A Narrative Review of Antiviral Drugs Used for COVID-19 Pharmacotherapy

Abstract

Purpose:

A number of research articles has been published evaluating safety and efficacy of drugs against COVID-19. This study was undertaken to collate and review the information regarding common proposed anti- viral drugs for easy reference.

Methods:

The literature was search was done using terms like severe acute respiratory syndrome or SARS-CoV-2 or 2019-nCoV or SARS-CoV or COVID-19 in combination with drugs or treatment or pharmaco-therapy using PubMed and google scholar to identify relevant articles.

Results:

Despite showing good early results, hydroxychloroquine and lopinavir-ritonavir has not shown clinical benefit in randomized controlled trials. However lopinavir in combination with other drugs specially interferon is being investigated. Remdesivir has shown positive effect in terms of clinical improvement and continued to being investigated alone or in combination with other drugs. Favipiravir has shown mixed results and more data from adequately powered study is needed to prove its efficacy.

Conclusions:

Many drugs which showed positive effect in initial studies could not replicate the same benefit in large randomized controlled trials. There is need to evaluate efficacy and safety of drugs based on high quality evidence before allowing it to be used in general population.

INTRODUCTION

A lot of research has been done recently to generate evidence of efficacy of pharmacotherapy for coronavirus disease-2019 (COVID-19). It includes multinational clinical trial started under the umbrella of the World Health Organization (WHO), multicentric randomized controlled trials (RCTs), as well as many other regional clinical studies. Apart from these well-designed controlled clinical trials, uncontrolled and observational studies have also been done; results of which have an important implication on clinical practice. Especially notable among these clinical trials are SOLIDARITY,[1] a global clinical trial under WHO and allies, and a multicentric RCT RECOVERY (Randomized Evaluation of COVID-19 Therapy),[2] which has been key to accept or refute therapeutic options and their findings have been incorporated in various guidelines. Particularly, it has led to the withdrawal of hydroxychloroquine (HCQ) for the treatment of COVID-19 in hospitalized patients, which was being promoted worldwide as a cheap and effective drug without evidence for the same. The findings from RECOVERY have also led to the approval of dexamethasone for the treatment of severe COVID-19. The adaptive trial design of these trials has helped in early stopping of the inefficacious or successful arm after an interim analysis. Many uncontrolled and observation studies have also contributed to our knowledge such as efficacy of tocilizumab in treatment of severe COVID-19, and it has been widely being used in clinical practice.[3,4,5] But, the data from any RCT about efficacy of tocilizumab are lacking and trials are underway for the same. Various agents have been used as per their in vitro activity against SARS-COV-2 and immune regulation.[6,7,8,9] The first group of drugs includes those having antiviral property viz. HCQ, remdesivir, favipiravir, and lopinavir-ritonavir. The second group of drugs is adjunctive therapies and includes drugs such as dexamethasone, tocilizumab, and other immunomodulator agents. This study is a review of selected proposed treatments for COVID-19 showing good in vitro activity against SARS-COV-2 virus and thus taken up into clinical studies. The agents that are being reviewed are HCQ, remdesivir, favipiravir, and lopinavir-ritonavir. All of these drugs were being used for some or other condition and has been in the market for some time, except remdesivir that was proposed for Ebola virus[10] and favipiravir for influenza,[11] which are comparatively new molecule. In general, most of these drugs that are being tried are repurposed drugs as these help to shorten the time for a drug which is showing good in vitro activity to undergo clinical trials. Repurposed drugs can be directly taken into phase II/III as the safety data are already available for fixed-dose range studies once it has shown the desired effect in the in vitro models. Further, the clinical trials being it SOLIDARITY, RECOVERY, or ACTT (Adaptive COVID-19 Treatment Trial) have used adaptive design to further cut short the time to identify any clinically meaningful effect and to evaluate the efficacy of two or more drugs simultaneously. Recovery trial has also used a factorial design to evaluate multiple interventions simultaneously.

MATERIALS AND METHODS

A literature search was performed using terms, namely severe acute respiratory syndrome or SARS-CoV-2 or 2019-nCoV or SARS-CoV or COVID-19 in combination with drugs or treatment or pharmacotherapy using PubMed and Google Scholar to identify relevant articles either preprint or published. Due to lack of RCTs, the authors also included nonrandomized interventional studies and observational studies.

RESULTS

Remdesivir

Remdesivir is a nucleotide analog prodrug and whose inhibitory effects have been shown on many viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in animal models of SARS-CoV-1 and the Middle East respiratory syndrome (MERS)-CoV and Ebola viruses.[12,13,14] Following are a list of studies which has been conducted with remdesivir as intervention drug [Supplementary Table 1]. The dosage consists of 200 mg administered intravenously on day 1, followed by 100 mg daily for up to 10 days or sometimes more depending upon the clinical situation. The primary outcome for all of these studies is a clinical improvement as measured by either median time or percentage of subjects experiencing clinical improvement. The clinical improvement was measured by an ordinal scale, which was developed by WHO to fine-tune the definition of the endpoint. It consists of an 8-point scale on the basis of the patient clinical state viz. uninfected, ambulatory, hospitalized mild disease, hospitalized severe disease, and death.[15] The population included in all these studies included hospitalized patients with moderate to severe COVID-19 disease.[16]

Supplementary Table 1.

General characteristics of the included studies of hydroxychloroquine

Name of first author	Study site	Research population	Research design	Intervention	Comparator	Primary outcome	Outcome measurement	*Sample size in intervention	*Sample size in comparator	Outcome in intervention	Outcome in control
Horby P et al., 2020	UK	Adult patients with COVID-19 irrespective of clinical status	Open label, randomized controlled trial	HCQ	No HCQ (SOC)	Mortality by 28 days after randomization	No.(%) of patients dead within 28 day	1561	3155	418 (26.8%)	788 (25.0%)
Cavalcanti AB et al., 2020	Brazil	Adults with mild to moderate Covid-19	Open label, randomized controlled trial	a. HCQ b. HCQ + AZT	Standard of care	Clinical status at 15 days after randomization	Median score on Seven-level ordinal scale (IQR)	a. 172 b. 159	173	a. 1 (1-2) b. 1 (1-2)	1 (1-2)
Mitjà O et al., 2020	Spain	Adults with mild COVID-19	Open label, randomized controlled trial	HCQ	No HCQ (SOC)	Reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment	a. Mean (SE) reduction of viral load at day 3 (Log10 copies/mL) b. at day 7	136	157	a. 1.41 (0.15) b. 3.44 (0.19)	a. 1.41 (0.14) b. 3.37 (0.18)
Tang W et al., 2020	China	Adults with COVID-19	Open label, randomized controlled trial	HCQ	No HCQ (SOC)	Viral negativity by 28 days	Probability of negative conversion by 28 days	75	75	85.4% (95% CI 73.8% to 93.8%)	81.3% (71.2% to 89.6%)
Chen Z et al., 2020	China	Adults with mild COVID-19	Double blind randomized controlled trial	HCQ	No HCQ	Time to clinical recovery: defined as return of body temperature and cough relief, maintained for more than 72 h	TTCR (mean (SD) a. Fever b. cough	31	31	a. 2.2d (0.4) b. 2.0 d (0.2)	a. 3.2 d (1.3) b. 3.1d (1.5)
Gautret P et al., 2020	France	COVID-19 Patients of age >12 years irrespective their clinical status	Single arm, open-label study	a. HCQ b. HCQ + AZT	Untreated patients from another center and cases refusing the protocol	Presence and absence of virus at Day6-post inclusion	No. of patients showing Viral clearance ay D6 (%)	a. 14 b. 6	16	a. 8 (57.1%) b. 6 (100%)	2 (12.5%)
GelerisJ et al., 2020	US	Adults with COVID-19	Observational study	HCQ	No HCQ (SOC)	composite of intubation or death (time-to-event analysis)	No. of patients having the event(%)	811	565	262 (32.3%)	84 (14.9%)
Gautret P et al., 2020	France	Patients with mild COVID-19	Observational study	HCQ + AZT	None	a. Aggressive clinical course requiring oxygen therapy or transfer to the ICU b. Contagiousness as assessed by PCR and culture, c. length of stay in the ID ward	a. No.(%) of patients b. No. of pts with Ct <34 at day 12 c. mean duration of stay	80	None	a. 18.7% b. zero c. 4.6 d
Magagnoli J, 2020	US	Male patients with COVID-19	Retrospective study	a. HCQ b. HCQ + AZT	No HCQ (SOC)	i. Mortality ii. Requirement for mechanical ventilation (MV)	i. No. of patients died(%) ii. Proportion of pts. Requiring MV	a, i. 97 ii. 90 b, i. 113 ii. . 101	i. 158 ii. 177	a, i. 27 (27.8%) ii. 12 (13.3%) b, i. 25 (22.1%) ii. 7 (6.95)	i. 18 (22.1%) ii. 25 (14.15)
Mahévas M et al., 2020	France	Adults with moderate to severe COVID-19	Retrospective study	HCQ	No HCQ	Death or transfer to ICU within day 7 post inclusion	No. of patients with primary outcome (weighted %)	84	97	16 (20.5%)	21 (21.6%)
Bo Yu et al.,	China	Critically ill patients with COVID-19	Retrospective study	HCQ	No HCQ	a. Mortality b. hospital stay time (day)	a. No. of patients died (%) b. avg. hospital stay in days	48	520	a. 9 (18.8%) b. 32 (26-41)	a. 238/520 (45.8%) b. 30 (18-40)

*Sample size is according to patients use for data analysis. HCQ hydroxychloroquine; AZT azithromycin; SOC standard of care

It was the biggest RCT involving a sample size of 1059 patients comparing remdesivir with placebo nicknamed ACTT for Adaptive COVID-19 treatment trial. The primary outcome was the time to recovery as defined by discharge from the hospital or hospitalization for infection control purposes only. The result showed that those who received remdesivir had a median recovery time of 11 days with (95% confidence interval [CI] 9–12 days) compared to 15 days (95% CI 13–19 days) for placebo, (rate ratio of 1.32; 95% CI 1.12–1.55; P < 0.001). Thus, remdesivir was significantly superior to placebo in shortening the time to recovery in adults hospitalized with COVID-19. An analysis was also done to adjust for baseline variability by stratifying to the overall effect on the primary outcome. This adjusted analysis also produced a similar outcome as remdesivir being clinically superior to placebo. The study also showed that mortality by 14 days for remdesivir was lower having hazard ratio (HR) for death was 0.70, but it was not statistically significant (95% CI, 0.47 to 1.04). Serious adverse events were lower in remdesivir group (21.1%) as compared to placebo group (27.0%).[17]

This study has been done to assess the efficacy of remdesivir in terms of median time to clinical improvement and safety in patients with severe COVID-19. A total of 236 patients were included in data analysis. The median time to clinical improvement in the remdesivir group was lower, that is, 21 days (IQR 13–28) but not significantly different to that of the control group (23 days 15–28 [15–28];[15,16,17,18,19,20,21,22,23,24,25,26,27,28] HR 1.23 [95% CI 0.87–1.75]). The author also noted that time to clinical improvement was shorter in those treated earlier by remdesivir but it too was not significant. It may be due to small sample size of the study and indeed similar study (Beigel et al.) with larger sample size was able to capture significant improvement. Day 28 mortality was not significantly different between the two groups, that is, 14% in the remdesivir group vs. 13% in the placebo group, a difference of 1·1% [95% CI –8.1 to 10.3]. Reported serious adverse events were more in the control group (26%) compared to remdesivir group (18%).[18]

This study was done to compare the efficacy of shorter duration (5 days) of treatment with remdesivir as compared to usual duration (10 days) which was obtained from animal studies and healthy volunteers. The clinical improvement was as defined as at least improvement of 2 points on the 7-point ordinal scale by day 14. The hypothesis was that shorter course of treatment could reduce the cost and potential adverse effects. But the groups were not matched for baseline disease characteristics and significantly greater proportions of patients with severe disease were in the 10-day group. The result showed that 65% of patients receiving 5-day course of remdesivir had better clinical improvement compared to 54% of patients those who received a 10-day course. But after adjusting for the baseline characteristics patients both 5 days vs. 10-day course had a similar result. The median time to recovery and percentages of patients experiencing adverse events were also similar in the two groups.[19]

It was a single-arm study in which 53 patients were included to evaluate the clinical outcomes in severely ill patients of COVID-19 who were treated with remdesivir. The clinical improvement was defined as either a decrease of 2 points or more on the 6-point ordinal scale or live discharge. The Kaplan–Meier analysis showed that the cumulative incidence of clinical improvement was 84% (95% CI 70–99) after 28 days of receiving the drug. Further, the clinical improvement was more frequent in patients receiving noninvasive oxygen support than those receiving invasive ventilation. Seven of the 53 patients (13%) died in remdesivir group which included six of those receiving invasive ventilation and one receiving noninvasive oxygen support. A total of 12 patients (23%) had serious adverse events.[20]

It was a prospective single-arm study in which 35 patients were included in data analysis. A total of 18 patients were admitted in the intensive care unit (ICU) and 17 in the infectious diseases ward (IDW). The primary outcome was clinical improvement which was measured as the change in hospitalization status based on a 7- category ordinal scale at days 10 and 28 after starting of treatment. After 10 days of remdesivir treatment, four (22.2%) of the ICU patients showed an improvement compared to six of IDW patients (35.3%). By the 28^th day of follow-up, the hospitalization status of 38.9% of the ICU patients showed improvement compared to 88.2% of the IDW patients. Notably there was 44.4% case fatality rate among the patients who were in ICU. Increased liver enzyme and acute kidney injury were the most frequent adverse events observed.

Hydroxychloroquine

HCQ and chloroquine were one of the few drugs, which showed promising results in vitro against the SARS-CoV-2, the underlying agent that causes COVID-19.[6] They inhibit the entry of the virus into host cells by interfering with viral particles binding to their cell surface receptor. The initial clinical studies from china also pointed toward its efficacy in treating patients with COVID-19. Given its widespread use and safety records and easy and cheap availability, the drug quickly took center stage as a treatment against COVID-19 infection despite limited data. Chloroquine has a narrow therapeutic index and acute severe toxicity is associated with 10–30% mortality due to a combination of direct cardiac effects and electrolyte disturbance resulting in cardiac dysrhythmias.[21] Chronic cumulative toxicity involves retinopathy and cardiomyopathy.[22,23] Here is the summary of clinical studies of HCQ with or without azithromycin in COVID-19 which has been mentioned in Supplementary Table 2. The trials for COVID-19 have used average dosing regimens starting with 1 g of chloroquine base on day 1 followed by 500 mg once daily for 4–7 days. All these studies were done on hospitalized adult patient except the study by Oriol Mitjà et al. which was on nonhospitalized patients with mild COVID-19.[24]

Supplementary Table 2.

General characteristics of the included studies for remdesivir

Name of first author, Year	Study site	Population€	Study Design	Intervention	Comparator	Primary Outcome measured	Primary Outcome: how it was measured	*Sample size in intervention	*Sample size in comparator	Outcome in intervention	Outcome in control
Beigel J H et al., 2020	North America, Europe, and Asia	Adults with Covid-19 (moderate and severe)	Double-blind, randomized, placebo-controlled trial	Remdesivir	Placebo	Clinical improvement	Median time to recovery (days) measured on a ordinal scale	538	521	11 days	15 days
Spinner CD et al	United States, Europe and Asia	Patients > 12 years of age With Moderate COVID-19	Open label randomized, controlled trial	a. Remdesivir for 5 days b. Remdesivir for 10 days	Standard Care	Clinical improvement	Difference in clinical status distribution vs standard care, odds ratio (95% CI)	a. 191 b. 193	200	a. 1.65 (1.09-2.48) b. NA	1 [Reference]
Wang Y et al., 2020	China	Adults with severe covid 19	Double-blind, randomized, placebo-controlled trial	Remdesivir	Placebo	Clinical improvement	Median Time to clinical improvement measured on ordinal scale	158	78	21 days	23 days
Goldman JD et al., 2020	North America, Europe, and in Asia	Patient >12 years of age with Severe Covid-19	Open label randomized, controlled trial	Remdesivir for 5 days	Remdesivir for 10 days	Clinical improvement	Clinical improvement, assessed on ordinal scale on day 14	200	197	65%	54%
Grein J et al., 2020	United States, Europe or Canada, and Japan	Patient with Severe Covid-19	Single arm prospective study	Remdesivir	None	#Clinical improvement	Clinical improvement on the ordinal scale or live discharge at day 28	53	-	84%	-
Antinori S, et al., 2020	Italy	Adults with severe Covid-19	Single arm prospective study	Remdesivir	None	#Clinical improvement	Change in hospitalization status based on a ordinal scale at day 28	35	-	62.80%	-

^€All of these were hospitalized patients. ^#There was no specified primary end point. *Sample size is according to number of subjects included in data analysis. NA - Odds ratio can not be determined as proportional odds assumption was not met

It was the largest published trial with a sample size of 4716 patients in 1:2 ratio. For the primary endpoint of death, 26.8% of patients in the HCQ group and 25% of patients receiving usual care died within 28 days (rate ratio 1.09; 95% CI 0.96 to 1.23; P = 0.18). For the secondary endpoint of discharge from hospital alive within 28 days, patients receiving HCQ were less likely to reach this outcome (60.3% vs. 62.8%; rate ratio 0.92; 95% CI 0.85–0.99). Further, those not on invasive mechanical ventilation at the start of the treatment, HCQ was associated with significantly more chances to reach the composite endpoint of invasive mechanical ventilation or death (29.8% vs. 26.5%), a risk ratio of 1.12; (95% CI 1.01–1.25).[25]

It was an open-label RCT. The primary endpoint was clinical status at 15 days after randomization as evaluated on a seven-level ordinal scale (1 = not hospitalized, 7 = death). The odds of getting a worse score is 1% less for HCQ and azithromycin combination (odds ratio, 0.99; 95% CI 0.57–1.73; P = 1.00) and 21% more for HCQ alone (odds ratio, 1.21; 95% CI, 0.69–2.11; P = 1.00) as compared to control group. No significant difference was found for the secondary outcomes including need for mechanical ventilation. Number of deaths, thromboembolic complications, elevated liver-enzymes, and prolongation of the corrected QT (QTc) interval was more common in patients receiving HCQ with or without azithromycin than in those receiving neither of these.[26]

It was an open-label RCT with the primary endpoint being reduction in viral load (measured as log10 copies/mL). No significant differences were observed in the mean reduction of viral load at day 3 (diff. 0.01 [95% CI –0.28 to 0.29]) or at day 7 (diff. –0.07 [95%CI –0.44 to 0.29]). Also, this treatment regimen did neither reduce risk of hospitalization nor shortened the time to complete resolution of symptoms (12 days in control vs. 10 days in intervention; P = 0.38). No clinically relevant adverse events were noted in the treatment group.[27]

It was an open-label RCT. For the primary endpoint of viral negativity by 28 days, the probability of negative conversion by in the standard of care plus HCQ group was 85.4%, and that in the standard of care group 81.3%. The difference between groups was not significant, 4.1% (95% CI –10.3% to 18.5%).[28]

It was a double-blind placebo-controlled trial with a sample size of 62 hospitalized patients. Time to clinical recovery measured by the body temperature recovery and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved CT chest finding in HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31).[29]

It was single-arm, open-label study. A total of 26 patients received HCQ but data analysis was done for 20 patients only. Six HCQ-treated patients who were lost to follow-up which included three patients who were transferred to ICU and one patient who died and one patient stopped the treatment because of adverse effect has not been included. For primary endpoint of virological clearance at day 6 post-inclusion, 70% of HCQ-treated patients were virologically cured comparing with 12.5% in the control group (P = 0.001). Moreover, 100% of patients treated with HCQ and azithromycin combination were virologically cured comparing with 57.1% in patients treated with HCQ only, and 12.5% in the control group (P < 0.001).[30]

It was an observational study based on data from consecutive patients hospitalized with COVID-19 at a large medical center in New York City. A total of 1376 patients were included in data analysis. HCQ-treated patients were more severely ill at baseline than those who did not receive HCQ. For the primary endpoint of death or intubation, the unadjusted analysis showed that those receiving HCQ were more likely to die or get intubated than were patients who did not (HR 2.37; 95% CI, 1.84 to 3.02, but after adjusting for baseline variation no significant association was found between HCQ use and the composite primary endpoint (HR 1.04; 95% CI, 0.82 to 1.32).[31]

It was a single-arm observational study on 80 patients. A total of 65 patients were discharged from the hospital, 12 required oxygen therapy, 3 were moved to ICU, and 1 patient died. A rapid fall of nasopharyngeal viral load tested by quantitative polymerase chain reaction (qPCR) was noted, with 83% negative at day 7 and 93% at day 8.[32]

It was retrospective analysis of data from patients hospitalized with confirmed SARSCoV-2 infection in the United States. Patients were categorized into HCQ alone or with azithromycin as treatments in addition to standard supportive management for COVID-19. The two primary outcomes were death and the need for mechanical ventilation. There were significant differences among the three groups in baseline characteristics including disease severity. After adjusting for the propensity of being treated with the drug compared to the no HC group, there was a higher risk of death from any cause in the HCQ group (adjusted HR, 2.61; 95% CI, 1.10 to 6 + 17; P = 0.03) but not in the combination group (adjusted HR, 1.14; 95% CI 0.56 to 2.32; P = 0.72). No significant difference was found for the risk of ventilation in either the HCQ group or combination group compared to the no standard supportive management.[33]

It was retrospective study. An inverse probability of treatment weighting (IPTW) approach was used for randomization and balance the differences in baseline variables between treatment groups. In the IPTW analysis, 20.5% of patients in the HCQ group were transferred to the ICU or died within 7 days, compared with 22.1% in the no-HCQ group (risk ratio 0.93, 95% CI 0.48–1.81). One of the secondary outcomes was occurrence of ARDS. It was also not significant. In total, 27.7% of the HCQ group and 24.1% of the no-HCQ group developed ARDS within 7 days (24 vs. 23 events, RR 1.15, 95% CI 0.66–2.01]). QTc prolongations was most common side effect.[34]

It was a retrospective study. The primary outcome measures were mortality and hospital stay time. Mortalities are 18.8% (9/48) in HCQ group and 45.8% (238/520) in NHCQ group (P < 0.001) The time of hospital stay before patient death is 15 (10–21) days and 8 (4–14) days for the HCQ and NHCQ groups, respectively (P < 0.05).

Favipiravir

Favipiravir is a viral RNA-dependent RNA polymerase inhibitor, similar to remdesivir. It was initially developed as anti-influenza drug and was approved in Japan.[35] Inhibition of RNA polymerase appears to be a promising target and reported efficacy of remdesivir also supports this line of inquiry. The general characteristics of these studies are shown in Supplementary Table 3.[36]

Supplementary Table 3.

General characteristics of the included studies for favipiravir

Name of first author, Year	Study site	Population	Research Design	Intervention	Comparator	Primary Outcome	Outcome measurement	Sample size in intervention	Sample size in comparator	Outcome in intervention	Outocme in control
Chen C et al.,2020	China	Adult patients with COVID-19, moderate, severe or critical	Open-label, randomized, controlled trial	Favipiravir	Umifenovir (Arbidol)	Clinical recovery rate of Day 7	Clinical recovery was defined as continuous recovery of body temp., respiratory rate, oxygen saturation and cough relief	116	120	61.21%	51.67%
Cai Q et al.,2020	China	Adults with moderate COVID-19	Open-label, non- randomized controlled study	Favipiravir + INF-α 1b	LPV/RTV + INF-α 1b	a. Time of viral clearance b. Improvement rate of chest computed tomography (CT) scans on Day 14 after treatment	a. Median time in days of viral clearance b. Chest CT score*	35	45	a. 4 d (IQR: 2.5-9) b. 91.4%	a. 11 d (IQR: 8-13) b. 62.2%
lou Y et al.,2020	China	COVID-19 patients	Open-label, randomized, controlled trial	a. Favipiravir b. Baloxavir	Existing antiviral treatment	a. Time to Viral negativity b. Time to clinical improvement	a.Viral negative at Day 14 b. Time to clinical improvement - median no. of days (IQR)	a. 9 b. 10	10	a. 70%, 77% b. 14 (6-49), 14 (6-38)	1. 100% 2.15 (6-24)
Doi Y et al., 2020	Japan	Patients of age >10 years with mild, moderate and severe COVID-19	Observational study	Favipiravir	None	Clinical improvement	a. Clinical improvement at 7 and 14 days b. Positive clinical outcome 1 month into hospitalization	2158+	None	a. 67%, 83% b. 57%	-

LPV/RTV - Lopinavir-ritonavir, INF- Interferon , +Clinical status at day 7, clinical status at day 14, clinical outcome at one month were available for 1,713, 1,282 and 1,918 cases

It was open-label randomized clinical trial with the hypothesis that favipiravir would be superior to arbidol in terms of efficacy for moderate symptoms, and would accelerate the clinical recovery. A total of 236 patients were included in data analysis: 116 in the Favipiravir group and 120 in the arbidol group. Primary outcome measure was clinical recovery rate at 7 days of starting treatment. At day 7, 51.67% in the arbidol group and 61.21% of patients in the favipiravir group were clinically recovered, but the difference was not statistically significant. Though the secondary endpoints latency to pyrexia reduction and cough relief in the favipiravir group was significantly shorter than that in the arbidol group.[37]

It was an open-label RCT comparing favipiravir with control (lopinavir-ritonavir) arm. Time to viral clearance was found to be significantly better in favipiravir group in comparison to control arm. Another outcome measured was improvement in chest computed tomography (CT scans) on the 14^th day of treatment. Favipiravir group had a significantly better improvement in CT findings (91.43%) as compared to control arm (62.22%).[38]

This study compared favipiravir with standard treatment in a small open-label study. It compared efficacy of favipiravir in accelerating viral negativity and improvement in clinical symptoms. However, the study did not find any advantage of adding favipiravir to standard treatment. In fact, the viral negativity rate was 100% in placebo group compared to 77% in favipiravir group. Adverse drug events were also found to be similar in both arms.[39]

Clinical status at 7 and 14 days showed improved outcome in mild and moderated disease (70.2% and 86.1%, respectively) compared to severe cases where improvement was seen in approximately 40% and 60% cases. Overall improvement was seen in approximately 67% of patients at day 7 and 83% patients at day 14. Clinical outcome one month from hospital admission showed that 57% patients were discharged or transferred for de-escalation of care against 17% which were either dead or transferred for escalation of care.

Lopinavir-ritonavir

Lopinavir-ritonavir has been used along with other drugs in combination for treating HIV. Ritonavir does not have any antiviral activity but only used to increase plasma half life of lopinavir through the inhibition of cytochrome P450. It has shown in vitro activity against SARS and MERS.[7,8] Based on these findings, this drug combination was tried in SARS-COV-2 infections, although there are no published data showing its effect on SARS-CoV-2. Few early case reports also suggested its effectiveness against novel virus[40,41] and it was later taken widely in clinical practice. The general characteristics of these studies are shown in Supplementary Table 4.[42]

Supplementary Table 4.

General characteristics of the included studies for lopinavir/ritonavir

Name of first author, Year	Study site	Population€	Research Design	Intervention	Comparator	Primary Outcome measured	Primary Outcome: how it was measured	Sample size in intervention	Sample size in comparator	Outcome in intervention	Outcome in control
Cao B et al.	China	Adult patients with severe Covid-19	Open label randomized controlled trial	Lopinavir- ritonavir	Standard care	Time to clinical improvement-median no. of days (IQR)	Improvement of two points on a seven-category ordinal scale or discharge from the hospital	99	100	16.0 (13.0-17.0)	16.0 (15.0-18.0)
Hung IF et al.	China	Adult patients with mild/moderate COVID-19	Open label randomized controlled trial	lopinavir- ritonavir + Ribavirin + IFN-beta-1b	lopinavir- ritonavir	Viral negativity at Day 21 of enrolment	Time to achieve primary outcome	86	41	(7 days [IQR 5-11	(12 days [8-15]
Li Y et al.,	China	Adult patients with mild/moderate COVID-19	Single blind RCT	Lopinavir- ritonavir	other supportive care except antivirals	Viral negativity at Day 21 of enrolment	Mean time (SD) to viral negativity in days	34	17	9.0 (5.0)	9.3 (5.2)
Zhu Z et al.,	China	Patients with COVID-19	Retrospective study	Lopinavir- ritonavir	Arbidol	Viral load day 14 after the admission	Patients with high viral load as determined by Ct <40%	34	16	15	0

^€All of these were hospitalized

It was an open-label RCT involving 199 participants. The median time to clinical improvement was not significantly different in two groups as shown by HR of 1.31 and 95% CI (0.95 to 1.80). The percentage of patients showing clinical improvement at day 28 (difference 8.8 [−3.3 to 20.9]) was not significant in intervention vs. control arm. The two groups also did not differ significantly regarding duration of stay in ICU, days of mechanical ventilation or oxygen support. The 28-day mortality was numerically lower but not statistically significant in the intervention arm than the control arm (19.2% vs. 25.0%; difference, −5.8 percentage points; 95% CI, −17.3 to 5.7). SARS-CoV-2 RNA concentrations in throat swabs obtained over time did not differ between the two groups. Lymphopenia was the most common adverse effect in intervention group.[43]

It was open-label RCT with a sample size of 127 patients divided randomly into 86 patients who were assigned to the combination drug and 41 patients were to the control group. The combination drug included lopinavir-ritonavir with ribavirin and interferon (IFN)-β-1b compared to control group which received lopinavir-ritonavir alone. The combination group had a significantly reduced median time to viral negativity (7 days [IQR 5–11]) than the control group (12 days;[8,9,10,11,12,13,14,15] HR 4.37 [95% CI 1.86–10.24], P = 0.0010). All the secondary clinical endpoints viz. symptoms resolution defined as a National Early Warning Score (NEWS2) of 0 maintained for 24 h, daily NEWS2, sequential organ failure assessment (SOFA) score, and the length of stay in hospital were significantly improved in combination group.[44]

It was single-blind RCT enrolled 86 patients with mild-to-moderate COVID-19, with 34 randomly assigned to receive lopinavir-ritonavir, 35 to arbidol, and 17 with no antiviral medication. There was no difference in the primary outcome, and the mean time to viral negativity was 9.0 days (SD 5.0) in the lopinavir-ritonavir group, 9.1 days (SD 4.4) in the arbidol group, and 9.3 days (SD 5.2) in the control group (P = 0.981) with respect to the secondary end points, namely cough resolution, pyrexia normalization, and improvement of chest CT scans were not significantly different between all three groups. A total of 12 patients in lopinavir-ritonavir group experienced adverse events which included diarrhea, loss of appetite, and raised serum enzymes.[45]

It was a retrospective analysis of data of sample size of 50 patients divided into lopinavir-ritonavir and arbidol arm. The outcome measure was viral load as determined by cycle threshold (Ct) value on day 14 after the admission. The viral load was found to be undetectable in all the patients in arbidol group, but the viral load was found in 15 (44.1%) of the 34 patients who received lopinavir/ritonavir (P < 0.01). No apparent side effects were found in both groups.

DISCUSSION

Remdesivir

Remdesivir, a nucleotide analog, has been shown to be effective in vitro and in animal models against SARS-COV-2. The study by Wang et al.[17] has found that remdesivir was associated with reduced time to clinical improvement when treated earlier by remdesivir but it too was not significant. It may be due to small sample size of the study and indeed similar study with larger sample size was able to capture significant improvement.[16] Another study by Goldman et al.,[18] which compared 5 days vs. 10 days regimen of remdesivir, found that numerically higher but not significant clinical improvement in those receiving 5-day treatment and indeed a recent study with higher sample size has found clinically and statistically significant improvement in 5 day course but not in 10 days course of remdesivir therapy compared to usual care.[46] The common adverse events associated with remdesivir were anemia, hyperglycemia especially raised live enzymes, and acute kidney injury.

Hydroxychloroquine

HCQ has been at the centre of stage as in vitro studies found its inhibitory effect on SARS-n COV. A few initial nonrandomized, observational, and retrospective study has also shown a beneficial effect on viral negativity and clinical course of COVID-19.[29,31,34] One RCT has also shown that the drug significantly reduced time to clinical recovery.[28] But, this study had a small sample size of 62 patients randomized in 1:1 ratio in HCQ and control group. This study included only mild patients with SARS-COV-2 infection and found early clinical recovery by approximately 1 day of fever and cough in HCQ group. One retrospective study showed that HCQ was associated with a significantly increased risk of death and intubation in hospitalized patients.[32] Similar finding of increased risk of death or intubation was reported in an observational study by Geleris et al.,[30] but in this study the patients receiving HCQ were more severely ill. After adjusting for the baseline the difference was not significant. Most of the other studies with more robust study designs and increased could not find any difference in outcome (viral negativity, clinical course, or mortality) after using HCQ. The result of these RCT showed that HCQ is no better than the standard of care for any favorable outcome. One of the largest RCT involving HCQ in the UK with a sample size of 4716 not only failed to find any significant difference in mortality in HCQ vs. standard of care but found an increased length of hospital stay and increased risk of progression to invasive mechanical ventilation or death associated with the drug.[24] In view of these findings U.S. Food and Drugs Administration has revoked the Emergency Use Authorization that allowed HCQ and chloroquine to be used for hospitalized patients with COVID-19. Another major study of HCQ, SOLIDARITY trial, which is a multinational study by WHO has also dropped HCQ arm on the grounds of lack of benefit.[47] But HCQ is continued to be used for mild COVID-19 treatment and prophylaxis widely. It is also being used prophylactically but the data to substantiate or refute this claim are still lacking. But there are sufficient data now to conclude that there is no clinical benefit from use of HCQ in hospitalized patients with COVID-19.

Favipiravir

The studies presented above have shown better clinical recovery rate in favipiravir group compared to control group. But there is a lack of quality data from robustly designed study as either these were either observational studies[39] or nonrandomized clinical trials.[37]

One RCT by Chen et al.[36] has failed to find any significant difference in terms of clinical recovery in favipiravir group. Currently, favipiravir is approved in India for mild-to-moderate COVID-19 under accelerated process by DCGI. It was reported that favipiravir achieves 40% faster recovery in mild-to-moderate COVID-19 than control in a phase-3 open-label multicente RCT which enrolled 150 subjects (not published yet in any peer-reviewed journal).

Lopinavir-ritonavir

This drug was taken into clinical studies based on previous evidence(s) which showed positive results against SARS-CoV-1 and MERS-CoV. It was thus included in both SOLIDARITY and RECOVERY trial along with many other studies. Open-label RCT[42,44] failed to find any beneficial effect on median time to clinical improvement for lopinavir-ritonavir compared to placebo. Another study by Zhu et al.[45] concluded that lopinavir-ritonavir were inferior to arbidol in terms of viral negativity on day 14. So none of these studies indicated any positive effect either in terms of clinical improvement or viral negativity. The recovery and solidarity study have also subsequently dropped the lopinavir-ritonavor arm of the trial following the report of lack of clinical benefit in hospitalized patients of COVID-19. But, another RCT evaluating lopnavir-ritonavir combination by IFN Hung[43] has found superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19. Lopinavir with IFN-β is still being evaluated in solidarity trial.

Apart from these drugs, there are several other antiviral drugs that are being investigated as antiviral therapy [Supplementary Table 5]. These drugs are in various stages of clinical trials as mentioned in the table.

Supplementary Table 5.

List of other investigational antiviral therapies against SARS-COV-2 infection

Investigation antiviral agents	Current status	Clinical trial identifier
Ivermectin	Positive in vitro activity against SAR-COV-2 Research is ongoing to evaluate its effectiveness but it’s already being used as both prophylaxis and treatment either alone or in combination with doxycycline	NCT04445311 (phase2/3) NCT04438850 (phase 2) NCT04523831 (phase 3)
Nitazoxanide	Positive in vitro activity against SARS-CoV-2. Being tried as prophylaxis and treatment	NCT04435314 (phase 2) NCT04463264 (phase2/3)
Merimepodib	Novel drug which is an inhibitor of the enzyme inosine monophosphate (IMP) dehydrogenase It is evaluated along with remdesivir.	NCT04410354 (phase 2)
Niclosamide	It is an anthelminthic drug which has shown activity against several viruses. A study has been planned in adults with moderate COVID-19 with gastrointestinal signs and symptoms.	NCT04436458
Umifenovir (arbidol)	It is a fusion inhibitor approved for influenza. Clinical studies of umifenvir alone and in combination with favipiravir has been planned in India.	CTRI/2020/06/025957 CTRI/2020/09/027535
Bemcitinib	Oral small-molecule inhibitor of AXL kinase Preclinical data suggest activity against SARS-CoV-2 infection. It is being evaluated in UK in Phase 2 clinical trial in patients with COVID-19	-
Plitidepsin	Positive in vitro studies. No clinical studies have been registered.	-

Limitation

The list of the drugs being discussed here is by no means complete as there are many other drugs being investigated as antiviral therapy including convalescent plasma therapy and monoclonal antibodies or for their role in suppressing hyperinflammatory state. But, this study has only included a limited number of drugs. Further, despite doing exhaustive literature search it is possible to miss a few studies either due to unavailability of full text and data or if research is published in language other than English or simply by chance.

CONCLUSION

HCQ has not shown any clinical benefit in hospitalized patients with COVID-19 and their use is not recommended. Lopinavir-ritonavir has been found ineffective in patients hospitalized with COVID-19 but its combination with IFN-β is still under investigation. Remdesivir has been given emergency use authorization (EUA) by the United States Food and Drug Administration (USFDA) and many other countries. It is also given EUA in India and is promoted as investigational therapy in clinical management protocol by MOHFW, Govt. of India. It is currently continued to be investigated alone and with other agents viz. baricitinib (ACTT-2) and IFN-β-1 (ACTT-3). HCQ despite showing lack of benefit is being used to treat mild cases in India and continued to be used as prophylaxis. Favipiravir is also approved in India but not approved in the US or UK.

The urgent need of drug during initial period of pandemic led to the widespread use of drugs like HCQ and lopinavir-ritonavir along with many other drugs on the basis of some positive effects in uncontrolled studies or case report. But none of them have shown conclusive evidence of efficacy and safety. Rather well-designed randomized controlled studies with large sample size were not able to find any clinical benefit but also worst outcome compared to usual care which led to downfall of these drugs. Favipiravir, another drug, has shown mixed results in clinical studies but is being used widely in countries like India, where it has been approved. Such steps are associated with risk of unnecessary exposure of drug to the patients and in the worst case increased mortality due to adverse events. The lesson which should be learnt from this that no drug should be promoted as treatment unless conclusive data for the efficacy and safety has been provided. Further in this period of overwhelming information arising from studies on COVID-19, a guidance to evaluate the studies to adopt best evidence based approach is also needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.