Clemency BM, Varughese R, Gonzalez-Rojas Y, et al. Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19 – A Randomized Clinical Trial. JAMA Intern Med November 22, 2021. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2786012?resultClick=1
According to this placebo-controlled RCT of 400 patients with symptomatic COVID-19, inhaled corticosteroids (ciclesonide) do not reduce the time to alleviation of all COVID-19–related symptoms. However, the ciclesonide treatment arm had fewer subsequent emergency department visits or hospital admissions for reasons related to COVID-19 (odds ratio, 0.18; 95% CI, 0.04-0.85). No participants died during the study.
Chuah CH, Chow TS, Hor CP, et al. Efficacy of Early Treatment with Favipiravir on Disease Progression among High Risk COVID-19 Patients: A Randomized, Open-Label Clinical Trial. Clinical Infectious Diseases, 19 November 2021, ciab962, https://doi.org/10.1093/cid/ciab962
In an open label study conducted at 14 public hospitals across Malaysia from February to June 2021 among 500 symptomatic COVID-19 patients, aged ≥ 50 years with ≥ 1 co-morbidity, and hospitalized within the first 7 days of illness, there was no effect seen with favipiravir.
RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet November 17, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01825-0/fulltext
In this randomised, open-label, platform trial, several possible treatments were compared with usual care in patients hospitalized with COVID-19. Among 14,892 patients enrolled, aspirin was not associated with reductions in 28 day mortality or in the risk of progressing to invasive mechanical ventilation or death, but was associated with a small increase in the rate of being discharged alive within 28 days (75% vs 74%; rate ratio 1.06, 95% CI: 1.02–1.10; p = 0.0062).
The CORIMUNO-19 Collaborative group. Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial. Lancet Rheumatology November 17, 2021. https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00315-5/fulltext
Treatment with sarilumab, a high-affinity anti-IL-6 receptor antibody, did not improve early outcomes in patients with moderate-to-severe COVID-19 pneumonia.
Labhardt ND, Smit M, Petignat I, et al. Post-exposure Lopinavir-Ritonavir Prophylaxis versus Surveillance for Individuals Exposed to SARS-CoV-2: The COPEP Pragmatic Open-Label, Cluster Randomized Trial. EClinical Medicine November 05, 2021. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00469-7/fulltext
Too early to forget lopinavir? In this pragmatic open-label, cluster-randomized trial in Switzerland and Brazil, persons with close contact to a SARS-CoV-2 case were randomized to receive lopinavir/ritonavir PEP (400/100 mg) twice daily for 5 days or no PEP. During 21-day follow-up, 35/209 (16.7%) vs 13/109 (11.9%) developed COVID-19. In the primary endpoint analysis, adjusted for baseline imbalance, the hazard ratio was 0.60 (95% CI: 0.29-1.26; p = 0.18). The authors believe that lopinavir for this indication “merits further testing”.
Absalón-Aguilar A, Rull-Gabayet M, Pérez-Fragoso A, et al. Colchicine Is Safe Though Ineffective in the Treatment of Severe COVID-19: a Randomized Clinical Trial (COLCHIVID). J Gen Intern Med November 9, 2021: 1–11.
See title (RCT in 116 hospitalized patients with severe COVID-19 in Mexico).
Siska PJ, Decking SN, Babl N, et al. Metabolic imbalance of T cells in COVID-19 is hallmarked by basigin and mitigated by dexamethasone. J Clin Invest November 15, 2021. https://www.jci.org/articles/view/148225
This study explains how dexamethasone works in COVID-19, suggesting that effects are at least partially due to an immunometabolic modulation. More specifically, dexamethasone was effective in preventing intracellular reactive oxygen species accumulation (“oxidative stress”) and basigin elevation in T cells, two important hallmarks of severe COVID-19.
Zapatero-Belinchón FJ, Moeller R, Lasswitz L, et al. Fluvastatin mitigates SARS-CoV-2 infection in human lung cells. iScience November 17, 2021. https://www.cell.com/iscience/fulltext/S2589-0042(21)01440-1
The authors investigated the effect of statins on SARS-CoV-2 infection in human lung cells and found that only fluvastatin (and not the other statins!) inhibited low and high pathogenic coronaviruses in vitro and ex vivo in a dose-dependent manner. Fluvastatin treatment specifically down-regulated proteins that modulate protein translation and viral replication.
Bierle DM, Ganesh R, Tulledge-Scheitel S, et al. Monoclonal Antibody Treatment of Breakthrough COVID-19 in Fully Vaccinated Individuals with High-Risk Comorbidities. The Journal of Infectious Diseases November 16, 2021, jiab570, https://doi.org/10.1093/infdis/jiab570
In this large retrospective cohort of fully vaccinated persons, anti-spike monoclonal antibody treatment was significantly associated with a lower risk of hospitalization (Odds Ratio: 0.23; 95% CI: 0.13 – 0.4; p < 0.001). The number needed to treat to prevent one hospitalization was 225 among the lowest-risk patient group compared to NNT of 4 among those with the highest numbers of medical co-morbidities.
Sinha S, Rosin NL, Arora R, et al. Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19. Nat Med November 15, 2021. https://www.nature.com/articles/s41591-021-01576-3
In severe COVID-19 cases, dexamethasone affected circulating neutrophils, altered the IFNactive state, downregulated interferon-responsive genes and activated IL-1R2+ neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing ARG1 and ANXA1, genes encoding immunosuppressive molecules, which were absent in healthy controls.
Mazeraud A, Jamme M, Mancusi RL, et al. Intravenous immunoglobulins in patients with COVID-19-associated moderate-to-severe acute respiratory distress syndrome (ICAR): multicentre, double-blind, placebo-controlled, phase 3 trial. Lancet Respiratory Diseases, November 11, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00440-9/fulltext
No benefit with IVIG in 146 COVID-19 patients who received invasive mechanical ventilation for moderate-to-severe ARDS.
Pulvirenti F, Milito C, Cinetto F, et al. SARS-CoV-2 monoclonal antibody combination therapy in patients with COVID-19 and primary antibody deficiency. J Inf Dis, November 8, 2021. https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab554/6423060
In this small prospective study on clinical outcome and antiviral effect of mAbs added to standard of care therapy in 18 patients with Primary Antibody Defects, median time of SARS-CoV-2 qPCR positivity was shorter in eight patients treated with mAbs (22 days) than in ten patients treated with standard of care therapy only (37 days, p=0.026).
Cox RM, Wolf JD, Lieber CM, et al. Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets. Nat Commun November 5, 2021, 12, 6415. https://www.nature.com/articles/s41467-021-26760-4
Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. This study has characterized the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Twice-daily oral reduced SARS-CoV-2 burden to near-undetectable levels in ferrets.
Li T, Han X, Gu C, et al. Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants. Nat Commun November 2021, 12, 6304. https://www.nature.com/articles/s41467-021-26539-7
New potent neutralizing Abs with unique mechanism targeting variants. 58G6 and 13G9 both recognize the steric region S470–495 on the RBD, overlapping the E484K mutation presented in B.1.351. In mice, 58G6 and 510A5 demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351.
Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial. BMJ 02 November 2021; 375 doi: https://doi.org/10.1136/bmj-2021-068060
No effect with ciclesonide (a corticosteroid used in inhaled form to treat asthma and intranasally to treat allergic rhinitis) in this RCT in 203 healthier young adults with covid-19 presenting with prominent respiratory symptoms.
Reis G, dos Santos Moreira-Silva EA, Medeiros Silva DC, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Global Health October 27, 2021. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(21)00448-4/fulltext
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). There are several potential mechanisms in the treatment of COVID-19 illness, including anti-inflammatory and possible antiviral effects. In this large RCT from Brazil, treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19 reduced the need for hospitalization. Despite the moderate effects, the authors sound enthusiastic as they “found a clinically important absolute risk reduction of 5.0%, and 32% RR reduction, on the primary outcome“. Let’s wait for more data.
Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. NEJM October 27, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2107934?query=featured_home
Paper of the day. Sotrovimab (brand name Xevudy), formerly known as VIR-7831 and developed by Vir Biotechnology and GlaxoSmithKline, is an engineered human monoclonal antibody that neutralizes SARS-CoV-2, including variants of concern and multiple other sarbecoviruses. In this prespecified interim analysis of 583 patients, 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction: 85%). Notably, a 500 mg dose may also permit intramuscular administration.
Rubin R. Monoclonal Antibodies for COVID-19 Preexposure Prophylaxis Can’t Come Fast Enough for Some People. JAMA October 27, 2021. https://jamanetwork.com/journals/jama/fullarticle/2785781?resultClick=1
Some people with compromised immune systems do not mount an effective response to COVID-19 vaccine. These people would qualify for a pre-exposure prophylaxis (PREP). Rita Rubin summarizes the problems and hurdles.
Cho H, Gonzales-Wartz KK, Huang D, et al. Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern. Science Transl Medicine, October 20, 2021. https://www.science.org/doi/10.1126/scitranslmed.abj5413
Monoclonal Abs, when combined as bispecific antibodies, neutralized SARS-CoV-2 better than cocktails of the parental mAbs. These bispecific antibodies bound to distinct regions of the SARS-CoV-2 spike protein, neutralized variants of concern, including the Delta variant, and conferred protection when administered to hamsters before SARS-CoV-2 infection.
Maisonnasse P, Aldon Y, Marc A, et al. COVA1-18 neutralizing antibody protects against SARS-CoV-2 in three preclinical models. Nat Commun 12, 6097 (2021). https://doi.org/10.1038/s41467-021-26354-0.
COVA1-18, an RBD-specific monoclonal Ab, is one of the most potent NAb in vitro. Using different experimental models as well as mathematical modeling, the authors demonstrate that COVA1-18 may work in vivo.
Temple C, Hoang R, Hendrickson RG. Toxic Effects from Ivermectin Use Associated with Prevention and Treatment of Covid-19. NEJM October 20, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2114907?query=featured_home
The Oregon Poison Center recently received an increasing number of calls regarding ivermectin exposure. Six of the 21 cases (from August 2021) were hospitalized for toxic effects, including severe episodes of confusion, ataxia, seizures, and hypotension. Just saying.
Malani AN, LaVasseur B, Fair J, et al. Administration of Monoclonal Antibody for COVID-19 in Patient Homes. JAMA Netw Open October 14, 2021;4(10):e2129388. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2784998?resultClick=1
Experience from Michigan, US, showing how home MAb infusion (performed by a team of 3 nurses) provided a critical framework to prevent high-risk patients from seeking ED care and requiring hospitalization.
Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial. Lancet Resp Med October 18, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00384-2/fulltext
No efficacy of interferon, administered subcutaneously every other day.
Wilkinson T. Subcutaneous interferon beta-1a in COVID-19: raking the ashes of an intervention trial. Lancet Resp Med October 18, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00412-4/fulltext
Nice comment by Tom Wilkinson. “This observation is a common narrative in recent COVID-19 trials, whereby small, early, uncontrolled studies, which show hopeful signals of benefit, are not subsequently replicated in more definitive, larger scale, and later phase studies”.
RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet Resp Med October 18, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00435-5/fulltext
Boras B, Jones RM, Anson BJ, et al. Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID-19. Nat Commun 12, 6055, October 18, 2021. https://www.nature.com/articles/s41467-021-26239-2
PF-07304814 is a phosphate pro-drug rapidly converted in vivo to PF-00835231, which exhibits high selectivity over human proteases, acts as a broad-spectrum coronavirus 3CL protease inhibitor, and demonstrates potent antiviral activity in vivo. The favorable pre-clinical profile presented here supported progression to clinical trials in healthy volunteers and COVID-19 patients.
Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med. 2021 Oct 7. PubMed: https://pubmed.gov/34617959. Full text: https://doi.org/10.1001/jamainternmed.2021.6203
In this randomized clinical trial of 253 adult in-patients with high risk COVID-19, the incidence of major thromboembolism or death was 28.7% with therapeutic-dose vs 41.9% with prophylactic/intermediate-dose heparins. The treatment effect was not seen in ICU patients.
Willyard C. How antiviral pill molnupiravir shot ahead in the COVID drug hunt. Nature 2021, published 8 October. Full text: https://www.nature.com/articles/d41586-021-02783-1
Molnupiravir is a nucleoside analog that gets incorporated into burgeoning RNA strands. The compound can shift its configuration, sometimes mimicking the nucleoside cytidine and sometimes mimicking uridine. The new RNA strands become faulty blueprints for the next round of viral genomes.
Weinreich DM, Sivapalasingam S, Norton T, et al. REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. NEJM September 29, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2108163?query=featured_home
A large Phase 3 trial, showing that the early use of the two antibodies casirivimab and imdevimab in outpatients with risk factors for severe COVID-19 can lower the risk of hospitalization or death from any cause. Both doses of intravenous REGEN-COV (1200 mg and 2400 mg) led to a reduction in hospitalization or death over a period of 28 days after treatment, compared to their concurrent placebo groups (1.0 and 1.3 % vs 4.6% and 3.2%, respectively). Both doses reduced viral loads, particularly in patients with higher viral loads, with a faster time to viral clearance than placebo.
Qian Y, Lei T, Patel PS, et al. Direct activation of endothelial cells by SARS-CoV-2 nucleocapsid protein is blocked by Simvastatin. J Virology September 22, 2021. https://journals.asm.org/doi/10.1128/JVI.01396-21
It was found that the nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through several signaling pathways. Simvastatin was identified as a potent inhibitor of NP-induced endothelial activation (in contrast to other statins).
Hastie KM, Li H, Bedinger D, et al. Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study. Science, September 23, 2021. https://www.science.org/doi/10.1126/science.abh2315
Incredible work, providing a detailed structural and competitive landscape of key antibody binding sites on Spike. The results of this effort can be used to predict and interpret effects of variants of concern, and for strategic selection of durable therapeutics and cocktails against emerging variants.
Siemieniuk RA, Bartoszko JJ, Díaz Martinez JP, et al. Antibody and cellular therapies for treatment of covid-19: a living systematic review and network meta-analysis. BMJ September 23, 2021;374:n2231. https://www.bmj.com/content/374/bmj.n2231
Review of 47 trials: in patients with non-severe COVID-19, casirivimab-imdevimab probably reduces hospitalization; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalization. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.
Huo J, Mikolajek H, Le Bas A, et al. A potent SARS-CoV-2 neutralising nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19. Nat Commun September 22, 2021, 12, 5469. https://www.nature.com/articles/s41467-021-25480-z
Neutralizing single domain antibodies (“nanobodies”) are small, stable and thus compatible with respiratory administration. The authors report four nanobodies (C5, H3, C1, F2) engineered as homotrimers with picomolar affinity for the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein. Administration of C5 trimer via the respiratory route showed potent therapeutic efficacy in the Syrian hamster model of COVID-19 along with being an effective prophylaxis.
Christie MJ, Irving AT, Forster SC, et al. Of bats and men: Immunomodulatory treatment options for COVID-19 guided by the immunopathology of SARS-CoV-2 infection. Science Immunology September 17, 2021, Vol 6, Issue 63. https://www.science.org/doi/10.1126/sciimmunol.abd0205
Another excellent review, summarizing current knowledge on COVID-19 immunopathogenesis in relation to three clinical disease stages. The article also focusses on immune evasion strategies used by pathogenic coronaviruses such as skewing type I, II, and III interferon responses and inhibiting detection via pattern recognition and antigen presentation.
Fenwick C, Turelli P, Perez L, et al. A highly potent antibody effective against SARS-CoV-2 variants of concern. Cell Rep September 20, 2021. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)01278-X
While screening B cells from COVID-19 donors, the authors identified P5C3, a highly potent and broadly neutralizing monoclonal antibody with picomolar neutralizing activity against all SARS-CoV-2 variants of concern (VOC). P5C3 shows complete prophylactic protection in a SARS-CoV-2 infected hamster challenge model.
Yamin R, Jones AT, Hoffmann HH, et al. Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy. Nature September 21, 2021. https://www.nature.com/articles/s41586-021-04017-w
The antiviral activity of IgG antibodies is the outcome of Fab-mediated virus neutralization coupled with the capacity of the Fc domain to mediate effector functions through interactions with Fcγ receptors (FcγRs) expressed on effector leukocytes. Here, the authors report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease.
Dong J, Zost SJ, Greaney AJ, et al. Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail. Nat Microbiol September 21, 2021. https://www.nature.com/articles/s41564-021-00972-2
Two non-competing antibodies, designated COV2-2196 and COV2-2130 (later engineered to be long-acting IgG molecules designated as AZD8895 and AZD1061, respectively), synergistically neutralize SARS-CoV-2 in animal models. This study provides a comprehensive mapping of the effect of RBD mutations on the binding of these two antibodies (both are currently being investigated in Phase III studies), underscoring their use as a rationally designed cocktail, given that they have different escape mutations.
Karbiener M, Farcet MR, Schwaiger J, et al. Plasma from post-COVID-19 and COVID-19-Vaccinated Donors Results in Highly Potent SARS-CoV-2 Neutralization by Intravenous Immunoglobulins. The Journal of Infectious Diseases September 20, 2021, jiab482, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab482/6372887
As of September 2020, some immunoglobulin (IG) lots from US plasma have contained neutralizing antibodies against the newly emerged SARS-CoV-2. Since then, antibody positivity and antibody titers have increased sharply.
Ananworanich J, Mogg R, Dunne MW, et al. Randomized study of rivaroxaban vs. placebo on disease progression and symptoms resolution in high-risk adults with mild COVID-19. Clinical Infectious Diseases September 15, 2021, ciab813, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab813/6370549
Large RCT, showing no impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19.
Cho H, Gonzales-Wartz KK, Huang D, et al. Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern. Science Translational Medicine September 14, 2021. https://www.science.org/doi/10.1126/scitranslmed.abj5413
Hyeseon Cho and colleagues from NIH have isolated a panel of monoclonal antibodies from plasmablasts and memory B cells from COVID-19 convalescent individuals that target distinct regions of the SARS-CoV-2 spike protein. From this antibody panel, the authors have designed bispecific antibodies that potently neutralize a range of SARS-CoV-2 variants of concern, including Delta.
Ader F, Bouscambert-Duchamp M, Hites M, et al. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial. Lancet Inf Dis September 14, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00485-0/fulltext
The end for remdesivir? This large RCT conducted in 48 sites in Europe found no clinical benefit in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. The authors believe that the discrepancy observed between the present results and those from the ACTT-19 (which contributed to obtaining its Emergency Use Authorization) might be explained by the differences in study populations. There was also no effect of remdesivir on SARS-CoV-2 viral kinetics, indicating a genuine absence of effect or that treatment was administered too late to be effective.
Murray J, Hogan RJ, Martin DE, et al. Probenecid inhibits SARS-CoV-2 replication in vivo and in vitro. Sci Rep September 10, 2021, 11, 18085. https://www.nature.com/articles/s41598-021-97658-w
Probenecid potently blocked SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Plasma concentrations were up to 50-fold higher than the protein binding adjusted IC90 value following a single oral dose, supporting “the potential clinical utility” of probenecid.
Bégin, P., Callum, J., Jamula, E. et al. Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial. Nat Med September 8, 2021. https://www.nature.com/articles/s41591-021-01488-2
Huge RCT, providing the last nail in the coffin for convalescent plasma (CP). CP did not reduce the risk of intubation or death in hospitalized patients with COVID-19. Moreover, transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care. “The lack of benefit and the potential concern of harm caution against the unrestricted use of convalescent plasma for hospitalized patients with COVID-19”.
Congly SE, Varughese RA, Brown CE, et al. Treatment of moderate to severe respiratory COVID-19: a cost-utility analysis. Sci Rep September 7, 2021, 11, 17787. https://www.nature.com/articles/s41598-021-97259-7
Dexamethasone for moderate-severe COVID-19 infections was the most cost effective strategy and would have minimal budget impact. Based on current data, remdesivir is unlikely to be a cost effective treatment for COVID-19.
Al Sulaiman K, Aljuhani O, Saleh KB, et al. Ascorbic acid as an adjunctive therapy in critically ill patients with COVID-19: a propensity score matched study. Sci Rep 11 September 3, 2021, 17648. https://www.nature.com/articles/s41598-021-96703-y
Retrospective study in which low dose ascorbic acid as an adjunctive therapy in COVID-19 critically ill patients was not associated with mortality benefits, but was associated with a lower incidence of thrombosis. And yes, “further studies are required to confirm these findings.”
Kyriazopoulou E, Poulakou G, Milionis H, et al. Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial. Nat Med September 3, 2021. https://www.nature.com/articles/s41591-021-01499-z
Paper of the day, presenting encouraging data on anakinra from the SAVE-MORE study, a double-blind randomized controlled trial in 594 patients with COVID-19 at risk of progressing to respiratory failure. It works! With anakinra, an IL-1α/β inhibitor, at day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point WHO scale) was only 0.36 (95% confidence interval 0.26–0.50). The clinical benefit with anakinra was already apparent from day 14 and was maintained until day 28. The magnitude of the efficacy was shown in all multivariate analyses.
Strich JR, Tian X, Samour M, et al. Fostamatinib for the treatment of hospitalized adults with COVD-19 A randomized trial. Clinical Infectious Diseases September 1, ciab732. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab732/6358811
Fostamatinib is a novel spleen tyrosine kinase inhibitor that could ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. In 59 COVID-19 patients requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared to placebo. According to the authors, this warrants further validation in larger confirmatory trials.
Marconi VC, Ramanan AV, de Bono S, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Resp Med September 01, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00331-3/fulltext
Baricitinib “is a potentially effective oral treatment option”. In this huge Phase III trial on 1527 hospitalized COVID-19 patients, the 28-day all-cause mortality was 8% for baricitinib and 13% for placebo (hazard ratio 0.57, 95% CI: 0.41–0.78), a 38% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants.
Kailil AC, Stebbing J. Baricitinib: the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial. Lancet Resp Med September 01, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00358-1/fulltext
Comment on the above study. According to Andre Kalil and Justin Stebbing, “the clinical benefits and significant reduction in mortality, as well as the absence of safety concerns found by both the COV-BARRIER and ACTT-2 studies, place baricitinib among the few proven treatments of choice for hospitalised patients with COVID-19”.
Kosmopoulos A, Bhatt DL, Meglis G, et al. A Randomized Trial of Icosapent Ethyl in Ambulatory Patients with COVID-19. IScience August 26, 2021. https://www.cell.com/iscience/fulltext/S2589-0042(21)01008-7
IPE is believed to afford potent vasculoprotective effects. This small randomized study provides “possible evidence” of an early anti-inflammatory effect of IPE, including an initial loading dose, in symptomatic COVID-19 outpatients. While the difference in change in hs-CRP between groups was not statistically significant, changes in inflammatory biomarker levels were associated with significant improvement in patient-reported symptoms over a 14+3-day period.
Van Blargan LA, Adams LJ, Liu Z, et al. A potently neutralizing SARS-CoV-2 antibody inhibits variants of concern by utilizing unique binding residues in a highly conserved epitope. Immunity August 18, 2021. https://doi.org/10.1016/j.immuni.2021.08.016
Presentation of a new mAb, SARS2-38, that potently neutralizes all SARS-CoV-2 variants of concern tested and protects mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engages a conserved epitope proximal to the receptor binding motif.
Ehrmann S, Li J, Ibarra-Estrada M, et al. Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a randomised, controlled, multinational, open-label meta-trial. Lancet Resp Med, August 20, 2021. https://doi.org/10.1016/S2213-2600(21)00356-8
This collaborative meta-trial of six randomized controlled open label superiority trials shows that awake prone positioning of patients with hypoxemic respiratory failure due to COVID-19 reduces the need for intubation with no signs of harm. 14 patients treated with awake prone positioning avoids one intubation.
Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. N Engl J Med. 2021 Aug 18. PubMed: https://pubmed.gov/34407339. Full text: https://doi.org/10.1056/NEJMoa2103784
Time to close the chapter on convalescent plasma? In this randomized, multicenter, single-blind trial (257 in the convalescent plasma group and 254 in the placebo group), the administration of COVID-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of COVID-19 did not prevent disease progression.
Crippa JAS, Zuardi AW, Guimarães FS, et al. Efficacy and Safety of Cannabidiol Plus Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and Burnout Among Frontline Health Care Workers During the COVID-19 Pandemic: A Randomized Clinical Trial. JAMA Netw Open. 2021 Aug 2;4(8):e2120603. PubMed: https://pubmed.gov/34387679. Full text: https://doi.org/10.1001/jamanetworkopen.2021.20603
Randomized trial of 120 frontline health care professionals. “Emotional exhaustion scores were reduced among participants receiving cannabidiol (CBD) [300 mg] plus standard care compared with those receiving standard care alone. Five participants who received CBD plus standard care experienced serious adverse events, with full recovery after discontinuation.”
Rizk JG, Gupta A, Sardar P, et al. Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review. JAMA Cardiol. 2021 Aug 10. PubMed: https://pubmed.gov/34374713. Full text: https://doi.org/10.1001/jamacardio.2021.3444
The recommendations of this review: treatment of vaccine-induced immune thrombotic thrombocytopenia (VITT) should consist of therapeutic anti-coagulation mostly with non-heparin products and high-dose intravenous immunoglobin (IVIG). In severe cases, plasma exchange should be used for clearing autoantibodies. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying risk of bleeding.
Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet 2021, published 10 August. Full text: https://doi.org/10.1016/S0140-6736(21)01744-X
Inhaled budesonide, 800 μg twice daily for 14 days, might improve time to recovery and possibly reduce hospital admissions or deaths. In this primary analysis of a randomized trial, time to first self-reported recovery was reduced by almost 3 days with budesonide (11.8 vs 14.7 days). For hospital admissions or deaths, the estimated rate was 6.8% in the budesonide group versus 8.8% in the usual care group. See also comment by Mangin D, Howard M. The use of inhaled corticosteroids in early-stage COVID-19. Lancet 2021, published 10 August. Full text: https://doi.org/10.1016/S0140-6736(21)01809-2
Tattersall RS, McGonagle D, Manson JJ. A role for interleukin-1 receptor antagonism in severe COVID-19? Lancet Rheumatol 2021, published 9 August. Full text: https://doi.org/10.1016/S2665-9913(21)00249-6
Dexamethasone and tocilizumab, an interleukin (IL)-6 receptor inhibitor, have an established role in the treatment of hyperinflammatory COVID-19. What about anakinra, a recombinant IL-1 receptor antagonist? The authors discuss a paper that finds that anakinra may not be beneficial above and beyond dexamethasone. One possible exception: patients with evidence of a significant inflammatory response, defined as a C-reactive protein concentration higher than 100 mg/L.
O’Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021 Aug 4. PubMed: https://pubmed.gov/34347950. Full text: https://doi.org/10.1056/NEJMoa2109682
Normally, articles published in the New England Journal of Medicine provide relevant and important information for the improvement of medical care. This one might fail to reach that benchmark. You would need to treat 753 people to prevent 48 household infections with SARS-CoV-2. That is, 16 people treated to prevent one infection. Disappointingly, apart from the ‘duration of symptoms’, this study doesn’t present any clinical data on the 70 people who got infected. The combination of vaccines and – later on – cheap antiviral drugs will help combat the COVID-19 pandemic, monoclonal antibodies won’t.
REMAP-CAP, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med 2021, published 4 July. Full text: https://doi.org/10.1056/NEJMoa2103417
No benefit for critically ill patients with COVID-19 from routine therapeutic-dose anticoagulation with unfractionated or low-molecular-weight heparin. See also the comment by ten Cate H. Surviving Covid-19 with Heparin? N Engl J Med 2021, published 4 July. Full text: https://doi.org/10.1056/NEJMe2111151
Abbasi J. Überantibodies From Recovered COVID-19 Patients Could Spur New Therapeutics and Vaccines. JAMA. 2021 Jul 28. PubMed: https://pubmed.gov/34319350. Full text: https://doi.org/10.1001/jama.2021.12915
A comment on the Wang paper that described antibodies with sub-nanomolar neutralization titers: Wang L, Zhou T, Zhang Y. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants. Science 01 Jul 2021: eabh1766. https://science.sciencemag.org/content/early/2021/06/30/science.abh1766
Butler CC, Yu LM, Dorward J, et al. Doxycycline for community treatment of suspected COVID-19 in people at high risk of adverse outcomes in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet Resp Med 2021, published 27 July. Full text: https://doi.org/10.1016/S2213-2600(21)00310-6
Don’t use doxycycline as a routine treatment for COVID-19! In patients with suspected COVID-19 who were at high risk of adverse outcomes, treatment with doxycycline was not associated with clinically meaningful reductions in time to recovery, hospital admissions or deaths related to COVID-19.
Tummino TA, Rezelj VV, Fischer B, et al. Phospholipidosis is a shared mechanism underlying the in vitro antiviral activity of many repurposed drugs against SARS-CoV-2. Science, 2021, published 30 July. PubMed: https://pubmed.gov/33791693. Full-text: https://science.sciencemag.org/content/373/6554/541
Why repurposing drugs for COVID-19 has drawn so much attention… and yielded so few results. See also the comment by Edwards A, Hartung IV. No shortcuts to SARS-CoV-2 antivirals. Science 2021, published 30 July. Full text: https://doi.org/ 10.1126/science.abj9488
Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021 Jul 29;385(5):406-415. PubMed: https://pubmed.gov/34133856. Full-text: https://doi.org/10.1056/NEJMoa2101643
Now in NEJM’s print edition. Our previous comment on the online publication (16 June): tofacitinib (Wikipedia) is an orally administered selective inhibitor of Janus kinase (Jak), that blocks intracellular transduction pathways after a cytokine is bound to its receptor (as a consequence, no cellular response is triggered, and cytokine production is indirectly suppressed). Among patients hospitalized with COVID-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than did placebo. The cumulative incidence of death or respiratory failure was 18.1% versus 29.0% in the placebo group (risk ratio, 0.63; 95% CI: 0.41 to 0.97; p = 0.04).
Drayman N, DeMarco JK, Jones KA, et al. Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2. Science 2021, published 20 July. Full text: https://doi.org/10.1126/science.abg5827
Masitinib is an orally bioavailable tyrosine kinase inhibitor used in the treatment of canine mast cell tumors. After screening a library of 1900 drugs, the authors show that the drug is a competitive inhibitor of 3Clpro, the SARS-CoV-2 main protease. In vitro, masitinib was effective against the Alfa, Beta and Gamma variants (B.1.1.7, B.1.351, P.1). Mice infected with SARS-CoV-2 and then with masitinib showed a > 200-fold reduction in viral titers in the lungs and nose.
Ohl ME, Miller DR, Lund BC, et al. Association of Remdesivir Treatment With Survival and Length of Hospital Stay Among US Veterans Hospitalized With COVID-19. JAMA Netw Open July 15, 2021, 4(7):e2114741. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781959?resultClick=1
In this cohort study of 2344 US veterans hospitalized with COVID-19, remdesivir therapy was not associated with improved 30-day survival but was associated with a significant increase in median time to hospital discharge.
Oldenburg CE, Pinsky BA, Brogdon J, et al. Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection – A Randomized Clinical Trial. JAMA July 16, 2021. doi:10.1001/jama.2021.11517
In this randomized trial that included 263 outpatients with SARS-CoV-2 infection, treatment with a single oral dose of azithromycin, 1.2 g, vs placebo resulted in self-reported absence of COVID-19 symptoms at day 14 in 50% vs 50%.
Dougan M, Nirula A, Azizad M, et al. Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19. for the BLAZE-1 Investigators. NEJM July 14, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2102685?query=featured_home
This RCT shows the clinical benefit of early testing for SARS-CoV-2 infection coupled with prompt intervention with neutralizing antibody therapy in high-risk ambulatory patients: By day 29, 11/518 patients (2.1%) in the bamlanivimab–etesevimab group had a COVID-19–related hospitalization or death from any cause, as compared with 36/517 patients (7.0%) in the placebo group. At day 7, a greater reduction from baseline (difference from placebo in the change from baseline, −1.20; P<0.001).
Mura C, Preissner S, Nahles S, et al. Real-world evidence for improved outcomes with histamine antagonists and aspirin in 22,560 COVID-19 patients. Sig Transduct Target Ther July 14, 2021, 6, 267. https://www.nature.com/articles/s41392-021-00689-y
In this analysis of 22,560 COVID-19 patients taking H1/H2 receptor antagonists, the combination of famotidine and aspirin exhibited a significant synergistic survival benefit (OR 0.55, CI 0.39–0.78). The RR for death decreased by 32.5%—an immense benefit. The authors anticipate that at least three prospective RCTs that have been underway (NCT04504240, NCT04370262, and NCT04545008) will illuminate famotidine’s potential therapeutic profile.
Starr TN, Czudnochowski N, Liu Z, et al. SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape. Nature Jul 14, 2021. https://www.nature.com/articles/s41586-021-03807-6
The authors have identified neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a previously undescribed cryptic epitope and prophylactically protects hamsters from viral challenge. Another RBM antibody (S2E128) had an unusual breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape.
Koehler J, Ritzer B, Weidlich S, et al. Use of monoclonal antibody therapy for nosocomial SARS-CoV-2 infection in patients at high risk for severe COVID-19: experience from a tertiary-care hospital in Germany. Infection July 6, 2021. https://doi.org/10.1007/s15010-021-01657-y
Because of an in-house transmission of SARS-CoV-2 infection, 11 patients received monoclonal antibodies shortly after an infection (eight cases received bamlanivimab, three received the combination of casirivimab and imdevimab), and prior to symptoms. Despite many risk factors, none of these 11 patients were admitted to the intensive care unit or died from any causes.
Hinks TS, Cureton L, Knight R, et al. Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial. Lancet Resp Med July 09, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00263-0/fulltext
In patients with mild-to-moderate COVID-19, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death.
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19A Meta-analysis. JAMA July 6, 2021. https://jamanetwork.com/journals/jama/fullarticle/2781880?resultClick=1
This prospective meta-analysis of 27 randomized trials included 10,930 patients. The 28-day all-cause mortality was lower among patients who received IL-6 antagonists compared with those who received usual care or placebo (summary odds ratio, 0.86). Administration of IL-6 antagonists was also associated with lower progression to IMV or death, cardiovascular support or death.
Leach DA, Mohr A, Giotis ES, et al. The antiandrogen enzalutamide downregulates TMPRSS2 and reduces cellular entry of SARS-CoV-2 in human lung cells. Nat Commun Jul 1, 2021, 12, 4068. https://www.nature.com/articles/s41467-021-24342-y
Treatment with the anti-androgen enzalutamide—a well-tolerated drug widely used in advanced prostate cancer—reduces TMPRSS2 levels in human lung cells and in mouse lungs. Anti-androgens significantly reduced SARS-CoV-2 entry and infection in lung cells.
Wang L, Zhou T, Zhang Y. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants. Science 01 Jul 2021: eabh1766. https://science.sciencemag.org/content/early/2021/06/30/science.abh1766
The authors identified four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526 and B.1.617 VOCs. Two antibodies were ultrapotent, with sub-nanomolar neutralization titers. The structural and functional determinants of binding for all four VOC-targeting antibodies were determined. Combinations of two antibodies decreased the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.
Roman YM, Burela PA, Pasupuleti V, et al. Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials. Clinical Infectious Diseases June 28, 2021, ciab591, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab591/6310839
In comparison to standard of care or placebo, ivermectin did not reduce all-cause mortality, length of stay or viral clearance in this review of 10 RCTs in COVID-19 patients with mostly mild disease. Ivermectin is not a viable option for treating COVID-19 patients.
Tummino TA, Rezelj VV, Fischer B, et al. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science 22 Jun 2021: eabi4708. https://science.sciencemag.org/content/early/2021/06/22/science.abi4708
Paper of the day. Why did so many drugs that were repurposed for antiviral activity against SARS-CoV-2 fail in vivo, despite promising effects in vitro? This milestone study may explain why. Many drugs are cationic amphiphiles, and despite their diverse structures and multiple targets, many likely have their antiviral effects via a single shared mechanism: phospholipidosis. Both because of the side effects with which it is associated, and the limited efficacy to which it leads, drugs active due to phospholipidosis are unlikely to translate in vivo. Many resources will be saved by counter-screening for phospholipidosis in simple cellular assays.
Case JB, Chen RE, Cao L, et al. Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease. Cell Host Microbe June 18, 2021. https://doi.org/10.1016/j.chom.2021.06.008
Compared to other SARS-CoV-2 antibody-based treatments, mini-proteins have several benefits: (a) due to their smaller size, they can bind each protomer of a single trimeric spike, resulting in greater potency for a given dose; (b) they can be manufactured cost-effectively; (c) if warranted, they can be refined and mixed to overcome escape and resistance by new variants. The authors have developed picomolar range mini-proteins targeting the SARS-CoV-2 spike receptor binding domain. Here, they investigated the capacity of modified versions of one lead mini-protein, LCB1, to protect against SARS-CoV-2-mediated lung disease in mice. Promising. The immunogenicity and pharmacokinetic and pharmacodynamic properties of the mini-binders in larger vertebrate animals will inform possible clinical evaluation in humans.
Aman J, Duijvelaar E, Botros L, et al. Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial. Lancet Resp Med June 17, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00237-X/fulltext
Early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. In this large RCT, imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in 385 patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (8% versus 14% with placebo) were attenuated after adjustment for baseline imbalances.
Guimarães PO, Quirk D, Furtado RH, et al. Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia. NEJM June 16, 2021. https://www.nejm.org/doi/full/10.1056/NEJMoa2101643?query=featured_home
Tofacitinib is an orally administered selective inhibitor of Janus kinase (Jak), that blocks intracellular transduction pathways after a cytokine is bound to its receptor (as a consequence, no cellular response is triggered, and cytokine production is indirectly suppressed). Among patients hospitalized with COVID-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than did placebo. The cumulative incidence of death or respiratory failure was 18.1% versus 29.0% in the placebo group (risk ratio, 0.63; 95% CI: 0.41 to 0.97; p = 0.04).
Bauer A, Schreinlechner M Sappler N, et al. Discontinuation versus continuation of renin-angiotensin-system inhibitors in COVID-19 (ACEI-COVID): a prospective, parallel group, randomised, controlled, open-label trial. Lancet Resp Med June 11, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00214-9/fulltext
In this open label RCT (ACEI-COVID) performed at 35 centers in Austria and Germany, 204 patients (median age 75 years) were randomly assigned to discontinue or continue RAS inhibitors. Of note, discontinuation had no significant effect on the maximum severity of COVID-19 but led to a faster and better recovery. At 30 days, 11 (11%) in the discontinuation group and 23 (23%) in the continuation group had signs of organ dysfunction (SOFA score ≥ 1) or were dead (p = 0·017).
Kerneis M, Montalescot G. RAS inhibition and COVID-19: more questions than answers? Lancet Resp Med June 11, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00233-2/fulltext
Comment on ACEI-COVID. See title. Mathieu Kerneis and Gilles Montalescot argue that the study should be interpreted with great caution, considering that it derives from secondary analyses of a study that did not meet its primary endpoint.
Vaughn VM, Yost M, Abshire C, et al. Trends in Venous Thromboembolism Anticoagulation in Patients Hospitalized With COVID-19. JAMA Netw Open June 11, 2021;4(6):e2111788. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780927?resultClick=1
In this cohort study of 1351 patients hospitalized with COVID-19 in which 1127 patients received anti-coagulation, prophylactic anti-coagulation remained associated with lower mortality at 60 days.
Lopes RD, de Barros e Silva PD, Furtado RH, et al. Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial. Lancet June 04, 2021. DOI:https://doi.org/10.1016/S0140-6736(21)01203-4
In this large RCT on 615 patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Moreover, the primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation.
Cohen MS, Nirula A, Mulligan MJ, et al. Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. JAMA June 3, 2021. https://jamanetwork.com/journals/jama/fullarticle/2780870?resultClick=1
Bamlanivimab (BAM), a neutralizing monoclonal antibody, is effective in reducing the incidence of mild or worse COVID-19 in residents and participants at high risk of severe COVID-19. This large Phase III RCT included 966 participants who were residents or staff at US skilled nursing facilities with at least one confirmed SARS-CoV-2 index case. The incidence of COVID-19 infection among those treated with a single infusion of BAM was 8.5% vs 15.2% with placebo, with an odds ratio of 0.43 (95% CI: 0.28-0.68). Moreover, participants who received BAM and acquired SARS-CoV-2 had lower baseline viral loads and shorter time to viral clearance. However, one limitation is that the study was conducted prior to the occurrence of variants that may have reduced susceptibility.
Ku Z, Xie X, Hinton PR. Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Nature June 3, 2021. https://www.nature.com/articles/s41586-021-03673-2
A breakthrough in treatment? The authors have engineered an immunoglobulin M (IgM) neutralizing antibody (IgM-14) to overcome resistance. IgM-14 is > 230-fold more potent than its parental IgG-14 in neutralizing SARS-CoV-2 and potently neutralizes almost all resistant viruses, including those that are resistant to the IgGs that have been authorized for emergency use. In mice.
Mariette X, Hermine O, Tharaux PL, et al. Effectiveness of Tocilizumab in Patients Hospitalized With COVID-19A Follow-up of the CORIMUNO-TOCI-1 Randomized Clinical Trial. JAMA Network May 24, 2021. https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2780021?resultClick=1
Post hoc analysis of a French RCT, including hospitalized patients who were receiving oxygen but did not require high-flow or mechanical ventilation. Results were stratified by CRP. In patients with CRP levels greater than 15.0 mg/dL, the percentage of patients who received ventilation or those who died was 18% and 57% in the tocilizumab and usual care groups, respectively. Day-90 mortality was 9% and 35% in the tocilizumab and usual care groups, respectively.
Bian H, Zheng ZH, Wei D, et al. Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial. Sig Transduct Target Ther May 17, 2021, 6, 194.
CD147 serves as a novel receptor for SARS-CoV-2 infection. Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication. Meplazumab is a humanized anti-CD147 IgG2 monoclonal antibody, which may effectively prevent SARS-CoV-2 infection. This small pilot study on 19 COVID-19 patients suggests that meplazumab could accelerate the recovery of patients from pneumonia with a favorable safety profile.
RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet May 14, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00897-7/fulltext
No, it’s not a matter of titres, antibodies, timing, endpoints etc: convalescent plasma (CP) has NO clinical benefit. In RECOVERY, the by far largest study to date on patients hospitalized with COVID-19, high-titre CP did not improve survival: 1399 (24%) of 5795 patients died in the CP group and 1408 (24%) of 5763 patients died in the usual care group. Of note, there were no differences in other prespecified clinical outcomes and the results were consistent across subgroups of age, sex, ethnicity, duration of symptoms before randomization, level of respiratory support received at randomisation, and use of corticosteroids. Time to face the reality.
Cáceres CJ, Cardenas-Garcia S, Carnaccini S et al. Efficacy of GC-376 against SARS-CoV-2 virus infection in the K18 hACE2 transgenic mouse model. Sci Rep May 4, 2021, 11, 9609. https://www.nature.com/articles/s41598-021-89013-w
GC-376 is a Mpro inhibitor with antiviral activity against SARS-CoV-2 in vitro. In mice challenged with a low virus dose, GC-376 treatment led to milder tissue lesions, reduced viral loads, less presence of viral antigen, and reduced inflammation in comparison to vehicle-treated controls.
Drake TM, Fairfield CJ, Pius R, et al. Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study. Lancet Rheumatology May 07, 2021. https://doi.org/10.1016/S2665-9913(21)00104-1
Do you remember the rumors surrounding ibuprofen use during the first wave? Forget it. Among 78,674 patients across 255 health-care facilities in England, Scotland, and Wales, NSAID use was not associated with higher mortality or increased severity of COVID-19.
Bartoszko JJ, Siemieniuk RA, Kum E, et al. Prophylaxis against covid-19: living systematic review and network meta-analysis. BMJ April 26, 2021; 373. https://www.bmj.com/content/373/bmj.n949
Bottom line of this review, including 9 RCTs: HCQ (hydroxychloroquine) is not protective and probably increases adverse effects, and any effect of ivermectin is “highly uncertain”.
RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet May 01, 2021. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00676-0/fulltext
Paper of the day: The RECOVERY results do support the use of tocilizumab (TCZ)! Overall, 621 (31%) of the 2022 patients allocated to TCZ and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0.85; 95% CI: 0.76–0.94; p = 0.0028). TCZ patients were more likely to be discharged from hospital within 28 days (57% vs 50%). Benefits were consistent across all patient groups studied, including those receiving invasive mechanical ventilation, non-invasive respiratory support, or no respiratory support other than simple oxygen. The benefits were also clearly seen among those also receiving steroids. Of note, the RECOVERY trial contains around four times as much information as all previous trials combined.
Huang L, Yuen TT, Ye Z et al. Berbamine inhibits SARS-CoV-2 infection by compromising TRPMLs-mediated endolysosomal trafficking of ACE2. Sig Transduct Target Ther 6, 168 April 24, 2021. https://www.nature.com/articles/s41392-021-00584-6
Berbamine compromises the endolysosomal trafficking of ACE2 via inhibition of TRPMLs, and this leads to an increase in the secretion of ACE2 via exosomes and a concomitant decrease in the levels of ACE2 at the cell surface, thereby preventing SARS-CoV-2 from entering the host cells. Before ordering (and drinking) barberry tea, however, let’s wait for clinical data.
Reis G, Moreira Silva EA, Medeiros Silva DC, et al. Effect of Early Treatment With Hydroxychloroquine or Lopinavir and Ritonavir on Risk of Hospitalization Among Patients With COVID-19The TOGETHER Randomized Clinical Trial. JAMA Netw Open April 22, 2021;4(4):e216468. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2779044?resultClick=1
In this large trial from Brazil, rates of COVID-19–associated hospitalization in 685 patients treated with hydroxychloroquine or lopinavir-ritonavir were not significantly different compared with those who received placebo. The trial was stopped after the interim analysis for futility.
Derington CG, Cohen JB, Mohanty AF, et al. Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans. PLOS April 23, 2021 https://doi.org/10.1371/journal.pone.0248080
One of the first observational study to show a protective association among outpatients between current users of an ARB compared to ACEI on COVID-19-related outcomes. In this retrospective cohort study of 4,969 Veterans with treated hypertension (and without compelling indications), current users of an ARB in the outpatient cohort had a 9% lower relative risk of all-cause hospitalization or mortality and 16% lower relative risk of ICU admission compared to ACEI users.
Sasisekharan R. Preparing for the Future — Nanobodies for Covid-19? NEJM April 22, 2021, 384:1568-1571. https://www.nejm.org/doi/full/10.1056/NEJMcibr2101205?query=featured_home
Intravenously administered antibody drugs are facing several problems, including the narrow therapeutic window, the relative paucity of infusion centers and medical staff professionals, and the emergence of mutations that affect the spike protein. This brief review focusses on nanobodies that may offer a cheap alternative, possibly formulated for aerosol or subcutaneous administration.
Taylor PC, Adams AC, Hufford MM, et al. Neutralizing monoclonal antibodies for treatment of COVID-19. Nat Rev Immunol April 17, 2021. https://doi.org/10.1038/s41577-021-00542-x
Excellent review. Early clinical trial data is encouraging, but many unanswered questions set a pressing research agenda. Which at-risk individuals would benefit most from prophylactic neutralizing mAbs? What is the duration of protection? Is there any potential impact of mAb therapy on subsequent vaccination? It will also be important to determine the optimum timing for administration of neutralizing mAbs on the basis of viral load, serology and other potential clinical factors.
Rosenke K, Hansen F, Schwarz B, et al. Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model. Nat Commun 12, 2295 (2021). https://doi.org/10.1038/s41467-021-22580-8
A new post-exposure prophylaxis? Molnupiravir (MK-4482), an orally administered nucleoside analog, inhibited SARS-CoV-2 replication in the Syrian hamster model. An inhibitory effect was observed in animals when the drug was administered either beginning 12 h before or 12 h after infection in a high-risk exposure model. Large clinical trials are planned (or ongoing). However, the potential treatment window for molnupiravir may be small. Direct acting antivirals seem to be most effective in modifying disease outcome when administered as early as possible following infection.
Keating SM, Mizrahi RA, Adams MS, et al. Generation of recombinant hyperimmune globulins from diverse B-cell repertoires. Nat Biotechnol April 14, 2021. https://www.nature.com/articles/s41587-021-00894-8
This paper describes a new technology (a microfluidics and molecular genomics strategy) for generating recombinant hyperimmune globulins that combines the advantages of recombinant antibodies (purity, consistency, potency) with the advantages of plasma-derived antibodies (proven efficacy, diversity, polyvalence, in vivo affinity maturation).
Gaziano L, Giambartolomei C, Pereira AC, et al. Actionable druggable genome-wide Mendelian randomization identifies repurposing opportunities for COVID-19. Nat Med. 2021 Apr 9. https://www.nature.com/articles/s41591-021-01310-z
Genetic variants acting in ‘cis’ on druggable protein levels or gene expression that encode druggable proteins may mimic the beneficial (or harmful) effects observed by pharmacological modification. This large-scale MR analysis of protein and gene expression data for 1263 actionable druggable genes revealed evidence for drug targets of type I IFNs (IFNAR2) and ACE2 modulators (ACE2) as priority drug candidates for evaluation.
Ramakrishnan S, Nicolau Jr DV, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Resp Med April 09, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00160-0/fulltext
In this open-label, phase 2 RCT in 146 adults with mild COVID-19 symptoms, early administration of inhaled budesonide within 7 days reduced the likelihood of needing urgent medical care (1% vs 14%) and reduced time to recovery after early COVID-19. The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. According to the authors, their findings “require urgent validation and dissemination”. However, this encouraging early data is good news, the difference in the primary endpoint impressive. Inhaled budesonide is a simple, safe, well studied, inexpensive, and widely available treatment. A game changer – if confirmed by a phase 3 RCT.
Wadvalla BA. Covid-19: Ivermectin’s politicisation is a warning sign for doctors turning to orphan treatments. BMJ April 1, 2021; 373. https://www.bmj.com/content/373/bmj.n747
Excellent feature on how a debate has reached fever pitch, concluding that doctors “are just as susceptible to the availability heuristic as anyone else and use the experience of ‘n-of-1’ experiments (on a single patient) to signify more importance than what observations might warrant.”
Bharat A, Machuca TN, Querrey M, et al. Early outcomes after lung transplantation for severe COVID-19: a series of the first consecutive cases from four countries. Lancet Resp Medicine March 31, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00077-1/fulltext
Twelve cases. The transplant procedures were technically challenging, with severe pleural adhesions, hilar lymphadenopathy, and increased intraoperative transfusion requirements. However, there was no recurrence of SARS-CoV-2 in the allografts and 11/12 were alive at a median of 80 days after transplantation.
Jagannathan P, Andrews JR, Bonilla H, et al. Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nat Commun March 30, 2021, 12, 1967. https://www.nature.com/articles/s41467-021-22177-1
Next disappointment: in this well-conducted, placebo-controlled RCT, a single dose of subcutaneous peg-interferon lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in out-patients with uncomplicated COVID-19.
Ho JS, Mok BW, Campisi L, et al. TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation. Cell March 30, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00382-2
Therapeutic treatment with two doses of topotecan, an FDA-approved topoisomerase inhibitor, suppressed infection-induced inflammation in hamsters. Treatment as late as four days post-infection reduces morbidity and mortality in a transgenic mouse model.
Driouich JS, Cochin M, Lingas G. et al. Favipiravir antiviral efficacy against SARS-CoV-2 in a hamster model. Nat Commun March 19, 2021, 12, 1735. https://www.nature.com/articles/s41467-021-21992-w
In hamsters, favipiravir has a strong dose effect, when treatment is initiated before or simultaneously with infection. This led to reduction of infectious titers in lungs and clinical alleviation of the disease.
Solaymani-Dodaran M, Ghanei M, Bagheri M, et al. Safety and efficacy of Favipiravir in moderate to severe SARS-CoV-2 pneumonia. Int Immunopharmacol. 2021 Mar 11;95:107522. PubMed: https://pubmed.gov/33735712. Full-text: https://doi.org/10.1016/j.intimp.2021.107522
In humans, this may be different. A large RCT from Iran, 380 patients randomly allocated into favipiravir and lopinavir/ritonavir, found no clinical benefit of favipiravir. Though the trial was hampered by some methodological issues (as well as its open label design), it seems obvious that patients who are hospitalized due to pneumonia and have passed the viral replication phase, are unlikely to benefit from antiviral treatment.
Cremer PC, Abbate A, Hudock K, et al. Mavrilimumab in patients with severe COVID-19 pneumonia and systemic hyperinflammation (MASH-COVID): an investigator initiated, multicentre, double-blind, randomised, placebo-controlled trial. Lancet Rheumatology March 17, 2021. DOI: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(21)00070-9/fulltext
Mavrilimumab is a monoclonal antibody that binds to the GM-CSF receptor and blocks intracellular signalling of GM-CSF. Based on this mechanism of action, the putative role of increased GM-CSF in adverse outcomes from COVID-19, and encouraging results from an observational study, the authors initiated a small RCT of 40 patients to evaluate whether mavrilimumab works in severe COVID-19. It didn’t.
Jevalikar G, Mithal A, Singh A, et al. Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19. Sci Rep 11, 6258 (2021). https://www.nature.com/articles/s41598-021-85809-y
Oh, again, no effect of vitamin D. In this prospective observational study on 404 patients, serum 25-OHD levels at admission did not correlate with inflammatory markers, clinical outcomes, or mortality in hospitalized COVID-19 patients. Treatment of vitamin D deficiency with cholecalciferol did not make any difference to the outcomes.
Yuan S, Yin X, Meng X, et al. Clofazimine broadly inhibits coronaviruses including SARS-CoV-2. Nature March 16, 2021). https://www.nature.com/articles/s41586-021-03431-4
Clofazimine, an anti-leprosy drug with a favorable safety profile, appears to possess pan-coronaviral inhibitory activity by inhibiting viral spike-mediated cell fusion and viral helicase activity. In hamsters, prophylactic or therapeutic administration of clofazimine significantly reduced viral load in the lung and also mitigated inflammation.
Bertoglio F, Meier D, Langreder N, et al. SARS-CoV-2 neutralizing human recombinant antibodies selected from pre-pandemic healthy donors binding at RBD-ACE2 interface. Nat Commun March 11, 2021, 12, 1577. https://www.nature.com/articles/s41467-021-21609-2
Successful isolation and characterization of a fully human, recombinant anti-spike neutralizing monoclonal antibody from a universal, human naïve antibody gene library that was constructed before the emergence of SARS-CoV-2. This work shows how neutralizing antibodies can be efficiently selected rapidly without the need of convalescent patient material.
Ozaki K, Reinhard CT. The future lifespan of Earth’s oxygenated atmosphere. Nat. Geosci. 14, 138–142 (2021). https://doi.org/10.1038/s41561-021-00693-5
We’d prefer to present other papers in this section. However, there is some good news: we’ll get some more weeks to find a potent treatment for SARS-CoV-2. Using a combined biogeochemistry and climate model to examine the likely timescale of oxygen-rich atmospheric conditions on Earth, these authors estimate that the mean future lifespan of Earth’s atmosphere, with oxygen levels more than 1% of the present atmospheric level, is 1.08 ± 0.14 billion years.
Loffredo M, Lucero H, Chen DY, et al. The in-vitro effect of famotidine on sars-cov-2 proteases and virus replication. Sci Rep March 8, 2021, 11, 5433. https://www.nature.com/articles/s41598-021-84782-w
In silico studies have proposed one of the two SARS-CoV-2 proteases, 3CLpro or PLpro, as potential molecular targets of famotidine activity. Somewhat disappointing: Madeline Loffredo and colleagues show here that the drug neither binds with nor inhibits the functions of these proteases.
Vimaleswaran KS, Frouhi NG, Khunti K. Vitamin D and covid-19. BMJ 04 March 2021; 372 doi: https://doi.org/10.1136/bmj.n544
Is there a role of vitamin D in prevention and management of COVID-19? The authors of this editorial believe that “existing evidence supports a compelling case for further research”.
PRINCIPLE Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet March 04, 2021. https://doi.org/10.1016/S0140-6736(21)00461-X
Azithromycin makes no sense. This UK-based, open-label, adaptive platform randomized trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE) randomly assigned people aged 65 years and older, or 50 years and older, with at least one co-morbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. In total, 402 (80%) of 500 participants in the azithromycin group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days.
López-Medina E, López P, Hurtado IC, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA March 4, 2021; doi: 10.1001/jama.2021.3071. https://jamanetwork.com/journals/jama/fullarticle/2777389
The next hydroxychloroquine? Because of some evidence of activity in vitro, ivermectin has attracted huge interest. Several countries have included ivermectin in their treatment guidelines, leading to a surge in the demand for the drug by the general population and even alleged distribution of veterinary formulations. In this RCT that included 476 patients from Cali, Colombia, the duration of symptoms was not significantly different for patients who received either a 5-day course of ivermectin or placebo (median time to resolution of symptoms, 10 vs 12 days; hazard ratio for resolution of symptoms, 1.07). This is consistent with PK models showing that ivermectin levels do not reach the IC50 even for a dose level 10-times higher than the approved dose.
Lescure FX, Honda H, Fowler RA, et al. Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Resp Med March 04, 2021. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00099-0/fulltext
This large placebo-controlled multinational Phase III trial evaluated two doses of sarilumab, an interleukin-6 receptor inhibitor, in 416 patients with severe or critical COVID-19. At day 29, no significant differences were seen between the arms. The authors bravely suggest several potential reasons for why sarilumab was not effective (IL-6 insufficient to quell the inflammatory phase of the disease, patient selection not based on inflammation markers, dosage too low, use of confounding concomitant steroids, etc). However, this strategy seems not be a game changer in this pandemic.
Touafchia A, Bagheri H, Carrié D, et al. Serious bradycardia and remdesivir for coronavirus 2019 (COVID-19): a new safety concerns. Clin Microbiol Infection February 26, 2021. DOI: https://doi.org/10.1016/j.cmi.2021.02.013
Oops: this post-marketing study in a real-world setting suggests that the use of remdesivir is significantly associated with an increased risk of reporting bradycardia and serious bradycardia when compared with the use of hydroxychloroquine, lopinavir/ritonavir, tocilizumab or glucocorticoids.
Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline on drugs to prevent covid-19. BMJ. 2021 Mar 1;372:n526. PubMed: https://pubmed.gov/33649077. Full-text: https://doi.org/10.1136/bmj.n526
This is the first version of a living (up-to-date, evolving and EBM) guideline, focusing on the evidence for hydroxychloroquine. 53 authors from 45 centers say on 12 pages, “Do not use it!”
Janiaud P, Axfors C, Ioannidis JP, et al. Recruitment and Results Reporting of COVID-19 Randomized Clinical Trials Registered in the First 100 Days of the Pandemic. JAMA Netw Open March 1, 2021;4(3):e210330. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2776802
All RCTs (n = 516) registered in ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform between January 1 and April 9, 2020, were included. Overall, 30% of COVID-19 RCTs initiated in the first 100 days of the pandemic did not begin recruitment, and only 10% had results reported by mid-October, suggesting the possibility of substantial research waste.
Li S, Liu S, Jiang Z, et al. Study on the promotion of lymphocytes in patients with COVID-19 by broad-spectrum chemokine receptor inhibitor vMIP-II and its Mechanism of signal transmission in vitro. Sig Transduct Target Ther March2, 2012. 6, 104. https://doi.org/10.1038/s41392-021-00516-4
Viral macrophage inflammatory protein (vMIP) is a homologue of a chemokine derived from the recombinant natural human herpes virus 8 gene. It has been proved that vMIP can effectively inhibit the process of HIV infecting target cells through chemokine receptors. In this pilot study, 10 patients and 35 uninfected volunteers from Wuhan were treated with vMIP (given as injection). vMIP-II significantly improved the lymphocyte decrease of COVID-19. It was shown that vMIP-II inhibits multiple chemokine receptors and their related phosphorylation signaling pathways. In other words, this study shows that vMIP-II can reconstruct the cellular immune function lost in acute SARS-CoV-2 infection. The elucidation of the molecular mechanism of vMIP-II increasing CD8+ TCM provides a new strategy for the treatment of COVID-19.
Piepenbrink MS, Park JG, Oladunni FS, et al. Therapeutic activity of an inhaled potent SARS-CoV-2 neutralizing human monoclonal antibody in hamsters. Cell Reports February 24, 2021. DOI: https://doi.org/10.1016/j.xcrm.2021.100218
Antibodies delivered via inhalation for the prevention and treatment of SARS-CoV-2: Michael S. Pipenbrink from Birmingham, US shows that this works. Fully human monoclonal antibodies (hmAbs) potently neutralize SARS-CoV-2. The most potent hmAb, 1212C2 was derived from an IgM memory B cell, exhibited in vivo prophylactic and therapeutic activity against SARS-CoV-2 in hamsters when delivered intraperitoneally, achieving a meaningful reduction in upper and lower respiratory viral burden and lung pathology. Furthermore, liquid nebulized inhaled treatment of SARS-CoV-2 infected hamsters with as low as 0.6 mg/kg of inhaled dose, corresponding to approximately 0.03 mg/kg of lung-deposited dose, mediated a reduction in respiratory viral burden that is below the detection limit, and mitigated lung pathology. The therapeutic efficacy achieved at an exceedingly low-dose of inhaled 1212C2 supports the rationale for local lung delivery and achieving dose-sparing benefits as compared to the conventional parenteral route of administration.
Bugin K, Woodcock J. Trends in COVID-19 therapeutic clinical trials. Nature Reviews Drug Discovery, 25 February 2021. https://www.nature.com/articles/d41573-021-00037-3
Janet Woodcock and Kevin Bugin have comprehensively assessed the ongoing COVID-19 therapeutic clinical development efforts worldwide. Surveying the clinical trial landscape, their most important finding is that the vast majority of trials of therapeutics for COVID-19 are not designed to yield actionable information; low randomization rates and underpowered outcome data render matters of safety and efficacy generally uninterpretable.
Milic J, Novella A, Meschiari M, et al. Darunavir/cobicistat is associated with negative outcomes in HIV-negative patients with severe COVID-19 pneumonia. AIDS Res Hum Retroviruses. 2021 Feb 23. PubMed: https://pubmed.gov/33619997. Full-text: https://doi.org/10.1089/AID.2020.0305
The HIV protease inhibitor darunavir doesn’t work in COVID. Didn’t we know this already? In this retrospective study in HIV-negative patients with COVID-19 pneumonia admitted to a tertiary care hospital in Modena, Italy, patients on darunavir/c (c=cobicistat is a pharmacoenhancer) had higher rates of mortality (25% vs 10%, p < 0.0001) and of mechanical ventilation and death (37% vs. 25%, p = 0.03). Multiple serious interactions associated with darunavir/c were observed in the 19 patients who died. According to the authors, darunavir/c “should not be recommended as a treatment option for COVID-19 pneumonia outside clinical trials”. The question is: why did the authors study this now?
Janiaud P, Axfors C, Schmitt AM, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021 Feb 26. PubMed: https://pubmed.gov/33635310. Full-text: https://doi.org/10.1001/jama.2021.2747
This review of all RCTs published until January 29 showed that compared with placebo or standard of care, convalescent plasma was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes.
Gupta A, Madhavan MV, Poterucha TJ, et al. Association between antecedent statin use and decreased mortality in hospitalized patients with COVID-19. Nat Commun 12, 1325 (2021). https://doi.org/10.1038/s41467-021-21553-1
Better take your statins! Among 1296 patients (648 statin users, 648 non-statin users) identified with 1:1 propensity-score matching, statin use was significantly associated with lower odds of in-hospital mortality within 30 days in the propensity-matched cohort (OR 0.47, 95% CI: 0.36–0.62, p < 0.001). The potential benefits from statins extend beyond cholesterol-lowering properties, as there is a robust literature supporting the anti-inflammatory properties of statins, suggesting that these drugs can stabilize and restore endothelial function. Randomized clinical trials are ongoing (and needed).
Herrett E, Williamson E, Brack K, et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ. 2021 Feb 24;372:n135. PubMed: https://pubmed.gov/33627334. Full-text: https://www.bmj.com/content/372/bmj.n135
And for those patients who supposedly can’t tolerate a statin, it’s probably not the case. In this nice study among 151 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms, no difference in muscle symptom scores was found between the statin and placebo periods. Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long-term treatment with statins.
Paper of the Day
Rubin EJ, Longo DL, Baden LR. Interleukin-6 Receptor Inhibition in Covid-19 – Cooling the Inflammatory Soup. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631064. Full-text: https://doi.org/10.1056/NEJMe2103108
In their nice editorial, Eric Rubin, Dan Longo, and Lindsey Baden discuss how we can make sense of these disparate results between COVACTA and the REMAP-CAP data. Differences among the trials (enrolment criteria, timing of therapy, primary outcome, and background care, especially steroid use) may account for the discrepancy. In addition, inflammation may not be the same: patients with severe disease at initial presentation may have a different pathogenesis than those in whom inflammatory disease develops later, which suggests that the timing of treatment may be crucial in understanding responses. However, according to the authors, these points raise thorny issues. Is the value of interleukin-6 inhibition dependent on the timing of treatment, being beneficial only if proximate to an acute late inflammatory decompensation event? We rely on clinical trials to either endorse or reject possible interventions. But what if the results of trials change as the underlying therapies improve, a particular problem with platform trials, which always need to include contemporaneous controls? For now, we are left with evidence of benefit from interleukin-6 inhibitors, but how to best use them remains unclear.
REMAP-CAP Investigators, Gordon AC, Mouncey PR, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631065. Full-text: https://doi.org/10.1056/NEJMoa2100433
Two weeks ago, encouraging (but not peer-reviewed) results from the RECOVERY trial revitalized the strategy of blocking interleukin-6 in patients with severe COVID-19 (https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19). Now we are getting some more evidence, provided by REMAP-CAP. REMAP-CAP is an international, adaptive platform trial designed to determine effective treatment strategies for patients with severe pneumonia in both pandemic and non-pandemic settings. Patients eligible for the platform are assessed for eligibility to potentially undergo randomization to multiple interventions across multiple domains. Adult patients with COVID-19, within 24 hours after starting organ support in the ICU, were randomly assigned to receive tocilizumab (8 mg per kg of body weight), sarilumab (400 mg), or standard care (control). Both tocilizumab and sarilumab met the predefined criteria for efficacy. At that time, 353 patients had been assigned to tocilizumab, 48 to sarilumab, and 402 to control. The median number of organ support–free days was 10 in the tocilizumab group, 11 (0 to 16) in the sarilumab group, and 0 in the control group. An analysis of 90-day survival showed improved survival in the pooled interleukin-6 receptor antagonist groups, yielding a hazard ratio for the comparison with the control group of 1.61 (95% credible interval, 1.25 to 2.08).
Rosas IO, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Feb 25. PubMed: https://pubmed.gov/33631066. Full-text: https://doi.org/10.1056/NEJMoa2028700
But can we trust these platform data? In COVACTA, a large randomized Phase III trial, 438 patients who were hospitalized with severe pneumonia were randomized 2:1 to receive TCZ or placebo, the use of TCZ did not result in significantly better clinical status or lower mortality (19.7% versus 19.4%) at 28 days.
Cross RW, Prasad AN, Borisevich V. Use of convalescent serum reduces severity of COVID-19 in nonhuman primates. Cell Rep February 23, 2021. Full-text: https://doi.org/10.1016/j.celrep.2021.108837
Several human clinical trials on the passive transfer of convalescent plama have yielded mixed results. In this animal experiment on 10 African green monkeys, sera with high SARS-CoV-2 neutralizing antibody titers showed the greatest benefit. Data suggested passive transfer as a therapy in humans in early stages of disease.
Xie C, Chen Y, Luo D, et al. Therapeutic potential of C1632 by inhibition of SARS-CoV-2 replication and viral-induced inflammation through upregulating let-7. Sig Transduct Target Ther 6, 84 (2021). https://doi.org/10.1038/s41392-021-00497-4
MicroRNAs (miRNAs) are small, non-coding RNAs that play regulatory roles in gene expression by targeting their mRNA. The authors report that let-7, an miRNA that is ubiquitously expressed in human cells, blocks SARS-CoV-2 replication by targeting S and M protein. In addition, let-7 suppresses the expression of multiple inflammatory factors. C1632, a small molecule serving as a let-7 stimulator, is capable of upregulating the expression of let-7, thus possibly reducing viral replication and secretion of inflammatory cytokines.
Hunt BJ, De Paula EV, McLintock C, Dumantepe M. Prophylactic anticoagulation for patients in hospital with covid-19. BMJ. 2021 Feb 19;372:n487. PubMed: https://pubmed.gov/33608304. Full-text: https://doi.org/10.1136/bmj.n487
The risk of hospital-associated venous thromboembolism for medical in-patients is greatest in the first 90 days post-discharge, and many units are using unlicensed extended thromboprophylaxis with LMWH or direct acting oral anticoagulants for patients discharged after COVID-19. Recent retrospective data showing low rates of hospital-associated venous thromboembolism post-discharge are reassuring, but according to this editorial, randomized trials formally evaluating the need for extended thromboprophylaxis are now required.
Ma S, Xu C, Liu S, et al. Efficacy and safety of systematic corticosteroids among severe COVID-19 patients: a systematic review and meta-analysis of randomized controlled trials. Sig Transduct Target Ther 6, 83 (2021). https://doi.org/10.1038/s41392-021-00521-7
In this meta-analysis including 7 RCTs and 6250 severe COVID-19 patients, corticosteroid treatment was related to a reduction of all-cause mortality and disease progression, but not with an increase in serious adverse events. Of note, survival benefit was absent if RECOVERY trial was excluded. More robust supporting data are required.
Mathews KS, Soh H, Shaefi S, et al. Prone Positioning and Survival in Mechanically Ventilated Patients With Coronavirus Disease 2019-Related Respiratory Failure. Crit Care Med. 2021 Feb 17. PubMed: https://pubmed.gov/33595960 . Full-text: https://journals.lww.com/ccmjournal/Abstract/9000/Prone_Positioning_and_Survival_in_Mechanically.95335.aspx
Pro-proning: among 2338 eligible patients in this multicenter cohort study, 702 (30.0%) were proned within the first 2 days of ICU admission. After inverse probability weighting, baseline and severity of illness characteristics were “well-balanced” between proned and non-proned patients. Patients proned within the first 2 days of ICU admission had a lower adjusted risk of death compared with non-proned patients (HR: 0.84; 95% CI: 0.73–0.97).
Paper of the Day
Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Feb 17. PubMed: https://pubmed.gov/33595634. Full-text: https://doi.org/10.1001/jama.2020.26848
The end of all speculations and hopes on immunomodulatory and anti-inflammatory properties of 25-hydroxyvitamin D? In this multicenter placebo-controlled trial from Brazil including 240 hospitalized patients with COVID-19 who were moderately to severely ill, vitamin D had no effect. A single high dose of vitamin D3, compared with placebo, did not significantly reduce hospital length of stay.
Comment: according to Adit Ginde and David Leaf, several limitations should be considered. The main issue: the study was underpowered. And as always, further studies should determine whether vitamin D3 supplementation could be useful in other settings, dosages and patient populations. It is important to remain open-minded.
Paper of the Day
de Vries RD, Schmitz KS, Bovier Full-text:, et al. Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets. Science 2021, published 17 February. Full-text: https://doi.org/10.1126/science.abf4896
Matteo Porotto, Rory de Vries and colleagues propose a highly stable SARS-CoV-2 specific lipopeptide as a candidate antiviral for pre-exposure and early post-exposure prophylaxis for SARS-CoV-2 transmission in humans. Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour co-housing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. The intranasal [SARSHRC-PEG4]2-chol peptide presented in this study is the first successful prophylaxis that prevents SARS-CoV-2 transmission in a relevant animal model, providing complete protection during a 24-hour period of intense direct contact.
Thomas S, Patel D, Bittel B, et al. Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial. JAMA Netw Open. 2021 Feb 1;4(2):e210369. PubMed: https://pubmed.gov/33576820. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0369
Commonly available oral supplements, such as zinc and ascorbic acid (ie, vitamin C), have been proposed to reduce the duration and severity of viral infections by boosting the immune response. In this randomized clinical trial (n = 214) of ambulatory patients diagnosed with SARS-CoV-2 infection, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the 2 supplements did not significantly decrease the duration of symptoms compared with standard of care. See also the comment by Michos ED, Cainzos-Achirica M. Supplements for the Treatment of Mild COVID-19-Challenging Health Beliefs With Science From A to Z. JAMA Netw Open. 2021 Feb 1;4(2):e210431. PubMed: https://pubmed.gov/33576814. Full-text: https://doi.org/10.1001/jamanetworkopen.2021.0431
Qiao J, Li YS, Zeng R. SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model. Science 18 Feb 2021: eabf1611. https://science.sciencemag.org/content/early/2021/02/17/science.abf1611.full
The authors designed and synthesized 32 new bicycloproline-containing protease inhibitors derived from either boceprevir or telaprevir, two (older) approved drugs for hepatitis C. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays and displayed good pharmacokinetic properties and safety in rats.
Raman AS, Barge VB, Darivenula AK, et al. A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in COVID-19 patients with Regular Intravenous Immunoglobulin Therapy. J Infect Dis. 2021 Feb 15:jiab098. PubMed: https://pubmed.gov/33585890 . Full-text: https://doi.org/10.1093/infdis/jiab098
Immunoglobulins for COVID-19? In this open-label, multicenter, randomized study on COVID-19 patients with moderate pneumonia in India, 100 patients were randomized 1:1 either to receive IVIG + standard of care (SOC) or SOC only. Duration of hospital stay was significantly shorter in the IVIG group compared to that of SOC alone (7,7 vs. 17,5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation were not significantly different (24% vs 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 vs 18 days).
Paper of the Day
Horby PW, Campbell M, Staplin N, et al. for the RECOVERY Collaborative Group, and others. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): preliminary results of a randomised, controlled, open-label, platform trial. medRxiv 2021, posted 11 February. Full-text: https://www.medrxiv.org/content/10.1101/2021.02.11.21249258v1
In COVID patients with low oxygen and inflammation, tocilizumab saves lives, keeps you off a ventilator, and gets you out of hospital quicker. This is another result of the great RECOVERY trial. After randomizing more than 4000 patients (oxygen saturation < 92% on air or requiring oxygen therapy; and evidence of systemic 31 inflammation [C-reactive protein ≥ 75 mg/L]), treatment with tocilizumab reduced mortality (29% vs 33%), increased the chances of successful hospital discharge, and reduced the chances of requiring invasive mechanical ventilation (33% vs 38%). These benefits were on top of those previously reported for dexamethasone. Clinical guidelines need an update.
See also Tocilizumab reduces deaths in patients hospitalised with COVID-19, 11 February 2021. Link: https://www.recoverytrial.net/news/tocilizumab-reduces-deaths-in-patients-hospitalised-with-covid-19
Ramakrishnan S, Nicolau DV, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial. medRxiv 2021, posted 8 February. Full-text: https://doi.org/10.1101/2021.02.04.21251134
Early administration of inhaled budesonide might reduce the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection. This is the result of a randomized, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild COVID-19 symptoms. The primary endpoint (COVID-19-related urgent care visit, emergency department assessment or hospitalization) occurred in 10 of 69 participants in the usual care arm and in 1 of 70 participants in the budesonide arms (p = 0,004). Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, p = 0,007). Importantly, fewer participants randomized to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Background of the study: multiple hospital cohorts have shown that patients with chronic respiratory disease are significantly under-represented. The authors hypothesize that the widespread use of inhaled glucocorticoids is responsible for this finding.
Feld JJ, Kandel C, Biondi MJ, et al. Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial. Lancet Respir Dis 2021, published 5 February. Full-text: https://doi.org/10.1016/S2213-2600(20)30566-X
Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. Here, Jordan Feld et al. randomly assigned (1:1) 30 patients to a single subcutaneous injection of peg-interferon lambda 180 μg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peg-interferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6,25 [95% CI: 1,49–31,06]; p = 0,012).
Hoertel N, Sánchez-Rico M, Vernet R, et al. Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Mol Psychiatry (2021). Full-text: https://doi.org/10.1038/s41380-021-01021-4
Antidepressant use could be associated with lower risk of death or intubation in patients hospitalized for COVID-19. This is the result of an observational study which included 7230 adults hospitalized for COVID-19, 345 patients of whom (4.8%) received an antidepressant within 48 h of hospital admission. Nicolas Hoertel etal. report a reduced risk of intubation or death (HR, 0.56; 95% CI, 0.43–0.73, p < 0.001). Next step: controlled randomized clinical trials.
Blanchard EL, Vanover D, Bawage SS, et al. Treatment of influenza and SARS-CoV-2 infections via mRNA-encoded Cas13a in rodents. Nat Biotechnol 2021, published 3 February. Full-text: https://doi.org/10.1038/s41587-021-00822-w
Cas13 treatment for influenza and SARS-CoV-2? In this study, Philip Santangelo, Chiara Zurla, Emmeline L. Blanchard and colleagues used messenger RNA (mRNA)-encoded Cas13a for mitigating influenza virus A and SARS-CoV-2 infection in mice and hamsters, respectively. In mice, Cas13a degraded influenza RNA in lung tissue efficiently when delivered after infection, whereas in hamsters, Cas13a delivery reduced SARS-CoV-2 replication and reduced symptoms.
RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet 2021, published 2 February. Full-text: https://doi.org/10.1016/S0140-6736(21)00149-5
In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other pre-specified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Read also the comment by Berwanger O. Azithromycin, RECOVERY, and the power of large, simple trials. Lancet 2021, published 2 February. Full-text: https://doi.org/10.1016/S0140-6736(21)00307-X
White KM, Rosales, Yildiz S. Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science 25 Jan 2021:eabf4058. Full-text: https://doi.org/10.1126/science.abf4058
SARS-CoV-2 viral proteins interact with the eukaryotic translation machinery and inhibitors of translation have potent antiviral effects. Plitidepsin has been clinically developed for the treatment of multiple myeloma with a well-established safety profile and pharmacokinetics. Kris White and colleagues report that the drug possesses antiviral activity 27,5-fold more potent than remdesivir against SARS-CoV-2 in vitro, with limited toxicity in cell culture. There was in vivo efficacy in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment.
Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021 Jan 20;372:n84. PubMed: https://pubmed.gov/33472855. Full-text: https://doi.org/10.1136/bmj.n84
Bad news from this randomized, open-label trial in nine hospitals in Brazil. Patients who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers were randomized to receive standard of care (SOC) plus tocilizumab (TCZ) or SOC alone. The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the SOC + TCZ group (17% vs 3%).
Chen JS, Alfajaro MM, Chow RD, et al. Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection. J Virol. 2021 Jan 13:JVI.00014-21. PubMed: https://pubmed.gov/33441348. Full-text: https://doi.org/10.1128/JVI.00014-21
SARS-CoV-2 infection induces COX-2 expression in cell lines, primary airway epithelial cells, and mice. Inhibition of COX-2 by NSAIDs did not affect viral entry or replication in vitro or in vivo. However, NSAID treatment impaired the production of pro-inflammatory cytokines and neutralizing antibodies in response to SARS-CoV-2 infection in mice. NSAIDs could therefore have complex effects on the host response to SARS-CoV-2.
Cohen MS. Monoclonal antibodies to disrupt progression of early Covid-19 infection. NEJM January 21, 2021; 384: 289-91.
Editorial, summarizing the two trials on the REGN-CoV-2 cocktail (casirivimab and imdevimab) and Lilly’s mAb bamlanivimab. Both trials were done in outpatients with early infection and showed “some” clinical benefit. However, Myron S. Cohen from Chapel Hill considers the findings from these trials “provocative and promising”. Read why.
Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. NEJM December 17, 2020, Full-text: https://doi.org/10.1056/NEJMoa2035002
Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2020, published 28 October. Full-text: https://doi.org/10.1056/NEJMoa2029849
Paper of the Day
Lopes RD, Macedo AV, Silva P, et al. Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial. JAMA January 19, 2021; 325(3):254-264. Full-text: https://doi.org/10.1001/jama.2020.25864
Paper of the day: does discontinuation compared with continuation of ACEIs or ARBs change anything? No. In this randomized open label clinical trial that included 659 patients from Brazil who were hospitalized with mild to moderate COVID-19 who were taking ACEIs or ARBs before hospital admission, the mean number of days alive and out-of-hospital for those assigned to discontinue versus continue these medications was 21,9 vs 22,9, respectively.
Gordon AC, Mouncey PR, Al-Beidh F, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. medRxiv 2021, posted 9 January. Full-text: https://doi.org/10.1101/2021.01.07.21249390
When administered within 24 hours of commencing organ support in an intensive care unit, tocilizumab or sarilumab may reduce mortality. This is the result of a not-yet-published (pre-print) paper by Anthony Gordon et al. Death rate in the control group (n = 402) was 36%, tocilizumab (n = 353) 28%, sarilumab (n = 48) 22%.
Anil SM, Shalev N, Vinayaka AC et al. Cannabis compounds exhibit anti-inflammatory activity in vitro in COVID-19-related inflammation in lung epithelial cells and pro-inflammatory activity in macrophages. Sci Rep 11, 1462 (2021). https://doi.org/10.1038/s41598-021-81049-2
Dope for SARS? Not yet. Although treatment with cannabis compounds CBD, CBG and THCV may have clinical value in reducing cytokine secretion in lung epithelial cells, Hinanit Koltai, Seegehalli Anil and colleagues from the Volcani Center in Rishon LeZion, Israel, caution that the increase of macrophage-secreted IL-6 and IL-8 levels by cannabis-based treatment may potentially lead to a worsening of the “cytokine storm” identified in severe COVID-19 patients. As for now, users and healthcare personnel should avoid the use of cannabis for COVID-19 prevention or treatment.
Joyner MJ, Carter RD, Senefeld JW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med 2021, published 13 January. Full-text:
Patients who have not yet received mechanical ventilation may benefit from transfusion of plasma with high anti–SARS-CoV-2 IgG antibody levels. However, in this study of 3082 patients there was no effect on the risk of death among patients who had received mechanical ventilation.
Barbui T, Vannucchi AM, Alvarez-Larran A, et al. High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib. Leukemia (2021). Full-text: https://doi.org/10.1038/s41375-020-01107-y
This study found an association between ruxolitinib and overall mortality in 40% of the 45 cases treated with this drug. This effect was due not so much to drug exposure but to its rapid discontinuation (median 0,5 days), that accounted for 75% of deaths. The authors speculate about the reasons for stopping the treatment: uncertainties about possible adverse events? risk of interactions with other drugs? missing interactions between managing physicians and referring hematologist?
“Only return to exercise after at least seven days free of symptoms and begin with at least two weeks of minimal exertion. Use daily self-monitoring to track progress, including when to seek further help.” In this nice 6-page paper, David Salman and colleagues give an excellent guide to physical activity after COVID-19. Clearly, patients with ongoing symptoms or who had severe COVID-19 or a history suggestive of cardiac involvement need thorough clinical assessment.
Garber K. Hunt for improved monoclonals against coronavirus gathers pace. Nat Biotechnol 39, 9–12 (2021). Full-text: https://doi.org/10.1038/s41587-020-00791-6
Bamlanivimab (Lilly) and the double-antibody cocktail casirivimab + imdevimab (Regeneron) have been recently given an Emergency Use Authorization (EUA) for use in high-risk COVID-19 patients with mild or moderate disease. Though both drugs represent new options for treating the coronavirus infection, neither is ideal. The future of monoclonals remains uncertain.
Cohen JB, Hanff TC, William P, et al. Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet Respir Health 2021, published 7 January. Full-text: https://doi.org/10.1016/S2213-2600(20)30558-0
Consistent with international society recommendations, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), inhibitors of the renin–angiotensin system, can be safely continued in patients admitted to hospital with COVID-19. A confirmation from a small study that enrolled 152 participants randomly assigned them to either continue or discontinue renin–angiotensin system inhibitor therapy. There were 16 (21%) of 75 participants in the continuation arm versus 14 (18%) of 77 in the discontinuation arm who required intensive care unit admission or invasive mechanical ventilation, and 11 (15%) of 75 participants in the continuation group versus ten (13%) of 77 in the discontinuation group who died.
Hashimoto K. Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor. Eur Arch Psychiatry Clin Neurosci. 2021 Jan 5. PubMed: https://pubmed.gov/33403480. Full-text: https://doi.org/10.1007/s00406-020-01231-x
Traditional central nervous system (CNS) drugs that have a high affinity at the sigma-1 receptor (i.e., fluvoxamine, donepezil, ifenprodil) for the treatment of SARS-CoV-2-infected patients? In this review, Kenji Hashimoto discusses the brief history of the sigma-1 receptor and its role in SARS-CoV-2 replication in cells.
Alschuler L, Chiasson AM, Horwitz R, et al. Integrative medicine considerations for convalescence from mild-to-moderate COVID-19 disease. Explore (NY). 2020 Dec 23:S1550-8307(20)30417-1. PubMed: https://pubmed.gov/33358750. Full-text: https://doi.org/10.1016/j.explore.2020.12.005
Could convalescence from mild-to-moderate (MtoM) COVID-19 disease be supported by integrative medicine (IM) strategies? Lise Alschuler et al. suggest adoption of an anti-inflammatory diet, supplementation with vitamin D, glutathione, melatonin, cordyceps, astragalus and garlic have potential utility. If you are also interested in osteopathic manipulation, qigong, breathing exercises and aerobic exercise, you should read this paper with 146 references.
Libster R, Marc PG, Wappner D, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med 2021, published 6 January. Full-text: https://doi.org/10.1056/NEJMoa2033700
Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults might reduce the progression of COVID-19. This is the result of a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 by Fernando P. Polack, Romina Libster and colleagues. The authors randomized 160 patients. Severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; p = 0.03). Relative risk reduction: 48%.
Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med 2021; 384:20-30. Full-text: https://doi.org/10.1056/NEJMoa2030340
In hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation, tocilizumab did not improve survival, but it reduced the likelihood of progression to the composite outcome of mechanical ventilation or death. This is the result of a trial that randomized 249 patients into the tocilizumab group and 128 patients into the placebo group. Shalini Mohan, Carlos Salama and colleagues report that death from any cause by day 28 occurred in 10,4% of the patients in the tocilizumab group and 8,6% of those in the placebo group.
Meduri GU, Annane D, Confalonieri M, et al. Pharmacological principles guiding prolonged glucocorticoid treatment in ARDS. Intensive Care Med. 2020 Dec;46(12):2284-2296. PubMed: https://pubmed.gov/33150472. Full-text: https://doi.org/10.1007/s00134-020-06289-8
In this review, Gianfranco Umberto Meduri et al. examine the pharmacological principles guiding glucocorticoids (GC) treatment in ARDS that demonstrates how each component of the treatment protocol is relevant to achieve optimal results. The authors integrate current clinical pharmacology knowledge of various GCs, including hydrocortisone, methylprednisolone and dexamethasone. Find more about the dosage, timing of initiation, mode of administration, duration, and tapering.
McCullough PA, Alexander PE, Armstrong R, et al. Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19). Rev Cardiovasc Med. 2020 Dec 30;21(4):517-530. PubMed: https://pubmed.gov/33387997. Full-text: https://doi.org/10.31083/j.rcm.2020.04.264
Prompt early initiation of sequenced multi-drug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. Here, Peter McCullough et al. present a multi-pronged therapeutic approach that includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine.
Padhi AK, Shukla R, Saudagar P, Tripathi T. High-Throughput Rational Design of the Remdesivir Binding Site in the RdRp of SARS-CoV-2: Implications for Potential Resistance. iScience 2020, published 26 December. Full-text: https://doi.org/10.1016/j.isci.2020.101992
SARS-CoV-2 can undergo positive selection and attain remdesivir resistance with very few mutations. This is the result of a study that generated a total of 100.000 mutations and provided insight into the functional outcomes of mutations in the remdesivir binding site in the nsp12 subunit of RdRp.
Trump S, Lukassen S, Anker MS, et al. Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19. Nat Biotechnol 2020, published 24 December. Full-text: https://doi.org/10.1038/s41587-020-00796-1
ACEI treatment in patients with SARS-CoV-2 infection and hypertension might warrant further investigation. This is the suggestion by Irina Lehmann, Saskia Trump and colleagues from Charité, Berlin, who combined clinical data (n = 144) and single cell sequencing data of airway samples (n = 48) with in vitro experiments. The authors observed a distinct inflammatory predisposition of immune cells in patients with hypertension that correlated with critical COVID-19 progression. ACEI treatment was associated with dampened COVID-19-related hyperinflammation and with increased cell intrinsic antiviral responses.
Zhang LK, Sun Y, Zeng H, et al. Calcium channel blocker amlodipine besylate therapy is associated with reduced case fatality rate of COVID-19 patients with hypertension. Cell Discov. 2020 Dec 22;6(1):96. PubMed: https://pubmed.gov/33349633. Full-text: https://doi.org/10.1038/s41421-020-00235-0
Might anti-hypertensive treatment with amlodipine be associated with a decreased case fatality rate of SARS-CoV-2 infection? Gengfu Xiao and Lei-Ke Zhang from Wuhan Institute of Virology, Center for Biosafety Mega-Science, report on 96 patients who only had hypertension as co-morbidity. 19 patients received amlodipine besylate, 14 received nifedipine, 8 received ARBs/ACEIs, 45 had no drug information, and 10 had no anti-hypertensive drug treatment. The numbers are too small to draw conclusions.
Esparza TJ, Martin NP, Anderson GP, Goldman ER, Brody DL. High affinity nanobodies block SARS-CoV-2 spike receptor binding domain interaction with human angiotensin converting enzyme. Sci Rep. 2020 Dec 22;10(1):22370. PubMed: https://pubmed.gov/33353972. Full-text: https://doi.org/10.1038/s41598-020-79036-0
Nanobodies are 12–15 kDa single-domain antibody fragments that can be delivered by inhalation and are amenable to relatively inexpensive large-scale production. Here, David Brody, Thomas Esparza and colleagues describe the nanobody candidate NIH-CoVnb-112 which binds to the SARS-CoV-2 spike protein RBD and blocks spike protein interaction with the ACE2 receptor. They are optimistic about the possibility that low-cost, stable, and safe nanobody-based therapeutics will be developed for inhaled use in the home outside of formal healthcare environments.
ACTIV-3/TICO LY-CoV555 Study Group. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med 2020, published 22 December. Full-text: https://doi.org/10.1056/NEJMoa2033130
The Lilly monoclonal antibody LY-CoV555, when co-administered with remdesivir, did not demonstrate efficacy among hospitalized patients who had COVID-19 without end organ failure. This is the result of a randomized study involving 314 hospitalized patients by Jens D. Lundgren and colleagues of the ACTIV-3/TICO LY-CoV555 Study Group.
Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. NEJM December 17. Full-text: https://doi.org/10.1056/NEJMoa2030340
In this RCT, 389 patients hospitalized with COVID-19 pneumonia who were not receiving mechanical ventilation were randomized to receive standard of care plus one or two doses of either tocilizumab (TCZ) or placebo. TCZ reduced the likelihood of progression to the composite outcome of mechanical ventilation or death (12% vs 19%), but it did not improve survival.
Dal-Ré R, Banzo R, Georgin-Lavialle S, et al. Remdesivir for COVID-19 in Europe: will it provide value for money? Lancet Resp Med December 17, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30568-3
In their comment on remdesivir pricing, Rafael Dal-Ré and colleagues review the clinical data available and argue that once remdesivir becomes available in Europe, governments should agree a substantially lower price with Gilead (amid a time of high incidence of COVID-19 cases in Europe, and with remdesivir in short supply, the European Commission had signed a joint procurement contract with Gilead, with an agreed price of $2340 for a 5-day course). Until the effectiveness of remdesivir in clinical practice is well defined in Europe, a pay-for-result agreement might also be considered.
Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. NEJM December 17, 2020, Full-text: https://doi.org/10.1056/NEJMoa2035002
Antibodies may work, but only in seronegative patients. Here, an interim analysis is presented for the two anti-spike antibodies casirivimab (REGN10933) and imdevimab (REGN10987). Both make up REGN-COV2 (and were given to Trump). This ongoing Phase I–III trial randomly assigned 275 non-hospitalized patients to receive placebo, 2,4 g or 8,0 g of REGN-COV2. The least-squares mean difference (REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was minus 0,56 log10 copies/mL among patients who were serum antibody–negative at baseline and minus 0,41 log10 copies/mL in the overall trial population. But did this translate into a clinical benefit? Maybe. At least one medical attended visit was necessary in 3% vs. 6% (placebo) overall and in 6% vs. 15% (placebo) in serum antibody–negative at baseline.
Sheppard JP, Nicholson B, Lee J, et al. The association between blood pressure control and Coronavirus Disease 2019 outcomes in 45,418 symptomatic patients with hypertension: An observational cohort study. Hypertension. 2020 Dec 16. PubMed: https://pubmed.gov/33325240. Full-text: https://doi.org/10.1161/HYPERTENSIONAHA.120.16472
This study examined the association between pre-infection blood pressure (BP) control and COVID-19 outcomes using data from 460 general practices in England. Eligible patients were adults with hypertension who were diagnosed with COVID-19. A total of 4277 patients (9,4%) were diagnosed with COVID-19 and 877 died within 28 days. There was no association between BP control and COVID-19 diagnosis or hospitalization. Of note, individuals with stage 1 uncontrolled BP had lower odds of COVID-19 death (OR 0.76, 95%CI 0.62-0.92) compared to patients with well-controlled BP. However, these patients were older, had more co-morbidities and had been diagnosed with hypertension for longer, suggesting more advanced atherosclerosis and target organ damage.
Buckland MS, Galloway JB, Fhogartaigh CN, et al. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report. Nat Commun 11, 6385 (2020). https://doi.org/10.1038/s41467-020-19761-2
The authors report the case of a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinemia (XLA). The patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. Over two independent courses of treatment, the authors observed a temporally correlated clinical and virologic response, leading to clinical resolution and viral clearance.
Kalil A, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med 2020, published 11 December. Full-text: https://doi.org/10.1056/NEJMoa2031994
Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among hospitalized adults with COVID-19, notably among those receiving high-flow oxygen or noninvasive ventilation. This is the result of double-blind, randomized, placebo-controlled trial involving 1033 patients. The 216 patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment (n=103) and 18 days with control (n=103) (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). We still need better drugs.
An EUA for Bamlanivimab—A Monoclonal Antibody for COVID-19. JAMA 2020, puublished 11 December. Full-text: https://doi.org/10.1001/jama.2020.24415
JAMA published a Medical Letter about the investigational neutralizing IgG1 monoclonal antibody bamlanivimab (LY-CoV555; Lilly) which has been granted an FDA Emergency Use Authorization (EUA) for treatment of recently diagnosed mild to moderate COVID-19 in patients who are ≥12 years old, weigh at least 40 kg, and are at high risk for progressing to severe disease and/or hospitalization. See also the FDA fact sheet of bamlanivimab at https://www.fda.gov/media/143603/download.
Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020 Dec 2:S1201-9712(20)32506-6. PubMed: https://pubmed.gov/33278625. Full-text: https://doi.org/10.1016/j.ijid.2020.11.191
Ivermectin, an inexpensive, over-the-counter medicine, is widely used as a preventative against COVID-19 in many South/Latin American countries. However, the evidence that ivermectin protects from COVID-19 is scant. This group from Bangladesh conducted a randomized, double-blind, placebo-controlled trial of oral ivermectin alone or in combination with doxycycline compared with placebo among 72 hospitalized patients. Virological clearance was earlier in the 5-day ivermectin treatment arm versus the placebo group (9,7 days vs. 12,7 days; p = 0.02); but not in the ivermectin + doxycycline arm (11,5 days; p = 0.27). There were no severe adverse drug events recorded in the study. According to the authors, “larger trials will be needed to confirm these preliminary findings”.
Honjo K, Russel RM, Li R, et al. Convalescent Plasma-Mediated Resolution of COVID-19 in a Patient with Humoral Immunodeficiency. Cell Rep Med December 05, 2020. Full-text: https://doi.org/10.1016/j.xcrm.2020.100164
Interesting case report. Convalescent plasma (CP) is widely used to treat COVID-19, but without formal evidence of efficacy. Here, Kazuhito Honjo and colleagues report the beneficial effects of CP in a severely ill COVID-19 patient with prolonged pneumonia and CLL, who was unable to generate an antiviral antibody response of her own. On day 33 after becoming symptomatic, the patient received CP containing high-titer neutralizing antibodies, defervesced and improved clinically within 48 hours, and was discharged on day 37. Hence, when present in sufficient quantities, NAbs to SARS-CoV-2 may have clinical benefit even if administered relatively late in the disease course.
Butt JH, Gerds TA, Schou M, et al. Association between statin use and outcomes in patients with coronavirus disease 2019 (COVID-19): a nationwide cohort study. BMJ Open. 2020 Dec 4;10(12):e044421. PubMed: https://pubmed.gov/33277291. Full-text: https://doi.org/10.1136/bmjopen-2020-044421
In this observational cohort study using data from Danish nationwide registries, 843/4842 (17%) COVID-19 patients redeemed a prescription of statins in the 6 months prior to COVID-19 diagnosis. Recent statin exposure was not associated with an increased or decreased risk of all-cause mortality or severe infection. The results were consistent across subgroups of age, sex and presumed indication for statin therapy. Among patients with statin exposure, there was no difference between statin drug or treatment intensity with respect to outcomes.
Spagnuolo V, Guffanti M, Galli L, et al. Viral clearance after early corticosteroid treatment in patients with moderate or severe covid-19. Sci Rep. 2020 Dec 4;10(1):21291. PubMed: https://pubmed.gov/33277573. Full-text: https://doi.org/10.1038/s41598-020-78039-1
In this retrospective analysis on 280 patients admitted to the San Raffaele Hospital (Milan, Italy) with moderate/severe COVID-19, time to negativization of nasopharyngeal swabs was similar in steroid and non-steroid users. According to multivariate analysis, SARS-CoV-2 clearance was associated with age ≤ 70 years, a shorter duration of symptoms at admission, a baseline PaO2/FiO2 > 200 mmHg, and a lymphocyte count at admission > 1.0 × 109/L. SARS-CoV-2 clearance was not associated with corticosteroid use.
WHO Solidarity Trial Consortium. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N Engl J Med 2020, published 2 December. Full-text: https://doi.org/10.1056/NEJMoa2023184
Harrington DP, Baden LR, Hogan JW (Editorial). A Large, Simple Trial Leading to Complex Questions. N Engl J Med 2020, published 2 December. Full-text: https://doi.org/10.1056/NEJMe2034294
Remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. This is the interim result of the WHO Solidarity Trial which of 11.330 adults at 405 hospitals in 30 countries. 2750 were randomly assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving the control. In the accompanying editorial, David Harrington, Lindsey Baden, and Joseph Hogan try to save the day for remdesivir; however, it is clear that the drug plays in an altogether different league than the powerful anti-HIV and anti-HCV drugs. Also, in future pandemics we will remember that repurposing old antiviral drugs was not successful.
Cox RM, Wolf JD, Plemper RK. Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets. Nat Microbiol 2020, published 3 December. Full-text: https://doi.org/10.1038/s41564-020-00835-2
Molnupiravir (MK-4482/EIDD-2801) is able to mitigate SARS-CoV-2 infection and block transmission when therapeutically administered to ferrets. The drug, initially developed as an inhibitor of influenza viruses, is currently in Phase II/III clinical trials (NCT04405570 and NCT04405739).
Wang G, Yang ML, Duan ZL, et al. Dalbavancin binds ACE2 to block its interaction with SARS-CoV-2 spike protein and is effective in inhibiting SARS-CoV-2 infection in animal models. Cell Res 2020, published 1 December. Full-text: https://doi.org/10.1038/s41422-020-00450-0
Dalbavancin is a once-a-week antibiotic (plasma half-life: 5–7 days) with activity against a broad range of Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and which has been approved for the treatment of acute bacterial skin and skin structure infections. Here, Ren Lai, Gan Wang and colleagues show that the drug effectively prevented SARS-CoV-2 replication in Vero E6 cells with an EC50 of ~12 nM. In both mouse and rhesus macaque models, viral replication and histopathological injuries caused by SARS-CoV-2 infection were significantly inhibited by dalbavancin administration.
Young B, Tan TT, Leo YS. The place for remdesivir in COVID-19 treatment. Lancet Inf Dis November 26, 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30911-7
Is there is a place for remdesivir? Last week, the WHO said no (https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients). In their comment on current data, Barnaby Young and colleagues from Singapore are not that strict. They believe that the natural history of COVID-19 suggests a window of opportunity for antivirals before fulminant inflammation sets in. However, they conclude that “for now, remdesivir is an important COVID-19 treatment option only in selected patient groups”.
Dangerfield TL, Huang NZ, Johnson KA. Remdesivir is effective in combating COVID-19 because it is a better substrate than ATP for the viral RNA-dependent RNA polymerase. iScience November 27, 2020. Full-text: https://doi.org/10.1016/j.isci.2020.101849
Tyler L. Dangerfield and colleagues compared binding and incorporation parameters for nucleoside analogs such as remdesivir relative to their natural counterparts (ATP). The specificity constant for remdesivir triphosphate incorporation was higher than that for competing ATP. Would be nice to see this effect in vivo.
Sörgel F, Nalin JJ, Hagman H, et al. Pharmacokinetics of remdesivir in a COVID-19 patient with end-stage renal disease on intermittent haemodialysis. Journal of Antimicrobial Chemotherapy November 30,2020. Full-text: https://doi.org/10.1093/jac/dkaa500
Jan Rybniker from Cologne and colleagues report the pharmacokinetics of remdesivir and its metabolites and the treatment outcome in a patient on renal replacement therapy without residual renal function suffering from severe COVID-19.
Figure 1. Pharmacokinetics of the prodrug remdesivir (GS-5734), its intermediate alanine metabolite (GS-704277) and the predominant circulating metabolite GS-441524 during a standard 5-day regimen in a patient with intermittent hemodialysis due to long-lasting ESRD. Arterial blood samples were drawn in conjunction with… | Continue reading at https://doi.org/10.1093/jac/dkaa500. Reproduced with permission.
Mishra GP, Mulani J. Corticosteroids for COVID-19: the search for an optimum duration of therapy. Lancet Resp Med November 26, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30530-0
According to this comment by Gyanshankar P Mishra and Jasmin Mulani, corticosteroids seem to be a double-edged sword and need to be used judiciously, considering the risk–benefit ratio, as a short-course (up to 10 days) therapeutic agent in a select group of patients with COVID-19 for whom a survival benefit has been reported. Extended courses of steroids may be detrimental.
WHO 20201120. WHO recommends against the use of remdesivir in COVID-19 patients. WHO 2020, published 20 November. Full-text: https://www.who.int/news-room/feature-stories/detail/who-recommends-against-the-use-of-remdesivir-in-covid-19-patients
First nail in the remdesivir coffin. On 20 November, WHO issued a conditional recommendation against the use of remdesivir (brand name: Veklury) in hospitalized patients, regardless of disease severity, as there is currently no evidence that remdesivir improves survival and other outcomes in these patients. Evidence from over 7000 patients across 4 trials suggests no important effect on mortality, need for mechanical ventilation, time to clinical improvement, and other patient-important outcomes. Happy France (see below, Covid-19 : comment Gilead a vendu son remdésivir à l’Europe)!
Simonovich VA, Burgos Pratx LD, Scibona P, et al for the PlasmAr Study Group. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Eng J Med, November 24, 2020. Full-text: https://doi.org/10.1056/NEJMoa2031304
A crushing failure for convalescent plasma (CP): this study from Argentina randomly assigned 338 hospitalized adult patients with severe COVID-19 pneumonia in a 2:1 ratio to receive CP or placebo. No significant differences were observed in clinical status or overall mortality and prespecified subgroup analyses failed to suggest any credible subgroup effects. Moreover, the trial ensured that more than 95% of the transfused CP units had a total anti–SARS-CoV-2 antibody titer of at least 1:800 and that the plasma volume infused had a correction factor according to the participant’s weight. The authors “believe the use of CP as a standard of care in such patients should be reevaluated”. Well said.
Fan H, Hong B, Luo Y et al. The effect of whey protein on viral infection and replication of SARS-CoV-2 and pangolin coronavirus in vitro. Sig Transduct Target Ther 5, 275 (2020). Full-text: https://doi.org/10.1038/s41392-020-00408-z
Human breastmilk inhibits SARS-CoV-2 virus infection in Vero E6 and A549 cell lines. Huaghao Fan and colleagues show for the first time that whey protein from human breastmilk effectively inhibited SARS-CoV-2 by blocking viral attachment and viral replication at entry and even post-entry. Moreover, human whey protein inhibited infectious virus production, as proved by a plaque assay. Whey protein from different species, such as cow and goat, also showed anti-coronavirus properties. Commercial bovine formula milk also showed similar anti-SARS-CoV-2 activity.
Bozzi G, Mangioni D, Minoia F, et al. Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: an observational cohort study. J Allergy Clin Immunol. 2020 Nov 18:S0091-6749(20)31621-3. PubMed: https://pubmed.gov/33220354. Full-text: https://doi.org/10.1016/j.jaci.2020.11.006
IL-1 receptor antagonist anakinra is one of the cytokine-blocking agents employed for COVID-19 treatment. Of 120 patients with hyperinflammation (33% on mechanical ventilation), 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 14% in treated patients and 36% in controls (p = 0,005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared to controls (HR 0,33, p = 0.007 and HR 0,18, p = 0,001, respectively). Randomized, controlled trials including use of either agent alone are needed to confirm these results.
Milewska A, Chi Y, Szczepanski A, et al. HTCC as a Polymeric Inhibitor of SARS-CoV-2 and MERS-CoV. J Virology November 20, 2020. Full-text: https://doi.org/10.1128/JVI.01622-20
The cationically modified chitosan, N-(2-hydroxypropyl)-3-trimethylammonium chitosan chloride (HTCC) is a potent inhibitor of all known human coronaviruses. Using in vitro and ex vivo models of human airway epithelium, the authors show that HTCC effectively blocks MERS-CoV and SARS-CoV-2 infection.
Schwaiger J, Karbiener M, Aberham C, Farcet MR, Kreil TR. No SARS-CoV-2 Neutralization by Intravenous Immunoglobulins Produced From Plasma Collected Before the 2020 Pandemic. J Infect Dis. 2020 Nov 13;222(12):1960-1964. PubMed: https://pubmed.gov/32941626. Full-text: https://doi.org/10.1093/infdis/jiaa593
Julia Schwaiger and colleagues from Baxter AG tested 54 intravenous immunoglobulin preparations, produced from plasma collected in Europe and the US. Although highly potent neutralization of a seasonal coronavirus HCoV-229E was seen, there was no cross-neutralization of the new SARS-CoV-2.
Hueso T, Pouderoux C, Péré H, et al. Convalescent plasma therapy for B-cell–depleted patients with protracted COVID-19. Blood 136 (20): 2290–2295. Full-text: https://doi.org/10.1182/blood.2020008423
The secondary humoral deficiency induced by anti-CD20 monoclonal antibodies such as rituximab may prevent the elicitation of a specific SARS-CoV-2 antibody response. Thomas Hueso and colleagues from France report on 17 consecutive patients with profound B cell lymphopenia and prolonged COVID-19 symptoms, negative SARS-CoV-2 serology, and positive RNAemia who were treated with four units of convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Of note, SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. This small series indicates that convalescent plasma could be promising at least in patients unable to mount a specific humoral response.
Mehew J, Johnson R, Roberts D, et al. Convalescent plasma for COVID-19: male gender, older age and hospitalisation associated with high neutralising antibody levels, England, 22 April to 12 May 2020. Euro Surveill. 2020;25(45):pii=2001754. Full-text: https://doi.org/10.2807/1560-7917.ES.2020.25.45.2001754
How to select donors of convalescent plasma (CP)? The answer: take older males with blood group AB and with severe disease – and don’t wait too long. In this study from the UK, 275/330 donors had detectable neutralizing antibodies against SARS-CoV-2. For these 275 donors, median levels of neutralizing antibodies were higher in men compared with women, in those hospitalized compared with non-hospitalized, in those with blood group AB compared with other groups. Neutralizing antibody levels decreased as the time between SARS-CoV-2 diagnosis and donation increased. According to the authors, their data will be of value in the timely recruitment of CP donors most likely to have high levels of neutralizing antibodies for ongoing studies investigating its effectiveness.
Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19A Randomized Clinical Trial. JAMA 2020, published 12 November. Full-text: https://doi.org/10.1001/jama.2020.22760
Fluvoxamine (a potent agonist of the sigma-1 receptor (σ1R)), is an antidepressant which functions pharmacologically as a selective serotonin reuptake inhibitor. In this small randomized trial that included 152 adult outpatients with COVID-19 and symptom onset within 7 days, Eric Lenze et al. found that clinical deterioration occurred in 0 patients treated with fluvoxamine vs 6 (8.3%) patients treated with placebo over 15 days. The authors acknowledge the limitations of their study: a small number of endpoint events, which makes the findings fragile; 20% of study participants stopped responding to surveys during the 15-day trial; the follow-up duration was short and did not measure the effect of fluvoxamine on persistent symptoms or late deterioration. The potential advantages of fluvoxamine for outpatient treatment of COVID-19 would include its safety, widespread availability, low cost, and oral administration. Note that fluvoxamine can cause drug-drug interactions, particularly via inhibition of cytochromes P450 1A2 and 2C19. Eagerly awaiting data from larger trials. See also the comment by Seymour CW, Bauchner H, Golub RM. COVID-19 Infection—Preventing Clinical Deterioration. JAMA 2020, published 12 November. Full-text: https://doi.org/10.1001/jama.2020.21720
Monk PD, Marsden R, Tear VJ, et al. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 2020, published 12 November. Full-text: https://doi.org/10.1016/S2213-2600(20)30511-7
SNG001 is a formulation of recombinant interferon beta for inhaled delivery by nebuliser that is in development for the treatment of virus-induced lower respiratory tract illnesses. In this pilot trial, Tom Wilkinson, Phillip Monk and colleagues show that patients randomly assigned to SNG001 (n = 48) had greater odds of improvement versus placebo on the WHO Ordinal Scale for Clinical Improvement (OSCI) and more rapid recovery to a point where patients were no longer limited in their activity, with a greater proportion of patients recovering during the 28-day study period. Note that there was no significant difference between treatment groups in the odds of hospital discharge by day 28 – so await results from larger trials before drawing any conclusions.
See also the comment by Peiffer-Smadja N, Yazdanpanah Y. Nebulised interferon beta-1a for patients with COVID-19. Lancet Respir Med 2020, published 12 November. Full-text: https://doi.org/10.1016/S2213-2600(20)30523-3
D’Alessio A, Del Poggio P, Bracchi F, et al. Low-dose ruxolitinib plus steroid in severe SARS-CoV-2 pneumonia. Leukemia (2020). https://doi.org/10.1038/s41375-020-01087-z
Results from a small non-randomized study might suggest a benefit from ruxolitinib in patients with severe COVID-19 pneumonia not requiring mechanical ventilation at baseline. D’Alessio et al. report an analysis of 32 patients (Group A) who received ruxolitinib, a JAK 1/2 (Janus Kinase) inhibitor, and 43 patients who served as a control group (Group B). Ruxolitinib was administered orally at a dose of 5 mg twice daily for 7 days and then tapered to 5 mg daily to complete a 10-day course of treatment. All patients received methylprednisolone. Concomitant administration of hydroxychloroquine, lopinavir/ritonavir or remdesivir was not permitted during treatment with ruxolitinib. Kaplan–Meier estimates of the percentage of patients who were alive and clinically recovered at the end of follow-up were 89% for group A and 57% for group B (SE ± 6.1). As always: to be confirmed in larger trials.
Hoang TN, Pino M, Boddapati AK. Baricitinib treatment resolves lower airway macrophage inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques. Cell November 09, 2020.ft https://doi.org/10.1016/j.cell.2020.11.007
Timothy Hoang and colleagues investigated the immunologic and virologic efficacy of baricitinib (approved JAK1/2 inhibitor) in rhesus macaques. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was NOT reduced with baricitinib and type I IFN antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. However, animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment.
Self WH, Semler MW, Leither LM. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19 – A Randomized Clinical Trial. JAMA. November 9, 2020. Full-text: https://doi.org/10.1001/jama.2020.22240
No, there was no effect of HCQ in this RCT among 479 adults hospitalized with respiratory illness from COVID-19. Do we need more clinical studies?
Saag MS. Misguided Use of Hydroxychloroquine for COVID-19. The Infusion of Politics Into Science. JAMA. November 9, 2020. Full-text: https://doi.org/10.1001/jama.2020.22389
Nice comment on the HCQ story. According to Michael Saag, the clear, unambiguous, and compelling lesson from the hydroxychloroquine story for the medical community and the public is that science and politics do not mix.
Xiang Y, Nambulli S, Xiao Z, et al. Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2. Science 05 Nov 2020. Full-text: https://doi.org/10.1126/science.abe4747
An early inhalation of nanobodies – the future treatment? VHH antibodies or nanobodies (Nbs) are minimal, monomeric antigen-binding domains derived from camelid single-chain antibodies. Unlike IgG antibodies, Nbs are small, highly soluble and stable, readily bioengineered into bi/multivalent forms, and are amenable to low-cost, efficient microbial production. They can also be administered by inhalation, making their use against respiratory viruses very appealing. The authors discovered several Nbs with picomolar to femtomolar affinities that inhibit viral infection at sub-ng/ml concentration and determined a structure of one of the most potent in complex with RBD. Multivalent Nb constructs achieved ultra-high neutralization potency and may prevent mutational escape. While the research is still preliminary, it is hoped that Nbs might someday be the key ingredient in an antiviral drug that could be easily delivered via nasal spray.
Schoof M, Faust B, Saunders RA, et al. An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike. Science 05 Nov 2020. Full-text: https://doi.org/10.1126/science.abe3255
Michael Schoof and colleagues from San Francisco focused on such an ultrapotent Nb. Nb6 binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multi-valency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.
Linsky TW, Vergara R, Codina N, et al. De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2. Science 05 Nov 2020. Full-text: https://doi.org/10.1126/science.abe0075
Another new way to combat COVID-19. Thomas W. Linsky and colleagues from Seattle and other US cities developed a computational protein design strategy that enables the rapid and accurate design of hyperstable de novo protein “decoys”. The decoys replicate the protein receptor interface that a virus binds to in order to infect a cell. Thus, they out-compete viral interaction with the cell. The best ACE2 decoy, CTC-445.2, did bind with low nanomolar affinity and high specificity to the RBD of the spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed 10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.
Tsai A, Diaware O, Nahass RG, et al. Impact of tocilizumab administration on mortality in severe COVID-19. Sci Rep 10, 19131 (2020). Full-text: https://doi.org/10.1038/s41598-020-76187-y
Another study that does not support the use of tocilizumab for the management of cytokine storm in patients with COVID-19. In this single-center propensity-score matched cohort study, 132 patients were included in the matched dataset (tocilizumab = 66; no tocilizumab = 66). Approximately 73% of the patients were male. Hypertension (55%), diabetes mellitus (31%), and chronic pulmonary disease (15%) were the most common co-morbidities present. There were 18 deaths (27.3%) in the tocilizumab group and 18 deaths (27.3%) in the no tocilizumab group.
Mattay MA, Thompson BT. Dexamethasone in hospitalised patients with COVID-19: addressing uncertainties. Lancet Resp Med October 29, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30503-8
An important comment on unanswered questions regarding the use of dexamethasone. Michael Matthay and Taylor Thompson discuss the limitations of the pragmatic RECOVERY trial (huge number of excluded patients, no data on oxygen support, no use of remdesivir, no data on viral clearance etc). They also discuss the steps need to be taken to learn more about the effects of dexamethasone in hospitalised patients with COVID-19.
Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med 2020, published 28 October. Full-text: https://doi.org/10.1056/NEJMoa2029849
Bamlanivimab (LY-CoV555) is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. In this interim analysis, the patients who received LY-CoV555 had fewer hospitalizations and a lower symptom burden than those who received placebo, with the most pronounced effects observed in high-risk cohorts. Be prepared: the results are not spectacular.
Ledford H. The race to make COVID antibody therapies cheaper and more potent. Nature 2020, published 23 October. Full-text: https://www.nature.com/articles/d41586-020-02965-3
Injections of antibodies might prevent mild COVID-19 from becoming severe, but the treatments are expensive and difficult to make.
Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939. PubMed: https://pubmed.gov/33093056. Full-text: https://doi.org/10.1136/bmj.m3939
Convalescent plasma (CP) (giving neutralizing antibodies of people who made it through SARS-CoV-2 infection) has been one of the biggest hopes. This open-label randomized controlled trial (RCT; the largest to date with results) investigated the effectiveness of CP in adults with moderate COVID-19 in 39 public and private hospitals across India. In total, 235 patients were assigned to two doses of 200 mL CP and 229 to standard of care only (control arm). Progression to severe disease or all-cause mortality at 28 days after enrolment occurred in 44 (19%) participants receiving CP and in 41 (18%) in the control arm. Moreover, CP treatment did not show anti-inflammatory properties and there was no difference between patients with or without neutralizing antibodies at baseline (who had produced their own antibodies or not). The main limitation: the authors did not measure the antibody titers in CP before transfusion because validated, reliable commercial tests were not available when the trial started. Let’s hope that low antibody titers were the reason for the lack of efficacy.
Pathak EB. Convalescent plasma is ineffective for covid-19. BMJ. 2020 Oct 22;371:m4072. PubMed: https://pubmed.gov/33093025. Full-text: https://doi.org/10.1136/bmj.m4072
A strong statement, after all (and some thoughts on how to deal with the bad results of the PLACID trial).
Chowdhury JF, Moores LK, Connors JM. Anticoagulation in Hospitalized Patients with Covid-19. N Engl J Med. 2020 Oct 22;383(17):1675-1678. PubMed: https://pubmed.gov/33085867. Full-text: https://doi.org/10.1056/NEJMclde2028217
The case of a 78-year-old man with hypertension and hyperlipidemia who was brought to the emergency department 48 hours ago. Now that the patient’s condition has worsened, with progressive hypoxemia, elevated inflammatory markers, and an increase in D-dimer level, it is to decide whether a) the prophylactic doses of anticoagulants should be maintained or whether b) they should be replaced by an increased dose (and if so, of what agent). Lisa Moores says a), Jean Connors says b). Both have good arguments. This is bad news, because after 9 months, we still don’t know what to do.
Well, you are still here? Brave. See you tomorrow. We will find a way through this.
Arabi YM, Asiri AY, Assiri AM, et al. Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome. N Engl J Med. 2020 Oct 22;383(17):1645-1656. PubMed: https://pubmed.gov/33026741. Full-text: https://doi.org/10.1056/NEJMoa2015294
In MERS, interferon and lopinavir/r seem to work: This double-blind, placebo-controlled RCT enrolled 95 hospitalized patients at nine sites in Saudi Arabia to receive recombinant interferon beta-1b plus lopinavir/r (intervention) or placebo for 14 days. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. In a pre-specified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Can we learn from this?
Salvarani C, Dolci G, Massari M, et al. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia. A Randomized Clinical Trial. JAMA Intern Med October 20, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.6615
The second RCT showing that tocilizumab (TCZ) doesn’t work in patients with less severe disease. This prospective, open-label RCT randomized patients hospitalized with COVID-19 pneumonia to receive TCZ or standard of care in 24 hospitals in Italy. Among 126 patients with a partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg at enrolment, the rate of the primary clinical end point (clinical worsening) was not significantly different between the control group and the TCZ group. The proportion of patients discharged within 14 and 30 days was the same (rate ratio, 0.99; 95% CI, 0.73-1.35; and 0.98; 95% CI, 0.87-1.09; respectively). According to the authors, however, their results “do not allow ruling out the possible role of tocilizumab in reducing the risk of death or intubation in patients presenting with more advanced disease”. Let’s hope.
Gupta S, Wang W, Hayek SS, et al. Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19. JAMA Intern Med October 20, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.6252
Does it work in severe COVID-19? This multicenter cohort study that included 3924 critically ill patients admitted to participating intensive care units (ICU) at 68 hospitals across the US, patients were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. The risk of in-hospital death was estimated to be lower with TCZ. A total of 1544 patients (39,3%) died, including 125/433 (28,9%) treated with TCZ and 1419/3491 (40,6%) not treated with the drug. However, this was an uncontrolled study and TCZ patients were younger, had fewer co-morbidities and were more likely to receive corticosteroids on ICU admission. According to the authors, the findings “may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed”. Again, let’s hope.
Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med 2020, published 22 October. Full-text: https://doi.org/10.1056/NEJMoa2028836
Tocilizumab was not effective for preventing intubation or death in moderately ill hospitalized patients with COVID-19. This is the result of a randomized, double-blind, placebo-controlled trial involving SARS-CoV-2 patients with hyperinflammatory states and at least two of the following signs: fever (body temperature > 38°C), pulmonary infiltrates, or the need for supplemental oxygen in order to maintain an oxygen saturation greater than 92%. John H. Stone and colleagues (for the BACC Bay Tocilizumab Trial Investigators) conclude that their data do not provide support for the concept that early interleukin 6 receptor blockade is an effective treatment strategy in moderately ill patients hospitalized with COVID-19.
Keretsu S, Bhujbal SP, Cho SJ. Rational approach toward COVID-19 main protease inhibitors via molecular docking, molecular dynamics simulation and free energy calculation. Sci Rep 10, 17716 (2020). Full-text: https://doi.org/10.1038/s41598-020-74468-0
Saquinavir instead of lopinavir? The authors found 15 potential 3CLpro inhibitors with higher binding affinity than that of an α-ketoamide inhibitor determined via X-ray structure. Among them, saquinavir and three investigational drugs aclarubicin, TMC-310911, and faldaprevir can be suggested as potential 3CLpro inhibitors. The authors recommend further experimental investigation of these compounds.
Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial. Clinical Infectious Diseases 17 October 2020. Full-text: https://doi.org/10.1093/cid/ciaa1571
No, HCQ does not work as prophylaxis, even in HCW. This huge double-blinded RCT included 1483 healthcare workers with ongoing exposure to persons with SARS-CoV-2. Participants across the US and Canada were randomized to HCQ 400 mg once weekly or twice weekly for 12 weeks. The incidence of COVID-19 (laboratory-confirmed or symptomatic compatible illness) was 0.27 events per person-year with once-weekly and 0.28 events per person-year with twice-weekly hydroxychloroquine, compared with 0.38 events per person-year with placebo. This was not statistically significant.
Rogers R, Shehadeh F, Mylona EK, et al. Convalescent plasma for patients with severe COVID-19: a matched cohort study. Clin Infect Dis 2020, published 10 October. Full-text: https://doi.org/10.1093/cid/ciaa1548
The efficacy of convalescent plasma (CP) for the treatment of COVID-19 remains unclear. In this matched cohort analysis of hospitalized patients with severe COVID-19, 64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. There was a signal for an increased rate of hospital discharge among patients 65 years old or greater, but no significant difference in the risk of in-hospital mortality between the two groups.
Baum A, Ajithdoss D, Copin R, et al. REGN-COV2 antibodies prevent and treat SARS-CoV-2 infection in rhesus macaques and hamsters. Science 2020, published 9 October. Full-txt: https://doi.org/10.1126/science.abe2402
The authors evaluate REGN-COV2, a cocktail of two neutralizing antibodies (REGN10987+REGN10933) targeting non-overlapping epitopes on the SARS-CoV-2 spike protein, in rhesus macaques and golden hamsters. REGN-COV2 can reduce virus load and decrease virus-induced pathological sequalae in rhesus macaques. In hamsters, the cocktail limited weight loss and evidence of pneumonia in the lungs. It is too early to predict the clinical usefulness of this cocktail in COVID-19 patients. It is currently being tested in clinical trials.
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 – Final Report. N Engl J Med. 2020 Oct 8:NEJMoa2007764. PubMed: https://pubmed.gov/32445440. Full-text: https://doi.org/10.1056/NEJMoa2007764
The final part of a preliminary report (see our May 23 Top 10) of a promotional presentation at the White House almost 6 months ago. The paper confirms that of a total of 1062 patients, those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo. John Beigel et al. also confirm that remdesivir had no statistically significant impact on mortality. Dexamethasone holds more promise than remdesivir: The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM July 17, 2020. Full-text: https://doi.org/10.1056/NEJMoa2021436 (see also our July 18 comment).
Abi Jaoude J, Kouzy R, El Alam MB, et al. Exclusion of Older Adults in COVID-19 Clinical Trials. Mayo Clin Proc. 2020 Oct;95(10):2293-2294. PubMed: https://pubmed.gov/33012364. Full-text: https://doi.org/10.1016/j.mayocp.2020.08.018
A data query of the ClinicalTrials.gov registry for trials regarding COVID-19 on June 8 revealed that 206/674 COVID-19 interventional trials (30.6%) had an upper age exclusion criterion. The median upper age exclusion was 75 years. Exclusion of older patients from clinical trials dramatically increases the risk of non-representative trial populations compared with real-world counterparts.
RECOVERY Collaborative Group, and others. Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet October 5, 2020. Full-text: https://doi.org/10.1016/S0140-6736(20)32013-4
After preliminary results were made public on June 29, 2020, this is now the full paper on the lopinavir/r arm in the RECOVERY trial. Between March 19, 2020, and June 29, 2020, 1,616 patients admitted to hospital were randomly allocated to receive lopinavir/r and 3,424 patients to receive usual care. Lopinavir/r had no benefit. Overall, 374 (23%) patients allocated to lopinavir/r and 767 (22%) patients allocated to usual care died within 28 days. Results were consistent across all prespecified subgroups. No significant difference in time until discharge alive from hospital (median 11 days in both groups) or the proportion of patients discharged from hospital alive within 28 days was found. Although the lopinavir/r, dexamethasone, and hydroxychloroquine groups have now been stopped, the RECOVERY trial continues to study the effects of azithromycin, tocilizumab, convalescent plasma, and REGN-CoV2 (see our Trump special yesterday).
Wilt TJ, Kaka AS, MacDonald R, Greer N, Obley A, Duan-Porter W. Remdesivir for Adults With COVID-19: A Living Systematic Review for an American College of Physicians Practice Points. Ann Intern Med Oct 5, 2020. PubMed: https://pubmed.gov/33017170 . Full-text: https://doi.org/10.7326/M20-5752
And what about remdesivir? This review of published studies through 31 August 2020 (4 RCTs) indicates that in hospitalized adults with COVID-19, remdesivir “probably” improves recovery and reduces serious adverse events and may reduce mortality and time to clinical improvement, although with little to no difference in hospital length of stay. Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity.
Jose Luis Rodriguez-Garcia, Gines Sanchez-Nievas, Juan Arevalo-Serrano, Cristina Garcia-Gomez, Jose Maria Jimenez-Vizuete, Elisa Martinez-Alfaro. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study. Rheumatology, October 6, 2020. Full-text: https://doi.org/10.1093/rheumatology/keaa587
Janus kinase (JAK) inhibitors such as baricitinib may be beneficial in treating SARS-CoV-2 infection by inhibiting ACE2-mediated endocytosis. This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia who received lopinavir/ritonavir and HCQ plus either corticosteroids (controls, n=50) or corticosteroids and baricitinib (n=62). A higher proportion of patients required supplemental oxygen both at discharge (62% vs 26%) and 1 month later (28% vs 13%) in the control group, providing the first evidence for a possible synergistic effect of baricitinib and corticosteroids in SARS-CoV-2 pneumonia.
Burki TK. Completion of clinical trials in light of COVID-19. Lancet Resp Med October 01, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30460-4
Some thoughts on how running randomized trials at the same time as dealing with large numbers of critically ill patients. No small task, but “we have to give the same urgency to research on COVID-19 as we do to the clinical need.”
Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med September 30, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.6319
This was one of the last open questions regarding hydroxychloroquine (HCQ): Does a regimen of 600 mg per day reduce the transmission of SARS-CoV-2 as a pre-exposure prophylaxis strategy when taken by hospital-based health care workers? The answer is clear: No. In this double-blind, placebo-controlled randomized clinical trial that included 132 HCW and was terminated early, there was not a significant difference in PCR–confirmed SARS-CoV-2 incidence between hydroxychloroquine and placebo cohorts. Mild adverse events were more common in participants taking hydroxychloroquine compared with placebo (45% vs 26%; p = .04).
Martinot M, Jary A, Fafi-Kremer S, et al. Remdesivir failure with SARS-CoV-2 RNA-dependent RNA-polymerase mutation in a B-cell immunodeficient patient with protracted Covid-19. Clinical Infectious Diseases, ciaa1474, https://doi.org/10.1093/cid/ciaa1474
The occurrence of a mutation in the RdRP (D484Y) gene following failure of remdesivir (given 5 days) in a 76-year-old woman with a post-rituximab B cell immunodeficiency and persistent SARS-CoV-2 viremia. The mutation was not present before treatment.
Vlaar AP, de Bruin S, Busch M, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatology September 28, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30341-6
In this open-label, randomized Phase 2 trial (part of the PANAMO trial), 15/30 patients with severe COVID-19 were treated with an anaphylatoxin and complement protein C5a blocking monoclonal antibody vilobelimab. Patients were randomly assigned 1:1 to receive vilobelimab (up to seven doses of 800 mg intravenously) or best supportive care only (control group). At day 5 after randomization, the primary endpoint of mean relative change in the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO2/FiO2) was not significantly different between groups. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0–31) for the vilobelimab group and 27% (4–49) for the control group. The frequency of serious adverse events was similar between groups and no deaths were considered related to treatment assignment. These secondary outcome results support the investigation of vilobelimab in a Phase 3 trial using 28-day mortality as the primary endpoint.
Campbell CM. The opening salvo of anti-complement therapy against COVID-19. Lancet Rheumatology September 28, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30353-2
Comment on the above study, considering the safe use and tolerability of vilobelimab as an important milestone. According to Courtney Campbell, the secondary outcomes reported are notable – in particular the fewer pulmonary embolisms (13% versus 40%). An important caveat, however, is that pharmacokinetic and pharmacodynamic analysis, including C5a, are to be published separately. Investigators using the C5 complement pathway inhibitors eculizumab and ravulizumab have significantly increased their dose and dosing frequency in the acute setting of COVID-19 compared with the doses approved for use in atypical hemolytic uremic syndrome. Whether vilobelimab in this trial successfully inhibited complement C5a in the setting of severe COVID-19 remains uncertain.
Tortorici A, Beltramello M, Lempp FA. Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms. Science 24 Sep 2020: eabe3354. Full-text: https://doi.org/10.1126/science.abe3354
- Alejandra Tortorici and colleagues report the isolation and characterization of two ultra-potent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that were identified among almost 800 screened Abs isolated from 12 individuals who recovered from COVID-19. Both nAbs protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block ACE2 attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Cocktails including S2M11, S2E12 or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. The authors propose that combinations of mAbs leveraging multiple distinct mechanisms of action with additive or synergistic effects could provide additional benefits for clinical application.
Pau AK, Aberg J, Baker J, et al. Convalescent Plasma for the Treatment of COVID-19: Perspectives of the National Institutes of Health COVID-19 Treatment Guidelines Panel. Ann Intern Med 2020, published 25 September. Full-text: https://doi.org/10.7326/M20-6448
The COVID-19 pandemic has intensified the tension between providing rapid access to promising therapies and generating the scientific evidence needed to establish whether those therapies are safe and effective. Here, Alice Pau et al. discuss the use of convalescent plasma for the treatment of COVID-19. They conclude that currently the data are insufficient to recommend for or against convalescent plasma for treating COVID-19.
Zoufaly A, Poglitsch M, Aberle JH, et al. Human recombinant soluble ACE2 in severe COVID-19. Lancet Resp Med September 24, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30418-5
Human recombinant soluble ACE2 (hrsACE2) may act by binding the viral spike protein (thereby neutralizing SARS-CoV-2) and by interfering with the renin–angiotensin system. Alex Zoufaly and colleagues from Vienna report on a case of a 45-year-old woman with severe COVID-19 who was treated with hrsACE2. The virus disappeared rapidly from the serum and the patient became afebrile within hours. Phase II/III studies of hrsACE2 are ongoing.
Doi Y, Hibino M, Hase R, et al. A prospective, randomized, open-label trial of early versus late favipiravir in hospitalized patients with COVID-19. Antimicrob Agents Chemother. 2020 Sep 21:AAC.01897-20. PubMed: https://pubmed.gov/32958718. Full-text: https://doi.org/10.1128/AAC.01897-20
No effect of viral clearance with favipiravir. In this RCT, 69 patients with asymptomatic to mild COVID-19 were randomly assigned to early or late favipiravir therapy (same regimen starting day 1 or day 6). Viral clearance occurred within 6 days in 67% and 56% (adjusted hazard ratio 1.42; 95% CI 0.76–2.62). Of 30 patients who had a fever (≥ 37.5°C) on day 1, time to no fever was 2.1 days and 3.2 days (aHR, 1.88; 95% CI 0.81–4.35). During therapy, 84% developed transient hyperuricemia. Favipiravir did not significantly improve viral clearance as measured by RT-PCR by day 6 but was associated with numerical reduction in time to no fever. Neither disease progression nor death occurred in any of the patients in either treatment group during the 28-day participation.
Baicus C, Pinte L, Stoichitoiu LE, Badea C. Hydroxychloroquine for prophylaxis of COVID-19 physicians survey: Despite lack of evidence, many would take or give to dear ones, and despite the perceived necessity of an RCT, few would participate. J Eval Clin Pract. 2020 Sep 21. PubMed: https://pubmed.gov/32955801. Full-text: https://doi.org/10.1111/jep.13484
It does not seem entirely impossible that the authors made themselves rather unpopular with their colleagues, publishing the results of this survey performed in early April. A total of 784 Romanian doctors were interviewed about their thoughts on HCQ. Despite the lack of evidence at that time, 36% considered the evidence as existing, and 22% were ready to take or to give hydroxychloroquine prophylactically to family. Almost all (92%) considered an RCT necessary, but only 42% were willing to participate. There was only a very weak correlation (Kendall’s tau _b = 0.255, p < 0.001) between the belief that an RCT is necessary and the willingness to enroll in such an RCT. In any case, the clearest paper title of the day (the discussion is remarkably short).
De Alencar JC, Moreira CL, Müller AD, et al. Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by COVID-19. Clinical Infectious Diseases, 23 September 2020, ciaa1443. Full-text: https://doi.org/10.1093/cid/ciaa1443
No effect of high-dose N-acetylcysteine. In this randomized clinical trial (RCT) from Brazil including 135 patients with severe COVID-19, 16 patients (24%) in the placebo group were submitted to endotracheal intubation and mechanical ventilation, compared to 14 patients (21%) in the NAC group (p = 0.675). No difference was observed in secondary endpoints.
Wang M, Zhao Y, Hu W, et al. Treatment of COVID-19 Patients with Prolonged Post-Symptomatic Viral Shedding with Leflunomide — a Single-Center, Randomized, Controlled Clinical Trial. Clin Infect Dis. 2020 Sep 21:ciaa1417. PubMed: https://pubmed.gov/32955081 . Full-text: https://doi.org/10.1093/cid/ciaa1417
No effect of leflunomide. Leflunomide is an approved antagonist of dihydroorotate dehydrogenase, has some antiviral and anti-inflammatory effects and has been widely used to treat patients with autoimmune diseases. In this small RCT from Wuhan on 50 COVID-19 patients with prolonged PCR positivity, no benefit in terms of the duration of viral shedding was observed with the combined treatment of leflunomide and IFN α-2a vs IFN α-2a alone.
Gentrey CA, Humphrey MB, Thind SK, et al. Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study. Lancet Rheumatology September 21, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30305-2
Did you expect that patients with rheumatological conditions receiving chronic hydroxychloroquine therapy would be at less risk of developing SARS-CoV-2 infection than those not receiving hydroxychloroquine? No? Then you are right. The incidence did not differ between patients with or without hydroxychloroquine in this large cohort (31 of 10,703 vs 78 of 21,406; odds ratio 0.79, 95% CI 0.52–1.20, p = 0.27).
Zhou Y, Wang F, Tang J, Nussinov R, Cheng F. Artificial intelligence in COVID-19 drug repurposing. Lancet Digital Health 2020, published 18 September. Full-text: https://doi.org/10.1016/S2589-7500(20)30192-8
Drug repurposing (a technique whereby existing drugs are used to treat emerging and challenging diseases such as COVID-19) might reduce development timelines and overall costs. This review introduces guidelines on how to use artificial intelligence (AI) for accelerating drug repurposing.
Liu STH, Lin H, Baine I, et al. Convalescent plasma treatment of severe COVID-19: a propensity score–matched control study. Nat Med (2020). https://doi.org/10.1038/s41591-020-1088-9
Retrospective, propensity score–matched case–control study assessment in 39 patients. Patients who received convalescent plasma required somewhat less oxygen; preliminary data might suggest a mortality benefit. The authors conclude that greater numbers and a randomized trial are needed to draw definitive conclusions about the efficacy of convalescent plasma for the treatment of COVID-19.
Furlow B. COVACTA trial raises questions about tocilizumab’s benefit in COVID-19. Lancet Rheumatology. September 09, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30313-1
At the end of the day, nothing but steroids? On July 29, Hoffmann-La Roche announced disappointing results from its much-anticipated phase 3 COVACTA trial of tocilizumab (TCZ), raising questions about the efficacy of IL-6 blockade in patients with severe COVID-19 pneumonia. TCZ did not improve patient mortality, although patients spent roughly a week less in hospital compared with those given placebo (the full results of the trial have not yet been published). Bryant Furlow argues that it may be too early to quit this strategy. Cautious interpretation of COVACTA is needed, in view of the study’s broad patient selection criteria and other study design factors. Tocilizumab continues to be evaluated in the RECOVERY trial. Let’s hope that it works.
Cheng LL, Guan WJ, Duan CY, et al. Effect of Recombinant Human Granulocyte Colony–Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia. A Randomized Clinical Trial. JAMA Intern Med September 10, 2020. Full-text: https://doi.org/10.1001/jamainternmed.2020.5503
G-CSF may be helpful in some patients. Lin-ling Cheng and colleagues performed an open-label trial at 3 participating centers in China, randomizing 200 patients with lymphopenia and no comorbidities to usual care alone or usual care plus 3 doses of recombinant human G-CSF (5 μg/kg, subcutaneously at days 0-2). Time to clinical improvement was similar between groups. However, the proportion of patients progressing to acute respiratory distress syndrome, sepsis, or septic shock was lower in the rhG-CSF group (2% vs 15%). Mortality was also lower (2% vs 10%). According to the authors, larger studies that include a broader range of patients with COVID-19 should be conducted.
Patell R, Bogue T, Koshy A, et al. Postdischarge thrombosis and hemorrhage in patients with COVID-19. Blood 2020, 136 (11): 1342–1346. Full-text: https://doi.org/10.1182/blood.2020007938
Rushad Patell and colleagues conducted a retrospective observational cohort study of 163 discharged COVID-19 patients not receiving anticoagulation (26% had required ICU care). The cumulative incidence of thrombosis (including arterial and venous events) at day 30 following discharge was 2.5% (95% CI, 0.8-7.6). The cumulative incidence of major hemorrhage was 0.7% and of clinically relevant non-major bleeds was 2.9%, emphasizing the need for randomized data to inform recommendations for universal post-discharge thromboprophylaxis.
Editorial. Curing COVID-19. Lancet Infect Dis 2020, published 10 September. Full-text: https://doi.org/10.1016/S1473-3099(20)30706-4
In the future, we will have effective therapies but for now we basically have just dexamethasone and hydrocortisone.
Cao L, Goreshnik I, Coventry B, et al. De novo design of picomolar SARS-CoV-2 miniprotein inhibitors. Science 2020, published 9 September. Full-text: https://doi.org/10.1126/science.abd9909
Targeting the interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor has become a global sport. The ultimate goal: delivery of a viral inhibitor into the nose and into the respiratory system for treatment of early infection, maybe even for prophylaxis. Now David Baker, Longxing Cao and colleagues report computer-designed mini-proteins (20-fold smaller than a full antibody molecule) that might rival SARS-CoV-2 neutralizing antibodies in its protective actions. The authors believe that in the future it will become possible to generate ultra-high-affinity, pathogen-neutralizing designs within weeks of obtaining a genome sequence.
Squillace N, Pozzi MR, Gustinetti G, et al. Therapy of SARS-Coronavirus-2 pneumonia: is there an optimal IL-6 cut-off for successful tocilizumab treatment? Clin Infect Dis. 2020 Sep 4:ciaa1282. PubMed: https://pubmed.gov/32886768 . Full-text: https://doi.org/10.1093/cid/ciaa1282
Nicola Squillace from Milano compared 16 patients who were discharged within 30 days from first tocilizumab (TCZ) dose (group A) vs 16 patients who had prolonged hospitalization or died within 30 days from first TCZ administration (group B). Before and after TCZ, IL-6 levels were markedly higher in group B, suggesting a high burden of inflammation, not sufficiently inhibited by receptor blockade. Larger, controlled trials on TCZ are urgently needed.
De Oliveira B, Mallat J. Efficacy of Tocilizumab for treatment of severe COVID-19 Pneumonia: more evidence is needed. Clin Infect Dis. 2020 Sep 4:ciaa1284. PubMed: https://pubmed.gov/32886762 . Full-text: https://doi.org/10.1093/cid/ciaa1284
This is exactly what this comment on another retrospective study is saying. Bruno De Oliveira and Jihad Mallat argue that the current level of evidence supporting the use of TCZ is weak and based on lower-quality studies.
Robinson PC, Richards D, Tanner HL, Feldmann M. Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment. Lancet 2020, published 4 September. Full-text: https://doi.org/10.1016/S2665-9913(20)30309-X
A major component of deteriorating lung function in patients with COVID-19 is capillary leak, a result of inflammation driven by key inflammatory cytokines: TNF, IL-1, IL-6, and vascular endothelial growth factor. Administration of anti-TNF to patients for treatment of autoimmune disease leads to reductions in all of these key inflammatory cytokines. Now Marc Feldmann and colleagues describe the rationale for trialing anti-TNF therapies for the COVID-19-related hyperinflammation (or cytokine release) syndrome. The authors advocate that few current treatments under investigation have this level of supportive evidence.
Furtado RHM, Berwanger O, Fonseca HA, et al. 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. Lancet 2020, published 4 September. Full-text: https://doi.org/10.1016/S0140-6736(20)31862-6
Hydroxychloroquine (HCl) was useless, the combination HCl + azithromycin was useless and azithromycin alone in the treatment of COVID-19 is useless too. In this randomized clinical trial at 57 centers in Brazil, Otavio Berwanger, Remo Furtado and colleagues enrolled patients who needed oxygen supplementation of more than 4 L/min flow, high-flow nasal cannula, or mechanical ventilation (non-invasive or invasive). 214 were assigned to the azithromycin group and 183 to the control group. Azithromycin had no effect.
See also the comment by Catherine Oldenburg and Thuy Doan [Oldenburg CE, Doan T. Azithromycin for severe COVID-19. Lancet 2020, published 4 September. Full-text: https://doi.org/10.1016/S0140-6736(20)31863-8].
The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM July 17, 2020. Full-text: https://doi.org/10.1056/NEJMoa2021436
With a press release on June 16, 2020 reporting the results of the UK-based RECOVERY trial, treatment of COVID-19 underwent a major change. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Why is this mentioned here again? Because the RECOVERY results had a huge impact on other randomized clinical trials (RCTs) around the world. Many trials were stopped prematurely following the press release and are now, unfortunately, underpowered. Three of them were now published in the JAMA:
Dequin PF, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19A Randomized Clinical Trial. JAMA September 2, 2020. Full-text: https://doi.org/10.1001/jama.2020.16761
- CAPE COD trial (France). Multicenter double-blinded RCT, in 149 (290 planned) critically-ill patients admitted to the intensive care unit (ICU) for COVID-19–related acute respiratory failure. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (p = 0.29).
Tomazini BM, Maia IS, Cavalcanti AB. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19. The CoDEX Randomized Clinical Trial. JAMA September 2, 2020. https://doi.org/10.1001/jama.2020.17021
- CoDEX (Brazil). Multicenter, open-label RCT in 299 COVID-19 patients (350 planned) with moderate-to-severe ARDS. Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n = 151) or standard care alone (n = 148). Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days during the first 28 days vs 4.0 ventilator-free days in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; p = 0.04). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days.
The Writing Committee for the REMAP-CAP Investigators. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19. JAMA September 2, 2020. https://doi.org/10.1001/jama.2020.17022
- REMAP-CAP (different countries). In this Bayesian RCT, 384 patients were randomized to fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone. Treatment with a 7-day fixed-dose course or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority, respectively, with regard to the odds of improvement in organ support–free days within 21 days. However, due to the premature halt of the trial, no treatment strategy met pre-specified criteria for statistical superiority, precluding definitive conclusions.
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19. A Meta-analysis. JAMA September 2, 2020. doi:10.1001/jama.2020.17023
A prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The fixed-effect summary odds ratios for the association with mortality were 0.64 (95% CI, 0.50-0.82; p < 0.001) for dexamethasone compared with usual care or placebo, 0.69 (95% CI, 0.43-1.12; p = 0.13) for hydrocortisone and 0.91 (95% CI, 0.29-2.87; p = 0.87) for methylprednisolone, respectively. There was no suggestion of an increased risk of serious adverse events. See also the editorial: Prescott HC, Rice TW. Corticosteroids in COVID-19 ARDS: Evidence and Hope During the Pandemic. JAMA 2020, published 2 September. Full-text: https://jamanetwork.com/journals/jama/fullarticle/2770275
Sterne J, Rice T, Diaz J. Corticosteroids for COVID-19 – New Evidence of Benefit. Jama Network 2020, published 2 September. Link: https://www.youtube.com/watch?v=XfDWjPxhKcE
Nadkarni GN, Lala A, Bagiella E, et al. Anticoagulation, Mortality, Bleeding and Pathology Among Patients Hospitalized with COVID-19: A Single Health System Study. J Am Coll Cardiol 2020, published 26 August. Full-text: https://doi.org/10.1016/j.jacc.2020.08.041
In this retrospective analysis of 4,389 patients, Valentin Fuster, Girish Nadkarni, Anuradha Lala and colleagues examine the association of in-hospital anticoagulation (AC) with in-hospital outcomes and describe thromboembolic findings on autopsies. Compared to no anticoagulation, therapeutic and prophylactic anticoagulation were associated with lower in-hospital mortality and intubation.
Mather JF, Seip RL, McKay RG. Impact of Famotidine Use on Clinical Outcomes of Hospitalized Patients With COVID-19. Am J Gastroenterol. 2020 Aug 26. PubMed: https://pubmed.gov/32852338 . Full-text: https://journals.lww.com/ajg/Documents/AJG-20-2074_R1.pdf
Another retrospective study reporting on a potential clinical benefit of famotidine. This propensity-matched observational study included 878 consecutive COVID-19-positive patients admitted to Hartford hospital (a tertiary care hospital in Connecticut, USA) between February 24 and May 13 2020. In total, 83 (9.5%) patients received famotidine. These patients were somewhat younger (63.5 vs 67.5 years) but did not differ with respect to baseline demographics or pre-existing comorbidities. Use of famotidine was associated with a decreased risk of in-hospital mortality (odds ratio 0.37, 95% CI 0.16-0.86) and combined death or intubation (odds ratio 0.47, 95% CI 0.23-0.96). Patients receiving famotidine displayed lower levels of serum markers for severe disease including CRP, procalcitonin and ferritin levels. Logistic regression analysis demonstrated that famotidine was an independent predictor of both lower mortality and combined death/intubation.
Matsuzawa Y, Ogawa H, Kimura K, et al. Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study. Hypertens Res. 2020 Aug 21. PubMed: https://pubmed.gov/32820236. Full-text: https://doi.org/10.1038/s41440-020-00535-8
Again, does a previous use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) affect the clinical manifestations and prognosis of COVID-19 patients? Yasushi Matsuzawa et al. analyzed 151 consecutive patients (mean age 60 ± 19 years) with SARS-CoV-2 infection in a retrospective observational study. Age ≥ 65 years was significantly associated (odds ratio 6.63) with the primary composite outcome (1. in-hospital death, 2. extracorporeal membrane oxygenation, 3. mechanical ventilation, including invasive and non-invasive methods, and 4. admission to the intensive care unit). In COVID-19 patients with hypertension, previous ACEI/ARB use was significantly associated with a lower occurrence of new-onset or worsening mental confusion (OR 0.06). The authors conclude that ACEIs/ARBs could be beneficial for the prevention of confusion in COVID-19 patients with hypertension.
Lane JCE, Weaver J, Kostka K. Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study. Lancet Rheumatol 2020, published 21 August. Full-text: https://doi.org/10.1016/S2665-9913(20)30276-9
Hydroxychloroquine (HCl) is like some presidents: it is useless and people should stop talking about it. As a matter of fact, we stopped reporting on the HCl soap opera weeks ago. If, nonetheless, you cannot resist watching newer episodes, here you go: when combined with azithromycin, as sung by a French bard, hydroxychloroquine increases the risk of heart failure and cardiovascular mortality.
Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA 2020, published 21 August. Full-text: https://doi.org/10.1001/jama.2020.16349
In this open-label trial, Christoph D. Spinner et al. found that hospitalized patients with moderate COVID-19 (pulmonary infiltrates and room-air oxygen saturation > 94%) who received a 5-day course of remdesivir had a better clinical status compared with those randomized to standard care at 11 days after initiation of treatment. There were no significant differences between the remdesivir and standard care groups in
- duration of oxygen therapy
- duration of hospitalization
- all-cause mortality
The authors acknowledge that the differences in clinical status between the remdesivir and control groups is of uncertain clinical importance.
Our forecast: remdesivir will be remembered as the AZT of the COVID-19 pandemic – cumbersome to administrate, low efficacy, expensive. As soon as truly efficient drugs are available, remdesivir will sink quietly into oblivion. The first nail in the remdesivir coffin is dexamethasone. As Erin McCreary and Derek Angus conclude in their editorial: “Whether remdesivir offers incremental benefit over corticosteroids, which are widely available and inexpensive, is unknown.” (McCreary EK, Angus DC. Efficacy of Remdesivir in COVID-19. JAMA 2020, published 21 August. Full-text: https://doi.org/10.1001/jama.2020.16337)
Karlsen APH, Wiberg S, Laigaard J, Pedersen C, Rokamp KZ, Mathiesen O. A systematic review of trial registry entries for randomized clinical trials investigating COVID-19 medical prevention and treatment. PLoS One. 2020 Aug 20;15(8):e0237903. PubMed: https://pubmed.gov/32817689 . Full-text: https://doi.org/10.1371/journal.pone.0237903
A global snapshot overview of COVID-19 interventions: Anders Peder Højer Karlsenand and colleagues systematically screened trial registry entries via the WHO ICTR Platform and 33 trial registries up to June 23, 2020. In total, 1,303 RCTs from 71 countries were identified (47% blinded), planning to include a total of 611,364 participants. Recruitment was ongoing in 54% of trials and completed in 8%. The five most frequent investigational categories were immune modulating drugs (20%), unconventional medicine (13%), antimalarial drugs (9%), antiviral drugs (8%) and respiratory adjuncts (6%). The five most frequently tested unimodal interventions were: chloroquine/hydroxychloroquine (113 trials with 199,841 participants); convalescent plasma (64 trials with 11,840 participants); stem cells (51 trials with 3,370 participants); tocilizumab (19 trials with 4,139 participants) and favipiravir (19 trials with 3,210 participants).
Park JJ, Decloedt EH, Rayner CR. Clinical trials of disease stages in COVID 19: complicated and often misinterpreted. Lancet August 20, 2020. Full-text: https://doi.org/10.1016/S2214-109X(20)30365-X
Important comment, emphasizing the nuances and differences of COVID-19 disease states in clinical trials. Although it is clear that some therapies have no clinical benefits in patients admitted to hospital, Jay JH Park and colleague argue that there is much uncertainty, and thus clinical equipoise, to justify continuing clinical trials in other COVID-19 disease states.
Lin DY, Zeng D, Eron JJ. Evaluating the Efficacy of Therapies in COVID-19 Patients. Clinical Infectious Diseases, August 21, 2020. Full-text: https://doi.org/10.1093/cid/ciaa1231
Some thoughts on clinical endpoints. To provide a full picture of the clinical course of a patient and make complete use of available data, the authors consider the trajectory of clinical status over the entire follow-up period. They also show how to combine the evidence of treatment effects on the occurrences of various clinical events and compare the proposed and existing endpoints through extensive simulation studies.
Kasgari HA, Moradi S, Shabani AM, et al. Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial. J Antimicrob Chemoth, 19 August 2020. Full-text: https://doi.org/10.1093/jac/dkaa332
The first randomized controlled trial in adult patients hospitalized with COVID-19 in Ghaem Shahr Razi Hospital (Iran) to evaluate the efficacy and safety of the two HCV drugs sofosbuvir and daclatasvir in combination with ribavirin (SDR) compared with standard of care. Though were trends in favor of the SDR arm for recovery and lower death rates, the trial was too small to make definite conclusions. In addition, there was an imbalance in the baseline characteristics between the arms.
Trezza A, Iovinelli D, Santucci A, et al. An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors. Sci Rep 10, 13866 (2020). Full-text: https://doi.org/10.1038/s41598-020-70863-9
Until an effective vaccine is available, repurposing FDA-approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. Here Ottavia Spiga and colleagues combine molecular dynamics simulations (MD), Supervised MD (SuMD), Steered MD (SMD) and interaction energy calculations, and showed that simeprevir (an HCV drug withdrawn from the European market in 2018) and lumacaftor (used in cystic fibrosis) bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.
Singh VP, El-Kurdi B, Rood C. What underlies the benefit of famotidine formulations used during COVID-19? Gastroenterology. 2020 Aug 7. PubMed: https://pubmed.gov/32777281. Full-text: https://doi.org/10.1053/j.gastro.2020.07.051
While results of the randomized clinical trial on the benefits of intravenous famotidine in treating COVID-19 (NCT04370262) are excitedly awaited, Vijay P. Singh and colleagues speculate on the potential mechanisms of action of this drug.
Jorgensen SC, Burry L, Tse CL, et al. Baricitinib: Impact on COVID-19 coagulopathy? Clin Infect Dis, August 2020. Full-text: https://doi.org/10.1093/cid/ciaa1208
The JAK-inhibitor baricitinib interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology and may also exert antiviral effects. Several trials are underway. Sarah Jorgensen and colleagues highlight a potential adverse effect that could be problematic for COVID-19 patients: baricitinib’s dose-dependent association with arterial and venous thromboembolic events. It is possible that the pro-thrombotic tendencies could exacerbate a hypercoagulable state, underscoring the importance of restricting the use of baricitinib to clinical trials.
Cerda-Contreras C, Nuzzolo-Shihadeh L, Camacho-Ortiz A. Baricitinib as treatment for COVID-19: friend or foe of the pancreas? Clin Infect Dis, August 14m 2020. Full-text: https://doi.org/10.1093/cid/ciaa1209
These authors present a case of pancreatitis occurring during baricitinib administration.
Biran N, Ip A, Ahn J, et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study. Lancet Rheumatol 2020, published 14 August. Full-text: https://doi.org/10.1016/S2665-9913(20)30277-0
Noa Biran, Andrew Ip and colleagues did a retrospective observational cohort study with 764 COVID-19 patients who required support in the ICU. In the final analysis, they included 210 patients who received tocilizumab (400 mg in a one-time scheme, with a second dose permitted at the point of worsening oxygenation) and 420 who did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (hazard ratio 0.64, 95% CI 0.47–0.87; p = 0.0040). Results of ongoing randomized controlled trials are awaited. See also the comment: Campochiaro C, Dagna L. The conundrum of interleukin-6 blockade in COVID-19. Lancet Rheumatol 2020, published 14 August. Full-text: https://doi.org/10.1016/S2665-9913(20)30287-3, where Corrado Campochiaro and Lorenzo Dagna superbly summarize the questions for the future: “Have we correctly identified the right COVID-19 population for treatment with anti-inflammatory drugs? Are systemic inflammatory markers reliable enough for selecting patients with hyperinflammation? Do increased concentrations of a specific cytokine imply that its neutralization will be effective in COVID-19? What is the degree of immunosuppression we are aiming for in SARS-CoV-2 infection?”
Ledford H. Antibody therapies could be a bridge to a coronavirus vaccine — but will the world benefit? Nature 2020, published 11 August. Full-text: https://www.nature.com/articles/d41586-020-02360-y
Are monoclonal antibodies a bridging solution before the general availability of a vaccine? Heidi Lenford reminds us that monoclonals are complex and expensive to produce, leaving people from poor countries locked out.
Bradfute SB, Hurwitz I, Yingling AV, et al. SARS-CoV-2 Neutralizing Antibody Titers in Convalescent Plasma and Recipients in New Mexico: An Open Treatment Study in COVID-19 Patients. J Infect Dis. 2020 Aug 11:jiaa505. PubMed: https://pubmed.gov/32779705. Full-text: https://doi.org/10.1093/infdis/jiaa505
This single-arm interventional trial measured neutralizing antibodies (Nab) and total antibody titers before and after CP transfusion over a 14-day period in 12 hospitalized COVID-19 patients. NAb titers in the donor CP units were low (<1:40 to 1:160) and had no effect on recipient neutralizing activity one day after transfusion. Pre-screening of CP may be necessary for selecting donors with high levels of neutralizing activity for infusion into patients with COVID-19.
Cain DW, Cidlowski JA. After 62 years of regulating immunity, dexamethasone meets COVID-19. Nat Rev Immunol 2020, published 10 August. Full-text: https://doi.org/10.1038/s41577-020-00421-x
The RECOVERY trial showed that treatment with dexamethasone, a synthetic glucocorticoid, enhanced the survival of critically ill patients with COVID-19. Not only was dexamethasone more effective than remdesivir (dexamethasone reduced COVID-19-related mortality while remdesivir didn’t), but it is also cheap, widely available and comes with 60 years of safety profiling. In this two-page comment, Derek Cain and John Cidlowski discuss the immunological impacts of glucocorticoid therapy for COVID-19.
Ivashchenko AA, Dmitriev KA, Vostokova NV, et al. AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial. Clin Infect Dis. 2020 Aug 9:ciaa1176. PubMed: https://pubmed.gov/32770240. Full-text: https://doi.org/10.1093/cid/ciaa1176
In May 2020 the Russian Ministry of Health granted fast-track marketing authorization to the RNA polymerase inhibitor favipiravir for the treatment of COVID-19 patients. In the pilot stage of a Phase II/III clinical trial, 60 patients hospitalized with COVID-19 pneumonia were randomized to two different dosing groups or standard of care. Favipiravir enabled SARS-CoV-2 viral clearance in 62.5% of patients within 4 days and was safe and well-tolerated. The proportion of patients who achieved negative PCR on day 5 on both dosing regimens was twice as high as in the control group (p < 0.05).
Hayem G, Huet T, Jouveshomme S, et al. Anakinra for severe forms of COVID-19 – Authors’ reply. Lancet August 07, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30274-5
Discussion about a cohort study on anakinra, an interleukin (IL)-1 receptor antagonist. The authors compared 52 consecutive patients with 44 historical patients. Now, three replies address mainly methodological issues. According to the authors, their study was “not perfect from a statistical point of view… only high-quality randomized trials can avoid confounding factors, but the urgent context of the COVID-19 pandemic means randomized trials are not always appropriate”. However, several randomized trials are underway: on August 10, https://clinicaltrials.gov listed 16 Phase II/III studies.
Xia X, Li K, Wu L, et al. Improved clinical symptoms and mortality among patients with severe or critical COVID-19 after convalescent plasma transfusion. Blood 2020, 136 (6): 755–759. Full-text: https://doi.org/10.1182/blood.2020007079
Same issue: uncontrolled, retrospective data (but huge numbers). This group presents the results of 1430 patients with severe or critical COVID-19 who received standard treatment only and 138 patients who also received ABO-compatible COVID-19 convalescent plasma (CCP). Despite the higher severity level, only 3 patients (2.2%) died in the CCP group through April 20, reducing the mortality rate compared with that in the standard treatment group (4.1%). However, confounding factors (i.e., biased patient assignments) in this retrospective study could not be ruled out. In addition, complete data on neutralizing antibody titers in CCP units were not available, limiting the power of evaluating the correlation between the quality of donor plasma and efficacy.
Hodge C, Marra F, Marzolini C, et al. Drug interactions: a review of the unseen danger of experimental COVID-19 therapies. J Antimicrob Chemother. 2020 Aug 4:dkaa340. PubMed: https://pubmed.gov/32750131 . Full-text: https://doi.org/10.1093/jac/dkaa340
Experimental COVID-19 therapies carry significant risk for drug-drug interactions (DDIs), especially the HIV protease inhibitor lopinavir/ritonavir, chloroquine, hydroxychloroquine and ruxolitinib. In contrast, anakinra, baricitinib, favipiravir, interferon-b, nitazoxanide, ribavirin, remdesivir, sarilumab and tocilizumab have lower propensity for drug interactions. In March 2020, this group from Liverpool (famous for their HIV interaction website) published a DDI resource for experimental COVID therapies (www.covid19-druginteractions.org). Here Saye Khoo and colleagues summarize the methodology and processes undertaken to establish this resource.
Moorlag SJ, van Deuren RX, van Werkhoven CH, et al. Safety and COVID-19 symptoms in individuals recently vaccinated with BCG: a retrospective cohort study. Cell Rep Med August 05, 2020. Full-text: https://www.sciencedirect.com/science/article/pii/S2666379120300938
Mihai Netea and colleagues retrospectively assessed COVID-19 related symptoms in three cohorts of healthy volunteers who either received BCG in the last five years (n = 266) or not (n = 164). BCG vaccination was not associated with increased incidence of symptoms and might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic, and lower incidence of extreme fatigue. However, caution is warranted in interpreting these findings: limitations include the retrospective nature of the study in two relatively small groups of volunteers, and the potential for selection bias.
Baum A, Copin R, Ajithdoss D, et al. REGN-COV2 antibody cocktail prevents and treats SARS-CoV-2 infection in rhesus macaques and hamsters. bioRxiv 2020, pre-published 3 August. Full-text: https://doi.org/10.1101/2020.08.02.233320
In this pre-print paper, Christos Kyratsous and colleagues report the in vivo efficacy in both rhesus macaques and golden hamsters of a cocktail of two neutralizing antibodies targeting non-overlapping epitopes on the SARS-CoV-2 spike protein. The animals were first dosed with the cocktail and challenged three days later with 1×105 PFU of virus through intranasal and intratracheal routes. The cocktail, termed ‘REGN-COV-2’, greatly reduced viral load in the lower and the upper airways; it also decreased virus induced pathological sequalae when administered prophylactically or therapeutically. The paper has not yet been peer reviewed.
Harrison C. Focus shifts to antibody cocktails for COVID-19 cytokine storm. Nat Biotechnol 2020; 38:905–908. Full-text: https://doi.org/10.1038/s41587-020-0634-9
Combining agents targeting different cytokines may one day be used in supportive care for COVID-19 patients with acute respiratory distress syndrome. Charlotte Harrison takes you on a tour around Roche’s Actemra (tocilizumab, a mAb targeting IL-6R), Russian Biocad’s Ilsira (levilimab), Bermuda-based Kiniksa Pharmaceuticals’ mavrilimumab (a human IgG4 mAb targeting GM-CSF), R-Pharm’s olokizumab, a humanized anti-IL-6 mAb, Sylvant (siltuximab), an anti-IL-6 chimeric IgG1 mAb from EUSA Pharma and BeiGene, and many more.
Fajgenbaum DC, Rader DJ. Teaching Old Drugs New Tricks: Statins for COVID-19? Cell Metabolism August 4, 2020, 32: 145-147. Full-text: https://doi.org/10.1016/j.cmet.2020.07.006
The authors review the literature and argue that, given the association between statin use and improved outcomes in a large observational study of hospitalized COVID-19 patients, but also given the widespread availability, low cost, and safety of statins, this drug class should be further investigated in randomized controlled trials.
Robson F, Khan KS, Le TK, et al. Coronavirus RNA proofreading: molecular basis and therapeutic targeting. Molecular Cell. August 04, 2020. Full-text: https://doi.org/10.1016/j.molcel.2020.07.027
These authors review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. They also consider existing nucleoside analogues and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism.
Clark KE, Collas O, Lachmann H, et al. Safety of intravenous Anakinra in COVID-19 with evidence of hyperinflammation, a case series. Rheumatol Adv Pract, August 4, 2020. Full-text: https://doi.org/10.1093/rap/rkaa040
Some more data on anakinra. Four patients with severe COVID-19 infection requiring intensive care admission and ventilatory support are described. Upon commencement of intravenous anakinra, there was subsequent improvement in the patients clinically with reduced ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers. But again, think about the earlier JAMA comment above (Califf RM et al.)
Touret F, Gilles M, Barral K et al. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Sci Rep 2020; 10, 13093. Full-text: https://doi.org/10.1038/s41598-020-70143-6
Do you remember Franck Touret? On 5 March, he published Of chloroquine and COVID-19 (Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020 May;177:104762. PubMed: https://pubmed.gov/32147496. Full-text: https://doi.org/10.1016/j.antiviral.2020.104762), a brilliant summary of chloroquine’s repeated failures in treating acute human viral diseases over the last decades. Now, Franck Touret, Bruno Coutard and colleagues screened 1,520 approved and off-patent drugs of the Prestwick Chemical Library in an infected cell-based assay. Eleven compounds such as macrolides antibiotics, proton pump inhibitors (omeprazole and vonoprazan), antiarrhythmic agents or CNS drugs emerged that show an antiviral potency with 2 of them < EC50 ≤ 20 µM.
Chan KK, Dorosky D, Sharma P, et al. Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2. Science 2020, published 4 August. Full-text: https://science.sciencemag.org/content/early/2020/08/03/science.abc0870
Soluble ACE2 (sACE2) has been proposed as a therapeutic candidate that neutralizes infection by acting as a decoy. Now Eric Procko and colleagues describe mutations in ACE2 that increase S binding across the interaction surface, in the N90 glycosylation motif and at buried sites. A stable dimeric sACE2 variant with improved properties for binding viral spike showed potent SARS-CoV-2 and -1 neutralization in vitro. The authors conclude that exceptional affinity for protein S can be engineered into the natural receptor for the virus, while also providing insights into the molecular basis for initial virus-host interactions.
Malhotra A, Hepokoski M, McCowen KC, Shyy JYJ. ACE2, Metformin, and COVID-19. iScience 2020, pulished 30 July. Summary: https://www.cell.com/iscience/fulltext/S2589-0042(20)30615-5. Full-text: https://doi.org/10.1016/j.isci.2020.101425
Angiotensin converting enzyme 2 (ACE2) is essential to COVID-19 pathogenesis. Preclinical data suggest that ACE2 may be downregulated after SARS-CoV-2 binding, and treatments which increase ACE2 might prevent cardiopulmonary injury. Now Atul Malhotra, John Shyy and colleagues hypothesize that patients with COVID-19 taking metformin might have higher circulating ACE2 levels, and lower morbidity and mortality. They propose to test this hypothesis through a combination of retrospective cohort studies, and prospective translational studies evaluating the ACE2 axis in COVID-19 patients. The authors also cite an observational study from Wuhan, China, which showed that in-hospital mortality was significantly lower in a metformin group than in a control group (3/104 (2.9%) versus 22/179 (12.3%), p = 0.01; Luo P, Qiu L, Liu Y, et al. Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis. Am J Trop Med Hyg 2020;103(1):69-72. PubMed: https://pubmed.gov/32446312. Full-text: https://doi.org/10.4269/ajtmh.20-0375).
Cheng GS, Hill JA. To Toci or Not to Toci for COVID-19: Is That Still the Question? Clin Infect Dis. 2020 Jul 31:ciaa1133. PubMed: https://pubmed.gov/32735642. Full-text: https://doi.org/10.1093/cid/ciaa1133
Joshua Hill and Guang-Shing Cheng first narrate the story of tocilizumab and the IL-6 receptor in such a way that you understand the impetus to use tocilizumab in hospitalized patients with COVID-19, despite the lack of data from controlled trials. They then go on to comment the study by Somers et al., Tocilizumab for treatment of mechanically ventilated patients with COVID-19, we presented on 12 July (https://covidreference.com/top-10-July-12). Excellent summary.
Riva L, Yuan S, Yin X, et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature (2020). Full-text: https://doi.org/10.1038/s41586-020-2577-1
After profiling a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules, the authors identified 100 molecules that inhibit viral replication. Thirteen were found to be able to achieve therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod and several cysteine protease inhibitors. The known pharmacological and human safety profiles of these compounds might enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
Wang N, Zhan Y, Zhu L, et al. Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients. Cell Host Microb, published July 22. Full-text: https://doi.org/10.1016/j.chom.2020.07.005
A retrospective multicenter cohort study of 446 COVID-19 patients, taking advantage of drug stock disparities between two medical centers in Hubei during the peak of the Chinese COVID-19 outbreak. Early administration (≤ 5 days after admission) of IFN-α2b was associated with reduced in-hospital mortality in comparison with no admission of IFN-α2b, whereas late administration of IFN-α2b was associated with increased mortality. IFN therapy was not associated with recovery time for COVID-19.
Ramiro S, Mostard RLM, Magro-Checa C, et al. 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. Ann Rheum Dis, 2020;0:1–9. Full-text: http://dx.doi.org/10.1136/annrheumdis-2020-218479
86 patients with COVID-19-associated cytokine storm syndrome received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2 – 5). If the respiratory condition did not improve sufficiently (in 43%), tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Compared to retrospectively matched patients (sex and age), treated patients had a 79% higher likelihood on reaching the primary outcome (defined as ≥ 2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital) (7 days earlier), 65% less mortality and 71% less invasive mechanical ventilation. Also, see the comment in BMJ.
The RECOVERY Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report. NEJM July 17, 2020. Full-text: https://doi.org/10.1056/NEJMoa2021436
Applause to these UK researchers! These first peer-reviewed results of the incredibly huge RECOVERY trial show that dexamethasone works in critically ill patients. In this open-label trial (comparing a range of treatments), hospitalized patients were randomized to receive oral or intravenous dexa (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. Overall, 482 patients (22.9%) in the dexa group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83). Death rate was lower among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support (17.8% vs. 14.0%).
Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19. Ann Int Med, Jul 16. Full-text: https://doi.org/10.7326/M20-4207
The last piece of the puzzle that HCQ doesn’t work, even when given early. Symptomatic, nonhospitalized adults with lab-confirmed or probable COVID-19 and high-risk exposure were randomized within 4 days of symptom onset to HCQ (800 mg once, followed by 600 mg at 6 to 8 hours, then 600 mg daily for 4 more days) or masked placebo. Among 423 patients, change in symptom severity over 14 days did not differ. At 14 days, 24% receiving HCQ had ongoing symptoms compared with 30% receiving placebo (p = 0.21). Adverse events occurred in 43% versus 22%. Although many letters can be expected (dosage wrong, too low, too high, too late, too early, wrong patients, too many unconfirmed patients etc), the lesson is learned: HCQ does NOT substantially reduce symptom severity in outpatients with early, mild COVID-19. Please, let’s forget it. Completely.
Schluger NW. The Saga of Hydroxychloroquine and COVID-19: A Cautionary Tale. Ann Int Med 2020, Jul 6. Full-text: https://doi.org/10.7326/M20-5041
Editorial, commenting on the above data. The saga of hydroxychloroquine and COVID-19 will likely reach its sad end. Many good ideas in medicine do not work. Some thoughts on how this HCQ hype could have happened.
Pruijssers AJ, George AS, Schäfer A, et al. Remdesivir Inhibits SARS-CoV-2 in Human Lung Cells and Chimeric SARS-CoV Expressing the SARS-CoV-2 RNA Polymerase in Mice. Cell Reports, July 14, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.107940
Good to know that remdesivir works in cells. It potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures. In mice infected (with a chimeric virus), remdesivir diminished lung viral load and improved pulmonary function.
Okafor EC, Pastick KA, Rajasingham R. Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. Reply. N Engl J Med. 2020 Jul 15. PubMed: https://pubmed.gov/32668109. Full-text: https://doi.org/10.1056/NEJMc2023617
Some discussion on this trial in which HCQ did not work as a COVID-19 PEP. Main messages: absence of evidence is not evidence of absence. It is argued that the PEP was started too late, the trial too small and that testing capacity was limited.
Mak YM, Chan FK, Ng SC. Probiotics and COVID-19 – Authors’ reply. Lancet Gastroenterology Hepatology Volume 5, ISSUE 8, P722-723, August 01, 2020. Full-text: https://doi.org/10.1016/S2468-1253(20)30197-7
COVID-19 patients have an altered gut microbiome. Well, okay, but who doesn’t? Several letters discuss whether probiotics represent a complementary approach for the prevention and restoration of SARS-CoV-2-induced mucosal damage or inflammation through the modulation of gut microbiota. Some groups are optimistic, others aren’t.
Davis MR, McCreary EK, Pogue JM. That Escalated Quickly: Remdesivir’s Place in Therapy for COVID-19. Infect Dis Ther. 2020 Jul 10. PubMed: https://pubmed.gov/32651941. Full-text: https://doi.org/10.1007/s40121-020-00318-1
After reviewing all remdesivir studies until May 31, the authors make some recommendations on use. Remdesivir (5 days) should be prioritized for hospitalized patients requiring low-flow supplemental oxygen as it appears these patients derive the most benefit. The data also support some benefit in hospitalized patients breathing ambient air (if there is adequate drug supply). Current data do NOT suggest benefit for those requiring high-flow oxygen or either non-invasive or invasive mechanical ventilation. While it appears that progression of disease plays an important role in the efficacy of remdesivir, the amount of time from onset of symptoms does not.
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 – Preliminary Report. Reply. N Engl J Med 2020 Jul 10;383. Full-text: https://doi.org/10.1056/NEJMc2022236
Discussion about the preliminary report on the large Phase III US trial of remdesivir (remember the Fauci press conference). Several letters elucidate the challenges arising from the dissemination of early results. The authors promise solemly that they have begun to analyze the final data and will revise the report after that analysis is complete, including a more detailed analyses of the duration of illness and its relationship to baseline disease severity and outcomes, as well as concomitant medications during the trial. Why this seemingly takes months (perceived years), remains unclear. We are very curious.
Somers EC, Eschenauer GA, Troost JP, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020 Jul 11. PubMed: https://pubmed.gov/32651997. Full-text: https://doi.org/10.1093/cid/ciaa954
Comparison of 78 patients who received tocilizumab (TCZ) and 76 who did not. TCZ-treated patients were younger, less likely to have chronic pulmonary disease, and had lower D-dimer values at time of intubation. In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death and improved status on the ordinal outcome scale. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%, mainly S. aureus), there was no difference in 28-day case fatality rate among TCZ-treated patients with versus without superinfection. We urgently need adequately powered RCT.
Wise J, Coombes R. Covid-19: The inside story of the RECOVERY trial. BMJ 2020; 370 Full-text: https://doi.org/10.1136/bmj.m2670
The UK’s flagship COVID-19 clinical trial may help in this regard. Patients enrolled in the open label RECOVERY trial are randomised to standard care or to one of six treatment arms: hydroxychloroquine (now closed), dexamethasone (also closed, press release June 16), lopinavir/ritonavir, azithromycin, convalescent plasma, and, in a second randomisation for patients who deteriorate, the anti-inflammatory drug tocilizumab. The authors unpack the criticisms that still surround this mammoth task, of mounting a large scale trial amid the first major pandemic in 100 years in record time.
Wadman M. Can boosting interferons, the body’s frontline virus fighters, beat COVID-19? Science News Jul 8, 2020. Full-text: https://doi.org/10.1126/science.abd7137
Brief overview on current trials evaluating synthetic interferons given before or soon after infection, in order to tame the virus before it causes serious disease. Controlled clinical trials are eagerly awaited.
Gladstone DE, Kim BS, Mooney K, et al. Regulatory T Cells for Treating Patients With COVID-19 and Acute Respiratory Distress Syndrome: Two Case Reports. Ann Int Med 2020, Jul 6. Full-text: https://www.acpjournals.org/doi/10.7326/L20-0681
Regulatory T cells (also known as Tregs) migrate into inflamed tissues, dampening inflammatory responses and hastening tissue repair. Two patients who became critically ill despite receiving tocilizumab were treated with Tregs and recovered. Infusions were rapidly followed by decreases in interleukin-6, tumor necrosis factor-α, and interferon-γ.
Wang J, Xing S, Ding L, et al. Human IgG neutralizing monoclonal antibodies block SARS-CoV-2 infection. Cell July 01, 2020. Full-text: https://doi.org/10.1016/j.celrep.2020.107918 l (Important)
Forget HCQ, lopinavir, etc. Over the last months, it has become increasingly clear that monoclonal antibodies will be the most promising therapeutic candidates for COVID-19. The authors identified 178 S1 and RBD binding human monoclonal antibodies from the memory B cells of 11 recently recovered patients. Of 8 antibodies showing robust authentic viral neutralizing activities, the best one, 414-1, showed neutralizing IC50 at 1.75 nM. Epitope mapping revealed that the antibodies bound to 3 different RBD epitopes, and epitope B antibody 553-15 could substantially enhance neutralizing abilities of most other neutralizing antibodies.
Li L, Tong X, Chen H, et al. Characteristics and serological patterns of COVID-19 convalescent plasma donors: optimal donors and timing of donation. Transfusion. 2020 Jul 6. PubMed: https://pubmed.gov/32627216. Full-text: https://doi.org/10.1111/trf.15918
When is the best time to donate plasma? In 49 donors, S‐RBD‐specific and N‐specific IgG antibodies increased after 4 weeks from the onset of symptoms, with no significant correlation to age, sex, or ABO blood type. Donors with disease presentation of fever exceeding 38.5°C or lasting longer than 3 days exhibited higher levels of S‐RBD‐specific IgG antibodies at the time of donation. The authors recommend the following selection criteria for optimal donation of COVID‐19 convalescent plasma: 28 days after the onset of symptoms and with a disease presentation of fever lasting longer than 3 days or a body temperature exceeding 38.5°C. Selection based on these criteria can ensure a high likelihood of achieving sufficiently high S‐RBD‐specific IgG titers.
Della-Torre E, Campochiaro C, Cavalli G, et al. Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study. Ann Rheum Dis. 2020 Jul 3. PubMed: https://pubmed.gov/32620597. Full-text: https://doi.org/10.1136/annrheumdis-2020-218122
Open-label study of sarilumab (a recombinant human IL-6Rα antagonist) in severe COVID-19 pneumonia with hyperinflammation. Sarilumab 400 mg was administered intravenously in addition to standard of care to 28 patients and results were compared with 28 contemporary matched patients treated with standard of care alone. At day 28, 61% of patients treated with sarilumab experienced clinical improvement and 7% died. These findings were not significantly different from the comparison group. However, sarilumab was associated with faster recovery in a subset of patients showing minor lung consolidation at baseline.
Gendelman O, Amital H, Bragazzi NL, Watad A, Chodick G. Continuous hydroxychloroquine or colchicine therapy does not prevent infection with SARS-CoV-2: Insights from a large healthcare database analysis. Autoimmun Rev 2020 Jul;19(7):102566. PubMed: https://pubmed.gov/32380315. Full-text: https://doi.org/10.1016/j.autrev.2020.102566
No protection with HCQ and colchicine. An overall sample of 14,520 subjects from Israel were screened for SARS-CoV-2 infection and 1317 resulted positive. No significant difference was found in terms of rates of usage of hydroxychloroquine or colchicine between those who were found positive for SARS-CoV-2 and those who were found negative (0.23% versus 0.25% for hydroxychloroquine, and 0.53% versus 0.48% for colchicine, respectively).
Kupferschmidt K. One U.K. trial is transforming COVID-19 treatment. Why haven’t others delivered more results? Science Jul. 2, 2020. Full-text: https://doi.org/10.1126/science.abd6417
Where are the results of the hundreds of clinical trials conducted during the last months? This article describes the challenges that clinical trials are facing world-wide. Some details on WHO’s SOLIDARITY are given. With recruitment running at about 500 patients per week now, SOLIDARITY’s three remaining treatment arms are likely to yield answers “soon” (whatever that means), raising the question of what drugs to test afterward. Some repurposed drugs such as camostat mesylate or favipiravir are still being discussed, but increasingly the attention is turning to monoclonal antibodies, designed to target the virus.
Tempestilli M, Caputi P, Avataneo V, et al. Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19. J Antimicr Chemoth, July 1, 2020. Full-text: https://doi.org/10.1093/jac/dkaa239
Small PK pilot study on remdesivir (Veklury®) and the nucleoside analog GS-441524 (of which remdesivir is a prodrug). After intravenous administration, in both patients remdesivir showed a peak at the end of infusion and a half-life of 1 h, while GS-441524 reached a peak 1 h after infusion and then remained detectable until the next remdesivir administration. GS-441524 plasma concentrations were higher in the patient with renal impairment, indicating that renal excretion was a major route of elimination.
Leegwater E, Strik A, Wilms EB, et al. Drug-induced liver injury in a COVID-19 patient: potential interaction of remdesivir with P-glycoprotein inhibitors. Clin Inf Dis, 28 June 2020. Full-text: https://doi.org/10.1093/cid/ciaa883
Acute hepatotoxicity related to remdesivir (now sold under the brand name Veklury®), with probable interaction of P-glycoprotein (P-gp) inhibitors. Five days after start of remdesivir, a patient developed an acute increase in ALT (1305 IU/L) and AST (1461 U/L). Total bilirubin was 8 μmol/L. The patient was treated with the P-gp inhibitors chloroquine (last administration nine days before remdesivir, with a half-life of two weeks) and amiodarone (concomitantly with remdesivir). Authors recommend physicians to be cautious with the prescription of P-gp inhibitors in patients receiving remdesivir therapy.
Li S, Hu Z, Song X. High-dose but not low-dose corticosteroids potentially delay viral shedding of patients with COVID-19. Clinical Infectious Diseases 2020, June 26. Full-text: https://doi.org/10.1093/cid/ciaa829
This study with 206 patients suggests that the effect of corticosteroids on viral shedding may be in a dose-response manner. High-dose (80 mg/d) but not low-dose corticosteroids (40 mg/d) delayed viral shedding of patients with COVID-19.
Yeleswaram S, Smith P, Burn T, et al. Inhibition of cytokine signaling by ruxolitinib and implications for COVID-19 treatment. Clin Immunol. 2020 Jun 22:108517. PubMed: https://pubmed.gov/32585295. Full-text: https://doi.org/10.1016/j.clim.2020.108517
Comprehensive review on ruxolitinib. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19-associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. However, it is important to consider that this work was supported by Incyte, a manufacturer of the drug.
Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatology. June 24, 2020. Full-text: https://doi.org/10.1016/S2665-9913(20)30173-9
The largest retrospective, observational cohort study (from Italy) to date, reporting on IL-6 receptor blocker tocilizumab which was given either intravenously or subcutaneously. 57 (16%) of 365 patients in the standard of care (SOC) group needed mechanical ventilation, compared with 33 (18%) of 179 patients treated with tocilizumab (88 patients treated intravenously). 73 (20%) patients in the SOC group died, compared with 13 (7%; p<0·0001) patients treated with tocilizumab. After adjustment for sex, age, duration of symptoms, and SOFA (Sequential Organ Failure Assessment) score, tocilizumab treatment was associated with a reduced risk of invasive mechanical ventilation or death (adjusted hazard ratio 0.61, 95% CI 0.40–0.92). However, the precise group of patients who might benefit from tocilizumab and the optimal biomarkers for identifying the cytokine storm in the setting of COVID-19 remain unknown.
Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019The GRECCO-19 Randomized Clinical Trial. JAMA Netw Open June 24, 2020;3(6. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.13136
In this prospective, open-label, randomized clinical trial, 105 patients hospitalized with COVID-19 in Greece were randomized to either standard medical treatment or colchicine plus standard medical treatment. Participants who received colchicine had statistically “significantly improved time to clinical deterioration”. However, there were no significant differences in biomarkers and the observed difference was based on a narrow margin of clinical significance; according to the authors their observations “should be considered hypothesis generating” and “be interpreted with caution”.
Sarpatwari A, Kaltenboeck A, Kesselheim AS, et al. Missed Opportunities on Emergency Remdesivir Use. JAMA. June 24, 2020 Full-text: https://doi.org/10.1001/jama.2020.11932
Important viewpoint on monitoring remdesivir use, pricing, and drug supply. Gilead has yet to comment what the bounds of a reasonable price could be. According to the authors, the FDA should revise its current EUA for remdesivir to require the creation of a patient registry that includes information on patient demographics, treatment dose and duration, and safety outcomes.
Chi X, Yan R, Zhang J, et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science 22 Jun 2020. Full-text: https://doi.org/10.1126/science.abc6952
The authors isolated and characterized monoclonal antibodies (mAbs) from ten convalescent COVID-19 patients, among them the most interesting mAb, named 4A8. Of note, 4A8 exhibited high neutralization potency but did not bind the RBD (like most other mABs). Cryo-EM revealed that the epitope of 4A8 seems to be the N terminal domain (NTD) of the S protein.
Contini C, Enrica Gallenga C, Neri G, Maritati M, Conti P. A new pharmacological approach based on remdesivir aerosolized administration on SARS-CoV-2 pulmonary inflammation: A possible and rational therapeutic application. Med Hypotheses. 2020 May 24;144:109876. PubMed: https://pubmed.gov/32562915. Full-text: https://doi.org/10.1016/j.mehy.2020.109876
Some ideas on remdesivir as an inhalation therapy. Local instillation or aerosol in the first phase of infection, both in asymptomatic but nasopharyngeal swab positive patients, together with antiseptic-antiviral oral gargles and povidone-iodine eye drops for conjunctiva would attack the virus directly through the receptors to which it binds, significantly decreasing viral replication and risk of severe COVID-19. Gilead is working on this (knowing that “early intravenous infusions” are not feasible).
Rojas-Marte GR, Khalid M, Mukhtar O, et al. Outcomes in Patients with Severe COVID-19 Disease Treated with Tocilizumab – A Case- Controlled Study. QJM. 2020 Jun 22:hcaa206. PubMed: https://pubmed.gov/32569363. Full-text: https://doi.org/10.1093/qjmed/hcaa206
Large retrospective, case-control, single-center study in patients with severe to critical COVID-19 disease. In total, 96 patients received tocilizumab, while 97 served as control group. There was a non-statistically significant lower mortality in the treatment group (52% versus 62%). When excluding intubated patients, there was statistically significant lower mortality in patients treated with tocilizumab (6% vs. 27%, p = 0.024). Bacteremia was more common in the control group, while fungemia was similar.
Stader F, Khoo S, Stoeckle M, et al. Stopping lopinavir/ritonavir in COVID-19 patients: duration of the drug interacting effect. J Antimicrob Chemother. 2020 Jun 17. PubMed: https://pubmed.gov/32556272. Full-text: https://doi.org/10.1093/jac/dkaa253
The duration of cytochrome P-450 (CYP) 3A inhibition after stopping lopinavir/r treatment is not well understood, leading to some uncertainty as to how long to maintain adjusted doses of co-medications or when to restart drug therapies against comorbidities. The authors investigated the duration of hepatic and intestinal CYP3A inhibition after stopping lopinavir/r treatment by a verified modelling approach. In all age groups, there was more than 80% disappearance of CYP3A inhibition 5 days after stopping lopinavir/r under the consideration of population variability. Complete disappearance of CYP3A inhibition, however, took 21 days in all simulated age groups.
Hegerova L, Gooley T, Sweerus KA, et al. Use of Convalescent Plasma in Hospitalized Patients with Covid-19 – Case Series. Blood. 2020 Jun 19. PubMed: https://pubmed.gov/32559767. Full-text: https://doi.org/10.1182/blood.2020006964
The next case series on early clinical experience of 20 hospitalized patients treated with CP. Compared to 20 matched controls with severe or life-threatening COVID-19 infection, laboratory and respiratory parameters were improved in patients following CP infusion. The 7- and 14-day case fatality rate in CP patients compared favorably to that in controls. However, sample size was small and the study was not randomized. Larger trials are eagerly awaited.
Robbiani DF, Gaebler C, Muecksch F et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 2020. https://doi.org/10.1038/s41586-020-2456-9 l (Important)
This may help to explain why convalescent plasma does not work in all patients. In plasma from 149 patients collected an average of 39 days after the onset of symptoms, neutralizing titres were extremely variable. Most plasmas did not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
Clementi N, Ferrarese R, Criscuolo E, et al. Interferon-β 1a inhibits SARS-CoV-2 in vitro when administered after virus infection. J Inf Dis, June 19 2020. Full-text: https://doi.org/10.1093/infdis/jiaa350
IFN may work, when given early. Several clinical trials into the administration of IFN to COVID-19 patients are currently ongoing. These in vitro observations shed light for the first time on antiviral activity of IFN-β1a against SARS-CoV-2 when administered after the infection of cells, highlighting its possible efficacy in an early therapeutic setting.
Dao W, Zhang W, Zhang B. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 19 Jun 2020. Vol. 368, Issue 6497, pp. 1331-1335. Full-text: https://doi.org/10.1126/science.abb4489 l (Important)
HIV protease inhibitors (PIs) such as darunavir or lopinavir probably don’t work. These authors have developed better ones, based on analyzing the structure of the Mpro active site. Both PIs strongly inhibited the activity of Mpro and showed good antiviral activity in cell culture. Compound 11a had good pharmacokinetic properties and low toxicity when tested in mice and beagle dogs, suggesting that it is a promising drug candidate.
De Luca G, Cavalli G, Campochiaro C, et al. GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study. Lancet Rheumatology 2020, June 16. Full-text: https://doi.org/10.1016/S2665-9913(20)30170-3
Mavrilimumab, an anti-granulocyte macrophage colony stimulating factor receptor-α monoclonal antibody, was added as a single intravenous dose to standard management in 13 patients with severe COVID-19 pneumonia, hypoxia, and systemic hyperinflammation (26 patients with “contemporaneous patients with similar baseline characteristics“ were used a control group. During the 28-day follow-up, no patients in the mavrilimumab group died, and seven (27%) patients in the control group died (p=0.086). At day 28, all patients in the mavrilimumab group and 17 (65%) patients in the control group showed clinical improvement (p=0.030), with earlier improvement in the mavrilimumab than in the control group. Comment: Interesting, but larger trials are needed. Small sample size, an absence of randomisation, and a short follow-up period may reduce the full generalisability.
Mehta P, Porter JC, Manson JJ, et al. Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. Lancet Respiratory Medicine June 16, 2020. Full-text: https://doi.org/10.1016/S2213-2600(20)30267-8
Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. In this nice review, the authors consider the scientific rationale and potential risks for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation.
Luo W, Li YX, Jiang LJ. Targeting JAK-STAT Signaling to Control Cytokine Release Syndrome in COVID-19. Trends Pharmacol Science June 17, 2020. Full-text: https://doi.org/10.1016/j.tips.2020.06.007
Several inflammatory cytokines that correlate with adverse clinical outcomes in COVID-19 employ a distinct intracellular signalling pathway mediated by Janus kinases (JAKs). JAK-STAT signalling may be an excellent therapeutic target. This article reviews the possibilities and challenges of targeting this pathway in COVID-19.
Marovich M, Mascola JR, Cohen MS. Monoclonal Antibodies for Prevention and Treatment of COVID-19. JAMA June 15, 2020. Full-text: https://doi.org/10.1001/jama.2020.10245 l (Important)
Neutralizing monoclonal antibodies to SARS-CoV-2 have the potential for both therapeutic and prophylactic applications (probably more than all antiviral drugs that are currently being tested). This viewpoint summarizes current knowledge. Several mAbs are poised to enter clinical trials during the summer of 2020. Trials will include treatment of patients with SARS-CoV-2 infection, with varying degrees of illness, to block disease progression. Given the long half-life of most mABs (approximately 3 weeks for IgG1), a single infusion should be sufficient.
Baum A, Fulton BO, Wloga E, et al. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 15 Jun 2020: eabd0831. Full-text: https://doi.org/10.1126/science.abd0831 l (Important)
Elegant cell experiments, showing that a combination of antibodies may provide a powerful way to minimize mutational escape by SARS-CoV-2; in particular, two antibodies were chosen so as to bind to distinct and non-overlapping regions of the viral target (in this case, the RBD of the spike protein), in order to thus require the unlikely occurrence of simultaneous mutations at two distinct genetic sites for viral escape.
Rogers TF, Zhao F, Huang D, et al. Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model. Science 15 Jun 2020: eabc7520. Full-text: https://doi.org/10.1126/science.abc7520
Using a high-throughput rapid system for antibody discovery, the authors isolated more than 1000 mAbs from 3 convalescent donors by memory B cell selection using SARS-CoV-2 S or RBD (receptor-binding domain) recombinant proteins. Of note, only a small fraction of these Abs was neutralizing, highlighting the value of deep mining of responses to access the most potent Abs. RBD-nAbs that directly compete with ACE2 are clearly the most preferred for prophylactic and therapeutic applications, and as reagents to define nAb epitopes for vaccine. With these nABs, Syrian hamsters were protected from weight loss. However, animals that received higher doses also showed body weight loss, possibly indicating antibody-mediated enhanced disease.
Brouwer PJ, Caniels TG, van der Straten K, et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science 15 Jun 2020: eabc5902. Full-text: https://doi.org/10.1126/science.abc5902
Antibodies from convalescent COVID-19 patients had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3 and VH1-24 gene usage. A subset of the antibodies were able to potently inhibit authentic SARS-CoV-2 infection as low as 0.007 μg/mL. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites. The authors isolated 19 neutralizing antibodies that target a diverse range of antigenic sites on the S protein, of which two showed picomolar (very strong!) neutralizing activities.
Tedder RS, Semple MG. Appropriate selection of convalescent plasma donors for COVID-19. Lancet Inf Dis June 15, 2020. Full-text: https://doi.org/10.1016/S1473-3099(20)30470-9
The authors report on unpublished data (their own), indicating that quantification of specific antibody to the receptor-binding domain (RBD) will indicate levels of neutralising antibodies. This may help to find the best plasma donors. So why don’t they publish their data?
Piller C. Who’s to blame? These three scientists are at the heart of the Surgisphere COVID-19 scandal. Science Mag 2020, June 8. Full-text: https://www.sciencemag.org/news/2020/06/whos-blame-these-three-scientists-are-heart-surgisphere-covid-19-scandal
More insights into the research scandal about two fake COVID-19 treatment papers (published in The Lancet and the NEJM) that were retracted last week. There were several red flags that the studies warranted intensive scrutiny – scrutiny that the two journals unforgivably failed to provide. This scandal tells us a lot about scientific publishing. Answers, comments, explanations by the two journals are still pending.
Lim SY, Osuna CE, Best K, et al. A direct-acting antiviral drug abrogates viremia in Zika virus–infected rhesus macaques. Science Transl Med 10 Jun 2020, Vol. 12, Issue 547. Full-text: https://doi.org/10.1126/scitranslmed.aau9135
Galidesivir is a nucleoside RNA polymerase inhibitor with a broad-spectrum activity in vitro against more than 20 RNA viruses in nine different families, including coronaviruses and viral disease families that include filoviruses, togaviruses, bunyaviruses, arenaviruses, paramyxoviruses, and flaviviruses. A NIAID-funded, randomized, double-blind, placebo-controlled clinical trial to assess the safety, clinical impact and antiviral effects of galidesivir in patients with COVID-19 is underway. Of note, the drug also works against Zika: In the study presented here, galidesivir dosing in rhesus macaques was safe and offered postexposure protection against Zika virus infection.
Jácome R, Campillo-Balderas JA, Ponce de León S, Becerra A, Lazcano A. Sofosbuvir as a potential alternative to treat the SARS-CoV-2 epidemic. Sci Rep. 2020 Jun 9;10(1):9294. PubMed: https://pubmed.gov/32518317. Full-text: https://doi.org/10.1038/s41598-020-66440-9
Some thoughts about the possibility of using sofosbuvir against SARS-CoV-2, a nucleoside analog antiviral approved for hepatitis C virus infections. The structural superposition of the hepatitis C virus polymerase bound to sofosbuvir with the SARS-CoV polymerase shows that the residues that bind to the drug are present in the latter.
Williamson BNس, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020 Jun 9. PubMed: https://pubmed.gov/32516797. Full-text: https://doi.org/10.1038/s41586-020-2423-5
In macaques, remdesivir works, if given early. Twelve rhesus macaques were inoculated with SARS-CoV-2. Twelve hours later, six animals received 10mg/kg intravenous remdesivir and the other six an equal volume of vehicle solution (2ml/kg). In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates and reduced virus titers in bronchoalveolar lavages. Virus shedding from the upper respiratory tract was not reduced. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. According to the authors, treatment should be initiated as early as possible to achieve the maximum treatment effect. But is this realistic in clinical practice? We would need a new way of application, instead of the current infusions (i.e., tablets, inhalators).
La Rosée F, Bremer HC, Gehrke I, et al. The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia. 2020 Jun 9. PubMed: https://pubmed.gov/32518419. Full-text: https://doi.org/10.1038/s41375-020-0891-0
In this retrospective study, 12/14 patients treated with the JAK inhibitor ruxolitinib achieved significant reduction of the newly developed “COVID-19 Inflammation Score” by ≥ 25% on day 7 with sustained clinical improvement in 11/14 patients without short-term red-flag warnings of Rux-induced toxicity. Rux treatment for COVID-19 in patients with hyperinflammation was safe with some signals of efficacy to prevent or overcome multi-organ failure. A multi-center Phase II clinical trial has been initiated (NCT04338958).
Tonn T, Corman VM, Johnsen M, et al. Stability and neutralising capacity of SARS-CoV-2-specific antibodies in convalescent plasma. Lancet Microbe 2020. Full-text: https://doi.org/10.1016/S2666-5247(20)30037-9
How stable are antibodies that are found in convalescent plasma? Very stable. Pathogen inactivation (using psoralen and UV light) did not impair the stability and neutralising capacity of SARS-CoV-2-specific antibodies that was also preserved at 100% when the plasma was shock frozen at −30°C after pathogen-inactivation or stored as liquid plasma for up to 9 days.
Magagnoli J, Narendran S, Pereira F, et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with COVID-19. Med 2020, June 05, 2020. Full-text: https://doi.org/10.1016/j.medj.2020.06.001
A total of 807 COVID-19 patients hospitalized in US Veterans Administration medical centers in March and April were classified based on their exposure to HCQ or with azithromycin (HCQ+AZ) or no HCQ as treatments. Compared to the no-HCQ group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HCQ group (adjusted hazard ratio (1.83; 95% CI, 1.16 to 2.89) but not in the HCQ+AZ group (1.31, 95% CI, 0.80 to 2.15). Both the propensity score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the two HCQ groups, compared to the no HCQ group.
Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Science Immunology 05 Jun 2020: Vol. 5, Issue 48, eabd0110. Full-text: https://doi.org/10.1126/sciimmunol.abd0110
Ex vivo analysis revealed significantly elevated bruton tyrosine kinase (BTK, regulates macrophage signalling and activation) activity, as evidenced by autophosphorylation, and increased IL-6 production in blood monocytes from patients with severe COVID-19 compared with blood monocytes from healthy volunteers. In a pilot study, 19 patients with severe COVID-19 received the BTK inhibitor acalabrutinib. Within 10-14 days, oxygenation improved “in a majority of patients”, often within 1-3 days, and inflammation markers and lymphopenia normalized quickly in most patients. At the end of acalabrutinib treatment, 8/11 (72.7%) patients in the supplemental oxygen cohort had been discharged on room air. These results suggest that targeting excessive host inflammation with a BTK inhibitor is a therapeutic strategy. A confirmatory RCT is underway.
Ucciferri C, Auricchio A, Di Nicola M, et al. Canakinumab in a subgroup of patients with COVID-19. Lancet Rheumatology, June 4, 2020. https://doi.org/10.1016/S2665-9913(20)30167-3
Canakinumab is human monoclonal antibody against IL-1β, approved for the treatment of juvenile rheumatoid arthritis and other chronic autoinflammatory syndromes. In a pilot trial, 10 patients with hyperinflammation (defined as CRP ≥ 50 mg/L) and respiratory failure showed a rapid improvement in serum inflammatory biomarkers and an improvement in oxygenation.
Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Jun 3. PubMed: https://pubmed.gov/32492084. Full-text: https://doi.org/10.1001/jama.2020.10044 l (Important)
The first randomized trial of well-characterized plasma units with a high titer of antibody to SARS-CoV-2. Unfortunately, the study was terminated before it reached its targeted original sample size of 200 patients; only 103 were enrolled (when the epidemic was under control in China, no more patients could be recruited). Consequently, the study was underpowered. Of 103 patients who were randomized, clinical improvement (discharged alive or reduction of 2 points on a 6-point disease severity scale) occurred within 28 days in 52% vs 43%. There was no significant difference in 28-day mortality (16% vs 24%) or time from randomization to discharge. Of note, convalescent plasma treatment was associated with a negative conversion rate of viral PCR at 72 hours in 87% of the convalescent plasma group versus 38% (OR, 11.39). Main take-homes: convalescent plasma is not a silver bullet and antiviral efficacy does not necessarily lead to better survival.
Casadevall A, Joyner MJ, Pirofski LA. A Randomized Trial of Convalescent Plasma for COVID-19-Potentially Hopeful Signals. JAMA. 2020 Jun 3. PubMed: https://pubmed.gov/32492105. Full-text: https://doi.org/10.1001/jama.2020.10218
Careful discussion of the previous study. According to the authors, the study provides an important signal of possible benefit in the subgroup of severely ill patients and suggests that high titer antibody against SARS-CoV-2 may have antiviral efficacy. These results suggest that future studies should focus on determining efficacy in less severely ill patients.
Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Jun 3:NEJMoa2016638. PubMed: https://pubmed.gov/32492293. Full-text: https://doi.org/10.1056/NEJMoa2016638 ll (Outstanding)
In total, 821 asymptomatic participants were randomized to receive hydroxychloroquine or placebo within 4 days after exposure (88% with a high-risk exposure). Incidence of confirmed SARS-CoV-2 was 11.8% with CQ and 14.3% with placebo. Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
This is bad news because after high-risk or moderate-risk exposure to Covid-19, HCQ did not prevent infection when used as postexposure prophylaxis within 4 days after exposure.
Irie K, Nakagawa A, Fujita H, et al. Pharmacokinetics of Favipiravir in Critically Ill Patients with COVID-19. Clin Transl Sci. 2020 May 31. PubMed: https://pubmed.gov/32475019. Full-text: https://doi.org/10.1111/cts.12827
In 7 patients with severe COVID-19 who were admitted to the intensive care unit and placed on mechanical ventilation, the favipiravir trough concentration was much lower than that of healthy subjects in a previous clinical trial. This is, however, good news, because this will lead to further PK studies that will help to optimize dosage and formulation – and improve efficacy of this drug.
Freedberg DE, Conigliaro J, Wang TC, et al. Famotidine Use is Associated with Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study. Gastroenterology. 2020 May 21. PubMed: https://pubmed.gov/32446698. Full-text: https://doi.org/10.1053/j.gastro.2020.05.053
Famotidine is a histamine-2 receptor antagonist that suppresses gastric acid production. It is thought to inhibit the 3-chymotrypsin-like protease (3CLpro) and/or to act via its antagonism or inverse-agonism of histamine signalling. This retrospective study looked at 1,620 patients, including 84 patients (5.1%) who received different doses of famotidine within 24 hours of hospital admission. After adjusting for baseline patient characteristics, use of famotidine remained independently associated with a reduced risk for death or intubation (adjusted hazard ratio 0.42, 95% CI 0.21-0.85) and this remained unchanged after careful propensity score matching to further balance the co-variables. Of note, there was no protective effect associated with use of PPIs. The maximum plasma ferritin value during hospitalization was lower with famotidine, indicating that the drug blocks viral replication and reduces the cytokine storm. RCTs are underway, keep an eye on this! This is damned good news!
Mahase E. Covid-19: WHO halts hydroxychloroquine trial to review links with increased mortality risk. BMJ. 2020 May 28. PubMed: https://pubmed.gov/32467095. Full-text: https://doi.org/10.1136/bmj.m2126
The World Health Organization has halted the hydroxychloroquine arm of the SOLIDARITY trial after a large registry study found that the drug was linked with an increased risk of mortality and heart arrhythmias. The registry data are discussed.
Whether or not to adopt HCQ to treat COVID-19 has turned into a political dispute that seems to benefit no one. This article describes how unfavorable outcomes have provoked animosity. Brazilian authors of the important JAMA study showing that higher doses are associated with higher mortality (the trial was discontinued) received death threats through social media and had to request police protection, which was kept for more than 2 weeks. The Brazilian president’s son Eduardo Bolsonaro (who has 2 million Twitter followers) had called it “a fake study aimed at demonizing the drug”.
Kupferschmidt K. Scientists put survivors’ blood plasma to the test. Science 29 May 2020: Vol. 368, Issue 6494, pp. 922-923. Full-text: https://doi.org/10.1126/science.368.6494.922
Nice article describing convalescent plasma as a promising new strategy. However, controlled clinical data are still lacking. Other issues such as supply (may become a challenge), consistency (concentration differs) and risks (transfusion-related acute lung injury, in which transferred antibodies damage pulmonary blood vessels, or transfusion-associated circulatory overload) are also discussed.
Salazar E, Perez KK, Ashraf M, et al. Treatment of COVID-19 Patients with Convalescent Plasma. Am J Pathol. 2020 May 27. PubMed: https://pubmed.gov/32473109. Full-text: https://doi.org/10.1016/j.ajpath.2020.05.014
Some more clinical data on this strategy. In 25 patients with severe and/or life-threatening COVID-19 disease enrolled at a Houston hospital, convalescent plasma was safe. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged.
Huet T, Beaussier H, Voisin O, et al. Anakinra for severe forms of COVID-19: a cohort study.Lancet Rheumatol 2020, May 29, 2020. https://doi.org/10.1016/S2665-9913(20)30164-8
This study from Paris compared 52 consecutive patients treated with anakinra with 44 historical patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 25% patients in the anakinra group and 73% patients in the historical group. Treatment effect of anakinra remained significant in the multivariate analysis. Controlled trials are needed.
Hernandez AV, Roman YM, Pasupuleti V, et al. Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review. Annals of Internal Medicine 27 May 2020. Full-text: https://doi.org/10.7326/M20-2496.
The main conclusion of this review is that there is insufficient and often conflicting evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19. As such, it is impossible to determine the balance of benefits to harms. There are no assessments of hydroxychloroquine or chloroquine for prophylaxis against COVID-19.
Goldman JD, Lye DC, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. May 27, 2020. https://www.nejm.org/doi/full/10.1056/NEJMoa2015301?query=featured_home
In this randomized, open-label, Phase III trial in 397 hospitalized patients with severe COVID-19 and not requiring IMV, clinical improvement at day 14 was 64% with 5 days remdesivir and 54% with 10 days. After adjustment for (significant) baseline imbalances in disease severity, outcomes were similar. The most common adverse events were nausea (9%), worsening respiratory failure (8%), elevated ALT level (7%), and constipation (7%). Because the trial lacked a placebo control, it was not a test of efficacy for remdesivir.
Shi R, Shan C, Duan X, et al. A human neutralizing antibody targets the receptor binding site of SARS-CoV-2. Nature. 2020 May 26. PubMed: https://pubmed.gov/32454512. Full-text: https://doi.org/10.1038/s41586-020-2381-y
Another interesting specific human monoclonal antibody (MAb) from a convalescent patient. CB6 demonstrated potent neutralization activity in vitro against SARS-CoV-2 and worked in 6 rhesus monkeys at both prophylactic and treatment settings. This MAb recognizes an epitope that overlaps with ACE2 binding sites in SARS-CoV-2 receptor binding domain (RBD), thereby interfering with the virus/receptor interactions by both steric hindrance and direct interface-residue competition.
Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19–infected patients. Blood 2020, 135: 1912–1915. https://doi.org/10.1182/blood.2020006288
Five Waldenstroem macroglobulinemia patients on Bruton tyrosine kinase (BTK) inhibitor ibrutinib, 420 mg/d, did not require hospitalization. Their course was marked by steady improvement, and resolution or near resolution of COVID-19 symptoms during the follow-up period. Clinical trials examining the benefit of BTK inhibitors to abrogate lung injury are being initiated.
Ju B, Zhang Q, Ge J, et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020 May 26. PubMed: https://pubmed.gov/32454513. Full-text: https://doi.org/10.1038/s41586-020-2380-z
As long as all other therapies fail or have only modest effects, antibodies are the hope for the near future. Isolation and characterization of 206 RBD-specific monoclonal antibodies were derived from single B cells of eight SARS-CoV-2 infected individuals. Some antibodies showed potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding. Surprisingly, neither the anti-SARS-CoV-2 antibodies nor the infected plasma cross-reacted with SARS-CoV or MERS-CoV RBDs, although substantial plasma cross-reactivity to their trimeric Spike proteins was found.
Remy KE, Brakenridge SC, Francois B, et al. Immunotherapies for COVID-19: lessons learned from sepsis. Lancet Respir Med. 2020 Apr 28. PubMed: https://pubmed.gov/32444269. Full-text: https://doi.org/10.1016/S2213-2600(20)30217-4
The hypothesis that quelling the cytokine storm with anti-inflammatory therapies directed at reducing interleukin-6 (IL-6), IL-1, or even tumour necrosis factor α (TNFα) might be beneficial has led to several ongoing trials. The authors are less enthusiastic and urge caution. Past attempts to block the cytokine storm associated with other microbial infections and with sepsis have not been successful and, in some cases, have worsened outcomes. Moreover, there is concern that suppressing the innate and adaptive immune system to address increased cytokine concentrations, could enable unfettered viral replication, suppress adaptive immunity, and delay recovery processes. There is growing recognition that potent immunosuppressive mechanisms are also prevalent in such patients. Giving immunosuppressive agents seems not to be a good idea.
Gregoire M, Le Turnier P, Gaborit BJ, et al. Lopinavir pharmacokinetics in COVID-19 patients. J Antimicrob Chemother. 2020 May 22. PubMed: https://pubmed.gov/32443151. Full-text: https://doi.org/10.1093/jac/dkaa195
Lopinavir concentrations in 12 COVID-19 patients at the Nantes University Hospital, France, were extremely high compared with those usually observed in HIV-infected patients (trough: 18,000 ng/mL versus 5365 ng/mL with 400/100 mg q12h).
Mehra MR, Desai SS, Ruschitzka F, Patel AM. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet May 22, 2020 Full-text: https://doi.org/10.1016/S0140-6736(20)31180-6
Probably the end of chloroquine. And the end of hydroxychloroquine. And the end of chloroquine plus azithromycin or clarithromycin. And, yes, the end of hydroxychloroquine plus azithromycin or clarithromycin. We should no longer use these four drug regimens as COVID-19 treatments! In this incredible large multinational registry, analysis from 671 hospitals in six continents, 14,888 patients treated with these regimens were compared with 81,444 control patients. Each drug regimen was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias. However, the study (including a 20-page supplement) is too complex to be discussed here in a few words. We will come back to this soon.
Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the Treatment of Covid-19 — Preliminary Report. NEJM 2020, May 22. Full-text: https://doi.org/10.1056/NEJMoa2007764 l (Important)
It took almost a month to publish this eagerly awaited paper: does remdesivir work? Yes, in some patients. The conclusion of this double-blinded study that randomized 1,063 COVID-19 patients throughout the world to the drug or to placebo, was remarkably short: “Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19 and evidence of lower respiratory tract infection”. Median recovery time was 11 versus 15 days. The benefit was most apparent in patients with a baseline ordinal score of 5 (requiring oxygen but no high-flow oxygen). In patients requiring mechanical ventilation or ECMO, there was no effect at all (although the numbers were low). Gender, ethnicity, age or symptom duration had no impact. The Kaplan-Meier estimates of mortality at 14 days were 7.1% and somewhat (not significantly) lower with remdesivir compared to 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). This is, however, preliminary. The full analysis of the entire trial population will occur soon, although more comparative data may be hard to find as all patients were rolled over to the active agent at this point in the study.”
Liu Y, Pang Y, Hu Z, et al. Thymosin alpha 1 (Tα1) reduces the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells. Clinical Infectious Diseases 2020, May 22. Full-text: https://doi.org/10.1093/cid/ciaa630
In this study of 76 patients with severe COVID-19, Tα1 supplement (subcutaneous injections of 10 mg) appeared to reduce mortality, especially in those with low CD4 and CD8 cell counts. This immunomodulating thymic peptide reversed T cell exhaustion and recovers immune reconstitution through promoting thymus output during SARS-CoV-2 infection. However, this is uncontrolled retrospective data and results should be interpreted with caution.
Fan J, Zhang X, Liu J, et al. Connecting hydroxychloroquine in vitro antiviral activity to in vivo concentration for prediction of antiviral effect: a critical step in treating COVID-19 patients. Clin Infect Dis. 2020 May 21:ciaa623. PubMed: https://pubmed.gov/32435791. Full-text: https://doi.org/10.1093/cid/ciaa623
The price for the most cryptic abstract of the day goes to this FDA group. “Translation of in vitro antiviral activity to the in vivo setting is crucial to identify potentially effective dosing regimens of hydroxychloroquine. In vitro EC50/EC90 values for hydroxychloroquine should be compared to the in vivo free extracellular tissue concentration, which is similar to the free plasma hydroxychloroquine concentration.” Did they not dare to tell the truth? Their (important, yet cryptic) message was: HCQ doses tolerable for humans are too low to have any antiviral effect.
Parang K, El-Sayed NS, Kazeminy AJ, Tiwari RK. Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs Against Human Coronavirus 229E (HCoV-229E). Molecules. 2020 May 17;25(10):E2343. PubMed: https://pubmed.gov/32429580. Full-text: https://doi.org/10.3390/molecules25102343.
Most almost-misleading title of the day: Comparative, not comparable. A series of anti-HIV nucleosides were compared with remdesivir for antiviral activity against seasonal HCoV-229E in MRC-5 cells. Remdesivir was found to be potent, with an EC50 value of 0.07 μM. Only emtricitabine (FTC) showed modest activity, with an EC50 value of 82 μM. Other NRTIs did not show comparable activity. But it was comparative, yes.
Pinto D, Park YJ, Beltramello M, et al. Cross-neutralization of SARS-CoV-2 by a Human Monoclonal SARS-CoV Antibody. Nature 2020 May 18. Full-text: https://doi.org/10.1038/s41586-020-2349-y
The next interesting antibody study. The authors describe multiple monoclonal antibodies targeting SARS-CoV-2 spike identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, authors show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment.
Why not favipiravir for COVID-19? This purine nucleoside analogue acts as a competitive inhibitor of RNA-dependent RNA polymerase and can be given orally (in contrast to remdesivir, another RdRp inhibitor). Authors give a brief overview on clinical studies. The results of several ongoing randomized controlled trials are eagerly awaited. 20 May
Cao Y, Sui B, Guo X, et al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell 2020, May 17, 2020. Full-text: https://doi.org/10.1016/j.cell.2020.05.025
Fantastic work, identifying 14 potent neutralizing antibodies by high-throughput single B-cell RNA- sequencing from 60 convalescent patients. The most potent one, BD-368-2, exhibited an IC50 of 15 ng/mL against SARS-CoV-2. This antibody displayed strong therapeutic and prophylactic efficacy in mice, the epitope overlaps with the ACE2 binding site. Time to go into the clinic!
Pawlotsky JM. SARS-CoV-2 pandemic : Time to revive the cyclophilin inhibitor alisporivir. Clin Infect Dis 2020 May 15. PubMed: https://pubmed.gov/32409832. Full-text: https://doi.org/10.1093/cid/ciaa587
Some arguments supporting the use of alisporivir, a non-immunosuppressive analogue of cyclosporine A developed by Novartis. Arguments include the cyclophilin-dependency of the lifecycle of many coronaviruses and preclinical data on antiviral and cytoprotective properties.
Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. PubMed: https://pubmed.gov/32275812. To the editor: https://www.nejm.org/doi/10.1056/NEJMc2015312#sa1
Four letters, making critical comments on the NEJM paper about the remdesivir compassionate use program. We have discussed many of these issues on April 16, see here: https://covidreference.com/remdesivir
Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyper-inflammation: a retrospective cohort study. Lancet Rheumatol 2020. Full-text: https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30127-2/fulltext
This retrospective cohort study at the San Raffaele Hospital in Milan, Italy, included patients with moderate-to-severe ARDS and hyperinflammation (serum C-reactive protein, CRP ≥100 mg/L) who were managed with non-invasive ventilation and HCQ and lopinavir/r. At 21 days, treatment with high-dose anakinra was associated with reductions in CRP and progressive improvements in respiratory function in 21/29 (72%) patients.
Dimopoulos G, de Mast Q, Markou N, et al. Favorable anakinra responses in severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis. Cell Host and Microbe 2020, May 14. Full-text: https://doi.org/10.1016/j.chom.2020.05.007
Another small case series of critically ill patients with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hypercoagulation, acute kidney injury and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors and significantly improved respiratory function. Although 3/8 patients died, the mortality was lower than historical series of patients with sHLH in sepsis.
Amir Qaseem A, Yost J, Etxeandia-Ikobaltzeta I, et al. Should Clinicians Use Chloroquine or Hydroxychloroquine Alone or in Combination With Azithromycin for the Prophylaxis or Treatment of COVID-19? Annals Internal Medicine May 13, 2020. Full-text: https://www.acpjournals.org/doi/10.7326/M20-1998
The answer is: no. These “Living Practice Points” From the American College of Physicians (based on an evidence review conducted on 17 April 2020) very clearly say that both drugs should not be used as prophylaxis or treatment of patients with COVID-19. In light of known harms and very uncertain evidence of benefit in patients with COVID-19, however, clinicians may treat hospitalized COVID-19–positive patients in the context of a clinical trial.
Schoergenhofer C, Jilma B, Stimpfl T, et al. Pharmacokinetics of Lopinavir and Ritonavir in Patients Hospitalized With Coronavirus Disease 2019 (COVID-19). Annals of Internal Medicine 12 May 2020. Full-text: https://www.acpjournals.org/doi/10.7326/M20-1550
Although lopinavir trough levels were approximately 2-fold higher in 8 COVID-19 patients than in HIV infected patients receiving the same dose, levels may be too low for COVID-19. Approximately 60- to 120-fold higher concentrations are required to reach the assumed EC50 at trough levels, making effective treatment of COVID-19 with lopinavir/r at the currently used dose unlikely.
Wang X, Cao R, Zhang H, et al. The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro. Cell Discov. 2020 May 2;6:28. PubMed: https://pubmed.gov/32373347. Full-text: https://doi.org/10.1038/s41421-020-0169-8
Among six anti-influenza drugs, only arbidol efficiently inhibited SARS-CoV-2 infection in cell experiments. Functionally, arbidol appeared to block virus entry by impeding viral attachment and release from the endolysosomes. However, higher dosages may be required to achieve therapeutic efficacy (800 mg?) than the current dose (200 mg, 3 times/day) as recommended by the Chinese Guidelines.
Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med (Cell Press) 2020. Full-text: https://doi.org/10.1016/j.medj.2020.04.001
This study randomized a total of 86 patients with mild to moderate COVID-19 to receive lopinavir/r, arbidol (200 mg TID) or no antiviral medication (control). The primary endpoint, the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid, was similar between groups. There were no differences between groups in the secondary endpoints, the rates of antipyresis, cough alleviation, or improvement of chest CT at days 7 or 14. Again, dosage of arbidol may have been too low.
Wu Y, Wang F, Shen C, et al. A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science. 2020 Jun 12;368(6496):1274-1278. PubMed: https://pubmed.gov/32404477. Full-text: https://doi.org/10.1126/science.abc2241 l (Important)
Neutralizing antibodies are promising candidates for prophylactic and therapeutic treatment against COVID-19 virus. Four human-origin monoclonal antibodies were isolated from a convalescent patient, all of which displayed neutralization abilities. B38 and H4 block the binding between virus S protein RBD and cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD. In a mouse model, both antibodies reduced virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity.
Rodel F, Arenas M, Ott OJ, et al. Low-dose radiation therapy for COVID-19 pneumopathy: what is the evidence? Strahlenther Onkol. 2020 May 9. PubMed: https://pubmed.gov/32388805. Full-text: https://doi.org/10.1007/s00066-020-01635-7
Given the lack of effective pharmacological concepts, this review (re)considers historical reports on low-dose radiation therapy for pneumonia. Although these reports are of low-level evidence, they indicate effectiveness in the dose range between 0.3 and 1Gy, similar to more recent dose concepts in the treatment of inflammatory/degenerative benign diseases with, e.g., a single dose per fraction of 0.5Gy. The authors (known experts in the field) critically review the evidence for low-dose radiation treatment of COVID-19 pneumopathy and discuss whether it is worth investigating (answer: yes).
Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020 May 11. PubMed: https://pubmed.gov/32392282. Full-text: https://doi.org/10.1001/jama.2020.8630
The next large retrospective cohort study of 1,438 patients from a random sample of all admitted patients with COVID-19 in 25 hospitals in the New York metropolitan region between March 15 and 28. In adjusted Cox models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine (HCQ) + azithromycin, HCQ alone, or azithromycin alone. In logistic models, cardiac arrest was significantly more likely in patients receiving HCQ + azithromycin (adjusted OR 2.13). The main limitation was the observational design. HCQ patients were more sick and had more comorbidities – the key (and unresolved) question is whether adjustment was sufficient.
Hung FN, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet May 08, 2020. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31042-4/fulltext l (Important)
Some evidence that interferon may be helpful, when given during the first week: this Phase II, multicentre, open-label trial from Hong Kong randomized 127 patients with mild-to-moderate COVID-19 (median 5 days from symptom onset) to receive lopinavir/r only or a triple combination. Triple therapy was given only to patients with less than 7 days from symptom onset and consisted of lopinavir/r, ribavirin (400 mg BID), and interferon beta-1b (1-3 doses of 8 Mio IE per week). Combination therapy led to a significantly shorter median time to negative results in nasopharyngeal swab (7 versus 12 days, p=0.001) and other specimens. Clinical improvement was significantly better, with a shorter time to complete alleviation of symptoms and a shorter hospital stay. Of note, all differences were driven by the 76 patients who started treatment less than 7 days after onset of symptoms.
Martin-Blondel G, Ruiz S, Murris M, et al. Hydroxychloroquine in COVID-19 patients: what still needs to be known about the kinetics. Clin Infect Dis. 2020 May 11. PubMed: https://pubmed.gov/32392332. Full-text: https://doi.org/10.1093/cid/ciaa558
Different dosage regimens of hydroxychloroquine are currently used to manage COVID-19. The concentrations measured in 57 patients showed that hydroxychloroquine exposure was relatively low and in most instances lower than the values reported in systemic lupus erythematosus patients, in particular for the standard regimen of 200 mg TID. A full hydroxychloroquine kinetic exploration is needed.
Spinelli FR, Conti F, Gadina M. HiJAKing SARS-CoV-2? The potential role of JAK inhibitors in the management of COVID-19. Sci Immunol. 2020 May 8;5(47). PubMed: https://pubmed.gov/32385052. Full-text: https://doi.org/10.1126/sciimmunol.abc5367
Targeting IL-6 and other cytokines with JAK-dependent signaling is one way to restrain the excessive level of cytokine signaling. JAK kinase inhibitors are being investigated as a way of managing the cytokine storm in severe COVID-19 patients. However, this well-balanced review also discusses potential concerns on side effects, such as the reduction of NK cells or thromboembolic risks seen with baricitinib and tofacitinib treatment.
Mojoli F, Mongodi S, Orlando A, et al. Our recommendations for acute management of COVID-19. Crit Care. 2020 May 8;24(1):207. PubMed: https://pubmed.gov/32384909. Full-text: https://doi.org/10.1186/s13054-020-02930-6
Some helpful (and very practical) clinical management suggestions, derived from the direct experience of Italian physicians.
Cohen J. The race is on for antibodies that stop the new coronavirus. Science 08 May 2020: Vol. 368, Issue 6491, pp. 564-565. https://science.sciencemag.org/content/368/6491/564 l (Important)
Great overview about antibodies as a potential treatment. Many researchers are optimistic that these antibodies will, relatively quickly, prove their worth as a preventive or as a remedy that buys the world some time until a vaccine arrives (if it does). The main questions will be the capacity to manufacture at scale, distribute, and the cost.
Wrapp D, De Vlieger D, Corbett KS, et al. Structural Basis for Potent Neutralization of Betacoronaviruses by Single-Domain Camelid Antibodies. Cell. 2020 Apr 29. PubMed: https://pubmed.gov/32375025. Full-text: https://doi.org/10.1016/j.cell.2020.04.031
Here is one. In addition to conventional antibodies, camelids also produce heavy-chain-only antibodies (HCAbs), which contain a single variable domain (VHH) instead of two variable domains (VH and VL) that make up the equivalent antigen-binding fragment (Fab) of conventional immunoglobulin G (IgG) antibodies. These so-called ‘nanobodies’ have several potential therapeutic advantages, including increased stability and ease of production. Using llamas immunized with prefusion-stabilized betacoronavirus spike proteins, the authors identified neutralizing cross-reactive VHH camelid antibodies, which may serve as potential therapeutic candidates. Crystal structures further reveal how these antibodies bind to spike proteins to prevent viral entry into cells.
Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020 May 7. PubMed: https://pubmed.gov/32379955. Full-text: https://doi.org/10.1056/NEJMoa2012410 l (Important)
The end of hydroxychloroquine (HCQ)? Incredible large observational study from New York City. Of 1,376 consecutive hospitalized patients, 811 (59%) received HCQ (600 mg BID day 1, then 400 mg QD, 60% also received azithromycin). The decision to prescribe the drugs was “left to the discretion of the treating team for each individual patient”. HCQ-treated patients were more severely ill at baseline. Authors adjusted for likely confounders, including age, race and ethnic group, body-mass index, diabetes, underlying kidney or lung disease, hypertension, baseline vital signs, Pao2:Fio2, and inflammatory markers of the severity of illness. There was no significant association between HCQ use and intubation or death. However, despite this extensive adjustment, it is still possible that some amount of unmeasured confounding remains. According to the authors, the study should not be taken to rule out either benefit or harm of HCQ but the results do not support the use of HCQ outside randomized clinical trials.
Hanley B, Roufosse CA, Osborn M, Naresh KN. Convalescent donor SARS-COV-2-specific cytotoxic T lymphocyte infusion as a possible treatment option for COVID-19 patients with severe disease – has not received enough attention till date. Br J Haematol. 2020 May 5. PubMed: https://pubmed.gov/32369628. Full-text: https://doi.org/10.1111/bjh.16780
Authors argue that therapeutic off-the-shelf SARS-COV-2-specific HLA-matched cytotoxic T cells prepared from convalescent COVID-19 patients is the most pressing need. It remains unclear why.
Wang C, Li W, Drabek D, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun. 2020 May 4;11(1):2251. PubMed: https://pubmed.gov/32366817. Full-text: https://doi.org/10.1038/s41467-020-16256-y ll (Outstanding)
The first report of a human monoclonal antibody that neutralizes SARS-CoV-2. 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition. This antibody could be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2.
Interesting discussion about the results of the large open-label randomized trial which was published in March. In this trial, administration of lopinavir/r did not result in a shorter time until clinical improvement compared to placebo. Bottom line of most comments: “absence of evidence is not evidence of absence”. Lopinavir/r may still be a potential therapeutic agent against COVID-19, especially when given earlier.
Bonam SR, Kaveri SV, Saluntabhai A, et al. Adjunct immunotherapies for the management of severely ill COVID-19 patients. Cell Rep Med April 29, 2020. DOI:https://doi.org/10.1016/j.xcrm.2020.100016. Full-text: https://www.cell.com/action/showPdf?pii=S2666-3791%2820%2930021-5
Comprehensive review on current immunotherapies which either neutralize cytokines, SARS-CoV-2 or exert immunomodulation. Immunotherapies may not only reduce inflammation, inflammation-associated lung damage, or viral load, but could also prevent intensive care unit hospitalization.
Zeng QL, Yu ZJ, Gou JJ, et al. Effect of Convalescent Plasma Therapy on Viral Shedding and Survival in COVID-19 Patients. J Infect Dis. 2020 Apr 29. PubMed: https://pubmed.gov/32348485. Full-text: https://doi.org/10.1093/infdis/jiaa228
Don’t be too late: Of 6 patients with respiratory failure receiving convalescent plasma at a median of 21 days after first detection of viral shedding, all tested RNA negative by 3 days after infusion. However, 5 died eventually.
Ledford H. Hopes rise on coronavirus drug remdesivir. Nature Medicine 29 April 2020. Full-text: https://doi.org//10.1038/d41586-020-01295-8
The next example of “Fauci said”. Anthony Fauci, director of the US National Institute of Allergy and Infectious Disease (NIAID) had announced that a clinical trial of “more than a thousand people showed that people taking remdesivir recovered in 11 days on average, compared to 15 days for those on a placebo”. That’s all. We believe that this is not an appropriate way to share data.
Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. PubMed: https://pubmed.gov/32423584. Full-text: https://doi.org/10.1016/S0140-6736(20)31022-9 l (Important)
And here it is, the first randomized, double-blind, placebo-controlled trial of remdesivir (and not the study Fauci was talking about)! This multicenter trial at ten hospitals in Hubei, China enrolled patients with severe COVID-19 to receive 10 days of single infusions or placebo. Clinical improvement up to day 28 was defined as the time (in days) to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. In the 237 patients enrolled between Feb 6 and March 12, remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1.23, 95% CI 0.87–1.75). Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early. The trial did not attain the predetermined sample size because the outbreak of COVID-19 was brought under control in China. Disappointing. More data are eagerly awaited.
Gates B. Responding to Covid-19 — A Once-in-a-Century Pandemic? NEJM April 30, 2020. N Engl J Med 2020; 382:1677-1679. Full-text: https://doi.org/10.1056/NEJMp2003762.
Bill Gates, talking about billions of dollars. He will donate some. According to this perspective, he has comitted “substantial resources”. Well done.
Strollo R, Pozzilli P. DPP4 inhibition: preventing SARS-CoV-2 infection and/or progression of COVID-19? Diabetes Metab Res Rev. 2020 Apr 26. PubMed: https://pubmed.gov/32336007. Full-text: https://doi.org/10.1002/dmrr.3330
The next new idea. Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase expressed ubiquitously in several tissues, including but not limited to lung, kidney, liver, gut, and immune cells. Some careful thoughts on whether DPP4 modulation or inhibition (by diabetes drugs such as gliptins) may prevent infection and/or progression of the COVID-19.
Ledford H. Chloroquine hype is derailing the search for coronavirus treatments. Nature Medicine, 24 April 2020. Full-text https://www.nature.com/articles/d41586-020-01165-3
After hearing politicians touting the potential benefits, many patients are turning away from clinical trials of other therapies that would require them to give up chloroquine treatments. This report reviews these issues which have already led to serious delays in trial enrolment, muddled efforts to interpret data and endangered clinical research on COVID-19.
Borrell B. New York clinical trial quietly tests heartburn remedy against coronavirus. Science April 26, 2020. Full-text: https://www.sciencemag.org/news/2020/04/new-york-clinical-trial-quietly-tests-heartburn-remedy-against-coronavirus
Famotidine for COVID-19? By reviewing 6212 Chinese patient records, it became obvious that many survivors had been suffering from chronic heartburn and were on famotidine rather than the more expensive omeprazole. On 7 April, the first COVID-19 patients at Northwell Health in the New York City area began receiving famotidine intravenously, at nine times the heartburn dose. Interim results of this clinical trial which has enrolled an incredibly huge number of patients, will be available within a few weeks. Don’t tell your politicians.
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 Apr 24;3(4.23):e208857. PubMed: https://pubmed.gov/32330277. Full-text: https://doi.org/10.1001/jamanetworkopen.2020.8857 l (Important)
Less is more? This double-masked, randomized, Phase IIb clinical trial in Manaus, Brazil allocated severe COVID-19 patients to receive high-dose CQ (600 mg BID for 10 days) or low-dose CQ (450 mg BID on day 1, QD for 4 days). The data safety monitoring board terminated the trial after 81/440 individuals had been enrolled. By day 13 of enrolment, 6 of 40 patients (15%) in the low-dose group had died, compared with 16 of 41 patients (39%) in the high-dose group. Viral RNA was detected in 78% and 76%, respectively. This trial also shows how dramatically mechanisms to execute research have accelerated: the first patient had been enrolled in this trial on March 26, 2020.
Mathian A, Mahevas M, Rohmer J, et al. Clinical course of coronavirus disease 2019 (COVID-19) in a series of 17 patients with systemic lupus erythematosus under long-term treatment with hydroxychloroquine. Ann Rheum Dis. 2020 Apr 24. PubMed: https://pubmed.gov/32332072. Full-text: https://doi.org/10.1136/annrheumdis-2020-217566
People with lupus (SLE) who take hydroxychloroquine (HCQ) are not protected. This cohort describes 17 SLE patients with COVID-19, among them several severe cases. The duration of HCQ treatment prior to COVID-19 was relatively long, with a median of 7.5 years. Some patients were also treated with prednisone and/or with immunosuppressants.
Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020 Apr 6. PubMed: https://pubmed.gov/32253226. Full-text: https://doi.org/10.1126/scitranslmed.abb5883
What if remdesivir doesn’t work? The next nucleoside analog is on its way. Beta-D-N(4)-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against all human and bat CoVs, including CoVs resistant to remdesivir. In mice, both prophylactic and therapeutic administrations improved pulmonary function and reduced virus titer.
Dai W, Zhang B, Su H, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020 Apr 22. PubMed: https://pubmed.gov/32321856. Full-text: https://doi.org/10.1126/science.abb4489
More on a key enzyme, SARS-CoV-2’s main protease (Mpro). The authors synthesized two lead compounds (11a and 11b) targeting Mpro, exhibiting good inhibitory activity, good PK properties and low toxicity in animal experiments. Pre-clinical.
Chorin E, Dai M, Shulman E. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nature Medicine. Published: 24 April 2020. Full-Text: https://www.nature.com/articles/s41591-020-0888-2 l (Important)
Check ECG if you do this! In this important study, authors followed the corrected QT (QTc) interval in a consecutive cohort of 84 patients receiving hydroxychloroquine and azithromycin which were administered orally for 5 days. A prolongation of the QTc from a baseline average of 435 ± 24 ms to a maximal average value of 463 ± 32 ms was found, occurring on day 3.6 ± 1.6 of therapy. In a subset of nine (11%) patients, the QTc was severely prolonged to > 500 ms, a known marker of high risk of malignant arrhythmia and sudden cardiac death. Five of nine patients with severe QTc prolongation had a normal QTc at baseline.
Prokunina-Olsson L, Alphonse N, Dickenson RE, et al. COVID-19 and emerging viral infections: The case for interferon lambda. J Exp Med. 2020 May 4;217(5). PubMed: https://pubmed.gov/32289152. Full-text: https://doi.org/10.1084/jem.20200653
In this Viewpoint article, the authors present their opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat SARS-CoV-2 infections.
Bhimray A, Morgan RL, Shumaker. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Published by IDSA, 4/11/2020. Full-text: https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
Evidence-based guidelines which are, in the absence of large RCTs, not very helpful. Recommendations for all drugs acknowledge the current “knowledge gap”. HCQ, lopinavir/r, tocilizumab and convalescent plasma should be given “only in the context of a clinical trial”. Great.
Hillaker E, Belfer JJ, Bondici A, Murad H, Dumkow LE. Delayed Initiation of Remdesivir in a COVID-19 Positive Patient. Pharmacotherapy. 2020 Apr 13. PubMed: https://pubmed.gov/32281114. Full-text: https://doi.org/10.1002/phar.2403
Were we wrong with our critical review on remdesivir? Again, we hope so. A case of successful late initiation of remdesivir is presented. Sixty hours after starting the drug, the patient was extubated and was able to transition to room air within 24 hours of extubation.
Zhu Z, Lu Z, Xu T, et al. Arbidol Monotherapy is Superior to Lopinavir/ritonavir in Treating COVID-19. J Infect. 2020 Apr 10. PubMed: https://pubmed.gov/32283143. Full-text: https://doi.org/10.1016/j.jinf.2020.03.060
Retrospective case series, comparing lopinavir/r (34 cases) and arbidol (16 cases). On day 14 after the admission, no viral load was detected in the arbidol group, but the viral load was found in 15 (44.1%) patients treated with lopinavir/ritonavir. Patients in the arbidol group had a shorter duration of positive RNA test compared to those in the lopinavir/ritonavir group (P < 0.01).
Smereka J, Puslecki M, Ruetzler K, et al. Extracorporeal membrane oxygenation in COVID-19. Cardiol J. 2020 Apr 14. PubMed: https://pubmed.gov/32285929. Full-text: https://doi.org/10.5603/CJ.a2020.0053
A brief review on ECMO which remains a therapeutic option in some well selected patients with severe COVID-19.
Di Giambenedetto S, Ciccullo A, Borghetti A, et al. Off-label Use of Tocilizumab in Patients with SARS-CoV-2 Infection. J Med Virol. 2020 Apr 16. PubMed: https://pubmed.gov/32297987. Full-text: https://doi.org/10.1002/jmv.25897
The humanized anti-IL-6 receptor antibody tocilizumab was given to three patients with severe COVID-19. All showed rapid relief of respiratory symptoms, resolution of fever and reduction in CRP following tocilizumab administration.
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Apr 13. PubMed: https://pubmed.gov/32282022. Full-text: https://doi.org/10.1001/jama.2020.6019
Fantastic review on current knowledge on potential therapies (as of April 5).
Rome BN, Avorn J. Drug Evaluation during the Covid-19 Pandemic. N Engl J Med. 2020 Apr 14. PubMed: https://pubmed.gov/32289216. Full-text: https://doi.org/10.1056/NEJMp2009457
Thoughts on how clinical trials should be performed during the current pandemic. And how the processes for evaluating and approving drugs can go awry during a public health crisis.
De Meyer S, Bojkova D, Cinati J, et al. Lack of Antiviral Activity of Darunavir against SARS-CoV-2. Full-text: https://doi.org/10.1101/2020.04.03.20052548
Usually we hesitate to refer to www.medrxiv.org. Preprints published at this website are preliminary reports of work that have not been certified by peer review. Well, it’s time to make an exception. Because this is important: Darunavir, an HIV protease inhibitor, is not active against SARS-CoV-2. There was no in vitro antiviral activity against a clinical isolate at clinically relevant concentrations (EC50 > 100 μM). Remdesivir, used as a positive control, showed potent activity (EC50 = 0.38 μM). However, the clinical trial on 3,040 participants treated with darunavir in Spain is still ongoing (www.clinicaltrials.gov assessment on April 13).
Bartiromo M, Borchi B, Botta A, et al. Threatening drug-drug interaction in a kidney transplant patient with Coronavirus Disease 2019 (COVID-19). Transpl Infect Dis. 2020 Apr 12. PubMed: https://pubmed.gov/32279418. Full-text: https://doi.org/10.1111/tid.13286
If you give HIV PIs, please be always aware of drug-drug interactions. Ritonavir is a strong pharmaco-enhancer. For example, tacrolimus has to be reduced by 10-100 fold to maintain concentration within the therapeutical range. In this case report, a woman with kidney transplantation was treated with lopinavir/r (the “r” indicates ritonavir) for COVID-19 while receiving the full dose of tacrolimus. Levels went incredibly high and were still above the therapeutic range 9 days after stopping both lopinavir/r and tacrolimus. Fortunately, everything turned out alright.
Feldmann M, Maini RN, Woody JN, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet. 2020 Apr 9. PubMed: https://pubmed.gov/32278362. Full-text: https://doi.org/10.1016/S0140-6736(20)30858-8
Treating the inflammatory excess in patients with COVID-19: why anti-tumour necrosis factor (TNF) antibodies could be a good idea.
McEnery T, Gough C, Costello RW. COVID-19: Respiratory support outside the intensive care unit. Lancet Respir Med. 2020 Apr 9. PubMed: https://pubmed.gov/32278367. Full-text: https://doi.org/10.1016/S2213-2600(20)30176-4
The debate about the optimal mode of respiratory support (outside ICU) continues. Advocate high flow nasal cannulae (HFNC) over non-invasive ventilation (NIV) or vice versa? In the absence of randomised control trials in the use of either HFNC or NIV in COVID-19, this commentary discusses current knowledge.
Lentz RJ, Colt H. Summarizing societal guidelines regarding bronchoscopy during the COVID-19 pandemic. Respirology. 2020 Apr 11. PubMed: https://pubmed.gov/32277733. Full-text: https://doi.org/10.1111/resp.13824
In whom to perform bronchoscopy and how to perform it safely? This paper describes different guidelines (based on expert opinions).
Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020 Apr 2;12(4). PubMed: https://pubmed.gov/32252338. Full-text: https://doi.org/10.3390/nu12040988
Evidence? Well. Serum 25(OH)D concentrations tend to decrease with age, which may be important for COVID-19 because case-fatality rates increase with age. That’s the whole story. After all, the “hypothesis that vitamin D supplementation can reduce the risk of influenza and COVID-19 incidence and death should be investigated in trials”.
In the year 1925, the BMJ cautiously endorsed Moellgaard’s gold treatment for tuberculosis, although it found his pharmacological reasoning “both interesting and instructive”. In 2020, the BMJ is similarly cautious about (hydroxyl)chloroquine treatment for SARS-CoV-2. In cell and animal studies, the effects on avian influenza, Epstein-Barr, chikungunya or Zika have been variable. Wide use of these drugs will expose patients to rare but potentially fatal harms, including serious cutaneous adverse reactions, fulminant hepatic failure, and ventricular arrhythmias (especially when prescribed with azithromycin).
Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020 Apr 10. PubMed: https://pubmed.gov/32275812. Full-text: https://doi.org/10.1056/NEJMoa2007016
A compassionate use program of remdesivir for patients with severe COVID-19 is described. Clinical improvement was observed in 36/53 (68%) patients. Since published yesterday, data are celebrated in the media. Unjustifiably. Although the authors have made some efforts to discuss their data carefully, even more caution is needed. We believe that with this “study”, any (yes, any!) clinical benefit of remdesivir remains unproven. Moreover, several issues in this data set seem to be very implausible. We have written a correspondence letter to NEJM and will keep you updated.
Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020 Apr 6. PubMed: https://pubmed.gov/32253226. Full-text: https://doi.org/10.1126/scitranslmed.abb5883
The ribonucleoside analog beta-D-N(4)-hydroxycytidine (NHC, EIDD-1931) has broad spectrum antiviral activity against all CoVs, as well as increased potency against resistance mutations to the nucleoside analog inhibitor remdesivir. But how long will it take to bring this compound to clinical trials?
Jin Z, Du X, Xu Y, et al. Structure of M(pro) from COVID-19 virus and discovery of its inhibitors. Nature. 2020 Apr 9. PubMed: https://pubmed.gov/32272481. Full-text: https://doi.org/10.1038/s41586-020-2223-y l (Important)
Virtual drug screening to identify new drug leads that target the COVID-19 virus main protease M(pro) which plays a pivotal role in mediating viral replication and transcription. Six compounds inhibited M(pro) with IC50 values ranging from 0.67 to 21.4 muM, among them with disulfiram and carmofur (a pyrimidine analogue used as an antineoplastic agent), two approved drugs.
Praveen D, Chowdary PR, Aanandhi MV. Baricitinib – a januase kinase inhibitor – not an ideal option for management of COVID-19. Int J Antimicrob Agents. 2020 Apr 4:105967. PubMed: https://pubmed.gov/32259575. Full-text: https://doi.org/10.1016/j.ijantimicag.2020.105967
Several studies have speculated that baricitinib could act on AT2 cells and AAK1 mediated endocytosis. The authors argue that the drug would not be an ideal option, due to the fact that baricitinib causes lymphocytopenia, neutropenia and viral reactivation. Sounds reasonable.
Perinel S, Launay M, Botelho-Nevers E, et al. Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients. Clin Infect Dis. 2020 Apr 7. PubMed: https://pubmed.gov/32255489. Full-text: https://doi.org/10.1093/cid/ciaa394
Ongoing clinical trials with HCQ use different dosing regimens. In this PK study on 13 patients critically ill with COVID-19, 200 mg three times daily was inappropriate to reach a supposed target blood level of 1 – 2 mg/L. Authors proposed 800 mg once daily on day 1, followed by 200 mg twice daily for 7 days. Further PK studies needed.
Bloch EM, Shoham S, Casadevall A, et al. Deployment of convalescent plasma for the prevention and treatment of COVID-19. J Clin Invest. 2020 Apr 7. Full-text: https://doi.org/1387454
An overview of treatment with convalescent plasma on current evidence of benefit, regulatory considerations, logistical work-flow (recruitment of donors, etc) and proposed clinical trials.
Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS 2020, April 6. https://doi.org/10.1073/pnas.2004168117
A single dose (200 mL) of convalescent plasma was given to 10 patients (9 treated with umifenovir, 6 with methylprednisolone, 1 with remdesivir). In all 7 patients with viremia, serum SARS-CoV-2 RNA decreased to an undetectable level within 2-6 days. Meanwhile, clinical symptoms and paraclinical criteria rapidly improved within three days. Using antibodies from convalescents could be an option in severe cases. It’s now time for larger studies.
Du YX, Chen XP. Favipiravir: pharmacokinetics and concerns about clinical trials for 2019-nCoV infection. Clin Pharmacol Ther. 2020 Apr 4. PubMed: https://pubmed.gov/32246834. Full-text: https://doi.org/10.1002/cpt.1844
This mini-review (not open access) focusses on the pharmacokinetics of favipiravir and potential drug-drug interactions (DDIs). As the parent drug undergoes metabolism in the liver mainly by aldehyde oxidase (AO), potent AO inhibitors such as cimetidine, amlodipine, or amitriptyline are expected to cause relevant DDIs.
Chen C, Huang J, Cheng Z, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. Posted March 27, medRxiv 2020.03.17.20037432. Full-text: https://doi.org/10.1101/2020.03.17.20037432
Important open-label, randomized trial conducted in 3 hospitals in China, comparing arbidol and favipiravir in 236 patients with COVID-19 pneumonia. Primary outcome was the 7-day clinical recovery rate (recovery of fever, respiratory rate, oxygen saturation and cough relief). In “ordinary” COVID-19 patients (not critical), the recovery rates were 56% with arbidol (n = 111) and 71% (n = 98) with favipiravir (p = 0.02) that was well tolerated, except for some elevated serum uric acid levels. Striking! But can we trust? In the whole study population, no difference was evident. Many cases were not confirmed by PCR. There were also imbalances between subgroups of “ordinary” patients and even favipiravir was incorrectly spelt 7 times: 3x famiravir, 4x fabiravir (come on guys – did anybody read the manuscript?). This paper needs a careful (and major) review…
Liu S, Zheng Q, Wang Z. Potential covalent drugs targeting the main protease of the SARS-CoV-2 coronavirus. Bioinformatics April 1, 2020. btaa224, Full-text: https://doi.org/10.1093/bioinformatics/btaa224
Some new ideas on treatment. Using a computer-aided drug discovery protocol, possible covalent drugs targeting 3CLpro protease of SARS-CoV-2 were identified. For drug repurposing, the following ones (indication) might have priority: Telcagepant (migraine), Vidupiprant (asthma), Poziotinib (breast cancer), and Fostamatinib (rheumatoid arthritis).