ pts were younger w/ higher prevalence of hypoxemia on ICU admission and more likely to receive CS
- TCZ had lower risk of death vs no TCZ (HR 0.71, 95% 0.56-0.92); 30-day mortality, TCZ 27.5% vs 37.1% (risk difference 9.6%, 95% CI 3.1-16%)
- Access JAMA Intern Med article
Efficacy of Tocilizumab in Patients Hospitalized With Covid-19 - KEY FINDINGS: TCZ did not prevent intubation or death in mod dz
- Study considerations: small sample size; SOC evolved during trial; significant baseline differences despite randomization
- Multicenter, RCT; 242 hospitalized pts (median age 59.8y) w/ moderate dz received TCZ 8 mg/kg x1 + SOC (n=161) or placebo (n=81); concomitant RDV, HCQ, CS use permitted
- No difference in intubation rate or death w/ TCZ vs placebo (HR 0.83, 95% CI 0.38-1.81; P=0.64), and disease worsening (HR 1.11, 95% CI 0.59-2.1)
- Access N Engl J Med article
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
Expanded Access/Compassionate Use:
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors
IL-1 inhibitors (eg, anakinra) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-1 receptors
- Drugs under investigation include: anakinra, canakinumab
Anakinra for Severe Forms of COVID-19: A Cohort Study - KEY FINDINGS: anakinra decr invasive mech vent or death risk in severe dz
- Study considerations: retrospective, small sample size, historical bias; imbalanced baseline characteristics
- Retrospective cohort study; 96 hospitalized non-ICU pts w/ severe COVID-19 managed w/ SOC, incl HCQ, AZ, other abx, CS, DVT prophylaxis; prospective cohort of 52 pts received anakinra (100 mg SC bid x72h, then 100 mg SC daily x7 days) + SOC; 44 pts as historical control treated w/ SOC only; anakinra group had lower BMI, longer sx duration, higher baseline plt count, higher concomitant HCQ and AZ use
- Composite primary outcome of mech vent or death: anakinra 25% vs SOC 73% (hazard ratio 0.22, 95% CI 0.1-0.49); elevated LFTs w/ anakinra 13% vs SOC 9%; similar results observed for death alone or need for mech vent alone
- Access full-text Lancet Rheumatol article
Interleukin-1 Blockade With High-dose Anakinra in Patients With COVID-19, Acute Respiratory Distress Syndrome, and Hyperinflammation: A Retrospective Cohort Study - KEY FINDINGS: high-dose anakinra assoc w/ clinical improvement and appears safe
- Study considerations: retrospective; small sample size; historical bias; selection bias; varied dosing regimens
- Retrospective cohort study; 52 hospitalized non-ICU pts w/ confirmed COVID-19, mod-severe ARDS, and hyperinflammation managed w/ non-invasive vent and SOC, incl HCQ and LPV/r; 29 pts (median age 62y) received high-dose (HD) anakinra 5 mg/kg IV bid until sustained clinical benefit; 16 pts (median age 70y) as historical comparator treated w/ SOC only; low-dose group (anakinra 100 mg SC bid; n=7) terminated early due to lack of efficacy
- Respiratory fxn improved in 72% HD vs 50% SOC; 10% HD pts died vs 44% SOC; higher cumulative survival in HD (90% vs 56%), no difference in mech vent-free survival; HD assoc w/ CRP decr at day 21 vs no decr w/ SOC
- 24% on high dose D/C due to ADRs; 14% HD pts vs 13% SOC pts developed bacteremia; 10% HD pts vs 31% SOC pts had incr LFTs; no rebound inflammation
- Access Lancet Rheumatol article
JAK inhibitors (eg, baricitinib, ruxolitinib) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of janus-associated kinases (JAK)
- Drugs under investigation include: baricitinib, ruxolitinib, tofacitinib
Emergency Use Authorization: Expanded Access/Compassionate Use - Ruxolitinib Managed Access Program (MAP) for Patients Diagnosed With Severe/Very Severe COVID-19 Illness, NCT04337359
Ruxolitinib in Treatment of Severe Coronavirus Disease 2019 (COVID-19): A Multicenter, Single-blind, Randomized Controlled Trial - KEY FINDINGS: ruxolitinib significantly improved chest CT and lymphopenia recovery and was well-tolerated
- Study considerations: randomized but single-blind; small sample size and early termination; excluded critically ill and mech vent pts; inconclusive results based on limited data and analysis
- Prospective, single-blind, multicenter RCT; 41 pts (median age 63y) w/ severe COVID-19 randomly assigned 1:1 to receive ruxolitinib 5 mg PO bid + SOC (n=20) or vitamin C 100 mg PO bid + SOC (n=21); SOC incl antivirals, CS, and abx; median time btwn sx onset and randomization 20 days; no significant differences in baseline demographics; antivirals and CS used in 90% and 71% of pts, respectively
- No difference in time to, or rate of, clinical improvement; significant CT improvement at day 14 w/ ruxolitinib (90% vs 62%); 28% overall mortality at day 28 (ruxolitinib 0% vs vitamin C 14%), no difference in cumulative incidence of death btwn 2 groups
- No difference in total number of ADRs btwn 2 groups; no difference in median time of viral clearance; shorter median time of lymphopenia recovery in ruxolitinib group; cytokine levels significantly decreased in ruxolitinib group
- Access J Allergy Clin Immunol abstract
Baricitinib Plus Remdesivir for Hospitalized Adults With Covid-19 - KEY FINDINGS: baricitinib + RDV superior to RDV alone in reducing recovery time and accelerating clinical status improvement, particularly in pts w/ high-flow O2 or noninvasive vent
- Study considerations: other COVID-19 tx allowed, per hospital protocols; 12% pts received corticosteroid tx (6.6% DEX); median sx onset 8 days before enrollment
- Multicenter, randomized, double-blind study; 1,033 hospitalized pts (mean age 55.4y) w/ COVID-19 (68% mod. dz, 32% severe dz) received baricitinib 4 mg PO qd x14 days (n=515) or placebo (n=518); both groups received RDV 200 mg IV x1, then 100 mg IV qd x9 days; other experimental or off-label COVID-19 tx prohibited unless part of hospital protocol
- Primary outcome of time to recovery: baricitinib 7 days vs placebo 8 days (RR 1.16, 95% CI 1.01-1.32); in pts w/ high-flow O2 or noninvasive vent, baricitinib 10 days vs placebo 18 days (RR 1.51, 95% CI 1.1-2.08); no difference in 28-day mortality; fewer serious ADRs and new infxns w/ baricitinib vs placebo
- Access N Engl J Med article
Pharmacology/Background - Proposed mechanism: no direct antiviral activity; indirect immunomodulatory effects
- Incr QT prolongation risk when used w/ HCQ or CQ; monitor ECG; FDA MedWatch (4/24/20): Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication - FDA Cautions Against Use Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems; see FDA alert
Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State - KEY FINDINGS: HCQ, AZ, or both not significantly assoc w/ in-hospital mortality vs no tx
- Study considerations: retrospective, random sampling; imbalanced baseline characteristics; treatment bias; varied dosing and duration; possible missed readmissions; ADRs at any time during hospital visit, potentially prior to tx
- Retrospective multicenter cohort study; 1,438 randomly selected hospitalized pts (median age 63y) in NYC metro area w/ confirmed COVID-19 treated w/ HCQ (n=271) or AZ (n=211) alone, HCQ+AZ (n=735), or no tx (n=221); significant imbalances btwn groups, incl gender, comorbidities, and clinical severity
- Unadjusted analysis for in-hospital mortality (overall 20%), HCQ+AZ 26%, HCQ 20%, AZ 10%, no tx 13%; adjusted analysis for in-hospital mortality showed no differences when comparing pts w/ no tx to each drug group, and when comparing HCQ vs AZ
- Abnormal ECG more common in HCQ+AZ (27%) and HCQ (27%) vs AZ (16%) and no tx (14%), but no difference in adjusted analysis; more pts w/ cardiac arrest in HCQ+AZ (16%) and HCQ (14%) vs AZ (6%) and no tx (7%)
- Access JAMA article
Note: Published data summaries include AZ as mono-tx. For published studies on combo tx, refer to HCQ.
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by selectively modulating T-cell activation
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by selectively inhibiting phosphodiesterase 4 (PDE4)
Pharmacology/Background - Proposed mechanism: reduces inflammatory response by reducing release of substance P via inhibition of neurokinin-1 receptors
BTK inhibitors (eg, acalabrutinib) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting malignant B-cell proliferation via inhibition of Bruton tyrosine kinase (BTK)
- Drugs under investigation include: acalabrutinib, ibrutinib, zanubrutinib
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting interleukin pathways via interference w/ inflammasome complex assembly; reduces cell infectivity by interrupting endocytosis via inhibition of microtubule polymerization
Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial - KEY FINDINGS: colchicine significantly decr clinical deterioration rate
- Study considerations: randomized but open-label; small sample size; inconclusive results based on limited data and analysis
- Prospective, open-label, multicenter, randomized study; 105 hospitalized pts (median age 64y) w/ confirmed COVID-19 tx w/ colchicine 1.5 mg x1 then 0.5 mg after 60min, then 0.5 mg bid (n=55) + SOC or SOC only (n=50) for up to 3wk; most pts received CQ/HCQ (98%) and AZ (92%); study terminated early due to low enrollment
- Clinical deterioration rate lower in colchicine group (2% vs 14%); mean event-free survival time greater in colchicine group (20.7 vs 18.6 days); no difference in max high-sensitivity cardiac troponin levels or peak CRP levels; overall adverse events similar, but diarrhea more frequent w/ colchicine
- Access full-text JAMA Netw Open article
Other studies: - Association Between Treatment With Colchicine and Improved Survival in a Single-Centre Cohort of Adult Hospitalised Patients With COVID-19 Pneumonia and Acute Respiratory Distress Syndrome; full-text Ann Rheum Dis article
complement inhibitors (eg, eculizumab) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by modulating activity of complement pathways
- Drugs under investigation include: eculizumab, ravalizumab
Expanded Access/Compassionate Use: Published studies: - Combination of Ruxolitinib and Eculizumab for Treatment of Severe SARS-CoV-2-Related Acute Respiratory Distress Syndrome: A Controlled Study; access Front Pharmacol article
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting T lymphocytes; shown to inhibit replication of several coronaviruses in vitro
Pharmacology/Background: - Proposed mechanism: anti-inflammatory and antioxidant activity reduces development of ARDS; alters certain signaling pathways via inhibition of DNA methylation
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of phosphatidylinositol 3-kinase (PI3K)
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response via binding and neutralizing interferon gamma
Pharmacology/background: - Proposed mechanism: reduces inflammatory response; has been effective for cytokine storm caused by other diseases; topoisomerase II inhibitors suppress RNA virus replication in vitro
Pharmacology/Background: - Proposed mechanism: Reduces inflammatory response by inhibiting spleen tyrosine kinase (SYK), potentially resulting in decreased lung injury
Pharmacology/Background: - Proposed mechanism: bioactive lipid w/ anti-inflammatory properties resulting from displacement of arachidonic acid (AA) from membrane phospholipids; AA metabolized into pro-inflammatory lipid mediators (eg, prostaglandins) vs icosapent ethyl metabolized into anti-inflammatory leukotrienes; may also inactivate enveloped viruses
Pharmacology/Background: - Proposed mechanism: binds to interferon receptors, modulates immune responses to some viral infxns; in vitro studies indicate weak IFN induction in SARS-CoV-2 infxn
- Generally used in combo w/ other antivirals; IFN beta more potent than IFN alpha for coronaviruses; IFN lambda has less inflammatory effects on respiratory tract
Repurposed Antiviral Drugs for Covid-19; Interim WHO Solidarity Trial Results - KEY FINDINGS: interferon had little/no effect on mortality, vent initiation, or length of stay
- Study considerations: not peer-reviewed; randomized; interim analysis; significant proportion of pts received other potential treatments for COVID (varied by tx arm); sx duration not reported; excluded peds pts
- Multinational, randomized study; 11,266 hospitalized pts (~10% ventilated) w/ COVID-19 received either RDV (n=2,750), HCQ (n=954), LPV/r (n=1,411), IFN beta 1a + LPV/r (n=651), IFN beta 1a (n=1,412) or SOC (n=4,088); pts could receive other therapies incl CS, immunomodulators, and other non-study antivirals
- Overall 28-day mortality 12%; no significant difference in reduced mortality w/ death rate ratio vs control: RDV (RR 0.95, 95% CI 0.81-1.11), HCQ (RR 1.19, 95% CI 0.89-1.59); LPV/r (RR 1.00, 95% CI 0.79-1.25) and IFN (RR 1.16, 95% CI 0.96-1.39); no significant difference in ventilation or hospitalization duration
- Access New Engl J Med article
kallikrein-kinin system modulators (eg, lanadelumab, icatibant) Pharmacology/Background: - Proposed mechanism: possible role for dysregulated bradykinin signaling in COVID-19 respiratory complications; mechanism incl inhibiting bradykinin generation by binding plasma kallikrein or inhibiting bradykinin receptors
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting dihydroorotate dehydrogenase; in vitro effects against SARS-CoV-2
- For U.S. trials, see ClinicalTrials.gov
Pharmacology/Background: - Proposed mechanism: may enhance viral immune response while mitigating cytokine storm
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting multiple tyrosine kinases
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by blunting catecholamine effects on cytokine production
Pharmacology/Background: - Proposed mechanism: stimulates granulocyte and macrophage proliferation and differentiation; critical cytokine for pulmonary fxn; necessary for maturation and maintenance of alveolar macrophages
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by disrupting cytokine pathways via inhibition of exportin 1 (XPO1); XPO1 inhibitors have activity against many viruses, incl RNA viruses, and expected to have activity against SARS-CoV
SSRIs (fluoxetine, fluvoxamine) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting IL-6 receptors or binding to sigma-1 receptors
Published studies: - Fluvoxamine vs Placebo and Clinical Deterioration in Out-Patients With Symptomatic COVID-10; A Randomized Clinical Trial; access full-text JAMA article
statins (eg, atorvastatin) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by mitigating cytokine activation pathways; attenuates CV component or complications assoc w/ COVID-19; epidemiological data suggest protective effects in influenza pneumonia
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response by inhibiting tumor necrosis factor alpha
- Drugs under investigation: adalimumab, infliximab
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Adjunctive drugs (eg, ascorbic acid, antithrombotics)
ascorbic acid (vitamin C) Pharmacology/Background: - Proposed mechanism: reduces inflammatory response and production of reactive oxygen species via anti-inflammatory and antioxidant properties; supports host defenses and protects host cells against oxidative stress
- For additional info, see Alt Med Remedy Use in COVID-19
Pharmacology/Background: - Proposed mechanism: reduces susceptibility to infxn by supporting antimicrobial peptide production in respiratory epithelium; reduces inflammatory response by countering downregulation of ACE2 by SARS-CoV-2
- For additional info, see Alt Med Remedy Use in COVID-19
Pharmacology/Background: - Proposed mechanism: impairs replication of various viruses, incl coronaviruses, by inhibiting RNA-dependent RNA polymerase; intracellular concentrations increased by HCQ and CQ
- For additional info, see Alt Med Remedy Use in COVID-19
Hydroxychloroquine and Azithromycin Plus Zinc vs Hydroxychloroquine and Azithromycin Alone: Outcomes in Hospitalized COVID-19 Patients; access pre-print medRxiv article
antithrombotics (eg, heparin, LMWH, dipyridamole, argatroban, fondaparinux) Pharmacology/Background: - Mechanism: See individual drugs
- COVID-19 assoc w/ hypercoagulable state; thrombotic events reported despite pharmacologic VTE prophylaxis; higher prophylactic doses and/or prolonged courses may be needed; unclear role for empiric therapeutic-dose anticoagulation
- Anticoagulants under investigation: enoxaparin, heparin (IV, SC, neb, intranasal), argatroban, fondaparinux, apixaban, rivaroxaban
- Antiplatelet agents under investigation: dipyridamole, aspirin/dipyridamole, clopidogrel
epocrates drug links: heparin, enoxaparin, Lovenox, Fragmin, argatroban, Argatroban, fondaparinux, Arixtra, dipyridamole, Persantine, aspirin/dipyridamole, Aggrenox, clopidogrel, Plavix, Eliquis, Xarelto
adenosine receptor agonists (adenosine inhaled, regadenoson) Pharmacology/Background: - Proposed mechanism: inhibits acute inflammatory processes and increases protective capacity of epithelial barrier resulting in reduced cellular damage and improved oxygenation
Pharmacology/Background: - Proposed mechanism: blocks interactions btwn endothelial cells, platelets, RBCs, leukocytes (monoclonal Ab)
Pharmacology/Background: - Proposed mechanism: attenuates dysregulation of various mechanistic processes involved in acute illness, incl energy metabolism, autophagy, oxidative stress, tissue hypoxia, and inflammation
Pharmacology/Background: - Proposed mechanism: hydrolyzes extracellular DNA, decreasing mucus viscosity
hormonal tx (eg, estrogen, antiandrogens) Pharmacology/Background: - Proposed mechanism: animal studies of SARS-CoV-1 suggest protective effects of estrogen, incl immunomodulating effects and wound repair processes; androgen receptor expression assoc w/ incr expression of host proteins needed for SARS-CoV-2 viral entry
- Drugs under investigation include: estrogen, progesterone, bicalutamide, degarelix, dutasteride, toremifene
Pharmacology/Background: - Proposed mechanism: interacts w/ GABA receptors in lungs to reduce cytokine production and stimulate bronchodilation, leading to improved oxygenation; possible activity against some viruses and bacteria
- Drugs under investigation: isoflurane
Pharmacology/Background: - Proposed mechanism: reduces inflammatory response via replenishment of glutathione and reduction of proinflammatory cytokines; supports host defenses and protects host cells against oxidative stress
- For additional info, see Alt Med Remedy Use in COVID-19
pulmonary vasodilators (eg, nitric oxide, epoprostenol, aviptadil) Pharmacology/Background: - Proposed mechanism: dilates pulmonary vasculature, leading to vasodilation and increased oxygenation
- Nitric oxide reported to have in vitro activity against other coronaviruses (eg, SARS-CoV)
- Drugs under investigation include: nitric oxide, sodium nitrite, epoprostenol, aviptadil
Expanded Access/Compassionate Use:
thrombolytics (eg, alteplase [tPA], tenecteplase) Pharmacology/Background: - Proposed mechanism: See individual drugs
- COVID-19 assoc w/ hypercoagulable state; thrombotic events reported despite pharmacologic VTE prophylaxis; unclear role for thrombolytic tx
- Drugs under investigation: alteplase (tPA), tenecteplase, defibrotide
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Antibody-based therapies (eg, convalescent plasma, monoclonal antibodies)
Emergency Use Authorization Expanded Access/Compassionate Use: A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia - KEY FINDINGS: convalescent plasma had no benefit in severe dz vs placebo
- Study considerations: randomized but open-label; tx non standardized among sites; CS and other tx used in both trial groups; cannot assess early admin effects
- Multicenter, randomized, controlled study; 333 hospitalized pts (median age 62y) w/ confirmed severe COVID-19 received convalescent plasma (n=228) or placebo (n=105); median time from sx onset to enrollment 8 days; median SARS-CoV-2 Ab titer 1:3200; >90% pts received CS; smaller percentage received LPV/r, TCZ, or ivermectin
- No significant difference in 7-, 14-, or 30-day clinical outcome, time to discharge, 30-day mortality, or overall ADRs
- Access N Engl J Med article
Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial - KEY FINDINGS: convalescent plasma did not significantly decr time to clinical improvement
- Study considerations: randomized, but open label; early termination due to epidemic containment; small sample size, possibly underpowered; median time 30 days btwn sx onset and randomization; SOC not protocolized, study center variability; limited f/u
- Multicenter, open-label, randomized study; 103 hospitalized pts (median age 70y) w/ confirmed severe or life-threatening COVID-19, randomized 1:1 by dz severity to receive convalescent plasma 200 mL (n=52) or SOC alone (n=51)
- Donors recovered from COVID-19, discharged from hospital >14 days, S-protein-specific Ab titers >1:640
- No significant difference in time to clinical improvement w/in 28 days overall (convalescent plasma 51.9%, control 43.1%); in pts w/ severe dz, time to clinical improvement rate higher w/ convalescent plasma (91.3%) vs control (68.2%); no significant difference vs placebo in 28-day mortality (15% vs 24%), time to discharge (51% vs 36%); higher negative viral PCR conversion rate w/ convalescent plasma (87.2%) vs control (27.5%)
- Access JAMA abstract
Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults - KEY FINDINGS: early admin of high-titer convalescent plasma reduced COVID-19 progression in older adults w/ mild dz
- Study considerations: early termination in October 2020 due to epidemic containment in Argentina; small sample size, possibly underpowered
- Randomized, double-blind, placebo-controlled study; 160 pts (mean age 77.2y) w/ mild COVID-19 received 250 mL convalescent plasma w/ IgG titer >1:1000 (n=80) or placebo (n=80) w/in 72h after sx onset
- Significantly less pts developed severe respiratory dz w/ convalescent plasma (16% vs 31%, RR 0.52, 95% CI 0.29-0.94); lower rates of dz progression w/ infusions w/ donor titers >1:3200 (73% relative risk reduction); no correlation w/ outcomes based on recipient antibody levels; no solicited ADRs observed
- Access N Engl J Med article
Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients - KEY FINDINGS: convalescent plasma appears safe; possible mortality benefit w/ early use
- Study considerations: non-comparative; safety data only, no efficacy data; some reported SAEs may represent natural dz progression; other transfusion-related theoretical risks not reported; detailed training of study personnel lacking; web-based case reporting
- Multicenter open-label Expanded Access Program; 20,000 hospitalized pts (60% of pts over 60y, 61% male, 58% ICU pts) w/ severe or life-threatening COVID-19 received ABO-compatible COVID-19 convalescent plasma 200-500 mL IV per protocol
- Outcomes w/in 1st 4h of transfusion: 146 (<1%) serious adverse events (SAEs) classified as transfusion rxn incl transfusion-assoc circulatory overload (n=37), transfusion-related acute lung injury (n=20), severe allergic transfusion rxn (n=26); 13 transfusion-related deaths
- Outcomes w/in 7 days of tx completion: 1,136 SAEs incl thromboembolic/thrombotic event (n=87), hypotensive events requiring pressor support (n=406), cardiac events (n=643); majority of thromboembolic/thrombotic complications (n=55) and cardiac events (n=596) deemed unrelated to plasma transfusion; overall 7-day mortality rate 8.6%
- Access Mayo Clin Proc article
SARS-CoV-2-specific monoclonal antibodies Pharmacology/Background:
- Proposed mechanism: binds to specific viral targets and acts as neutralizing antibodies; most agents target spike protein, preventing viral entry and replication
- Drugs under investigation include: casirivimab (REGN10933), imdevimab (REGN10987), bamlanivimab (LY-CoV555), etesevimab (LY-CoV016)
Emergency Use Authorization: Expanded Access/Compassionate Use
- Compassionate Use of REGN-COV2 for the Treatment of COVID-19; NCT04617535
Neutralizing Monoclonal Antibody for Hospitalized Patients With Covid-19 - KEY FINDINGS: bamlanivimab + RDV did not demonstrate efficacy in hospitalized pts w/o end-organ failure
- Study considerations: preliminary report w/ limited f/u; enrollment stopped for futility; platform protocol; concomitant RDV and CS use
- Randomized, double-blind, platform trial; 314 hospitalized pts (median age 61y) w/ COVID-19, sx <12 days, and w/o end-organ failure received bamlanivimab 7000 mg IV x1 (n=163) or placebo (n=151); pts received SOC, incl RDV (95%), CS (49%), and other tx as indicated
- Interim analysis: no difference in sustained recovery (hospital discharge to home and remaining at home for >14 days) and pulmonary ordinal outcome at Day 5
- Access NEJM article
Pharmacology/Background: - Proposed mechanism: provided passive immunity
Clinical efficacy of intravenous immunoglobulin therapy in critical patients with COVID-19: a multicenter retrospective cohort study - KEY FINDINGS: no benefit in overall cohort; early high-dose use may improve prognosis in critically ill, per subgroup analysis
- Study considerations: retrospective; treatment bias; IVIG timing, dosing, and duration varied among sites
- Retrospective study; 325 hospitalized pts (mean age, 58y) w/ confirmed SARS-CoV-2 (68% severe, 32% critical); 174 pts received IVIG 0.1-0.5 g/kg daily x5-15 days, 151 pts received SOC only; IVIG pts had more severe dz (higher APACHE II, SOFA scores, O2 needs
- No significant difference in 28-day in-hospital mortality (13% in both groups) or 60-day in-hospital mortality (19% IVIG, 14% non-IVIG); IVIG group had longer LOS (23.5 vs 16 days) and longer dz duration (31 vs 23 days)
- Access Clin Transl Immunology article
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