There is ongoing search for effective therapies in COVID-19 infection in the face of the unabated spread of the disease in several countries, including India. Considering the lack of a vaccine and therapeutic breakthroughs, several drugs already in use for other diseases are being investigated and repurposed for use in COVID-19 infection. Recently, there have been several promising reports of treatment modalities that may improve clinical outcomes. I have summarized an updated literature review on potentially beneficial therapeutic options in COVID-19.
Antiviral agents
Remdesivir
The nucleotide analogue remdesivir has in vitro activity against SARS-CoV-2. It was used on a compassionate basis in 61 patients with COVID-19 who had oxygen saturation of less than 94% on room air or required supplemental oxygen. Remdesivir was administered intravenously in a dose of 200 mg on day 1, followed by 100 mg per day for 9 days. Clinical outcomes of 53 of the 61 patients were analyzed. At baseline, 30 patients (57%) were invasively ventilated and 4 patients were on extracorporeal membrane oxygenation (ECMO). The median follow-up period was 18 days. The level of the oxygen support device (ECMO, invasive mechanical ventilation, non-invasive ventilation, high-flow oxygen, or low-flow oxygen) could be scaled down in 36 patients (68%). Seventeen of 30 patients (57%) who were invasively ventilated could be extubated. Twenty-five patients (47%) had been discharged, and seven (13%) had died at the time of follow up. The mortality among invasively ventilated patients was 18% (6/34); mortality was 5% (1/19) among those who did not receive invasive ventilation.1
The efficacy of remdesivir in COVID-19 was evaluated in a double-blind, randomized controlled trial, involving 73 centers including the United States, Denmark, United Kingdom, Greece, Germany, South Korea, Mexico, Spain, Japan, and Singapore.2 The study patients had to meet one of the inclusion criteria: oxygen saturation ≤94% on room air, oxygen supplementation, radiographic infiltrates on imaging, requirement for mechanical ventilation or extracorporeal membrane oxygenation (ECMO). COVID-19 infection was confirmed by RT-PCR from a respiratory specimen. Intravenous remdesivir 200 mg was administered on day 1, followed by 100 mg daily until day 10 or until death or discharge from hospital. Supportive care was provided according to the local standard of care. The use of other treatment modalities for COVID-19 was allowed only if a written policy or guideline was available. Patients were evaluated daily during hospitalization, using an eight-category ordinal scale ranging from 1–8. On April 27, 2020, the data and safety monitoring board reviewed the results. Subsequently, a preliminary report of 1059 patients, including 538 who received remdesivir and 521 in the placebo arm, was published. The primary outcome was the time to recovery, defined as the first day on which the patient was in category 1,2, or 3 of the eight-category ordinal scale. Category 1 included patients who were not in hospital, with no limitations of activities; category 2 were those who were not hospitalized, but with some limitation of activities or requirement for home oxygen, and category 3 included patients who were still hospitalized but not requiring supplemental oxygen or ongoing medical care.
The median recovery time was significantly lower with remdesivir compared to placebo [11 days (95% CI, 9–12 days) vs.15 days (95% CI, 13–19 days)] (P<0.001). Mortality at 14 days was also lower with remdesivir (7.1% vs. 11.9%), although the difference was not statistically significant. There was no difference in serious adverse events between groups. On subgroup analysis, the time to recovery was not significantly different among patients who were on high-flow nasal oxygen, invasive or non-invasive ventilation, and extracorporeal membrane oxygenation. Remdesivir treatment was found to be most effective among patients with an ordinal score of 5 (oxygen supplementation alone).
Favipiravir
An RNA polymerase inhibitor, favipiravir, is currently being evaluated in several clinical trials. In a non-randomized trial from China, favipiravir was compared with the lopinavir-ritonavir combination in patients with COVID-19 infection. Favipiravir was administered orally in a dose of 1.6 g twice daily on day 1, followed by 600 mg twice daily until day 14 of illness. Patients in both treatment arms also received aerosolized interferon-alpha. Time to viral clearance was significantly shorter with favipiravir compared to lopinavir-ritonavir; improvement on CT-imaging was also significantly better with favipiravir. Fewer adverse events were observed in the favipiravir arm.3 This study was open-labeled, non-randomized, and involved multiple treatment modalities. Hence, the results must be interpreted with caution until confirmed by ongoing larger, randomized controlled trials.
Convalescent plasma
Convalescent plasma was evaluated in a randomized controlled trial in seven medical centers in the Hubei province of China.4 Patients were categorized into those with severe (respiratory rate ≥30 breaths/min; oxygen saturation ≤ 93% on room air; or a PaO2/FiO2 ratio of ≤ 300 mm Hg) or life-threatening illness (requirement for mechanical ventilation; shock; extra-pulmonary organ failure). Convalescent plasma was prepared as FFP with the SARS-CoV-2 spike receptor-RBD-specific IgG antibody titer of at least 1:640. Donors had recovered from COVID-19 and were discharged from hospital for more than 2 weeks. The primary outcome was clinical improvement defined as discharge from hospital or a reduction by 2 points on a 6-point severity scale. Overall, there was no difference in the primary outcome with the use of convalescent plasma compared to the control arm; however, clinical improvement was significantly greater among patients with “severe” disease. There was no significant difference in secondary outcomes, including the 28-d mortality, duration of hospitalization, and time to discharge from hospital. Negative conversion by RT-PCR was significantly higher at 24, 48, and 72 hours. The study was terminated early, before the sample size could be achieved as enrollment ceased due to containment of the disease in Wuhan. The study was unblinded, and there was a prolonged time interval between symptom onset and randomization (30 days). However, this study, along with a previous case series,5 offers promise in the treatment of patients with COVID-19 infection that needs to be confirmed in larger cohorts of patients.
Corticosteroids
Dexamethasone
The RECOVERY trial was planned as a randomized clinical trial to evaluate several treatment modalities for COVID-19, including dexamethasone. The study aims to enroll more than 11,000 patients from 175 hospitals of the National Health Services in the UK. Dexamethasone was administered in a dose of 6 mg intravenously or orally for 10 days to 2104 patients and compared with 4321 patients who received usual care. The dexamethasone arm of the study was stopped on June 8, 2020, as the Steering Committee of the trial considered that an appropriate sample size had been reached to establish benefit from dexamethasone therapy.
Among patients who received usual care, the 28-day mortality was highest among those who required ventilation (41%). Patients who received supplemental oxygen revealed a mortality of 25%. Mortality was 13% among patients who did not require respiratory support.
Dexamethasone reduced the risk ratio for death among ventilated patients by one third (risk ratio: 0.65; 95% CI 0.48 to 0.88, p=0.0003). Mortality was reduced by one fifth among patients who received supplemental oxygen alone (risk ratio: 0.80; 95% CI: 0.67 to 0.96; p=0.0021). There was no evidence of benefit among patients who did not require respiratory support (risk ratio:1.22; 95% CI: 0.86 to 1.75; p=0.14). Based on this study, 8 ventilated patients would need to be treated with dexamethasone to save one life. The number needed to treat to save a life was 25 in patients requiring supplemental oxygen alone. 6 This study has not been published yet and would require detailed analysis to examine possible beneficial effects with dexamethasone in COVID-19 infection.
Other agents
Hydroxychloroquine
Hydroxychloroquine was one of the therapeutic modalities investigated in the RECOVERY trial. In this randomized controlled trial, 1542 patients were randomized to receive hydroxychloroquine compared with 3132 patients provided with usual care. The 28-day mortality, the primary endpoint, was 25.7% with hydroxychloroquine compared to 23.5% with usual care alone [hazard ratio 1.11 (95% confidence interval 0.98–1.26); p=0.10]. No beneficial effects were observed in the duration of hospital stay and other outcomes studied.7 Following this interim report, enrolment was suspended in the hydroxychloroquine arm of the RECOVERY trial.
A randomized, placebo-controlled trial was conducted in the United States and Canada to evaluate the efficacy of hydroxychloroquine prophylaxis among subjects who reported exposure to COVID-19 infection. The study subjects were randomized to receive hydroxychloroquine or placebo within 4 days of exposure. Hydroxychloroquine was administered in a dose of 800 mg initially, and 600 mg after 6–8 hours, followed by 600 mg daily for 4 more days. Among 821 participants enrolled, 719 (87.6%) reported a high-risk exposure. The incidence of laboratory-confirmed COVID-19 infection or a new-onset illness suggestive of COVID-19 was not significantly different between subjects who received hydroxychloroquine compared to those receiving placebo (11.8% vs. 14.3%; p = 0.35).8 This study offers conclusive evidence that hydroxychloroquine is ineffective as prophylaxis against COVID-19 infection.
Tocilizumab
Severe COVID-19 infection is characterized by high levels of inflammatory markers and cytokines, including IL-6. Treatment modalities aimed at blocking inflammatory pathways have evinced interest. Tocilizumab, an IL-6 inhibitor, has been studied in limited case series and observational studies. It has been shown to improve PaO2/FiO2 ratio and decrease the levels of ferritin, C-reactive protein, D-dimer.9 In a retrospective observational study of limited sample size, a reduced number of ICU admissions and mortality was observed.10 A pilot, single-arm, study evaluated off-label administration of tocilizumab in patients with severe COVID-19 infection. A significant improvement in the levels of inflammatory markers was noted with improvement in the PaO2/FiO2 ratio. Early administration of tocilizumab within 6 days of hospital admission was observed to increase the likelihood of survival.11 The largely observational data currently available needs confirmation in controlled studies.
Summary
- Despite several completed and ongoing clinical trials, the search for effective therapy for COVID-19 remains largely elusive
- In a multicentric randomized controlled trial, remdesivir resulted in reduced time to recovery, although it did not lead to improvement in the 14-d survival
- Convalescent plasma was shown to reduce the time to recovery among patients with “severe” illness. No difference was observed in the 28-d mortality, duration of hospitalization, and time to discharge from hospital compared to the control group
- Preliminary reports from the RECOVERY trial suggests lack of benefit with hydroxychloroquine. Dexamethasone may improve survival, especially among the more severely ill patients; the full report is awaited
- There is no robust evidence to support improved outcomes with immunomodulatory agents, including IL-6 blockers
References
1. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020;382(24):2327-2336. doi:10.1056/NEJMoa2007016
2. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 – Preliminary Report. N Engl J Med. Published online May 22, 2020. doi:10.1056/NEJMoa2007764
3. Cai Q, Yang M, Liu D, et al. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering. Published online March 2020:S2095809920300631. doi:10.1016/j.eng.2020.03.007
4. 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. Published online June 3, 2020. doi:10.1001/jama.2020.10044
5. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. Published online March 27, 2020. doi:10.1001/jama.2020.4783
6. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19 — RECOVERY Trial. Accessed June 21, 2020. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19
7. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19 — RECOVERY Trial. Accessed June 21, 2020. https://www.recoverytrial.net/news/statement-from-the-chief-investigators-of-the-randomised-evaluation-of-covid-19-therapy-recovery-trial-on-hydroxychloroquine-5-june-2020-no-clinical-benefit-from-use-of-hydroxychloroquine-in-hospitalised-patients-with-covid-19
8. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020;0(0):null. doi:10.1056/NEJMoa2016638
9. Sciascia S, Aprà F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol. 2020;38(3):529-532.
10. Klopfenstein T, Zayet S, Lohse A, et al. Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect. Published online May 6, 2020. doi:10.1016/j.medmal.2020.05.001
11. Sciascia S, Aprà F, Baffa A, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol. 2020;38(3):529-532.
