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Department of Surgery, Division of Trauma and Acute Care Surgery, Kendall Regional Medical Center, Miami, FL, USADepartment of Surgery, University of South Florida, Tampa, FL, USA
There is a pressing need for COVID-19 transmission control and effective treatments. We aim to evaluate the safety and effectiveness of SARS-CoV-2 pharmacologic therapies as of August 2, 2020 according to study level of evidence.
Methods
PubMed, ScienceDirect, Cochrane Library, JAMA Network and PNAS were searched. The following keywords were used: ((COVID-19) OR (SARS-CoV-2)) AND ((((((therapeutics) OR (treatment)) OR (vaccine)) OR (hydroxychloroquine)) OR (antiviral)) OR (prognosis)). Results included peer-reviewed studies published in English.
Results
15 peer-reviewed articles met study inclusion criteria, of which 14 were RCTs and one was a systematic review with meta-analysis. The following pharmacologic therapies were evaluated: chloroquine (CQ), hydroxychloroquine (HCQ), antivirals therapies, plasma therapy, anti-inflammatories, and a vaccine.
Conclusion
According to level 1 evidence reviewed here, the most effective SARS-Co-V-2 pharmacologic treatments include remdesivir for mild to severe disease, and a triple regimen therapy consisting of lopinavir-ritonavir, ribavirin and interferon beta-1b for mild to moderate disease. Also, dexamethasone significantly reduced mortality in those requiring respiratory support. However, there is still a great need for detailed level 1 evidence on pharmacologic therapies.
]. The source of human infection was suggested to be zoonotic in origin, with human-to-human transmission occurring through respiratory droplets, fomites, and fecal-oral spread [
]. The burden on the United States (US) healthcare system has increased dramatically, especially on hospitals and intensive care units (ICUs). A systematic review and meta-analysis reported that 20.3% of COVID-19 positive patients were admitted to the ICU [
]. After it has entered the host's system, it primarily replicates in the mucosal epithelium of the upper respiratory tract and, in some instances, the gastrointestinal mucosa. Data strongly suggests that the virus gains entry into host cells through the same mechanism as SARS-CoV, through angiotensin-converting enzyme 2 (ACE2) [
]. It has been postulated that the development of ACE2 downregulation and the over-activation of T-cells are one of the first factors in the cascade that leads to ARDS. Specifically, downregulation of ACE2 leads to pulmonary edema mediated by a dysfunction in RAS. Meanwhile, over-activation of T-cells leads to an immune dysfunction, which can result in cytokine storm. Both cytokine storm and pulmonary edema are contributors to the development of ARDS [
The first-line methods for diagnosing and detecting SARS-CoV-2 are molecular-based. Currently, the most common and reliable option for diagnosis is reverse-transcription polymerase chain reaction (RT-PCR) [
]. Additionally, although rapid antigen tests exist, the World Health Organization (WHO) recommends against these tests as a result of their low accuracy [
]. A presumptive diagnosis of COVID-19 may be made with adequate clinical and epidemiological evidence. For example, the most common clinical presentations have been fever followed by development of dyspnea shortly thereafter. Among hospitalized patients, lymphopenia, elevated aminotransferase levels, and elevated inflammatory markers have been reported [
]. With the increased strain on the healthcare system and the need for immediate disease and transmission control, pharmacologic development is necessary. In consideration of the evolving data, this review aims to evaluate and compare the effectiveness of different SARS-CoV-2 pharmacologic treatments as of August 2, 2020 and assess their safety and clinical outcomes according to study level of evidence.
2. Methods
2.1 Data search and collection strategy
PubMed, ScienceDirect, the Cochrane Library, JAMA Network and Proceedings of the National Academy of Sciences (PNAS) were reviewed. A literature search was conducted using the following query: ((COVID-19) OR (SARS-CoV-2)) AND ((((((therapeutics) OR (treatment)) OR (vaccine)) OR (hydroxychloroquine)) OR (antiviral)) OR (prognosis)). Titles and abstracts were screened for eligibility and duplicate results. Next, full-text screening was conducted independently by three authors (AB, CS, and AE). Results were categorized in descending order based on the level of evidence, with level 1 evidence being randomized control clinical trials and meta-analyses of systematic reviews [
]. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were used. Literature review was conducted for articles that met study inclusion criteria between October 1st, 2019 through August 2nd, 2020. (Fig. 1 and Table 1).
Fig. 1PRISMA flow diagram of studies included in the clinical review.
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.
Hospitalized patients with clinical suspicion of COVID-19, aged 18 years or older, with respiratory rate higher than 24 rpm and/or heart rate higher than 125 bpm (in the absence of fever) and/or peripheral oxygen saturation lower than 90% in ambient air and/or shock.
RCT
Chloroquine diphosphate (Antimalarial)
Reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group.
Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).
Small sample size.
Single-center design.
Lack of a placebo control group.
Absence of exclusion criteria based on the QTc interval at baseline.
Patients 18 years and older with mild or moderate ongoing SARS CoV-2 infection.
RCT
Hydroxychloroquine (Antimalarial)
Negative conversion of SARS CoV-2 by 28 days.
The probability of negative conversion in the standard of care plus hydroxychloroquine group was 85.4% (95% CI 73.8–93.8) versus 81.3% in the standard of care group (95% CI 71.2–89.6), however this difference were not significant.
Two studies reported possible benefit in “time to body temperature normalization” and one study reported less “cough days” in the HCQ arm. Treatment with HCQ resulted in a smaller number of cases showing radiological progression of lung disease (OR 0.31, 95% CI 0.11–0.9). No difference was observed in virologic cure (OR 2.37, 95% CI 0.13–44.53), death or clinical worsening of disease (OR 1.37, 95% CI 1.37–21.97) and safety (OR 2.19, 95% CI 0.59–8.18), when compared to the control/ conventional treatment.
Limited number of clinical studies with limited number of participants.
Virologic cure on day 6 to 7 post-initiation of therapy.
Death or clinical worsening of disease condition during treatment.
Lack of control/conventional/standard group.
Radiological progression during drug treatment.
Recurrence of infection during treatment.
Did not specify whether the studies included assessed patients with mild, moderate or severe COVID-19.
Hospitalized patients with suspected or confirmed mild/moderate COVID-19 with 14 or fewer days since symptom onset, who were receiving either no supplemental oxygen or a maximum of 4 L/min of supplemental oxygen.
Clinical status at 15 days evaluated using a 7-level ordinal scale.
There was no significant difference in seven-point ordinal scale at 15 days between those treated with hydroxychloroquine and standard care (OR 1.21, 95% CI 0.69–2.11, p = 1.00), or between those treated with hydroxychloroquine + azithromycin and standard care (OR 0.99, 95% CI 0.57–1.73, p = 1.00).
Not blinded.
There were no significant differences in six-level ordinal outcome at day 7, the number of days free from respiratory support, use of high-flow nasal cannula or non-invasive ventilation, use of mechanical ventilation, duration of hospital stay, in-hospital death, thromboembolic complications, or acute kidney injury between the groups.
Some patients concomitantly treated with other pharmacologic agents.
Prolongation of QT interval and elevation of liver enzymes was more frequent in the experimental groups.
Some patients were previously treated with hydroxychloroquine ± azithromycin at other hospitals prior to enrollment in this trial.
Adults with household or occupational exposure to someone with confirmed COVID-19 at a distance of less than 6 ft. for more than 10 min without a face mask and/or eye shield.
RCT
Hydroxychloroquine (Antimalarial)
Laboratory confirmed COVID-19 or illness compatible with COVID-19 within 14 days.
The incidence of new illness compatible with COVID-19 did not significantly differ between participants receiving HCQ (11.8%) and placebo (14.3%) (p = .35). There was no meaningful difference in the effectiveness according to the time of starting post-exposure prophylaxis.
Use of an a priori symptomatic case definition in some patients as opposed to diagnostic testing.
Adults hospitalized with COVID-19 with evidence of lower respiratory tract involvement.
RCT
Remdesivir (Antiviral)
Time to recovery defined by either discharge from the hospital or hospitalization for infection-control purposes only.
The remdesivir group had a median recovery time of 11 days (95% CI 9–12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; p < .001)
Preliminary data.
The remdesivir group had higher odds of improvement in the 8-level ordinal scale score at day 15 compared to placebo (OR 1.50, 95% CI 1.18–1.91.
Mortality was numerically lower in the remdesivir group, but this difference was not statistically significant.
Adults (aged ≥18 years) admitted to hospital with laboratory-confirmed severe SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mmHg or less, and radiologically confirmed pneumonia.
RCT
Remdesivir (Antiviral)
Time to clinical improvement up to day 28, defined as the time (in days) from randomization 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.
Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1.23 [95% CI 0.87–1.75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1.52 [95% CI 0.95–2.43]).
Insufficient power.
Initiation of treatment late in COVID-19.
Mortality at day 28 was not significantly different between the groups.
Absence of data on infectious virus recovery or on possible emergence of reduced susceptibility to remdesivir.
Some patients concomitantly treated with other pharmacologic agents.
Hospitalized patients with confirmed SARS-CoV-2 infection, O2 saturation ≤ 94% on ambient air, and radiologic evidence of pneumonia.
RCT
Remdesivir (Antiviral)
Clinical status on day 14 measured on a 7-point ordinal scale.
Clinical improvement of 2 points or more occurred in 65% of patients in the 5-day group and 54% of patients in the 10-day group. After correction of imbalance of baseline clinical status, clinical status at day 14 was similar between the 5-day and 10-day groups (p = .14).
The patients in the 10-day group had a significantly worse clinical status than those in the 5-day group (p = .02).
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.
Age at least 18 years, a national early warning score 2 (NEWS2) of at least 1, and symptom duration of 14 days or less upon recruitment.
RCT
IFN beta-1b (Anti-inflammatory), lopinavir-ritonavir and ribavirin (Antivirals)
Time to providing a nasopharyngeal swab negative for severe acute respiratory syndrome coronavirus 2 RT-PCR.
The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 days [IQR 5–11]) than the control group (12 days [
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.
Male and non-pregnant female patients 18 years of age or older with diagnostic specimen that was positive on RT-PCR, had pneumonia confirmed by chest imaging, and had an oxygen saturation of 94% or less while they were breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen at or below 300 mg Hg.
RCT
Lopinavir-ritonavir (Antiviral)
Time to clinical improvement, defined as the time from randomization to either an improvement of two points on a seven-category ordinal scale or discharge from the hospital, whichever came first.
Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (hazard ratio for clinical improvement 1.24 (95% CI 0.90–1.72)). Mortality at 28 days was similar in the lopinavir–ritonavir group and the standard-care group (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI −17.3-5.7).
Non-blinded.
Higher throat viral loads in the lopinavir–ritonavir group on baseline.
Absence of data on lopinavir exposure levels in severe and critically ill patients.
Patients with severe COVID-19, between 18 and 75 years of age.
RCT
Ruxolitinib (JAK inhibitor)
Time to clinical improvement (time from randomization to an improvement of 2 points on a 7-category ordinal scale or live discharge from the hospital).
Ruxolitinib plus standard-of-care was associated with a non-statistically significant decrease in median time clinical improvement (12 [IQR, 10–19] days vs. 15 [IQR, 10–18] days).
Small sample size.
90% of ruxolitinib patients had significant CT improvement at day 14 compared to 61.9% of control patients (p = .0495).
Use of an ordinal scale to assess primary end points.
Levels of 7 cytokines (including IL-6, IL-12 and VEGF) were significantly decreased in the experimental group.
Some patients concomitantly treated with other pharmacologic agents.
The 28-day overall mortality was 0% in the experimental group and 14.3% in the control group.
Critically ill patients and patients with invasive ventilator dependence were not included.
Hospitalized patients with clinically suspected or laboratory confirmed SARS-CoV-2 infection, including those under 18 and pregnant or breastfeeding women.
RCT
Dexamethasone (Corticosteroid)
28-day mortality
Mortality at day 28 was significantly lower in the experimental group. 22.9% of patients treated with dexamethasone died within 28 days, compared to 25.7% of patients treated with standard care (age-adjusted rate ratio 0.83, 95% CI 0.75–0.93).
Preliminary data.
Compared to the standard of care group, the incidence of death lower in dexamethasone patients receiving mechanical ventilation (rate ratio 0.64, 95% CI 0.51–0.81) and in those receiving oxygen without mechanical ventilation (rate ratio 0.82, 95% CI 0.72–0.94), but not in those receiving no respiratory support (rate ratio 1.19, 95% CI 0.91–1.55).
Open label design.
Patients treated with dexamethasone also had a shorter duration of hospitalization (median 12 days vs. 13 days).
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Healthy, HIV-negative adults ≥18 years old who were not previously infected with SARS-CoV-2.
RCT
Ad5-vectored COVID-19 vaccine (vaccine)
Immunogenicity as measured by the geometric mean titers (GMT) of RBD-specific ELISA antibody responses and neutralizing antibody responses against live virus or pseudovirus at day 28 post-vaccination.
Participants who received either a low or high viral particles dose had a significant increase in RBD-specific ELISA antibodies, seroconversion rates and neutralizing antibody responses compared to the placebo group.
52% of participants had high pre-existing immunity, and 48% of the participants had low pre-existing immunity.
Placebo group showed no antibody increase from baseline.
No IFNγ-ELISpot responses in placebo group.
Immunogenicity as measured by RBD-specific ELISA antibody responses at day 14, and specific T-cell responses at day 28 post-vaccination.
High dose (1 × 1011 viral particles)
Low dose (5 × 1010 viral particles)
Did not calculate sample size based on study power in advance.
Seroconversion of the humoral response.
• RBD-specific ELISA antibodies peaked at 656.5 (95% CI 575.2–749.2).
• RBD-specific ELISA antibodies peaked at 571.0 (95% CI 476.6–697.3).
Only reported data within 28 days of vaccination.
• GMTs were 19.5 (95% CI 16.8–22.7).
• GMTs were 18.3 (95% CI 14.4–23.3).
• Seroconversion rates were 96% (95% CI 93–98).
• Seroconversion rates were 97% (95% CI 92–99).
• Specific interferon γ enzyme-linked immunospot assay responses observed in 90% (95% CI 85–93).
• Specific interferon γ enzyme-linked immunospot assay responses observed in 88% (95% CI 81–92).
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Patients with severe (respiratory distress and/or hypoxemia) or life threatening (shock, organ failure, mechanical ventilation) COVD-19.
RCT
Convalescent plasma (Immunotherapy)
Time to clinical improvement within 28 days, as defined by a reduction of 2 points on a 6-point disease severity scale, or discharge.
Clinical improvement within 28 days occurred in 51.9% of patients in the convalescent plasma group compared to 43.1% in the control group (8.8% difference, 95% CI −10.4–28.0%, p = .26). Clinical improvement occurred at a higher rate in those with severe disease compared to those with life threatening disease (91.3% vs 68.2%).
Small sample size.
There was no significant difference in 28-day mortality (OR 0.65, 95% CI 0.29–1.46) or time to discharge (HR 1.61, 95% CI 0.88–2.93).
Study terminated early. Open-label design.
Use of convalescent plasma resulted in an 87.2% negative conversion rate of viral PCR at 72 h compared to 37.5% in the control group.
Only articles published in English were included. In addition, we only included the higher level of evidence studies (level 1) in our final analysis.
2.3 Exclusion criteria
Abstracts were screened for eligibility. Those that did not meet our search inclusion criteria or were duplicates were excluded. Articles on coronavirus strains other than SARS-CoV-2, articles without established outcomes from specific therapies, and articles on theoretical pharmacologic applications were excluded.
3. Results
Initial inclusion criteria yielded 15,077 PubMed, 12,682 ScienceDirect, 745 Cochrane, 64 JAMA, and 16 PNAS results. After applying exclusion criteria, 15 studies remained for analysis, 14 of which were randomized clinical trials (RCTs) and one being a systematic review with meta-analysis. Pharmacologic therapies including chloroquine/hydroxychloroquine, antivirals, anti-inflammatory agents, immunomodulatory agents, vaccines, anticoagulants, plasma therapy and traditional Chinese medicine were found upon initial search, although level 1 evidence was only available for chloroquine/hydroxychloroquine, various antivirals, plasma therapy, anti-inflammatories, and a vaccine.
4. Level 1 evidence
4.1 Randomized controlled trials
4.1.1 Hydroxychloroquine/chloroquine
A parallel, double-masked, phase IIb RCT was conducted comparing high and low doses of chloroquine diphosphate (CQ) in patients with severe COVID-19 [
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.
]. Patients were either administered 600 mg CQ bid for 10 days, or 450 mg CQ bid for 1 day followed by 450 mg CQ once daily for 4 days. Patients were concurrently given 500 mg azithromycin daily for 5 days [
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.
]. 86.8% and 92.5% of low dose and high dose patients received 75 mg oseltamivir twice daily for 5 days on the basis of suspected influenza infection [
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.
]. The primary outcome was dose-related CQ lethality, and it was hypothesized that the lethality rate of the high dose group would decrease by at least 50% compared to the low dose group. However, results showed the opposite, with 39% lethality in the high dose group and 15% in the low dose group [
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.
]. Results also showed that the high-dose group had a higher incidence of QT prolongation greater than 500 ms. Following an unplanned interim analysis of study findings due to CQ dosages related safety concerns, the study independent data safety and monitoring board (DSMB) recommended the immediate interruption of the trial for patients on high dose CQ from all age groups, unmasking, and converting all to low dose CQ [
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.
]. They concluded that patients with severe COVID-19 should not be given a high dose of CQ especially with azithromycin and oseltamivir due to risk of QT prolongation and associated lethality. However, findings from patients with prolonged QT showed no clear association between the first day of prolonged QT and day of death, and that cumulative dosages were not higher among prolonged QT associated fatalities [
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.
]. In addition, it is important to be aware that this study had a small sample size, lacked of a placebo control group and used a historical control group. Instead, findings were only adjusted by age, and pre-protocol analysis was not conducted due to inability to register daily untaken or mistaken CQ doses because or renal or liver failures [
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.
An open label RCT conducted on patients 18 years and older with mild or moderate ongoing SARS CoV-2 investigated the effects of hydroxychloroquine (HCQ) on negative conversion by 28 days [
]. Patients were administered 1200 mg of HCQ daily for three days followed by a maintenance dose of 800 mg daily (11 days if mild, 18 days if moderate) [
]. Results showed that those treated with standard care plus HCQ had an 85.4% probability of negative conversion by day 28 (95% CI 73.8–93.8), whereas those treated with standard care alone had an 81.3% chance (95% CI 71.2–89.6) [
]. However, this difference was reportedly not significant. Due to the trial ending early and only two patients (out of 150) with severe disease being enrolled, results on clinical improvement were not presented [
A more recent, multicenter, open-labeled controlled trial was conducted to assess the efficacy of HCQ with and without azithromycin compared to the standard of care [
]. The study was performed on patients with suspected or confirmed mild to moderate COVID-19 with 14 or fewer days since symptom onset. Patients in the HCQ group received a dose of 400 mg twice daily for seven days. Patients in the HCQ plus azithromycin additionally received a dose of 500 mg of azithromycin once daily for seven days. Clinical status at 15 days was evaluated using a 7-level ordinal scale. Results showed no significant difference in the 7-level ordinal scale at 15 days between those treated with HCQ and standard care (OR 1.21, 95% CI 0.69–2.11, p = 1.00), or between those treated with HCQ + azithromycin and standard care (OR 0.99, 95% CI 0.57–1.73, p = 1.00) [
]. There were also no significant differences in the number of days free from respiratory support, use of high-flow nasal cannula or non-invasive ventilation, use of mechanical ventilation, duration of hospital stay, in-hospital death, thromboembolic complications, or acute kidney injury between the groups [
]. They also found that prolongation of QT interval was more frequent in the experimental groups (especially the HCQ plus azithromycin group), and elevation of liver enzymes was more frequent in the HCQ plus azithromycin group than the control group [
]. Limitations of this study include lack of blinding, concomitant treatment of patients with other pharmacologic agents, and the fact that some patients were previously treated with HCQ ± azithromycin at other hospitals prior to enrollment in this trial [
]. Participants were adults with household or occupational exposure to someone with laboratory confirmed COVID-19 at a distance of less than 6 ft. for more than 10 min without a face mask and/or eye shield. Time from exposure to enrollment varied between 1 and 4 days in all participants. Patients in the HCQ group were administered 800 mg HCQ once, followed by 600 mg in 6 to 8 h, then 600 mg daily for 4 additional days for a total course of 5 days. Results showed that the incidence of new illness compatible with COVID-19 did not significantly differ between participants receiving HCQ (11.8%) and placebo (14.3%) (p = .35) [
]. Side effects were significantly more frequent in the HCQ group by day 5 (p < .001), with nausea, loose stools and abdominal discomfort being the most commonly reported side effects [
]. No serious adverse reactions or cardiac arrhythmias were reported. This study is limited by its use of an a priori symptomatic case definition in some patients as opposed to diagnostic testing [
Preliminary results of a double-blind randomized controlled trial by Beigel et al. suggest that a 10-day course of remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) is superior to placebo. This study, which was conducted in 60 sites throughout the world, analyzed 1059 patients and aimed to assess the effect of remdesivir on time to recovery, clinical improvement, and mortality in patients with varying baseline severity [
]. Those who received remdesivir had a statistically significant different median recovery time than placebo, 11 days vs 15 days (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; p < .001) [
]. The authors additionally stratified these results by disease severity, where the beneficial effects of remdesivir appeared to be more pronounced in the severe disease stratum. Also, the remdesivir group had higher odds of improvement in the 8-level ordinal scale score at day 15 compared to placebo (OR 1.50, 95% CI 1.18–1.91) [
]. Patients on remdesivir who were receiving high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation did not achieve significant differences compared to placebo [
Another double blind, placebo-controlled, multicenter RCT was conducted on the effectiveness of remdesivir in confirmed SARS-CoV-2 positive patients with severe COVID-19 [
]. Patients were either assigned to receive intravenous remdesivir or placebo infusions. Remdesivir was administered at 200 mg on day 1 followed by 100 mg on days 2–10. Their primary outcome was time to clinical improvement within 28 days after randomization. Some patients were concomitantly treated with corticosteroids, lopinavir-ritonavir or interferons. Intention to treat analysis revealed a non-significant decrease in the time to clinical improvement for the remdesivir group compared to placebo. Survival at 28 days and clinical improvement at 14 and 28 days were also not statistically significantly different, although numerically higher in the remdesivir group. Serious adverse events occurred in 18% and 26% of the remdesivir and placebo groups respectively [
]. Intravenous remdesivir did not provide significant improvements in patients with severe COVID-19. This study was limited by insufficient power, the late initiation of therapy and absence of data on viral recovery [
]. Clinical status on day 14 as measured by a 7-point ordinal scale was the primary endpoint. Patients were administered 200 mg of remdesivir on day 1, followed by 100 mg once daily for the next 4 or 9 days. Results showed that clinical improvement of 2 points or more occurred in 65% of patients in the 5-day group and 54% of patients in the 10-day group [
]. After correction of imbalance of baseline clinical status, clinical status at day 14 was similar between the 5-day and 10-day groups (p = .14). It was concluded that there was no significant difference in efficacy between a 5-day or 10-day course. This study is limited by the fact that the patients in the 10-day group had a significantly worse clinical status than those in the 5-day group (p = .02), however the authors state that results were adjusted for this discrepancy [
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.
]. This open-label, randomized trial tested a triple medication regimen including interferon beta-1b, lopinavir-ritonavir, and ribavirin. Patients enrolled had mild to moderate COVID-19. The dosage for the experimental group was lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million IU of interferon beta-1b on alternate days. The control group received 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h. Patients who were admitted to the clinical trial after the 7th day of experiencing symptoms were not treated with interferon beta-1b due to its proinflammatory properties. Their primary outcome measure was time to a negative RT-PCR assay by nasopharyngeal swab. The combination group had a significantly shorter median time to a negative RT-PCR than the control group. A negative SARS-CoV-2 was achieved in a median time of 7 days in the experimental group vs 12 in the control. Additionally, clinical improvement was significantly better in the experimental group than the control with a median time to alleviation of symptoms of 4 vs 8 days [
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.
]. This study had an open-label design, absence of placebo group, and was also confounded by subgroup omitting of interferon beta-1b within the combination group, depending on time from symptom onset [
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.
Another randomized controlled open-label trial in 199 hospitalized patients with confirmed SARS-CoV-2 with severe COVID-19 was done to compare the clinical effectiveness of lopinavir-ritonavir to standard care alone [
]. Severe COVID-19 was defined as SARS-CoV-2 positivity, pneumonia confirmed by chest imaging, and an oxygen saturation of 94% or less while breathing ambient air or a ratio of the partial pressure of oxygen to the fraction of inspired oxygen at or below 300 mg Hg. Patients in the experimental group were treated with 400 mg/100 mg of lopinavir-ritonavir for 14 days. The time to clinical improvement, mortality at day 28, and detectable viral load were not significantly different between groups [
]. Limitations of this study include a non-blinded protocol, higher baseline throat viral loads in the lopinavir–ritonavir group, and absence of data on lopinavir exposure levels in severe and critically ill patients [
A more recent RCT done on patients with mild to moderate COVID-19 aimed to compare the difference in rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid between lopinavir/ritonavir and arbidol (umifenovir) [
]. Patients were administered either 400 mg/100 mg lopinavir/ritonavir PO twice daily for 7–14 days, or 200 mg of umifenovir PO three times daily for 7–14 days. Results showed no significant difference in the rate of positive-to-negative conversion between the lopinavir/ritonavir, arbidol, and control groups (p > .05) [
]. There was also no significant differences between the groups for the rates of antipyresis, cough alleviation, or improvement of CT findings at day 7 or 14 (p > .05) [
A multicenter, single-blind RCT was conducted to assess the time to clinical improvement in patients with severe COVID-19 treated with ruxolitinib, a JAK inhibitor [
]. Time to clinical improvement was measured as time from randomization to an improvement of 2 points on a 7-category ordinal scale, or live discharge from the hospital. Patients in the experimental group received 5 mg twice daily of ruxolitinib. Results showed that ruxolitinib plus standard-of-care was associated with a non-statistically significant decrease in median time clinical improvement (12 [IQR, 10–19] days vs. 15 [IQR, 10–18] days) [
]. However, 90% of ruxolitinib patients had significant CT improvement at day 14 compared to 61.9% of control patients (p = .0495), and levels of 7 cytokines (including IL-6, IL-12 and VEGF) were significantly decreased in the experimental group, demonstrating the anti-inflammatory effects of ruxolitinib [
]. This study is limited by its small sample size, use of an ordinal scale to assess primary end points, concomitantly treatment of some patients with other pharmacologic agents, and lack of inclusion of critically ill patients and patients with invasive ventilator dependence [
A preliminary, open-label RCT was conducted to assess the effect of dexamethasone on 28-day mortality in hospitalized patients with clinically suspected or laboratory confirmed SARS-CoV-2 infection [
]. The study included patients under 18 years old and pregnant or breastfeeding women. Patients in the dexamethasone group were administered 6 mg of oral or intravenous dexamethasone once daily for up to 10 days or hospital discharge if sooner. Results showed that mortality at day 28 was significantly lower in the experimental group; 22.9% of patients treated with dexamethasone died within 28 days, compared to 25.7% of patients treated with standard care (age-adjusted rate ratio 0.83, 95% CI 0.75–0.93) [
]. Compared to the standard of care group, the incidence of death lower in dexamethasone patients receiving mechanical ventilation (rate ratio 0.64, 95% CI 0.51–0.81) and in those receiving oxygen without mechanical ventilation (rate ratio 0.82, 95% CI 0.72–0.94), but not in those receiving no respiratory support (rate ratio 1.19, 95% CI 0.91–1.55) [
]. Patients with a longer duration of symptoms benefitted more (in terms of reducing mortality) from dexamethasone treatment. Patients treated with dexamethasone also had a shorter duration of hospitalization (median 12 days vs. 13 days). Limitations include an open-label design and provision of preliminary data [
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
]. There were two experimental groups, one of which received a higher dose of viral particles (1 × 1011 particles) and another that received a lower dose of viral particles (5 × 1010 particles). Participants who received either a low or high dose of viral particles had a significant increase in RBD-specific ELISA antibodies, seroconversion rates, and neutralizing antibody responses compared to the placebo group [
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
]. Severe adverse reactions occurred in 9% of the high dose patients and 1% of the low dose patients, although no serious adverse reactions were documented [
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Another RCT sought to evaluate the effects of convalescent plasma therapy on the time to clinical improvement within 28 days in patients with severe or life threatening COVID-19 [
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
]. Patients were administered a dose of approximately 4 to 13 mL/kg of recipient body weight. Clinical improvement was defined by either a reduction of 2 points on a 6-point disease severity scale, or discharge. Clinical improvement within 28 days occurred in 51.9% of patients in the convalescent plasma group compared to 43.1% in the control group (8.8% difference, 95% CI -10.4-28.0%, p = .26), and clinical improvement occurred at a higher rate in those with severe disease compared to those with life threatening disease (91.3% vs 68.2%) [
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
]. In patients treated with HCQ, two of the studies reviewed showed a reduction in the time to body temperature normalization, and one study showed a reduction in the duration of cough [
]. Meta-analysis revealed that treatment with HCQ resulted in fewer cases of radiological progression of lung damage and no difference in virologic cure (on day 6–7) or death in patients compared to control groups undergoing conventional treatment [
According to the level 1 evidence reviewed here, the most effective treatments against SARS-CoV-2, measured by time to negative RT-PCR and time to clinical improvement, are remdesivir therapy and a triple medication regimen (lopinavir-ritonavir, ribavirin, and interferon beta-1b) [
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.
]. Remdesivir showed beneficial effects in patients with varying baseline severity. It resulted in a decrease in mean recovery time, higher odds of improvement on an 8-level ordinal scale at day 15, and a non-statistically significant decrease in mortality in patients with mild to severe COVID-19 [
]. It also resulted in a non-statistically significant reduction in time to clinical improvement in patients with severe COVID-19 with no effect on mortality [
]. However, there was no difference in clinical improvement between a 5-day and 10-day course of remdesivir in patients with varying baseline clinical status [
]. In patients with mild to moderate COVID-19, the triple medication regimen appeared to be most beneficial, as it resulted in a significantly shorter median time to negative RT-PCR compared to therapy with just lopinavir-ritonavir [
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.
Evidence gathered from other RCTs show several additional findings. First, in patients with severe COVID-19, treatment with lopinavir-ritonavir showed no significant difference in time to clinical improvement, mortality at day 28, or detectable viral load compared to standard care alone [
]. Also, treatment with lopinavir/ritonavir did not significantly affect the rate of positive-to-negative conversion when compared to arbidol in patients with mild to moderate COVID-19 [
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.
]. Additionally, HCQ showed no significant effect on the probability of negative conversion by day 28 or virologic cure compared to standard care alone in patients with mild to moderate COVID-19 [
]. It also did not reduce the prevalence of unfavorable secondary outcomes such as need for respiratory support, mechanical ventilation, or thromboembolic complications in patients with mild to moderate COVID-19 [
]. Furthermore, treatment of severe COVID-19 patients with ruxolitinib resulted in a non-statistically significant decrease in median time to clinical improvement, and a statistically significant decrease in levels of seven cytokines including IL-6, IL-12 and VEGF, indicating that it may be useful in treating cytokine storm [
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
]. Oral or intravenous dexamethasone was shown to significantly reduce mortality among hospitalized COVID-19 patients receiving mechanical ventilation or oxygen without mechanical ventilation [
]. Finally, vaccination of healthy individuals using an Ad5-vectored COVID-19 vaccine showed significant increase in immunity to SARS-CoV-2 by 28 days [
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
While we await higher quality evidence from randomized control trials and meta-analyses, these results provide some context on the efficacy of pharmacologic therapy in COVID-19 patients. As of May 20, 2020, the FDA has granted emergency use authorization for intravenous remdesivir for severe COVID-19 [
COVID-19 has undoubtedly posed a detrimental health burden worldwide. There is still a great need for detailed evidence on individual pharmacologic therapies. The findings from our review suggest that there is currently inconclusive evidence for one therapy. It is difficult to conduct studies on one category of pharmacologic treatment due to the lack of a universal systematic approach to treating COVID-19. In the absence of a vaccine available to the public, there is a great need for level 1 evidence from randomized controlled trials and meta-analyses to support the development of evidence-based guidelines to treat COVID-19 patients.
Aside from being novel, part of what makes treatment of SARS-CoV-2 difficult is its ability to affect multiple organ systems [
]. The disease is characterized as an acute respiratory failure but may have systemic outcomes such as gastrointestinal, cardiovascular, and nervous system symptoms in addition to multi-organ failure. There has been evidence of high incidence of pulmonary embolism and thrombotic events. These severe cases often present with thrombocytopenia, elevated D-dimer levels, and PT prolongation. The hypercoagulable state often seen in COVID-19 patients can be explained by the overwhelming production of inflammatory cytokines. This increase in inflammatory markers leads to an activation of the coagulation cascade and inhibits the fibrinolytic pathway [
]. Aside from thrombotic disease, a proportion of patients with COVID-19 also present with acute kidney injury. Certain renal cells express ACE2 and TMPRSS2 receptors that the virus uses for its pathogenesis. Studies have shown that upon autopsy, kidney cells had evidence of virus particles on kidney podocytes and proximal tubule cells [
]. Treating multisystemic manifestations becomes especially difficult in patients with existing comorbidities that require pharmacologic therapy. For example, patients with arrhythmia are particularly complicated due to their increased risk for QT prolongation, making it more risky to use treatments such as HCQ, CQ and azithromycin [
Assessment of QT intervals in a case series of patients with Coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit.
]. Interestingly, an observational study done on 20,133 hospitalized COVID-19 patients reported that the median age of patients was 73 (IQR 58–82), and increasing age was associated with mortality with a hazard ratio of 11.09 in patients over 80 compared to a hazard ratio of 8.51 in patients aged 70–79, 4.99 in patients aged 60–69 and 2.63 in patients aged 50–59 [
Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study.
Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study.
Another important point to be discussed is the increase of non-evidence-based treatment and the unintended morbidity and mortality that results from it. There has been a large increase in the spread of false information and non-evidence-based remedies, such as consumption of cow urine and high proof alcohol that have resulted in illness and even death [
Furthermore, there has been a recent concern for patients who are using ACE-inhibitors. A case-population study in Spain on the admission rate of COVID-19 patients on ACE-inhibitors compared to other antihypertensive medications revealed that there was no increased risk of COVID-19 related admission to a hospital, and concluded that ACE-inhibitors not be discontinued [
]. However, there remains a concern, especially among uninformed providers and patients, on whether use of ACE-inhibitors pose a risk to patients during this pandemic.
A similar review done by Sanders et al. on pharmacologic treatment for COVID-19 report similar findings regarding the available pharmacologic options and the inconclusive nature of the available data on these drugs [
]. They additionally offer useful resources for clinical treatment guidance. In contrast, we have tailored our review to provide a more up to date, in-depth and systematic analysis using only level 1 evidence. Additionally, our discussion touches on the multisystem effects of SARS-CoV-2.
Undoubtedly, it is of utmost importance to discuss the safety profile of all the medications included. Many of these pharmacologic agents result in side effects ranging from mild to severe. First, HCQ and CQ have both been shown to cause cardiac electrical disturbances and cardiomyopathy [
]. One clinical trial using a dose of 600 mg twice daily for ten days was terminated early due to the death of 11 patients as a result of arrhythmias by the 6th day [
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.
]. Additionally, agents like HCQ and CQ can cause QT prolongation and their toxicity may be exacerbated when combined with other agents that also prolong the QT interval, such as Azithromycin [
]. Patients who develop QT prolongation without torsades de pointes should be treated immediately by correcting oxygen, potassium, calcium, and magnesium concentrations. Magnesium sulphate is recommended as the first-line therapy for torsades de pointes [
]. Cardiotoxicity has not been reported with remdesivir use. However, side effects of remdesivir include allergic reactions and increased liver enzymes [
]. Adverse effects associated with triple therapy using interferon beta 1b, lopinavir-ritonavir and ribavirin include diarrhea, nausea, and increased alanine transaminase levels, all of which stopped in one trial upon discontinuation of the drugs [
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.
]. Adverse reactions of dexamethasone were not evaluated in the RCT included in this study; however, clinicians treating COVID-19 patients with dexamethasone should monitor their patients for hyperglycemia, secondary infections, psychiatric effects and avascular necrosis [
]. The Ad5-vectored vaccine also showed a favorable side-effect profile with most side effects being a result of the injection itself such as skin induration, redness, and swelling [
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
These findings lead us to recommend that physicians follow updated guidelines from reputable sources. The Society of Surgical Oncology also offers frequently updated resources to assist physicians in treating particularly vulnerable patients with cancer [
]. Currently, there is also a great deal of randomized clinical trials that are ongoing and should provide the medical community with more conclusive evidence in the near future. According to the NIH, there are 2962 active studies on COVID-19 as of August 2, 2020 [
Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
]. Another limitation to the findings is the inability to generalize them to all patients as a result of specific exclusion criteria such as individuals with mild or severe disease [
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.
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.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
]. Also, several studies reviewed above aimed to focus on the efficacy and safety of one drug, but employed multiple drugs in the treatment of patients [
]. These limitations make it difficult to compare the efficacy and safety profiles of the drugs being used. The findings listed are dependent on the accuracy and validity of data used to assess SARS-CoV-2 pharmacological therapies. Lastly, given the rapidly evolving nature of the COVID-19 pandemic, it is difficult to ensure that all the existing evidence has been included up until this article’s publication date and new information and trials will arriving.
6. Conclusion
There remains uncertainty regarding the safest and most effective pharmacologic therapy for COVID-19 disease. However, the findings from this review conclude that, according to level 1 evidence, remdesivir therapy in mild to severe disease, and the triple medication regimen (lopinavir-ritonavir, ribavirin and interferon beta-1b) in mild to moderate disease are the most efficacious against SARS-CoV-2 in terms of symptom improvement and time to a negative RT-PCR. Also, dexamethasone was significantly able to reduce mortality in patients receiving respiratory support. We recommend that physicians remain informed on up to date evidence such as preliminary data from RCTs, and work with their institution and scientific societies in developing evidence-based systematic guidelines in the treatment of COVID-19 patients.
Funding
None.
Declaration of Competing interest
Nothing to disclose.
References
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Zoonotic origins of human coronaviruses.
Int J Biol Sci.2020; 16 (Published 2020 Mar 15): 1686-1697
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.
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.
Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial.
Assessment of QT intervals in a case series of patients with Coronavirus disease 2019 (COVID-19) infection treated with hydroxychloroquine alone or in combination with azithromycin in an intensive care unit.
Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO clinical characterisation protocol: prospective observational cohort study.
