key: cord-1010205-lbrk51fc
authors: Singh, Manmeet; de Wit, Emmie
title: Antiviral agents for the treatment of COVID-19: progress and challenges
date: 2022-02-11
journal: Cell Rep Med
DOI: 10.1016/j.xcrm.2022.100549
sha: 48a66c79c4045c2607056df9dd98e48d2950d48a
doc_id: 1010205
cord_uid: lbrk51fc

The COVID-19 pandemic has seen clinical development and use of antiviral therapies at an unprecedented speed. Antiviral therapies have greatly improved the clinical outcome in COVID-19 patients, especially when administered early after diagnosis. Here, we discuss the successes and challenges of COVID-19 antiviral therapies, and lessons for future pandemics.

The COVID-19 pandemic has seen clinical development and use of antiviral therapies on a scale 25 unprecedented for an acute viral infection. Although antivirals have been used effectively on a large 26 scale to treat chronic virus infections like HIV and hepatitis C virus, their use to treat acute viral 27

infections has been limited until now by a lack of effective antiviral therapies and a small window of 28 opportunity to apply treatment and improve patient outcomes. 1 Two years after the emergence of 29 SARS-CoV-2, antiviral therapies are available that can be administered early after diagnosis in patients at 30 risk of developing severe disease, as well as therapies to improve outcome once severe disease has 31 developed ( Figure) . 2 These treatments are generally divided into two classes: direct-acting antivirals and 32

host-directed therapies. Direct-acting antivirals are those therapies that target components of the virus 33 and inhibit its replication. For these direct-acting antivirals to be effective, they must be administered 34 early during infection before the virus reaches its replication peak and are therefore used to prevent 35 progression to severe disease. 3 Host-directed therapies on the other hand target either components of 36 the host cell required for replication of the virus or aim to dampen the dysregulated inflammatory 37 response to infection; in the case of COVID-19, only the latter class of host-directed therapies are 38 currently available. These target the outsize inflammatory response involved in severe COVID-19 disease 39 manifestations. These manifestations -ranging from dyspnea and hypoxia to acute respiratory distress 40 syndrome and multi-organ failure-occur later during infection. Therefore, host-directed therapies are 41 used during the later stages of COVID-19 disease, when virus replication is typically past its peak, the 42 patient is hospitalized, and requires respiratory support. 3 43 44

There are currently no uniform, global COVID-19 treatment guidelines; for the purpose of clarity, this 45 article mainly focuses on the current US treatment guidelines. 2 Remdesivir, a nucleotide analog, was the 46 first direct-acting antiviral to receive FDA Emergency Use Authorization (EUA) for the treatment of 47 COVID-19 patients just months after the COVID-19 pandemic was declared, 4 based on data showing a 48 reduced time to recovery in hospitalized COVID-19 patients. Next, a neutralizing monoclonal antibody, 49 bamlanivimab, was shown to reduce symptoms of COVID-19 and hospitalization rates; it received EUA 50

for the treatment of COVID-19 patients. 4 This monoclonal antibody was followed by several other 51 monoclonal antibodies and cocktails thereof ( Figure) ; other neutralizing monoclonal antibodies are in 52 use outside the US, and many monoclonal antibodies are still being evaluated in clinical trials. In 53

December 2021, two orally-available direct-acting antivirals with clinical benefit in preventing 54 progression to severe disease, hospitalization, and/or death received FDA EUA: molnupiravir, a 55 nucleotide analog and paxlovid, a protease inhibitor. 2 Together, the direct-acting antivirals have greatly 56

improved the outlook of COVID-19 patients known to be at risk of developing severe COVID-19 due to 57 underlying conditions (Table) . 58 59

In patients that have already progressed to more severe disease, host-directed treatments are used to 60 achieve either general immune suppression through use of dexamethasone or other corticosteroids. 61

Other therapies involve a more targeted manipulation of the immune response using inhibitors of IL6, 62

one of the hallmarks of severe COVID-19 identified early in the pandemic, or inhibiting Janus kinase and 63 thereby cytokine signaling ( Figure) . 2 Although these immunomodulators have resulted in a decreased 64 mortality in severe cases of COVID-19, the effect of these late-stage treatments is much smaller than 65 that of direct-acting antivirals administered in the early disease stage (Table) . Therefore, patient survival 66 depends heavily on advanced supportive care including prone positioning, mechanical ventilation, and 67

ECMO. 2 68 69

Several therapeutics (direct-acting and host-directed) are still in the preclinical and clinical stages of 70 development 5 and more treatment options will hopefully become available before too long. For 71 example, clinical trial data for fluvoxamine recently showed a clinical benefit in preventing disease 72 progression 6 through a currently unknown mechanism. Through the investment of an inordinate 73 amount of money and time, as well as unprecedented collaborations between scientists, clinicians and 74 the biopharmaceutical industry, we now have several effective antiviral therapies to treat COVID-19. 2 75

However, we must also acknowledge that many severe cases of COVID-19 still occur and more antiviral 76 therapies are needed. A critical assessment of gaps in treatment success is necessary so we can define 77 ways to speed up recovery, reduce the long-term effects of SARS-CoV-2 infection, and increase the rate 78 of survival in severe COVID-19 patients. We should also look beyond COVID-19 and draw lessons from 79 this pandemic that will prepare us better for future pandemics that will undoubtedly emerge. 80 81

Challenges for development of direct-acting antivirals 82

The value of administering direct-acting antivirals to at-risk patients early after diagnosis is clear from 83

the Table: the majority of severe COVID-19 cases can be prevented through timely administration of (a 84 combination of) direct-acting antivirals. Currently, these direct-acting therapeutics are only used in 85 patients at known risk for severe COVID-19 due to the presence of risk factors such as age and obesity, 86 or comorbidities like diabetes and heart conditions. 2 Ideally, direct-acting antivirals would be used on an 87 even larger scale, in symptomatic patients not known to be at risk of severe disease, to reduce the time 88

to recovery, potentially reduce long-lasting effects of infection, and potentially even reduce onward 89 transmission of the virus. Due to the nature of direct-acting antivirals, their efficacy increases even with 90 small reductions in time to treatment initiation. Therefore, the availability of rapid diagnostics with a 91 low limit of detection, combined with a low threshold for prescription, and availability in local 92

pharmacies are essential to get the largest possible clinical benefit from direct-acting antivirals. 93 94

Another important consideration is the administration route of direct-acting antivirals. As mentioned 95 above, remdesivir was the first antiviral therapy to receive FDA EUA and the only fully licensed antiviral 96 therapy to date. However, remdesivir treatment is complicated by the need to administer it 97 intravenously on 5 consecutive days. Therefore, use of remdesivir has so far mostly been limited to 98 patients already hospitalized with COVID-19. A recent clinical trial studying the effect of outpatient 99 treatment with remdesivir (i.e. sooner after diagnosis) showed a much larger beneficial effect of 100 remdesivir with this early administration. 7 Thus, efforts should be made to develop direct-acting 101 antivirals that can be self-administered, preferentially orally, or subcutaneously or intranasally if oral 102 administration is not feasible. Alternatively, facilities and protocols that can ensure daily outpatient 103 treatment administration could be developed -this has occurred for monoclonal antibody 104 administration, and would be possible for other treatments, even if those antiviral therapies might have 105 to be administered on several consecutive days. However, at-home use of antivirals puts a high bar on 106 these drugs: they must lack significant side effects or negative interactions with other medications since 107 patients taking them would not be under continuous medical supervision. 108 109

Treatment of patients upon diagnosis rather than at the time of hospitalization means treating a 110 significantly larger number of people, since most patients never progress to severe disease, even 111 without treatment. Therefore, next-generation direct-acting antivirals should be easy to administer, 112 mass-produce, distribute, and store. Additionally, the pricing of these antivirals should be such that they 113

would be affordable to all patients. Since the majority of the world population resides in low-or middle-114 income countries, equitable access to antiviral therapies has to be ensured through waving of patent 115 licensing fees; international financial support; or investment in production, storage and distribution 116 infrastructure in these countries to help reduce the cost. 117 J o u r n a l P r e -p r o o f 118

Finally, the selection of viral variants with mutations conferring resistance to direct-acting antivirals is a 119 major concern. Even though SARS-CoV-2 causes an acute infection in immune-competent individuals, 120 treatment courses are short. SARS-CoV-2 has proof-reading abilities when copying its RNA -the 121 emergence of several Variants of Concern (VOC) 8 has put a focus on the ability of SARS-CoV-2 to escape 122 from effective therapeutics. The B.1.351 (beta) and P.1 (gamma) VOC encode amino acid substitutions in 123 their spike proteins that sharply reduced the efficacy of the bamlanivimab and etesivimab monoclonal 124 antibody cocktail. The FDA EUA for these monoclonals was therefore temporarily withdrawn. 2 The 125 emergence of the B.1.1.529 (omicron) VOC is posing even larger problems, since most monoclonal 126

antibody treatments under FDA EUA have reduced neutralizing capacity against this VOC in vitro. 9 127

Combination treatments consisting of two or more direct-acting antivirals from a different class (e.g., a 128 nucleotide analog plus monoclonal antibody) will likely reduce the chance of escape variants to emerge 129 and may improve the clinical benefit of treatment. Combination treatment should therefore be 130 investigated in clinical trials. 131 132 133

Challenges for development of host-directed therapies 134

Severe lower respiratory tract infections have historically been extremely difficult to treat, and COVID-135 19 is no exception. As explained above, direct-acting antivirals have very limited effect once severe 136 disease manifests because the virus replication is already much reduced. Rather, the disease is driven by 137 the host's hyperinflammatory response to infection, resulting in acute respiratory distress and multi-138 organ failure. 10 Although a few immunomodulatory therapies have led to an increase in survival in 139 COVID-19 patients, 2 they are ineffective in a large subset of patients (Table) . Moreover, the 140 administration of these therapeutics in relation to disease progression must be timed correctly to avoid 141 negative effects on patient outcome. 3 Thus, one major remaining challenge is to identify additional host-142 directed therapies for the treatment of severe COVID-19. Unfortunately, a clear path forward for host-143 directed therapies has not emerged from years of research on acute respiratory distress syndrome and 144 multi-organ failure, and many clinical trials evaluating potential therapeutics 11 . We must use this 145 pandemic, and the unprecedented amount of patient information acquired so far, to advance our 146 understanding -and the treatment -of viral lower respiratory tract disease. Never before have 147 researchers had access to such a large data and clinical sample set derived from patients and animal 148 models that can be used as the basis for this research. Additionally, technological innovations like single-149 cell transcriptomics and the use of respiratory tract organoids are tools that have not been applied to 150 this problem before but could lead to significant discoveries. Combining these tools with the data and 151 samples available from COVID-19 patients, will result in a mechanistic understanding of the cascade of 152 specific cellular processes underlying severe disease, as well as biomarkers indicating which phase of the 153 cascade patients are in. Individual components of this cascade form novel targets for time-resolved 154 host-directed therapies. This will require large investments in terms of research funding, but the added 155 benefit of this investment would be that it will likely result in effective treatments for pneumonia and 156 acute respiratory distress from causes other than SARS-CoV-2 infection as well. 157 158

Research also needs to focus on the effects of COVID-19 in convalescent patients, as long-lasting effects 159

of COVID-19 are common. While this issue may have been overlooked early on, when the focus was on 160 finding treatments for acute disease, the enormous number of convalescents with persisting problems is 161 now too urgent to ignore. One obvious area of study is lung regeneration, since many patients who 162 J o u r n a l P r e -p r o o f recover from severe COVID-19 will have long-lasting damage to their lungs such as pulmonary fibrosis 163 that may negatively impact recovered patients' quality of life. 12 164

Another area that requires additional clinical and mechanistic research is post-acute COVID-19 165 syndrome (PACS; also known as 'long COVID'). Many recovered COVID-19 patients experience long-166 lasting effects of COVID-19 infection with problems arising from many different organ systems besides 167 the lung, regardless of the severity of the acute stage of SARS-CoV-2 infection and without evidence of 168 continued virus replication. 13 More clinical research on patients with PACS is urgently needed to 169 understand this syndrome better and find effective therapeutics to treat it. 170 171

Future directions: pandemic preparedness 172

Clinicians and scientists from all medical and scientific disciplines redirected their focus to COVID-19 in 173 the past two years, resulting in rapid progress in the prevention and treatment of COVID-19 and a 174 significantly reduced disease burden on the level of the individual patient. However, it is clear from the 175 above that we need additional antiviral therapies in our COVID-19 arsenal. Now that pandemic response 176 and pandemic preparedness are high on everyone's agenda, a thorough analysis of the antiviral therapy 177

research & development pipeline needs to be conducted to identify bottlenecks that impede the clinical 178 development of antiviral therapies. For example, treatments like molnupiravir and paxlovid were 179 developed years before the emergence of SARS-CoV-2 as potential antiviral therapies for SARS and 180

influenza, respectively. Still, it has taken almost two years since the emergence of SARS-CoV-2 for these 181 drugs to receive FDA EUA for COVID-19. Why did this take so long, and could this have been 182

accomplished faster? Why do all the now-approved treatments use a mechanism of action found in 183 previously approved antiviral therapies ( 195 but it is safe to assume that many more potential antiviral therapies for COVID-19 failed in the 196 preclinical development phase than we know of. Yet, much knowledge could be gained from analyzing 197 which compounds were found to be ineffective during preclinical development, why they were 198 ineffective (if known), which assays were used to include the compound in preclinical studies, and which 199 assays were used to exclude them later. A repository of compounds that were ineffective during 200 preclinical development containing this information could be a great tool to streamline the preclinical 201 development of antiviral therapies since it would allow us to define assays with the best predictive value 202

for the efficacy of potential antiviral therapies. Assays with low predictive value could then be replaced 203 with more predictive ones. One important example in this context is the use of Vero cells for screening 204 of direct-acting antivirals. Chloroquine performed well in these cells, but was later shown not to be 205 effective in more representative primary cells and multiple animal models. Thus, the chloroquine 206 debacle could have been avoided if a better initial screening assay had been used. 14 A more streamlined 207 preclinical development pipeline would likely greatly reduce the number of potential antiviral therapies 208 that successfully make it through the pipeline. 209 210

Countless previously unknown viral genomes have been discovered in recent years 15 representing new 211 members of virus families known to have zoonotic potential. In response, there is an ongoing search for 212 broad-acting antivirals that are effective against multiple viruses within one family, or even against 213 viruses from different families. However, we also need to invest in research that will help us determine 214 which of these newly discovered viruses form a pandemic threat. We can then apply the lessons learned 215 from the COVID-19 pandemic to pre-emptively develop direct-acting antivirals against these viruses to 216 supplement the broad-acting antivirals. Only then can we hope to fare better in the next pandemic. 217 218 219

Acknowledgements 220

We would like to thank Rose Perry-Gottschalk for help with figure design, and Vincent Munster, Sonja 221

Best 

Antiviral Therapy. Molecular Virology of Human Pathogenic Viruses

The Importance of Understanding the Stages of COVID-19 in 240 Treatment and Trials

The Emergency Use Authorization of Pharmaceuticals: 242 History and Utility During the COVID-19 Pandemic

Effect 248 of early treatment with fluvoxamine on risk of emergency care and hospitalisation among 249 patients with COVID-19: the TOGETHER randomised, platform clinical trial

Early Remdesivir to Prevent Progression to Severe Covid-253 19 in Outpatients

Considerable escape of SARS-CoV-2 258 Omicron to antibody neutralization

Systemic and organ-specific immune-260 related manifestations of COVID-19

Pathogenesis of Acute Respiratory Distress 263 Syndrome

Pulmonary fibrosis secondary to COVID-19: a call to arms?

Post-acute COVID-19 syndrome

Emerging preclinical 272 evidence does not support broad use of hydroxychloroquine in COVID-19 patients

Beyond coronavirus: the virus discoveries transforming biology