Evaluation of Current Therapies for COVID-19 Treatment
Abstract
:1. Introduction
2. Chemotherapies
2.1. Hydroxychloroquine ± Azithromycin
2.1.1. Efficacy of Hydroxychloroquine in a Randomized Clinical Trial
2.1.2. Hydroxychloroquine and Azithromycin as a Treatment of COVID-19 in a Non-Randomized Clinical Trial
2.1.3. Clinical and Microbiological Effects of a Combination of Hydroxychloroquine and Azithromycin in 80 COVID-19 Patients with at Least a Six-Day Follow-Up: An Observational Study
2.1.4. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection
2.1.5. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin
3. Antiviral Therapies
3.1. Lopinavir/Ritonivir
3.1.1. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe COVID-19
3.1.2. An Exploratory Randomized, Controlled Study on the Efficacy and Safety of Lopinavir/Ritonavir or Arbidol Treating Adult Patients Hospitalized with Mild/Moderate COVID-19 (ELACOI)
3.1.3. Factors Associated with Prolonged Viral Shedding and Impact of Lopinavir/Ritonavir Treatment in Patients with SARS-CoV-2 Infection
3.2. Remdesivir
3.2.1. Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) in Vitro
3.2.2. Prophylactic and Therapeutic Remdesivir (GS-5734) Treatment in the Rhesus Macaque Model of MERS-CoV Infection
3.2.3. First Case of 2019 Novel Coronavirus in the United States
3.2.4. First 12 Patients with Coronavirus Disease 2019 (COVID-19) in the United States
3.2.5. Adaptive COVID-19 Treatment Trial (ACTT)
3.3. Oseltamivir and Amantadine
Inhibition of SARS Coronavirus Infection in Vitro with Clinically Approved Antiviral Drugs
4. Other therapies
4.1. Colchicine
COLCORONA Trial
4.2. Glucocorticoids
4.2.1. Early, Low-Dose and Short-Term Application of Corticosteroid Treatment in Patients with Severe COVID-19 Pneumonia: Single-Center Experience from Wuhan, China
4.2.2. Clinical Evidence Does Not Support Corticosteroid Treatment for 2019-nCoV Lung Injury
4.2.3. Effect of Dexamethasone in Hospitalized Patients with COVID-19-Preliminary Report (RECOVERY Trial)
5. Serotherapy
5.1. Convalescent Plasma (CP) Transfusion/Antibody Therapy
5.1.1. The Feasibility of Convalescent Plasma Therapy in Severe COVID19 Patients: A Pilot Study
5.1.2. A Highly Conserved Cryptic Epitope in the Receptor-Binding Domains of SARS-CoV-2 and SARS-CoV
5.1.3. Convalescent Plasma for COVID-19. A Randomized Clinical Trial
5.2. Tocilizumab
5.2.1. Tocilizumab for Patients with COVID-19 Pneumonia
5.2.2. Tocilizumab for Treatment of Mechanically Ventilated Patients with COVID-19
5.2.3. Comparative Survival Analysis of Immunomodulatory Therapy for COVID-19 “Cytokine Storm”: A Retrospective Observational Cohort Study
6. Anticoagulant and Recombinant Human Soluble ACE2 Therapies
6.1. Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2
6.2. Anticoagulant Treatment Is Associated with Decreased Mortality in Severe Coronavirus Disease 2019 Patients with Coagulopathy
7. Conclusions
Funding
Conflicts of Interest
References
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Therapeutic Agent | Methodology | Key Findings | Reference |
---|---|---|---|
Chemotherapy | |||
Hydroxychloroquine +/− Azithromycin | n = 64 Study: double blind randomized control trial Treatment: HCQ 400 mg/day × 5 days | Improved total time to recovery, resolution of fever, cough remission, and pneumonia severity | [5] |
n = 36 Study: preliminary trial Treatment: HCQ 200 mg TID for 10 days | Showed large reduction in viral carriage following treatment with HCQ and HCQ + Az | [6] | |
n = 80 Study: single hospital in-patients, non-randomized, no control, no blinding Treatment: HCQ 200 mg TID for 10 days Az 500 mg OD (Day 1), 250 mg OD (Days 2–5) | 93% patients negative viral RNA PCR by day 8. 97.5% negative viral cultures by Day 5. 81% of patients had mild disease; initiation to discharged mean 4.1 days | [7] | |
n = 11 Numerous comorbidities Treatment: HCQ 600 mg/day for 10 days, Az 500 mg OD (Day 1), 250 mg OD (Days 2–5) | 5–6 days post treatment, 8/10 nasal swabs positive. One patient death, two transferred to ICU. Discontinuation due to QTc prolongation in 1 patient | [8] | |
n = 84 Consecutive admissions, retrospective trial | 11% of patients developed a QTc >500 (high risk for arrhythmia). 30% demonstrated a QTc increase > 40 ms | [9] | |
Antivirals | |||
Lopinavir/Ritonavir (LPV/R) | n = 199 Study: open label randomized control trial LPV: 400 mg/day R: 100 mg/day × 14 days | No significant improvement in mortality or viral load. No benefit compared to standard care | [10] |
n = 120 Study: Retrospective trial of admitted patients in Wuhan LP: 400 mg/day R: 100 mg/day | Lack of treatment with LPV/R is associated with an increase in duration of viral shedding vs. control. Old age is associated with an increase. Benefits of LPV/R present when treated <10 days after symptom onset | [11] | |
+Abridol | n = 44 Study: exploratory randomized control trial LPV: 400 mg/day R: 100 mg/day Arbidol: 600 mg/day × 7–14 days | No significant difference in time to viral conversion from positive to negative. 24% of LPV/R group experienced adverse effects | [12] |
Remdesivir | Study: Investigation of in vitro activity of chloroquine and remdesivir | Remdesivir: 1.76 µmol/L for EC90 in nonhuman primates Chloroquine: 6.09 µmol/L for EC90 in non-human primates | [13] |
n = 18 Study: Rhesus macaques drug vehicle control, prophylactic vs. therapeutic. Inoculated with MERS-CoV | When given prophylactically, prevents infection. When given therapeutically, leads to clinical improvement. Decreased number and severity of lung lesions, reduced viral replication in the lungs | [14] | |
Single case study | Patient showed improvement within a day of remdesivir treatment. Oropharyngeal swab converted to negative, nasopharyngeal remained positive | [15] | |
n = 12 Study: 3/12 patients received remdesivir under compassionate use. Treatment: 200 mg IV first day, then 100 mg IV once daily | Mild GI symptoms, transient aminotransferase elevations. One episode of bloody stool | [16] | |
Clinical trial in progressPhase 3 | n = 1063 Study: multi-center randomized control trial | Improved time to recovery (11 vs. 15 days, p < 0.001), mortality (8% vs. 11.6, p = 0.059). Modest effect size | [17] |
Oseltamivir/Amantadine | In vitro investigation of the anti-SARS-CoV activity of numerous approved drugs | No inhibition of SARS-CoV-2 cytopathic effect with use of oseltamivir or amantadine in vitro | [18] |
Colchicine | |||
Clinical trial in progressPhase 3 | n = 6000 Study: Multi center, double blinded randomized control trial | N/A | [19] |
Glucocorticoids | |||
n = 46 Study: retrospective review, methylprednisolone 1–2 mg/kg/day 5–7 days | Improvement in time to resolution of fever, duration of supplemental oxygen use, and CT absorption degree of focus | [20] | |
Review of literature surrounding corticosteroid use during SARS and MERS | Corticosteroids use for SARS and MERS showed no benefit, but harming in some cases | [21] | |
Recovery Trial | n = 2104 (dexamethasone) Study: open-label randomized controlled trial | In patients with mechanical ventilation, dexamethasone reduced mortality by 1/3, and by 1/5 in those receiving oxygen alone. No survival benefit for those not requiring respiratory support | [22] |
Convalescent plasma | |||
n = 10 severely ill patients Treatment: 200 mL IV | In all 10 patients, fever, cough, shortness of breath, and chest pain disappeared or largely improved within 1–3 days of therapy initiation | [23] | |
In vitro study determining the activity of convalescent plasma from a recovered SARS-1 patient against SARS-CoV-2 | Demonstrates conserved epitope in SARS-1 and SARS CoV-2. Viral inhibition of SARS-CoV-2 with specific biochemical configuration | [24] | |
Study: Randomized control trial | Trial halted early due to 53/66 patients having anti SARS-CoV-2 antibodies at baseline. No difference in mortality, severity, or duration of hospital stay was observed over 15 days | [25] | |
Anticoagulants | |||
Heparin | In vitro study exploring pathophysiology of SARS-CoV-2 infection. Human blood vessel and kidney cell organoids | Demonstrates ability for SARS-CoV-2 to infect blood vessel and kidney organoids | [26] |
n = 449 Study: stratification based on risk level for coagulopathy. n = 94 enoxaparin 40–60 mg/day, n = 5 unfractionated heparin 10,000 U/day | Demonstrates benefit for those with sepsis induced coagulopathy scores ≥4 or D-dimer >6 × ULN | [27] | |
Recombinant Human Soluble Angiotensin Converting Enzyme 2 (rhsACE2) | |||
In vitro study exploring pathophysiology of SARS-CoV-2 infection. Human blood vessel and kidney cell organoids | Rates of infection of blood vessel and kidney organoids were reduced compared to controls in the presence of recombinant human serum ACE2 | [26] | |
Biological Treatment-Tocilizumab | |||
TOCIVID-19 | n = 301 Study: a multicenter, single arm trial Hypothesis driven – null = 20 and 35% lethality rate at 14 and 30 days | Tocilizumab reduced lethality rate at the 30-day interval (22.4%), rejected null hypothesis (35%). p ≤ 0.001. Null hypothesis not rejected for 14-day interval. Suggest use of tocilizumab awaiting phase 3 trials | [28] |
n= 154 Study: single center observational cohort study | 45% reduction in hazard of death in those who received tocilizumab vs. untreated. Increased risk of superinfection with tocilizumab (54% vs. 26%), but no difference in case fatality due to superinfection | [29] | |
n= 3098 Study: retrospective analysis of health records. COVID-19 hospitalizations with cytokine storm over a month and a half period | The use of corticosteroids alone, or in conjunction with tocilizumab improved hospital survival compared to standard care (no immunomodulatory medication) alone | [30] |
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Sethi, A.; Bach, H. Evaluation of Current Therapies for COVID-19 Treatment. Microorganisms 2020, 8, 1097. https://doi.org/10.3390/microorganisms8081097
Sethi A, Bach H. Evaluation of Current Therapies for COVID-19 Treatment. Microorganisms. 2020; 8(8):1097. https://doi.org/10.3390/microorganisms8081097
Chicago/Turabian StyleSethi, Atin, and Horacio Bach. 2020. "Evaluation of Current Therapies for COVID-19 Treatment" Microorganisms 8, no. 8: 1097. https://doi.org/10.3390/microorganisms8081097