Remdesivir
Remdesivir is an adenosine nucleotide analogue that interferes with the action of viral RNA polymerases that ultimately decreases viral RNA production. It was originally developed to treat Ebola virus and has been found to have inhibitory effects on other viruses. With demonstrated in vitro activity against SARS-CoV-2 and in vivo activity against similar coronaviruses, remdesivir became an early contender among the potential treatment options against SARS-CoV-2 (Table
4) [
24,
79]. As a result of high demand, the manufacturer (Gilead Sciences, Inc.) transitioned from individual compassionate use requests to an expanded access program in concert with the FDA [
80]. New individual compassionate use requests were accepted specifically for pregnant women and children under 18 years of age [
81]. On April 29, 2020, the FDA granted emergency use authorization (EUA) for the investigational intravenous antiviral drug to treat severe COVID-19 (defined as oxygen saturation ≤ 94%). An EUA is intended to provide the availability of a drug during an emergency. It is a temporary approval and does not take the place of the formal new drug application submission, review, and approval process.
Table 4
Evidence review summary of pharmacologic treatment for COVID-19
Antiviral | Remdesivir | SOLIDARITY, Pan et al. [ 15] | RDV vs. PBO, HCQ vs. PBO, LPV/r vs. PBO, LPV/r + INF vs. PBO, INF vs. PBO | I | 0 |
ACTT-1, Beigel et al. [ 16, 17] | RDV vs. PBO | I | + |
| RDV vs. PBO | I | 0 |
| RDV 5d vs. RDV 10d | I | 0 |
| RDV 5d vs. RDV 10d vs. Std | I | RDV 5d + RDV 10d 0 |
| RDV | II | N/A |
| Case report | III | |
| RDV in rhesus macaques | V | |
| RDV, CLQ in vitro | VI | |
Hydroxychloroquine/chloroquine | SOLIDARITY, Pan et al. [ 15] | RDV vs. PBO, HCQ vs. PBO, LPV/r vs. PBO, LPV/r + INF vs. PBO, INF vs. PBO | I | 0 |
| Std vs. HCQ vs. HCQ + AZI | I | HCQ − HCQ + AZI − |
HCQ: RECOVERY trial, Horby et al. [ 26] | Std vs. HCQ | I | − |
| Std vs. HCQ | I | − |
| Std vs. HCQ | I | + |
| Std vs. HCQ vs. HCQ + AZI | II | HCQ − − HCQ + AZI 0 |
| HCQ vs. PBO | II | 0 |
| Std vs. HCQ vs. AZI vs. HCQ + AZI | II | HCQ 0 AZI 0 HCQ + AZI − |
| Std vs. HCQ vs. AZI vs. HCQ + AZI | II | HCQ + + AZI 0 HCQ + AZI + |
| Std vs. HCQ | II | + + + |
| Outpt: Std vs. HCQ | II | + |
| Std vs. HCQ | II | 0 |
| Std vs. HCQ | II | + + |
| Std vs. HCQ ± AZI | III | |
| HCQ + AZI PCR-time | III | |
| RDV, CLQ in vitro | VI | |
Favipiravir | | FPV vs. LPV/r | II | + |
Galidesivir | | Phase I and II | I | P |
Lopinavir/ritonavir | | Std vs. LPV/r vs. arbidol | I | − |
SOLIDARITY, Pan et al. [ 15] | RDV vs. PBO, HCQ vs. PBO, LPV/r vs. PBO, LPV/r + INF vs. PBO, INF vs. PBO | I | 0 |
| Std vs. LPV/r | I | 0 |
| Std. vs. LPV/r | I | 0 |
Sofosbuvir/daclatasvir | | SOF/DCV vs. RBV | II | + + + |
Oseltamivir | | In vitro | VI | |
Immunomodulators | Colchicine | | Std vs. Colc | I | + |
Corticosteroids | Dexamethasone | Dex: RECOVERY trial, Horby et al. [ 48] | Std vs. Dex | I | + + |
Methylprednisolone | METCOVID, Jeronimo et al. [ 49] | Std vs. MP | I | 0 |
Corral-Gudino et al. [ 50] | Std vs. MP | I | + |
IL-1 inhibitors | Anakinra | | Std vs. Ana | II | + + |
| Std vs. Ana-high vs. Ana-low | II | Ana-H + Ana-L 0 |
| Ana | III | |
IL-6 inhibitors | Tocilizumab | | Std vs. Toci | I | 0 |
| Std vs. Toci | I | 0 |
CORIMUNO-19, Hermine et al. [ 56, 57] | Std vs. Toci | I | 0 |
| Std vs. Toci | I-P, stopped | 0 |
| Std vs. Toci | II | + + + |
| Std vs. Toci | II | + + + |
| Toci | III | |
| Tocilizumab pts | III | |
Sarilumab | REGENERON/SANOFI trial [ 64] | Std vs. Sari | I-P, stopped | 0 |
JAK inhibitors | Ruxolitinib | | Rux vs. PBO | I | + |
| Rux | III | |
Tofacitinib | | Std vs. Toci | I-P | |
Baricitinib | | Bar + LPV/r vs. HCQ + LPV/r | II | 0 |
BTK inhibitors | Acalabrutinib | | Acalabrutinib | II | + |
Ibrutinib | | Ibrutinib | III | |
Antibodies | Convalescent plasma | | Std vs. CP | I | 0 |
| Std vs. CP | I | 0 |
| CP | III | |
Monoclonal antibody | LY-CoV555 | | Outpt: Std. vs. LY-Low vs. LY-Med vs. LY-High | I | LY-Low 0 LY-Med + LY-High 0 |
Antibiotics | Azithromycin | | Std vs. HCQ vs. AZI vs. HCQ + AZI | II | HCQ 0 AZI 0 HCQ + AZI − |
| Std. vs. HCQ vs. AZI vs. HCQ + AZI | II | HCQ + + AZI 0 HCQ + AZI + |
Vitamin/mineral | Zinc | | HCQ + AZI vs. HCQ + AZI + Zn | II | + |
Combination | Remdesivir + baricitinib | | RDV + Bara vs. RDV | I-P | N/A |
Multiple clinical trials remain underway to assess remdesivir’s role in the treatment of COVID-19 [
16,
18‐
23]. It was also the first COVID-19 therapy used in the first documented patient case in the USA [
22]. Initially, the data for compassionate use of remdesivir was released for patients hospitalized with severe COVID-19 to support its use. The design was an observational study of patients who were provided compassionate use remdesivir, with no control group. There were 53 patients who received at least one dose (200 mg or 100 mg IV) of remdesivir with analyzable data at different clinical sites, 30/53 (57%) were mechanically ventilated and 4/53 (8%) were on extracorporeal membrane oxygenation (ECMO). At a median of 18-day follow-up, 36/53 (68%) had an improvement in oxygen-support class, 25/53 (47%) of patients were discharged, and 7/53 (13%) patients died. While 68% of patients improved on therapy defined as oxygen-support class, it is difficult to assess the significance of results with the lack of a control group [
21].
However, the EUA that came after the order for compassionate use was based on a stronger set of data from the Adaptive COVID-19 Treatment Trial (ACTT) group in an RCT. In one of the strongest volumes of evidence to date, the National Institute of Allergy and Infectious Diseases (NIAID) ACTT-1 Study was a randomized, double-blind, placebo-controlled clinical trial evaluating remdesivir (200 mg daily × 1 day followed by 100 mg daily × 9 days, up to 10 days total) in hospitalized adult patients with COVID-19. The trial enrolled 1063 hospitalized patients who received remdesivir or placebo allocated in a 1:1 ratio. In a preliminary analysis of the primary endpoint after 606 recoveries were attained, the median time to recovery was 11 days in the remdesivir group compared to 15 days in the placebo group (HR 1.31; 95% confidence interval [CI] 1.12–1.54,
p < 0.001). All-cause mortality was 8.0% for the remdesivir group versus 11.6% for the placebo group (
p = 0.059) [
16]. This study provided initial strong evidence for a modest benefit of remdesivir. Subsequently to this, Gilead Sciences, Inc. has given drug to the federal government to distribute to in-need hospitals while ramping up production for more cases. Another of Gilead’s clinical trials compared 5 days versus 10 days of therapy for remdesivir. The randomized, open-label, multicenter study (GS-US-540-5773) suggested that patients receiving a 10-day treatment course had similar improvement in clinical status compared with those receiving a 5-day treatment course (10-day vs. 5-day odds ratio 0.76; 95% CI 0.51–1.13 on day 14). This gives rise to the suggestion of a 5-day duration, with possible extension to 10 days if no clinical improvement is demonstrated in an intensive care unit (ICU) setting [
82]. The NIH guidelines have provided specific recommendations for 5 days of remdesivir when on supplemental oxygen but not mechanical ventilation, while NIH recommended 10 days for those patients on mechanical ventilation or ECMO.
After this set of initial studies and results, remdesivir’s portfolio of evidence became further filled with completed trials. The full results for the ACTT-1 trial have been released that finalized a total of 1062 patients’ results and provide the strongest piece of evidence for utilizing remdesivir. The primary results showed that the median recovery time for the remdesivir group was 10 days compared to standard of care’s 15 days (RR for recovery 1.29; 95% CI 1.12–1.49,
p < 0.001) and showing 29-day mortality of 11.4% in the remdesivir group and 15.2% in the placebo group (HR 0.73; 95% CI 0.52–1.03). Adverse events were lower at 24.6% who received remdesivir and at 31.6% for placebo [
17]. Over 15 RCTs are being conducted to determine the efficacy and safety of remdesivir in the treatment of COVID-19 [
83]. In stark contrast to the positive results from ACTT-1 in the USA, in one of the most recent and broadest clinical trials to date, the World Health Organization (WHO) international SOLIDARITY trial allocated 2750 patients to remdesivir and 4088 to no study drug and found a 28-day mortality relative risk ratio of 0.95 (95% CI 0.81–1.11,
p = 0.50) which showed no statistically significant reduction in mortality. Total 28-day mortality was 12%, and this was measured along Kaplan–Meier curves. SOLIDARITY, when gathering the great amount of patients in combination with the finalized ACTT-1 results, has shown that there is no statistically significant difference in mortality with remdesivir use [
15]. While initial results with the ACTT-1 trial seemed promising, final results in combination with the SOLIDARITY trial have shown remdesivir has limited utility in curbing mortality rates and that it may have limited efficacy. This complete picture of evidence has complicated many healthcare centers’ aggressive uptake of this drug as one of the few pharmacological options for patients with COVID-19. Guidelines have split on remdesivir’s ultimate use, with the NIH and IDSA guidelines advocating for remdesivir’s use in severe COVID-19, and WHO issuing a conditional recommendation against remdesivir’s use in hospitalized patients given the lack of evidence that it improves survival or has an important effect on need for mechanical ventilation or time to clinical improvement [
14,
84]. The dosing table below provides complete context on how the drug should be used and is the current recommended dosage under the NIH guidelines.
-
Remdesivir dosing table
Dosing | 200 mg IV once × 1 day, 100 mg IV QD × 4 or 9 days |
Duration | 5 days (≤ 94% SpO2, and not requiring mechanical ventilation and/or ECMO) Can extend to (if no clinical improvement demonstrated) 10 days (mechanical ventilation and/or ECMO) |
Adverse effects | Adverse events were mostly mild–moderate: hepatic enzyme elevations, diarrhea, rash, etc. [ 21] |
Chloroquine/Hydroxychloroquine
Chloroquine (CQ) and hydroxychloroquine (HCQ) are pharmacologic therapies exhibit in vitro antiviral activity against SARS-CoV-2 [
24]. HCQ is a derivative of chloroquine with an extra hydroxyl group and has been shown to be less toxic than CQ in animal studies [
85]. Initially, both agents had been used as antimalarial drugs as derivatives of quinine, then later became used as immunomodulatory drugs for autoimmune and rheumatic diseases upon approval in 1956. In addition to their immunoregulatory and anti-inflammatory properties, their proposed antiviral effects are thought to be mediated by changes in the cell membrane pH necessary for viral fusion and interference of glycosylation of viral proteins [
86]. The chloroquine analogues seemed to emerge in clinical trials as potential treatment options against the novel coronavirus [
87]. Initially, chloroquine had been studied in 23 clinical trials in China, in addition to promising in vitro research. Hydroxychloroquine, alone and in combination, had even more results available in late spring 2020. This initial treatment use for hydroxychloroquine and chloroquine was driven by a lower quality of evidence until RCTs confirmed the lack of efficacy of the treatment [
15,
24‐
27,
37].
One such early study, a non-randomized trial, emerged in mid-March from a group of researchers in Marseille, France, which described the preliminary use of HCQ (200 mg TID) ± azithromycin (AZI) (500 mg on day 1 followed by 250 mg per day, the next 4 days) in 26 patients compared to a control group, which received supportive care only [
37]. The addition of azithromycin in this trial is interesting for its noted anti-inflammatory properties, but additional data suggested potential antiviral mechanisms [
88]. Viral clearance in nasopharyngeal swabs was achieved in 6/6 (100%) patients in the HCQ + AZI group and 8/14 (57%) in the HCQ monotherapy group [
37]. This study drove much of the fervent interest in HCQ and AZI as a potential combination therapy for COVID-19. However, while preprint popularity drove initial use, full results have been published along with other results from similar studies. In the full results of the Gautret study, 80 patients were included with no control group, and the results can only be interpreted by inference to other studies on COVID-19 patients with standard supportive care. The final polymerase chain reaction (PCR) results in the complete study were less impressive with roughly 40% of 80 patients having a PCR-positive sample at day 5 compared with 0% in the interim results of HCQ + AZI above [
37,
38].
The full Gautret study did not have a control group, so interpreting treatment efficacy is a challenge and represents a significant limitation of the study. However, since the publishing of the initial study results in Marseille, a group in Paris, France failed to replicate the positive preliminary results of Gautret and colleagues in a prospective study designed to assess both virologic and clinical outcomes in patients with severe COVID-19. The study included 11 patients who received hydroxychloroquine (600 mg/day for 10 days) and azithromycin (500 mg day 1 and 250 mg days 2–5) using the same dosing regimen reported by Gautret et al. Repeated nasopharyngeal swabs at days 5–6 after treatment initiation were still positive in 8/10 patients (80%, 95% CI 49–94). The virologic results contrast those reported by Gautret, et al., which left unanswered questions regarding the role of this combination therapy in the treatment of COVID-19 [
39]. After this series of studies, prospective randomized trials began to result, beginning in late March. The first of these came from Wuhan with somewhat positive results. In this study, 31 patients were randomized to 5 days of hydroxychloroquine (400 mg/day) and 31 patients were randomized to placebo. In the treatment group, chest CTs significantly improved in 25/31 (80.6%) patients from day 0 to 6, compared with the control group of 17/31 (54.8%) [
28]. While promising, the trial was underpowered to detect a significant outcome, and it was intended to recruit 300 patients at the outset, instead of the published 62 patients. In early May with the Tang study, RCTs began to illuminate the treatment’s lack of efficacy more clearly and adverse events came to be more clearly documented. This trial had 75 participants in each group, HCQ and standard of care, across 16 hospital sites in China in February. Results focused on negative conversion of SARS-CoV-2 by 28 days, which was non-significantly different between the two groups, because only two patients with severe COVID-19 were enrolled for clinical outcome analysis. Frequency of adverse events was 9% in the standard of care group and 30% in the HCQ group [
27]. The lack of efficacy and higher adverse event results continued in three further large RCTs for hydroxychloroquine [
15,
25,
26].
At the time of this review, there are now at least five significant RCTs evaluating the use of hydroxychloroquine and azithromycin [
15,
25‐
28]. The RCTs have shown a lack of efficacy of hydroxychloroquine or azithromycin, in comparison to results from some non-randomized clinical retrospective trials [
32,
33,
36]. Indeed, the addition of azithromycin may cause more harm than intended given the noted QT prolongation that can occur [
89]. Hydroxychloroquine, chloroquine, and azithromycin have now fully fallen out of favor because of the overall study results. The SOLIDARITY trial in combination with other RCTs like ACTT-1 has now settled the question of any therapeutic efficacy for hydroxychloroquine. For historical dosing reference when they were utilized, refer to the hydroxychloroquine dosing table for a brief review on regimens.
Note: Most dosing regimens have been extrapolated from pharmacokinetics (PK) parameters described in patients with rheumatic diseases or healthy volunteers; therefore, PK studies are still needed to determine the optimal dosing regimen in patients with COVID-19 [
90].
800 mg followed by 400 mg at 6, 24, 48, 72, and 96 h 3 days (acute malaria treatment) 5–10 days | FDA approved adult dosing for treatment of acute malaria extended to 5 days. Recommended most reasonable, efficacious, and safest approach by Downes’ dosing simulations [ 91] |
400 mg BID × 2 doses, then 200 mg PO BID 5 days Prefer to give with food | Optimal regimen recommended by Yao et al. [ 92] |
200 mg TID × 10 days | Dosing from Gautret et al. [ 37] |
400 mg QD × 10 days | Maximal approved adult dosing for rheumatologic conditions |
800 mg on day 1, then 200 mg BID for 7 days | For ICU patients with COVID-19, recommended from prospective study describing PK of HCQ in 13 patients [ 90] |
Adverse effects: Usually mild severity—GI intolerances, cytopenias, QT prolongation, headaches, dizziness |
Warning: A recent cohort study found that the addition of azithromycin to hydroxychloroquine was associated with greater changes in QTc as compared to hydroxychloroquine alone. Close monitoring of QTc should be utilized with concomitant medication usage [ 89] |
Lopinavir/Ritonavir
Lopinavir/ritonavir (LPV/r) is a combination drug that is FDA approved for the treatment of HIV infection. It combines a protease inhibitor and a pharmacokinetic enhancer, where the enhancer is used to increase the effectiveness and concentration of lopinavir. Lopinavir/ritonavir has been identified as a potential treatment option against SARS-CoV-2 given its documented in vitro antiviral activity against SARS-CoV-1 [
93]. The proposed mechanism of action suggests lopinavir inhibits the main protease of SARS-CoV-1, which stops viral replication [
94]. One of the first RCTs evaluating lopinavir/ritonavir’s efficacy was conducted in patients with severe COVID-19 in January to February in China, with results published mid-March. This study helped to temper any enthusiasm for lopinavir/ritonavir as a potential treatment early in the US COVID-19 treatment experience. The study included 199 patients and compared the clinical outcomes between patients who received LPV/r and supportive care only. The study found no significant difference mortality at 28 days or viral clearance, nor did it identify an association between the addition of LPV/r and clinical improvement, defined as improvement of two points on a seven-category ordinal scale or discharge from the hospital. However while primary results showed little efficacy, post hoc analyses found statistical significance in median time to clinical improvement for the LPV/r group (1 day shorter, HR 1.39, 95% CI 1.00–1.91) when removing patients that experienced death before getting the drug and for patients receiving therapy within 12 days of onset of symptoms [
44]. This minor positive signal in the data would continue questions of efficacy around lopinavir/ritonavir until further studies confirmed the lack of a benefit. One study conducted in China evaluated LPV/r in mild–moderate COVID-19 and compared this against usual care with a comparator arm of umifenovir (Arbidol), a broad antiviral medication used against influenza. The study was limited by its low sample size of 86 patients, but found no benefit of LPV/r in the rate of positive-to-negative conversion of SARS-CoV-2 nucleic acid or improvement in symptoms or imaging. In fact, the therapy only increased adverse events from primarily diarrhea and loss of appetite in the LPV/r arm [
42].
While a somewhat positive signal for treatment deep in the data from the Cao et al. study may have been present, any question of therapeutic benefit has since been ended with the RECOVERY trial results from over 4500 patients. With 1596 patients randomized to LPV/r and 3376 randomized to standard of care, it was found that there was no significant difference in mortality, progression to mechanical ventilation, or length of hospital stay in either group [
43]. In addition to the RECOVERY trial results, results were further solidified with the subsequent SOLIDARITY trial data which showed a lack of any mortality benefit to lopinavir/ritonavir. The SOLIDARITY trial involved 1411 patients randomized to lopinavir, 651 to interferon plus lopinavir, and 4088 no study drug at 405 hospitals in 30 countries. Lopinavir showed no statistically significant effect on mortality (RR1.00, CI 0.79–1.25,
p = 0.97) [
15]. Given the volume of patients involved in these two major trials, this has since shuttered further research into this drug being of benefit to patients with COVID-19. The dosing for lopinavir/ritonavir is documented below for completeness and historical sake, but it is no longer considered a viable treatment option for COVID-19.
-
Lopinavir/ritonavir dosing table
Dosing | PO: 400/100 mg (2 tabs) BID |
Duration | 5–10 days. Up to 14 total days of therapy have been reported, but most patients have adverse effects requiring early termination of drug combination |
Adverse effects | Occur in most patients and can be moderate/severe—GI intolerance, hepatitis, and LFT abnormalities |
Other Antiviral Drugs
Other antiviral drugs have been studied for the treatment of COVID-19, and these include favipiravir, umifenovir (Arbidol), galidesivir, drugs currently utilized against influenza (oseltamivir, etc.), and sofosbuvir/daclatasvir. These antiviral drugs have not shown significant data to support their use. Some, like oseltamivir, have been ruled out as agents to use for COVID-19 given the lack of positive in vitro data and absence of plausible mechanism of action [
46]. Favipiravir and umifenovir are broad antivirals approved in countries outside the USA that were used as anti-influenza agents. Both drugs have had limited clinical data supporting their use, although there has been some in vitro data [
40,
42,
95,
96]. Sofosbuvir/daclatasvir is a treatment for hepatitis C infection that has also been found to bind to SARS-CoV-2 [
97]. In a limited non-randomized study, it was found to have positive outcomes in COVID-19. However the trial was of limited participants and the comparison group was against ribavirin, which had significantly more adverse events as a therapy and it is not one commonly used in COVID-19 [
45].