Review of Selected Repurposed Drugs
Agents previously used to treat SARS and MERS are potential candidates to treat COVID-19. Various agents with apparent in vitro activity against SARS-CoV and MERS-CoV were used during the SARS and MERS outbreaks, with inconsistent efficacy. Meta-analyses of SARS and MERS treatment studies found no clear benefit of any specific regimen.37,38 Below, the in vitro activity and published clinical experiences of some of the most promising repurposed drugs for COVID-19 are reviewed.
Chloroquine and Hydroxychloroquine
Chloroquine and hydroxychloroquine have a long-standing history in the prevention and treatment of malaria and the treatment of chronic inflammatory diseases including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).7 Chloroquine and hydroxychloroquine appear to block viral entry into cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification. These agents also have immunomodulatory effects through attenuation of cytokine production and inhibition of autophagy and lysosomal activity in host cells.9,10 Chloroquine inhibits SARS-CoV-2 in vitro with a half-maximal effective concentration (EC50) in the low micromolar range. Hydroxychloroquine has in vitro activity with a lower EC50 for SARS-CoV-2 compared with chloroquine after 24 hours of growth (hydroxychloroquine: EC50 = 6.14 μM and chloroquine: EC50 = 23.90 μM).15
No high-quality evidence exists for the efficacy of chloroquine/hydroxychloroquine treatment of SARS or MERS. A news briefing from China reported chloroquine was successfully used to treat a series of more than 100 COVID-19 cases resulting in improved radiologic findings, enhanced viral clearance, and reduced disease progression.39 However, the clinical trial design and outcomes data have not yet been presented or published for peer review, preventing validation of these claims. A recent open-label nonrandomized French study of 36 patients (20 in the hydroxychloroquine group and 16 in the control group) reported improved virologic clearance with hydroxychloroquine, 200 mg, by mouth every 8 hours compared with control patients receiving standard supportive care. Virologic clearance at day 6, measured by nasopharyngeal swabs, was 70% (14/20) vs 12.5% (2/16) for the hydroxychloroquine and control groups, respectively (P = .001). The authors also reported that addition of azithromycin to hydroxychloroquine in 6 patients resulted in numerically superior viral clearance (6/6, 100%) compared with hydroxychloroquine monotherapy (8/14, 57%).16
Despite these promising results, this study had several major limitations: a small sample size (only 20 in the intervention arm and only 6 receiving hydroxychloroquine and azithromycin); the removal of 6 patients in the hydroxychloroquine group from analysis due to early cessation of treatment resulting from critical illness or intolerance of the medications; variable baseline viral loads between hydroxychloroquine monotherapy and combination therapy groups; and no clinical or safety outcomes reported. These limitations coupled with concerns of additive cardiotoxicity with combination therapy do not support adoption of this regimen without additional studies. Another prospective study of 30 patients in China randomized patients to hydroxychloroquine, 400 mg, daily for 5 days plus standard of care (supportive care, interferon, and other antivirals) or standard care alone in a 1:1 fashion; there was no difference in virologic outcomes. At day 7, virologic clearance was similar, with 86.7% vs 93.3% clearance for the hydroxychloroquine plus standard of care group and standard care group, respectively (P > .05).17 Currently, there are several RCTs of both chloroquine and hydroxychloroquine examining their role in COVID-19 treatment. Studies of chloroquine prophylaxis in health care workers (NCT04303507) and hydroxychloroquine for postexposure prophylaxis after high-risk exposures (NCT04308668) are planned or enrolling.40
Dosing of chloroquine to treat COVID-19 has consisted of 500 mg orally once or twice daily.11,12 However, a paucity of data exists regarding the optimal dose to ensure the safety and efficacy of chloroquine. Hydroxychloroquine dosing recommendations for SLE generally are 400 mg orally daily.18 However, a physiologically based pharmacokinetic modeling study recommended that the optimal dosing regimen for hydroxychloroquine in COVID-19 treatment is a loading dose of 400 mg twice daily for 1 day followed by 200 mg twice daily.15 In contrast, alternative recommendations are made for 600 mg total daily dose based on safety and clinical experience for Whipple disease.11 Further studies are needed to delineate the optimal dose for COVID-19.
Chloroquine and hydroxychloroquine are relatively well tolerated as demonstrated by extensive experience in patients with SLE and malaria. However, both agents can cause rare and serious adverse effects (<10%), including QTc prolongation, hypoglycemia, neuropsychiatric effects, and retinopathy.41,42 Baseline electrocardiography to evaluate for prolonged QTc is advisable prior to and following initiation of these medications because of the potential for arrhythmias, especially in critically ill patients and those taking concomitant QT-interval prolonging medications such as azithromycin and fluoroquinolones.13 No significant adverse effects have been reported for chloroquine at the doses and durations proposed for COVID-19.39 Use of chloroquine and hydroxychloroquine in pregnancy is generally considered safe.13,18 A review of 12 studies including 588 patients receiving chloroquine or hydroxychloroquine during pregnancy found no overt infant ocular toxicity.43
Lopinavir/Ritonavir and Other Antiretrovirals
Lopinavir/ritonavir, a US Food and Drug Administration (FDA)–approved oral combination agent for treating HIV, demonstrated in vitro activity against other novel coronaviruses via inhibition of 3-chymotrypsin-like protease.21,22 No published SARS-CoV-2 in vitro data exist for lopinavir/ritonavir.44 A systematic review of lopinavir/ritonavir for the treatment of SARS and MERS found limited available studies, with most of these investigating SARS. Clinical studies in SARS were associated with reduced mortality and intubation rates, but their retrospective, observational nature prevents definitive conclusions. The timing of administration during the early peak viral replication phase (initial 7-10 days) appears to be important because delayed therapy initiation with lopinavir/ritonavir had no effect on clinical outcomes.45,46
Early reports of lopinavir/ritonavir for the treatment of COVID-19 are mostly case reports and small retrospective, nonrandomized cohort studies, making it difficult to ascertain the direct treatment effect of lopinavir/ritonavir.45,46 More recently, Cao and colleagues23 reported the results of an open-label RCT comparing the efficacy of lopinavir/ritonavir vs standard care in 199 patients with COVID-19. Importantly, the median time from symptom onset to randomization was 13 days (interquartile range [IQR], 11-16), with no between-group difference. The primary outcome of time to clinical improvement defined by a 2-point improvement on a 7-category ordinal scale or hospital discharge was similar in both groups (16 days [IQR, 13-17] vs 16 days [IQR, 15-17]; hazard ratio [HR], 1.31 [95% CI, 0.95-1.85]; P = .09). Additionally, no significant differences in viral clearance or 28-day mortality rates (19.2% vs 25.0%; absolute difference, −5.8% [95% CI, −17.3% to 5.7%]) were observed. Although delayed treatment initiation may partially explain the ineffectiveness of lopinavir/ritonavir for treating COVID-19, a subgroup analysis did not find shorter time to clinical improvement for patients who received therapy within 12 days (HR, 1.25 [95% CI, 0.77-2.05]).23 Although additional RCTs of lopinavir/ritonavir are ongoing, the current data suggest a limited role for lopinavir/ritonavir in COVID-19 treatment.
The most commonly used and studied lopinavir/ritonavir dosing regimen for COVID-19 treatment is 400 mg/100 mg twice daily for up to 14 days.12,23 Given the significant drug-drug interactions and potential adverse drug reactions (summarized in Table 1), careful review of concomitant medications and monitoring are required if this drug is used. Adverse effects of lopinavir/ritonavir include gastrointestinal distress such as nausea and diarrhea (up to 28%) and hepatotoxicity (2%-10%).24 In patients with COVID-19, these adverse effects may be exacerbated by combination therapy or viral infection because approximately 20% to 30% of patients have elevated transaminases at presentation with COVID-19.47 A recent RCT showed approximately 50% of lopinavir/ritonavir patients experienced an adverse effect and 14% of patients discontinued therapy due to gastrointestinal adverse effects.23 Drug-induced transaminitis is of particular concern because it may exacerbate liver injury resulting from COVID-19. Importantly, alanine transaminase elevations are an exclusion criterion in several COVID-19 investigational trials, meaning that lopinavir/ritonavir-induced hepatotoxicity could limit patients’ ability to access these other drugs.40
Other antiretrovirals, including protease inhibitors and integrase strand transfer inhibitors, were identified by enzyme activity screening as having SARS-CoV-2 activity.44 In vitro cell models demonstrated activity of darunavir against SARS-CoV-2. There is no human clinical data in COVID-19 with these drugs, but an RCT of darunavir/cobicistat in China is underway.40
Ribavirin, a guanine analogue, inhibits viral RNA-dependent RNA polymerase. Its activity against other nCoVs makes it a candidate for COVID-19 treatment. However, its in vitro activity against SARS-CoV was limited and required high concentrations to inhibit viral replication, necessitating high-dose (eg, 1.2 g to 2.4 g orally every 8 hours) and combination therapy. Patients received either intravenous or enteral administration in previous studies.37 No evidence exists for inhaled ribavirin for nCoV treatment, and data with respiratory syncytial virus suggest inhaled administration offers no benefit over enteral or intravenous administration.48
A systematic review of the clinical experience with ribavirin for the treatment of SARS revealed inconclusive results in 26 of the 30 studies reviewed, with 4 studies demonstrating possible harm due to adverse effects including hematologic and liver toxicity.37 In the treatment of MERS, ribavirin, generally in combination with interferons, demonstrated no discernible effect on clinical outcomes or viral clearance.38,49 A paucity of clinical data with ribavirin for SARS-CoV-2 means its therapeutic role must be extrapolated from other nCoV data.
Ribavirin causes severe dose-dependent hematologic toxicity. The high doses used in the SARS trials resulted in hemolytic anemia in more than 60% of patients.37 Similar safety concerns were seen in the largest MERS observational trial, with approximately 40% of patients taking ribavirin plus interferon requiring blood transfusions.49 Seventy-five percent of patients taking ribavirin for SARS experienced transaminase elevations.37 Ribavirin is also a known teratogen and contraindicated in pregnancy.50
The inconclusive efficacy data with ribavirin for other nCoVs and its substantial toxicity suggest that it has limited value for treatment of COVID-19. If used, combination therapy likely provides the best chance for clinical efficacy.
Oseltamivir, a neuraminidase inhibitor approved for the treatment of influenza, has no documented in vitro activity against SARS-CoV-2. The COVID-19 outbreak in China initially occurred during peak influenza season so a large proportion of patients received empirical oseltamivir therapy until the discovery of SARS-CoV-2 as the cause of COVID-19.51 Several of the current clinical trials include oseltamivir in the comparison group but not as a proposed therapeutic intervention.40 This agent has no role in the management of COVID-19 once influenza has been excluded.
Umifenovir (also known as Arbidol) is a more promising repurposed antiviral agent with a unique mechanism of action targeting the S protein/ACE2 interaction and inhibiting membrane fusion of the viral envelope.27 The agent is currently approved in Russia and China for the treatment and prophylaxis of influenza and is of increasing interest for treating COVID-19 based on in vitro data suggesting activity against SARS.28 The current dose of 200 mg orally every 8 hours for influenza is being studied for COVID-19 treatment (NCT04260594). Limited clinical experience with umifenovir for COVID-19 has been described in China. A nonrandomized study of 67 patients with COVID-19 showed that treatment with umifenovir for a median duration of 9 days was associated with lower mortality rates (0% [0/36] vs 16% [5/31]) and higher discharge rates compared with patients who did not receive the agent.29 This observational data cannot establish the efficacy of umifenovir for COVID-19, but ongoing RCTs in China are further evaluating this agent.
Interferon-α and -β have been studied for nCoVs, with interferon-β demonstrating activity against MERS.37,38 Most published studies reported results of therapy combined with ribavirin and/or lopinavir/ritonavir. Similar to other agents, delayed treatment may limit effectiveness of these agents. Given conflicting in vitro and animal data and the absence of clinical trials, the use of interferons to treat SARS-CoV-2 cannot currently be recommended.52 Current Chinese guidelines list interferons as an alternative for combination therapy.12 Several other immunomodulatory agents traditionally used for noninfectious indications demonstrate in vitro activity or possess mechanisms purported to inhibit SARS-CoV-2, including, but not limited to, baricitinib, imatinib, dasatinib, and cyclosporine.53-57 However, no animal or human data exist to recommend their use for COVID-19, and it remains to be seen whether they confer protection for patients already taking them for other indications.
Nitazoxanide, traditionally an antihelminthic agent, has broad antiviral activity and a relatively favorable safety profile. Nitazoxanide has demonstrated in vitro antiviral activity against MERS and SARS-CoV-2.58,59 Pending further evidence, the antiviral activity, immunomodulatory effects, and safety profile of nitazoxanide warrant its further study as a treatment option for SARS-CoV-2.
Camostat mesylate, an approved agent in Japan for the treatment of pancreatitis, prevents nCoV cell entry in vitro through inhibition of the host serine protease, TMPRSS2.3 This novel mechanism provides an additional drug target for future research.
SARS-CoV-2 uses the ACE2 receptor for entry into the host cell.3 This discovery has stimulated discussions about whether ACE inhibitors and/or angiotensin receptor blockers may potentially treat COVID-19 or, conversely, worsen disease.60 These drugs upregulate ACE2 receptors, which could theoretically lead to worse outcomes if viral entry is enhanced. In contrast, angiotensin receptor blockers could theoretically provide clinical benefit via blockade of ACE2 receptors. Conflicting in vitro data exist to determine if these agents have a detrimental or protective effect in patients with COVID-19. Pending further research, clinical societies and practice guidelines are recommending continuing therapy for patients already taking 1 of these agents.
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