diff --git a/content/20.pharmaceuticals.md b/content/20.pharmaceuticals.md index 7728b2369..0cf197de7 100644 --- a/content/20.pharmaceuticals.md +++ b/content/20.pharmaceuticals.md @@ -1,4 +1,5 @@ -## Identification and Development of Prophylactics and Therapeutics for COVID-19 +## Identification and Development of Therapeutics for COVID-19 + ### Abstract @@ -6,7 +7,7 @@ After emerging in China in late 2019, the novel coronavirus SARS-CoV-2 spread wo Only a small number of coronaviruses are known to infect humans, and only two are associated with the severe outcomes associated with SARS-CoV-2: SARS-CoV-1, a closely related species of SARS-CoV-2 that emerged in 2002, and MERS-CoV, which emerged in 2012. Both of these previous epidemics were controlled fairly rapidly through public health measures, and no vaccines or robust therapeutic interventions were identified. However, previous insights into the immune response to coronaviruses gained during the outbreaks of SARS and MERS have proved beneficial to identifying approaches to the treatment and prophylaxis of COVID-19. -A number of potential therapeutics against SARS-CoV-2 were rapidly identified, leading to a large number of clinical trials investigating a variety of possible therapeutic approaches being initiated early on in the pandemic. +A number of potential therapeutics against SARS-CoV-2 and the resultant COVID-19 illness were rapidly identified, leading to a large number of clinical trials investigating a variety of possible therapeutic approaches being initiated early on in the pandemic. As a result, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA) in the United States, and many other therapeutics remain under investigation. Here, we describe a range of approaches for the treatment of COVID-19, along with their proposed mechanisms of action and the current status of clinical investigation into each candidate. The status of these investigations will continue to evolve, and this review will be updated as progress is made. @@ -30,7 +31,7 @@ However, as of early 2021, COVID-19 remains a significant worldwide concern (Fig Due to the continued threat of the virus and the severity of the disease, the identification and development of prophylactic and therapeutic interventions have emerged as significant international priorities. Both approaches hold valuable potential for controlling the impact of the disease. Prophylactics bolster immunity to prevent an individual from contracting a disease, whereas therapeutics treat a disease in individuals who have already been infected. -While vaccine development programs have attracted significant attention and produced a number of promising candidates, there is also an immediate need for treatments that palliate symptoms and prevent the most severe outcomes from infection. +While a number of vaccines have recently been developed, approved, or are currently being evaluated by the US Food and Drug Administration and other regional and international bodies, vaccination programs only started being rolled out at the very end of 2020 and beginning of 2021, meaning that treatments that palliate symptoms and prevent the most severe outcomes have been necessary for much of 2020 and will continue to be necessary for the foreseeable future [@url:https://github.com/greenelab/covid19-review/blob/master/content/22.vaccines.md]. Fortunately, prior developments during other recent pandemics, especially those caused by human coronaviruses (HCoV), have provided a number of hypotheses guiding a biomedical approach to the novel coronavirus infection. {{csse_deaths}} COVID-19 deaths had been reported worldwide as of {{csse_date_pretty}} (Figure @fig:csse-deaths). @@ -48,47 +49,52 @@ Similarly, the first case of SARS was reported in November 2002 in the Guangdong In fact, genome sequencing quickly revealed the virus causing COVID-19 to be a novel betacoronavirus closely related to SARS-CoV-1 [@doi:10.46234/ccdcw2020.017]. There are many similarities but also some differences in the characteristics of the two viruses that determine how they spread. -SARS infection is severe, with an estimated death rate of 9.5% [@doi:10.1093/ajcp/aqaa029], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [@individual-pathogenesis]. +SARS-CoV-1 infection is severe, with an estimated death rate for SARS of 9.5% [@doi:10.1093/ajcp/aqaa029], while estimates of the death rate associated with COVID-19 are much lower, at approximately 2% [@individual-pathogenesis]. SARS-CoV-1 is highly contagious via droplet transmission and has a basic reproduction number (R~0~) of 4 (i.e., each person infected was estimated to infect four other people) [@doi:10.1093/ajcp/aqaa029]. SARS-CoV-2 also appears to be spread primarily by droplet transmission [@doi:10.1001/jama.2020.12458; @doi:10/gg6br7], and most estimates of its R~0~ fall between 2.5 and 3 [@individual-pathogenesis]. -Furthermore, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community's response. +However, the 17-year difference in the timing of these two outbreaks has led to some major differences in the tools available for the international community's response. At the time that SARS-CoV-1 emerged, no new HCoV had been identified in almost 40 years [@doi:10.1038/nrmicro.2016.81]. The identity of the virus underlying the SARS disease remained unknown until April of 2003, when the SARS-CoV-1 virus was characterized through a worldwide scientific effort spearheaded by the World Health Organization (WHO) [@doi:10.1038/nrmicro.2016.81]. In contrast, the SARS-CoV-2 genomic sequence was released on January 3, 2020 [@doi:10.46234/ccdcw2020.017], only days after the international community became aware of the novel pneumonia-like illness now known as COVID-19. -While SARS-CoV-1 belonged to a distinct lineage from the two other HCoV known at the time of its discovery [@doi:10.1093/ajcp/aqaa029], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, _Middle East respiratory syndrome-related coronavirus_ [@doi:10/ggjr43; @doi:10.1056/NEJMoa1211721]. +While SARS-CoV-1 belonged to a distinct lineage from the two other HCoVs known at the time of its discovery [@doi:10.1093/ajcp/aqaa029], SARS-CoV-2 is closely related to SARS-CoV-1 and a more distant relative of another HCoV characterized in 2012, _Middle East respiratory syndrome-related coronavirus_ [@doi:10/ggjr43; @doi:10.1056/NEJMoa1211721]. -Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoV. +Despite their phylogenetic similarity, SARS-CoV-2 emerged under very different circumstances than SARS-CoV-1 in terms of scientific knowledge about HCoVs. The trajectories of the pandemics associated with each of the viruses have also diverged significantly. By July 2003, the SARS outbreak was officially determined to be under control, with the success credited to infection management practices such as mask wearing [@doi:10.1038/nrmicro.2016.81]. In contrast, MERS is still circulating and remains a concern; although the fatality rate is very high at almost 35%, the disease is much less easily transmitted, as its R~0~ has been estimated to be 1 [@doi:10.1093/ajcp/aqaa029]. The low R~0~ in combination with public health practices allowed for its spread to be contained [@doi:10.1093/ajcp/aqaa029]. Neither of these trajectories are comparable to that of SARS-CoV-2, which remains a serious threat worldwide more than a year after the first cases of COVID-19 emerged. -Early results suggest that pharmaceutical interventions for COVID-19 may be more successful than efforts to develop prophylactics and therapeutics for SARS and MERS were. +Current results suggest that pharmaceutical interventions for COVID-19 appear to be more successful than the previous efforts to develop therapeutics for SARS and MERS. Care for SARS and MERS patients prioritized supportive care and symptom management [@doi:10.1093/ajcp/aqaa029]. To the extent that clinical treatments for SARS and MERS were explored, there is generally a lack of evidence supporting their efficacy. For example, Ribavirin is an antiviral that was often used in combination with corticosteroids and sometimes interferon (IFN) medications to treat SARS and MERS [@doi:10.1038/nrmicro.2016.81], but its effects have been found to be inconclusive in retrospective and _in vitro_ analyses of SARS and the SARS-CoV-1 virus, respectively [@doi:10.1038/nrmicro.2016.81]. IFNs and Ribavirin have shown promise in _in vitro_ analyses of MERS, but their clinical effectiveness remains unknown [@doi:10.1038/nrmicro.2016.81]. Therefore, only limited pharmaceutical advances from prior HCoV outbreaks can be adopted to COVID-19. -Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV provide a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential prophylactic and therapeutic approaches. +Importantly, though, prior analyses of the virological and pathogenic properties of SARS-CoV-1 and MERS-CoV have provided a strong foundation for the development of hypotheses about SARS-CoV-2 that have served to accelerated the development and identification of potential therapeutic approaches. +Even during the early months of the pandemic, a number of studies have emerged investigating the potential effects of drugs with mechanisms suggested based on prior understanding of coronavirus-host interactions. +Initially, these were primarily observational studies, which simply compare groups of patients who did and did not receive a treatment to determine whether it may have an effect. +However, these studies are subject to confounding, and randomized controlled trials are the standard means of assessing the effects of medications. +In randomized controlled trials, patients are prospectively and randomly assigned to treatment conditions, allowing for much stronger interpretations to be drawn; however, data from these trials takes much longer to collect. +Both have proven to be important sources of information during the COVID-19 crisis, but as more results are released from randomized controlled trials, more definitive answers are becoming available about various proposed therapeutics. -#### Therapeutic Approaches +#### Overview of Therapeutic Approaches Therapeutic approaches to the current pandemic can utilize two potential avenues: they can reduce the symptoms that are harmful to COVID-19 patients, or they can directly target the virus to hinder the spread of infection. The goal of the former is to reduce the severity and risks of an active infection, while for the latter, it is to inhibit the replication of the virus once an individual is infected. A variety of symptom profiles with a range of severity are associated with COVID-19, many of which are not life-threatening. A study of COVID-19 patients in a hospital in Berlin, Germany found that the symptoms associated with the highest risk of death included infection-related symptoms, such as sepsis, respiratory symptoms such as ARDS, and cardiovascular failure or pulmonary embolism [@doi:10.1101/2020.06.15.20131540]. -Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll. -On the other hand, therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms. -These treatments typically fall into the broad category of antivirals. +Therapeutics that reduce the risks associated with these severe outcomes hold particular potential to reduce the pandemic death toll, while therapeutics that directly target the virus itself would hold the potential to prevent people infected with SARS-CoV-2 from developing potentially damaging symptoms. +The treatments in this latter category typically fall into the broad category of antivirals. Antiviral therapies hinder the spread of a virus within the host, rather than destroying existing copies of the virus, and these drugs can vary in their specificity to a narrow or broad range of viral targets. For both categories, uncertainty often surrounds the treatments' exact mechanisms of action, as most therapies have secondary or off-target effects. -A large number of clinical trials investigating a range of possible therapeutics and prophylactics for COVID-19 are currently in progress or have already been completed (Figure @fig:ebm-trials). -The purpose of this review is to critically appraise the literature surrounding a subset of clinical trials and to evaluate a range of approaches to repurpose existing or develop novel approaches to the prevention, mitigation, and treatment of coronavirus infections. -The treatments and prophylactics evaluated here are classified according to their biological properties, specifically whether they are biologics (produced from components of organisms) or small molecules. +A large number of clinical trials investigating a range of possible therapeutics for COVID-19 are currently in progress or have already been completed (Figure @fig:ebm-trials). +The purpose of this review is to critically appraise the literature surrounding a subset of clinical trials and to evaluate a range of approaches to repurpose existing or develop novel approaches to the mitigation and treatment of coronavirus infections. +The treatments evaluated here are classified according to their biological properties, specifically whether they are biologics (produced from components of organisms) or small molecules. Small molecule drugs include drugs targeted at viral particles, drugs targeted at host proteins, and broad spectrum pharmaceuticals, while biologics include antibodies and interferons. -As results become available from additional clinical trials, we will continue to update this manuscript to keep pace with the current understanding of which therapeutics may be effective against SARS-CoV-2 or for COVID-19. +As we cover vaccines in a separate manuscript [@url:https://github.com/greenelab/covid19-review/blob/master/content/22.vaccines.md], we only consider therapies for the prevention of SARS-CoV-2 infection or COVID-19 in a very limited context here, for example when a drug is studied to see whether it can prevent infection or disease in recently-exposed individuals. +As results become available from additional clinical trials, we will continue to update this manuscript to keep pace with the current understanding of which therapeutics may be effective against SARS-CoV-2 or COVID-19. ![ **COVID-19 clinical trials.** @@ -112,7 +118,7 @@ Small molecule drugs today encompass a wide range of therapeutics beyond antibio #### Small Molecule Antivirals Antiviral drugs against SARS-CoV-2 are designed to inhibit replication of a virus within an epithelial host cell. -This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [@isbn:978-1405136457]. +This process requires inhibiting the replication cycle of a virus by disrupting one of six fundamental steps [@isbn:978-1405136457] (Figure @fig:therapeutics). In the first of these steps, the virus attaches to and enters the host cell through endocytosis. Then the virus undergoes uncoating, which is classically defined as the release of viral contents into the host cell. Next, the viral genetic material enters the nucleus where it gets replicated during the biosynthesis stage. @@ -120,7 +126,7 @@ During the assembly stage, viral proteins are translated, allowing new viral par In the final step new viruses are released into the extracellular environment. Many antiviral drugs are designed to inhibit the replication of viral genetic material during the biosynthesis step. Unlike DNA viruses, which can use the host enzymes to propagate themselves, RNA viruses like SARS-CoV-2 depend on their own polymerase, the RNA-dependent RNA polymerase (RdRP), for replication [@doi:10.1007/978-1-4939-2438-7; @doi:10.1002/jmv.25761]. -Targeting RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [@doi:10.1080/17460441.2019.1581171]. +Targeting the RdRP is therefore an effective strategy for antivirals against RNA viruses and is the proposed mechanism underlying the treatment of SARS and MERS with Ribavirin [@doi:10.1080/17460441.2019.1581171]. However, although antivirals are designed to target a virus, they can also impact other processes in the host and may have unintended effects. Therefore, these therapeutics must be evaluated for both efficacy and safety. @@ -147,13 +153,12 @@ It should be noted that although the control patients received antivirals, two s Treatment was applied on days 2-14; treatment stopped either when viral clearance was confirmed or at day 14. The efficacy of the treatment was measured by, first, the time until viral clearance using Kaplan-Meier survival curves, and, second, the improvement rate of chest computed tomography (CT) scans on day 14 after treatment. The study found that favipiravir increased the speed of recovery, measured as viral clearance from the patient by RT-PCR, with patients receiving favipiravir recovering in four days compared to 11 days for patients receiving antivirals such as lopinavir and ritonavir. -Additionally, the lung CT scans of patients treated with favipiravir showed significantly higher improvement rates (91%) on day 14 compared to control patients (62%). +Additionally, the lung CT scans of patients treated with favipiravir showed significantly higher improvement rates (91%) on day 14 compared to control patients (62%, _p_ = 0.004). However, there were adverse side effects in 4 (11%) favipiravir-treated patients and 25 (56%) control patients. The adverse side effects included diarrhea, vomiting, nausea, rash, and liver and kidney injury. -Overall, despite the study reporting clinical improvement in favipiravir-treated patients, due to some issues with study design, it cannot be determined whether treatment with favipiravir had an effect or whether these patients would have recovered regardless of any treatment. -For example, despite the significant differences observed between the two treatment groups, follow-up analysis is necessary due to the small sample size. -The selection of patients did not take into consideration important factors such as previous clinical conditions or sex, and there was no age categorization. -The study was neither randomized nor blinded, and the baseline control group was another antiviral instead of a placebo. +Despite the study reporting clinical improvement in favipiravir-treated patients, several study design issues are problematic and lower confidence in the overall conclusions. +For example, the study was neither randomized nor blinded. +Moreover, the selection of patients did not take into consideration important factors such as previous clinical conditions or sex, and there was no age categorization. Additionally, it should be noted that this study was temporarily retracted and then restored without an explanation [@url:https://retractionwatch.com/retracted-coronavirus-covid-19-papers/]. In late 2020 and early 2021, the first randomized controlled trials of favipiravir for the treatment of COVID-19 released results [@doi:10.1016/j.ejps.2020.105631; @doi:10.1007/s00705-021-04956-9; @doi:10.1093/cid/ciaa1176]. @@ -161,23 +166,22 @@ The first [@doi:10.1016/j.ejps.2020.105631] used a randomized, controlled, open- Here, SOC included antivirals such as lopinavir/ritonavir and was administered to all patients. The primary endpoint analyzed was viral clearance at day 14. The sample size for this study was very small, with 29 total patients enrolled, and no significant effect of the treatments was found for the primary or any of the secondary outcomes analyzed, which included mortality. -The second study was larger, with 96 patients enrolled, and also utilized a randomized design. -This study enrolled only patients with mild to moderate symptoms and randomized them into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC. -This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay and less likelihood of progressing to mechanical ventilation or to an oxygen saturation < 90%. -However, given the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, these results do not suggest that favipiravir was likely to have had a strong effect on these outcomes. +The second study [@doi:10.1007/s00705-021-046-9] was larger, with 96 patients enrolled, and included only individuals with mild to moderate symptoms who were randomized into two groups: one receiving chloroquine (CQ) in addition to SOC, and the other receiving favipiravir in addition to SOC. +This study reported a non-significant trend for patients receiving favipiravir to have a shorter hospital stay (13.29 days compared to 15.89 for CQ, _p_ = 0.06) and less likelihood of progressing to mechanical ventilation (_p_ = 0.118) or to an oxygen saturation < 90% (_p_ = 0.129). +These results, combined with the fact that favipiravir was being compared to CQ, which is now widely understood to be ineffective for treating COVID-19, thus do not suggest that favipiravir was likely to have had a strong effect on these outcomes. On the other hand, another trial of 60 patients reported a significant effect of favipiravir on viral clearance at four days (a secondary endpoint), but not at 10 days (the primary endpoint) [@doi:10.1093/cid/ciaa1176]. This study, as well as a prior study of favipiravir [@doi:10/ftgm], also reported that the drug was generally well-tolerated. Thus, in combination, these small studies suggest that the effects of favipiravir as a treatment for COVID-19 cannot be determined based on the available evidence, but additionally, none raise major concerns about the safety profile of the drug. ###### Remdesivir -Remdesivir (GS-5734) is an intravenous antiviral that was developed by Gilead Sciences to treat Ebola Virus Disease (EVD). +Remdesivir (GS-5734) is an intravenous antiviral that was proposed by Gilead Sciences as a possible treatment for Ebola virus disease (EVD). At the outset of the COVID-19 pandemic, it did not have any have any FDA-approved use. However, on May 1, 2020, the FDA issued an Emergency Use Authorization (EUA) for remdesivir for the treatment of hospitalized COVID-19 patients [@url:https://www.fda.gov/media/137564/download]. The EUA was based on information from two clinical trials, NCT04280705 and NCT04292899 [@clinicaltrials:NCT04292899; @clinicaltrials:NCT04280705; @doi:10.1056/NEJMoa2007764; @doi:10.1056/NEJMoa2007016]. Remdesivir is metabolized to GS-441524, an adenosine analog that inhibits a broad range of polymerases and then evades exonuclease repair, causing chain termination [@doi:10.1074/jbc.AC120.013056; @doi:10.1128/mBio.00221-18; @doi:10.1038/s41422-020-0282-0]. A clinical trial in the Democratic Republic of Congo found some evidence of effectiveness against EVD, but two antibody preparations were found to be more effective, and remdesivir was not pursued [@doi:10.1056/NEJMoa1910993]. -Although it was developed against EVD, remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [@doi:10.1126/scitranslmed.aal3653]. +Remdesivir also inhibits polymerase and replication of the coronaviruses MERS-CoV and SARS-CoV-1 in cell culture assays with submicromolar IC50s [@doi:10.1126/scitranslmed.aal3653]. It has also been found to inhibit SARS-CoV-2, showing synergy with CQ _in vitro_ [@doi:10.1038/s41422-020-0282-0]. Remdesivir was first used on some COVID-19 patients under compassionate use guidelines [@doi:10.1126/science.abb7243, @doi:10.1056/NEJMoa2001191; @doi:10.1101/2020.03.09.20032896]. @@ -190,7 +194,7 @@ The inclusion criteria were variable: some patients only required low doses of o The study included many sites, potentially with variable inclusion criteria and treatment protocols. The patients analyzed had mixed demographics. There was a short follow-up period of investigation. -Some patients worsened, some patients died, and eight were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for. +Eight patients were excluded from the analysis mainly due to missing post-baseline information; thus, their health was unaccounted for. Therefore, even though the study reported clinical improvement in 68% of the 53 patients ultimately evaluated, due to the significant issues with study design, it could not be determined whether treatment with remdesivir had an effect or whether these patients would have recovered regardless of treatment. Another study comparing 5- and 10-day treatment regimens reported similar results but was also limited because of the lack of a placebo control [@doi:10.1056/NEJMoa2015301]. These studies did not alter the understanding of the efficacy of remdesivir in treating COVID-19, but the encouraging results provided motivation for placebo-controlled studies. @@ -202,7 +206,7 @@ The treatment was 200 mg on day 1, followed by 100 mg on days 2 through 10. Data was analyzed from a total of 1,059 patients who completed the 29-day course of the trial, with 517 assigned to remdesivir and 508 to placebo [@doi:10.1056/NEJMoa2007764]. The two groups were well matched demographically and clinically at baseline. Those who received remdesivir had a median recovery time of 10 days, as compared with 15 days in those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; _p_ < 0.001). -The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI: 0.52 to 1.03). +The Kaplan-Meier estimates of mortality by 14 days were 6.7% with remdesivir and 11.9% with placebo, with a hazard ratio (HR) for death of 0.55 and a 95% CI of 0.36 to 0.83, and at day 29, remdesivir corresponded to 11.4% and the placebo to 15.2% (HR: 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients in the placebo group (31.6%). This study also reported an association between remdesivir administration and both clinical improvement and a lack of progression to more invasive respiratory intervention in patients receiving non-invasive and invasive ventilation at randomization [@doi:10.1056/NEJMoa2007764]. Largely on the results of this trial, the FDA reissued and expanded the EUA for remdesivir for the treatment of hospitalized COVID-19 patients ages twelve and older [@url:https://www.fda.gov/media/137564/download]. @@ -215,22 +219,21 @@ Patients were randomized in equal proportions into four experimental conditions The 2,750 patients in the remdesivir group were administered 200 mg intravenously on the first day and 100 mg on each subsequent day until day 10 and assessed for in-hospital death (primary endpoint), duration of hospitalization, and progression to mechanical ventilation. There were also 2,708 control patients who would have been eligible and able to receive remdesivir were they not assigned to the control group. A total of 604 patients among these two cohorts deceased during initial hospitalization, with 301 in the remdesivir group and 303 in the control group. -The rate ratio of death between these two groups was therefore not significant (_p_ = 0.50), suggesting that the administration of remdesivir did not affect survival. +The rate ratio of death between these two groups was therefore not significant (0.95, _p_ = 0.50), suggesting that the administration of remdesivir did not affect survival. The two secondary analyses similarly did not find any effect of remdesivir. Additionally, the authors compared data from their study with data from three other studies of remdesivir (including [@doi:10.1056/NEJMoa2007764]) stratified by supplemental oxygen status. -The adjusted rate ratio for death based on this meta-analysis was 0.91. +A meta-analysis of the four studies yielded an overall rate ratio for death of 0.91 (_p_ = 0.20). These results thus do not support the previous findings that remdesivir reduced median recovery time and mortality risk in COVID-19 patients. -In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of the statement had not been peer reviewed [@url:https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-solidarity-trial]; these sentiments have been echoed elsewhere [@doi:10.1093/eurheartj/ehaa934]. +In response to the results of the Solidarity trial, Gilead, which manufactures remdesivir, released a statement pointing to the fact that the Solidarity trial was not placebo-controlled or double-blind and at the time of release, the statement had not been peer reviewed [@url:https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-solidarity-trial]; these sentiments have been echoed elsewhere [@doi:10.1093/eurheartj/ehaa934]. Other critiques of this study have noted that antivirals are not typically targeted at patients with severe illness, and therefore remdesivir could be more beneficial for patients with mild rather than severe cases [@url:https://www.sciencemag.org/news/2020/10/very-very-bad-look-remdesivir-first-fda-approved-covid-19-drug; @doi:10.1056/NEJMe2034294]. -However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52), although the results of a significance test were not provided [@doi:10.1056/NEJMoa2007764]. +However, the publication associated with the trial sponsored by Gilead did purport an effect of remdesivir on patients with severe disease, identifying an 11 versus 18 day recovery period (rate ratio for recovery: 1.31, 95% CI 1.12 to 1.52) [@doi:10.1056/NEJMoa2007764]. Additionally, a smaller analysis of 598 patients, of whom two-thirds were randomized to receive remdesivir for either 5 or 10 days, reported a small effect of treatment with remdesivir for five days relative to standard of care in patients with moderate COVID-19 [@doi:10.1001/jama.2020.16349]. These results suggest that remdesivir could improve outcomes for patients with moderate COVID-19, but that additional information would be needed to understand the effects of different durations of treatment. -Therefore, the arguments put forward in defense of remdesivir do not necessarily seem robust in light of the large sample size used in the Solidarity trial, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [@doi:10.1056/NEJMe2034294]. -On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [@doi:10.1056/NEJMoa2023184], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [@doi:10.1056/NEJMe2034294]. +Therefore, the Solidarity trial may point to limitations in the generalizability of other research on remdesivir, especially since the broad international nature of the Solidarity clinical trial, which included countries with a wide range of economic profiles and a variety of healthcare systems, provides a much-needed global perspective in a pandemic [@doi:10.1056/NEJMe2034294]. +On the other hand, only 62% of patients in the Solidarity trial were randomized on the day of admission or one day afterwards [@doi:10.1056/NEJMoa2023184], and concerns have been raised that differences in disease progression could influence the effectiveness of remdesivir [@doi:10.1056/NEJMe2034294]. Despite the findings of the Solidarity trial, remdesivir remains available for the treatment of COVID-19 in many places. Follow-up studies are needed and, in many cases, are underway to further investigate remdesivir-related outcomes, with possibilities including combinations of remdesivir with other drugs such as baricitinib, which is an inhibitor of Janus kinase 1 and 2 [@doi:10.1056/NEJMoa2031994]. - Similarly, the extent to which the remdesivir dosing regimen could influence outcomes continues to be under consideration. A randomized, open-label trial compared the effect of remdesivir on 397 patients with severe COVID-19 over 5 versus 10 days [@doi:10.1056/NEJMoa2015301; @ClinicalTrials:NCT04292899], complementing the study that found that a 5-day course of remdesivir improved outcomes for patients with moderate COVID-19 but a 10-day course did not [@doi:10.1001/jama.2020.16349]. Patients in the two groups were administered 200 mg of remdesivir intravenously on the first day, followed by 100 mg on the subsequent four or nine days, respectively. @@ -240,7 +243,7 @@ It reported no significant differences across several outcomes for patients rece The data did suggest that the 10-day course might reduce mortality in the most severe patients at day 14, but the representation of this group in the study population was too low to justify any conclusions [@doi:10.1056/NEJMoa2015301]. Thus, additional research is also required to determine whether the dosage and duration of remdesivir administration influences outcomes. -In summary, remdesivir is a first in class drug due to its FDA approval. +In summary, remdesivir is the first FDA approved anti-viral against SARS-CoV-2 as well as the first FDA approved COVID-19 treatment. Early investigations of this drug established proof of principle that drugs targeting the virus can benefit COVID-19 patients. It also shows proof of principle that SARS-CoV-2 can be targeted at the level of viral replication, since remdesivir targets the viral RNA polymerase at high potency. Moreover, one of the most successful strategies for developing therapeutics for viral diseases is to target the viral replication machinery, which are typically virally encoded polymerases. @@ -304,13 +307,13 @@ This category of drugs has also received significant attention from the media an ##### ACE Inhibitors and Angiotensin II Receptor Blockers -Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today's most commonly prescribed medications [@url:https://clincalc.com/DrugStats/Drugs/Lisinopril; @doi:10.1056/NEJMp1901657]. -In the United States, for example, they are prescribed well over 100,000,000 times annually. +Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are among today's most commonly prescribed medications, often being used to control blood pressure [@url:https://clincalc.com/DrugStats/Drugs/Lisinopril; @doi:10.1056/NEJMp1901657]. +In the United States, for example, they are prescribed well over 100,000,000 times annually [@doi:10.18553/jmcp.2010.16.9.671]. Data from some animal models suggest that several, but not all, ACE inhibitors (ACEIs) and several ARBs increase ACE2 expression in the cells of some organs [@doi:10.1093/cvr/cvaa097]. Clinical studies have not established whether plasma ACE2 expression is increased in humans treated with these medications [@doi:10.1093/europace/euw246]. While randomized clinical trials are ongoing, a variety of observational studies have examined the relationship between exposure to ACEIs or ARBs and outcomes in patients with COVID-19. -An observational study of the association of exposure to ACEIs or ARBs with outcomes in COVID-19 was retracted from the _New England Journal of Medicine_ [@doi:10.1056/NEJMoa2007621]. -Moreover, because observational studies are subject to confounding, randomized controlled trials are the standard means of assessing the effects of medications, and the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [@doi:10.1161/CIRCRESAHA.120.317205; @doi:10.2215/CJN.03530320]. +An observational study of the association of exposure to ACEIs or ARBs with outcomes in COVID-19 was retracted from the _New England Journal of Medicine_ [@doi:10.1056/NEJMoa2007621] due to concerns related to data availability [@doi:10.1056/nejmc2021225]. +Clinical trials are needed because the findings of the various observational studies bearing on this topic cannot be interpreted as indicating a protective effect of the drug [@doi:10.1161/CIRCRESAHA.120.317205; @doi:10.2215/CJN.03530320]. Several clinical trials testing the effects of ACEIs or ARBs on COVID-19 outcomes are ongoing [@clinicaltrials:NCT04338009; @clinicaltrials:NCT04353596; @clinicaltrials:NCT04311177; @clinicaltrials:NCT04312009; @clinicaltrials:NCT04330300; @clinicaltrials:NCT04366050; @clinicaltrials:NCT04364893]. Two of these analyses [@clinicaltrials:NCT04338009; @clinicaltrials:NCT04364893] have reported no effect of continuing or discontinuing ARBs and ACEIs on patients admitted to the hospital for COVID-19. @@ -335,6 +338,7 @@ Therefore, despite the promising potential mechanism, initial results have not p CQ and hydroxychloroquine (HCQ) are lysosomotropic agents, meaning they are weak bases that can pass through the plasma membrane. Both drugs increase cellular pH by accumulating in their protonated form inside lysosomes [@doi:10.1186/1743-422X-8-163; @doi:10.1111/j.1529-8019.2007.00131.x]. +These drugs are used for the treatment and prophylaxis of malaria, as well as the treatment of lupus erythematosus and rheumatoid arthritis in adults [@url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341]. This shift in pH inhibits the breakdown of proteins and peptides by the lysosomes during the process of proteolysis [@doi:10.1111/j.1529-8019.2007.00131.x]. A number of mechanisms have been proposed through which these drugs could influence the immune response to pathogen challenge. For example, CQ/HCQ can interfere with digestion of antigens within the lysosome and inhibit CD4 T-cell stimulation while promoting the stimulation of CD8 T-cells [@doi:10.1111/j.1529-8019.2007.00131.x]. @@ -348,7 +352,7 @@ An _in vitro_ study of SARS-CoV-2 infection of Vero cells found both HCQ and CQ Additionally, an early case study of three COVID-19 patients reported the presence of antiphospholipid antibodies in all three patients [@doi:10.1056/NEJMc2007575]. Antiphospholipid antibodies are central to the diagnosis of the antiphospholipid syndrome, a disorder that HCQ has often been used to treat [@doi:10.1182/blood.V128.22.5023.5023; @doi:10.1016/j.autrev.2014.01.053; @doi:10.1182/asheducation-2016.1.714]. Because the 90% effective concentration (EC~90~) of CQ in Vero E6 cells (6.90 μM) can be achieved in and tolerated by rheumatoid arthritis (RA) patients, it was hypothesized that it might also be possible to achieve the effective concentration in COVID-19 patients [@doi:10.1093/jac/dkaa114]. -Additionally, HCQ has been found to be effective in treating HIV [@doi:10/cq2hx9] and chronic Hepatitis C [@doi:10.1002/jmv.24575]. +Additionally, clinical trials have reported HCQ to be effective in treating HIV [@doi:10/cq2hx9] and chronic Hepatitis C [@doi:10.1002/jmv.24575]. Together, these studies triggered initial enthusiasm about the therapeutic potential for HCQ and CQ against COVID-19. HCQ/CQ has been proposed both as a treatment for COVID-19 and a prophylaxis against SARS-CoV-2 exposure, and trials often investigated these drugs in combination with azithromycin (AZ) and/or zinc supplementation. However, as more evidence has emerged, it has become clear that HCQ/CQ offer no benefits against SARS-CoV-2 or COVID-19. @@ -359,7 +363,8 @@ The initial study evaluating HCQ as a treatment for COVID-19 patients was publis This non-randomized, non-blinded, non-placebo clinical trial compared HCQ to SOC in 42 hospitalized patients in southern France. It reported that patients who received HCQ showed higher rates of virological clearance by nasopharyngeal swab on days 3-6 when compared to SOC. This study also treated six patients with both HCQ + AZ and found this combination therapy to be more effective than HCQ alone. -However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the lack of randomization, lack of blinding, lack of placebo, lack of Intention-To-Treat analysis, lack of correction for sequential multiple comparisons, trial arms entirely confounded by hospital, false negatives in outcome measurements, lack of trial pre-registration, and small sample size. +However, the design and analyses used showed weaknesses that severely limit interpretability of results, including the small sample size and the lack of: randomization, blinding, placebo (no "placebo pill" given to SOC group), Intention-To-Treat analysis, correction for sequential multiple comparisons, and trial pre-registration. +Furthermore, the trial arms were entirely confounded by hospital and there were false negative outcome measurements (see [@doi:10.5014/ajot.2013.006015]). Two of these weaknesses are due to inappropriate data analysis and can therefore be corrected _post hoc_ by recalculating the p-values (lack of Intention-To-Treat analysis and multiple comparisons). However, all other weaknesses are fundamental design flaws and cannot be corrected for. Thus, the conclusions cannot be generalized outside of the study. @@ -378,7 +383,7 @@ On April 10, 2020, a randomized, non-placebo trial of 62 COVID-19 patients at th This study investigated whether HCQ decreased time to fever break or time to cough relief when compared to SOC [@doi:10.1101/2020.03.22.20040758]. This trial found HCQ decreased both average time to fever break and average time to cough relief, defined as mild or no cough. While this study improved on some of the methodological flaws in Gautret et al. by randomizing patients, it also had several flaws in trial design and data analysis that prevent generalization of the results. -These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration and published protocol, and small sample size. +These weaknesses include the lack of placebo, lack of correction for multiple primary outcomes, inappropriate choice of outcomes, lack of sufficient detail to understand analysis, drastic disparities between pre-registration [@url:http://www.chictr.org.cn/showprojen.aspx?proj=48880] and published protocol (including differences in the inclusion and exclusion criteria, the number of experimental groups, the number of patients enrolled, and the in the outcome analyzed), and small sample size. The choice of outcomes may be inappropriate as both fevers and cough may break periodically without resolution of illness. Additionally, for these outcomes, the authors reported that 23 of 62 patients did not have a fever and 25 of 62 patients did not have a cough at the start of the study, but the authors failed to describe how these patients were included in a study assessing time to fever break and time to cough relief. It is important to note here that the authors claimed "neither the research performers nor the patients were aware of the treatment assignments." @@ -405,7 +410,7 @@ For all of these 15 identifiers, no data uploads or links to publications could At the very least, the lack of availability of the primary data means the claim that HCQ is efficacious against COVID-19 pneumonia cannot be verified. Similarly, a recent multinational registry analysis [@doi:10/ggwzsb] analyzed the efficacy of CQ and HCQ with and without a macrolide, which is a class of antibiotics that includes Azithromycin, for the treatment of COVID-19. The study observed 96,032 patients split into a control and four treatment conditions (CQ with and without a macrolide; HCQ with and without a macrolide). -They concluded that treatment with CQ and HCQ was associated with increased risk of _de novo_ ventricular arrhythmia during hospitalization. +They concluded that treatment with CQ or HCQ was associated with increased risk of _de novo_ ventricular arrhythmia during hospitalization. However, this study has since been retracted by _The Lancet_ due to an inability to validate the data used [@doi:10/ggzqng]. These studies demonstrate that increased skepticism in evaluation of the HCQ/CQ and COVID-19 literature may be warranted, possibly because of the significant attention HCQ and CQ have received as possible treatments for COVID-19 and the politicization of these drugs. @@ -414,34 +419,35 @@ A patient with systemic lupus erythematosus developed a prolonged QT interval th A prolonged QT interval is associated with ventricular arrhythmia [@doi:10.1016/j.hrthm.2008.05.008]. Furthermore, a separate study [@doi:10.1101/2020.04.08.20054551] investigated the safety associated with the use of HCQ with and without macrolides between 2000 and 2020. The study involved 900,000 cases treated with HCQ and 300,000 cases treated with HCQ + AZ. -The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (15-20% increased risk of chest pain) and a two-fold increased risk of mortality. +The results indicated that short-term use of HCQ was not associated with additional risk, but that HCQ + AZ was associated with an enhanced risk of cardiovascular complications (such as a 15% increased risk of chest pain, calibrated HR = 1.15, 95% CI, 1.05 to 1.26) and a two-fold increased 30-day risk of cardiovascular mortality (calibrated HR = 2.19; 95% CI, 1.22 to 3.94). Therefore, whether studies utilize HCQ alone or HCQ in combination with a macrolide may be an important consideration in assessing risk. -As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ has led to the removal of CQ/HCQ from SOC practices in several countries [@doi:10.1101/2020.04.07.20056424; @url:https://www.cnn.com/2020/04/13/health/chloroquine-risks-coronavirus-treatment-trials-study/index.html]. +As results from initial investigations of these drug combinations have emerged, concerns about the efficacy and risks of treating COVID-19 with HCQ and CQ have led to the removal of CQ/HCQ from SOC practices in several countries [@doi:10.1101/2020.04.07.20056424; @url:https://www.cnn.com/2020/04/13/health/chloroquine-risks-coronavirus-treatment-trials-study/index.html]. As of May 25, 2020, WHO had suspended administration of HCQ as part of the worldwide Solidarity Trial [@raw:WHO_briefing_2020_5_25], and later the final results of this large-scale trial that compared 947 patients administered HCQ to 906 controls revealed no effect on the primary outcome, mortality during hospitalization (rate ratio: 1.19; _p_ = 0.23) Additional research has emerged largely identifying HCQ/CQ to be ineffective against COVID-19 while simultaneously revealing a number of significant side effects. A randomized, open-label, non-placebo trial of 150 COVID-19 patients was conducted in parallel at 16 government-designated COVID-19 centers in China to assess the safety and efficacy of HCQ [@doi:10.1101/2020.04.10.20060558]. The trial compared treatment with HCQ in conjunction with SOC to SOC alone in 150 infected patients who were assigned randomly to the two groups (75 per group). -The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups. +The primary endpoint of the study was the negative conversion rate of SARS-CoV-2 in 28 days, and the investigators found no difference in this parameter between the groups (estimated difference between SOC plus HCQ and SOC 4.1%; 95% CI, –10.3% to 18.5%). The secondary endpoints were an amelioration of the symptoms of the disease such as axillary temperature ≤36.6°C, SpO2 >94% on room air, and disappearance of symptoms like shortness of breath, cough, and sore throat. -The median time to symptom alleviation was similar across different conditions (19 days in HCQ + SOC versus 21 days in SOC). +The median time to symptom alleviation was similar across different conditions (19 days in HCQ + SOC versus 21 days in SOC, _p_ = 0.97). Additionally, 30% of the patients receiving SOC+HCQ reported adverse outcomes compared to 8.8% of patients receiving only SOC, with the most common adverse outcome in the SOC+HCQ group being diarrhea (10% versus 0% in the SOC group, _p_ = 0.004). However, there are several factors that limit the interpretability of this study. Most of the enrolled patients had mild-to-moderate symptoms (98%), and the average age was 46. -SOC in this study included the use of antivirals (Lopinavir-Ritonavir, Arbidol, Oseltamivir, Virazole, Entecavir, Ganciclovir, and Interferon alfa), which appeared to introduce confounding effects. -Thus, to isolate the effect of HCQ, SOC would need to exclude the use of antivirals. +SOC in this study included the use of antivirals (Lopinavir-Ritonavir, Arbidol, Oseltamivir, Virazole, Entecavir, Ganciclovir, and Interferon alfa), which the authors note could influence the results. +Thus, they note that an ideal SOC would need to exclude the use of antivirals, but that ceasing antiviral treatment raised ethical concerns at the time that the study was conducted. In this trial, the samples used to test for the presence of the SARS-CoV-2 virus were collected from the upper respiratory tract, and the authors indicated that the use of upper respiratory samples may have introduced false negatives (e.g., [@doi:10.1001/jama.2020.3786]). Another limitation of the study that the authors acknowledge was that the HCQ treatment began, on average, at a 16-day delay from the symptom onset. The fact that this study was open-label and lacked a placebo limits interpretation, and additional analysis is required to determine whether HCQ reduces inflammatory response. Therefore, despite some potential areas of investigation identified in _post hoc_ analysis, this study cannot be interpreted as providing support for HCQ as a therapeutic against COVID-19. +This study provided no support for HCQ against COVID-19, as there was no difference between the two groups in either negative seroconversion at 28 days or symptom alleviation, and in fact, more severe adverse outcomes were reported in the group receiving HCQ. Additional evidence comes from a retrospective analysis [@doi:10.1101/2020.04.16.20065920] that examined data from 368 COVID-19 patients across all United States Veteran Health Administration medical centers. The study retrospectively investigated the effect of the administration of HCQ (n=97), HCQ + AZ (n=113), and no HCQ (n=158) on 368 patients. The primary outcomes assessed were death and the need for mechanical ventilation. Standard supportive care was rendered to all patients. Due to the low representation of women (N=17) in the available data, the analysis included only men, and the median age was 65 years. -The rate of death in the HCQ-only treatment condition was 27.8% and in the HCQ + AZ treatment condition, it was 22.1%. -In comparison to the 14.1% rate of death in the no-HCQ cohort, these data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, _p_ = 0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; _p_ = 0.72). +The rate of death was 27.8% in the HCQ-only treatment group, 22.1% in the HCQ + AZ treatment group, and 14.1% in the no-HCQ group. +These data indicated a statistically significant elevation in the risk of death for the HCQ-only group compared to the no-HCQ group (adjusted HR: 2.61, _p_ = 0.03), but not for the HCQ + AZ group compared to the no-HCQ group (adjusted HR: 1.14; _p_ = 0.72). Further, the risk of ventilation was similar across all three groups (adjusted HR: 1.43, _p_ = 0.48 (HCQ) and 0.43, _p_ = 0.09 (HCQ + AZ) compared to no HCQ). The study thus showed evidence of an association between increased mortality and HCQ in this cohort of COVID-19 patients but no change in rates of mechanical ventilation among the treatment conditions. The study had a few limitations: it was not randomized, and the baseline vital signs, laboratory tests, and prescription drug use were significantly different among the three groups. @@ -459,9 +465,9 @@ In the HCQ arm of the study, patients received 800 mg at baseline and again afte The primary outcome analyzed was all-cause mortality, and patient vital statistics were reported by physicians upon discharge or death, or else at 28 days following HCQ administration if they remained hospitalized. The secondary outcome assessed was the combined risk of progression to invasive mechanical ventilation or death within 28 days. By the advice of an external data monitoring committee, the HCQ arm of the study was reviewed early, leading to it being closed due a lack of support for HCQ as a treatment for COVID-19. -Patients who received HCQ had a longer duration of hospitalization than patients receiving usual care, were less likely to be discharged alive within 28 days, and were more likely to progress to mechanical ventilation. +The rates of COVID-19-related mortality reported in the RECOVERY trial did not differ between the control and HCQ arms (rate ratio, 1.09; 95% confidence interval, 0.97 to 1.23; _p_ = 0.15), but patients receiving HCQ were slightly more likely to die due to cardiac events (0.4 percentage points). +Patients who received HCQ also had a longer duration of hospitalization than patients receiving usual care, being less likely to be discharged alive within 28 days (rate ratio 0.90; 95% CI, 0.83 to 0.98), and were more likely to progress to mechanical ventilation or death (risk ratio 1.14; 95% CI, 1.03 to 1.27). This large-scale study thus builds upon studies in the United States and China to suggest that HCQ is not an effective treatment, and in fact may negatively impact COVID-19 patients due to its side effects. -The rates of COVID-19-related mortality reported in the RECOVERY trial did not differ between the control and HCQ arms, but patients receiving HCQ were more likely to die due to cardiac events. Therefore, though none of the studies have been blinded, examining them together makes it clear that the available evidence points to significant dangers associated with the administration of HCQ to hospitalized COVID-19 patients, without providing any support for its efficacy. ###### HCQ for the Treatment of Mild Cases @@ -471,7 +477,7 @@ This possibility was assessed in a randomized, open-label, multi-center analysis This analysis enrolled adults 18 and older who had been experiencing mild symptoms of COVID-19 for fewer than five days. Participants were randomized into an HCQ arm (N=136) and a control arm (N=157), and those in the treatment arm were administered 800 mg of HCQ on the first day of treatment followed by 400 mg on each of the subsequent six days. The primary outcome assessed was viral clearance at days 3 and 7 following the onset of treatment, and secondary outcomes were clinical progression and time to complete resolution of symptoms. -They found no significant differences between the two groups. +No significant differences between the two groups were found: the difference in viral load between the HCQ and control groups was 0.01 (95% CI, -0.28 to 0.29) at day 3 and -0.07 (95% CI -0.44 to 0.29) at day 7, the relative risk of hospitalization was 0.75 (95% CI, 0.32 to 1.77), and the difference in time to complete resolution of symptoms was -2 days (_p_ = 0.38). This study thus suggests that HCQ does not improve recovery from COVID-19, even in otherwise healthy adult patients with mild symptoms. ###### Prophylactic Administration of HCQ @@ -488,17 +494,17 @@ One possible confounder is that a patient presenting one or more symptoms, which Additionally, four of the twenty PCR-confirmed cases did not develop symptoms until after the observation period had completed, suggesting that the 14-day trial period may not have been long enough or that some participants also encountered secondary exposure events. Finally, in addition to the young age of the participants in this study, which ranged from 32 to 51, there were possible impediments to generalization introduced by the selection process, as 2,237 patients who were eligible but had already developed symptoms by day 4 were enrolled in a separate study. It is therefore likely that asymptomatic cases were over-represented in this sample, which would not have been detected based on the diagnostic criteria used. -Therefore, while this study does represent the first effort to conduct a randomized, double-blind, placebo-controlled investigation of HCQ's effect on COVID-19 symptoms in a large sample, the lack of PCR tests and several other design flaws significantly impede interpretation of the results. +Therefore, while this study does represent the first effort to conduct a randomized, double-blind, placebo-controlled investigation of HCQ's effect on COVID-19 prevention after SARS-CoV-2 exposure in a large sample, the lack of PCR tests and several other design flaws significantly impede interpretation of the results. However, in line with the results from therapeutic studies, once again no evidence was found suggesting an effect of HCQ against COVID-19. A second study [@doi:10.1001/jamainternmed.2020.6319] examined the effect of administering HCQ to healthcare workers as a pre-exposure prophylactic. The primary outcome assessed was the conversion from SARS-CoV-2 negative to SARS-CoV-2 positive status over the 8 week study period. This study was also randomized, double-blind, and placebo-controlled, and it sought to address some of the limitations of the first prophylactic study. -They aimed to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA. +The goal was to enroll 200 healthcare workers, preferentially those working with COVID-19 patients, at two hospitals within the University of Pennsylvania hospital system in Philadelphia, PA. Participants were randomized 1:1 to receive either 600 mg of HCQ daily or a placebo, and their SARS-CoV-2 infection status and antibody status were assessed using RT-PCR and serological testing, respectively, at baseline, 4 weeks, and 8 weeks following the beginning of the treatment period. The statistical design of the study accounted for interim analyses at 50 and 100 participants in case efficacy or futility of HCQ for prophylaxis became clear earlier than completion of enrollment. The 139 individuals enrolled comprised a study population that was fairly young (average age 33) and made of largely of people who were white, women, and without pre-existing conditions. -At the second interim analysis, more individuals in the treatment group than the control group had contracted COVID-19 (4 versus 3), causing the estimate z-score to fall below the pre-established threshold for futility. +At the second interim analysis, more individuals in the treatment group than the control group had contracted COVID-19 (4 versus 3), causing the estimated z-score to fall below the pre-established threshold for futility. As a result, the trial was terminated early, offering additional evidence against the use of HCQ for prophylaxis. ###### Summary of HCQ/CQ Research Findings @@ -520,10 +526,10 @@ Several countries have now removed CQ/HCQ from their SOC for COVID-19 due to the ##### Dexamethasone Dexamethasone (9α-fluoro-16α-methylprednisolone) is a synthetic corticosteroid that binds to glucocorticoid receptors [@doi:10.1021/cr068203e; @url:https://www.cebm.net/covid-19/dexamethasone/]. -It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [@doi:10.1021/ja01545a061; @doi:10.1001/jama.1960.03030070009002]. +It was first synthesized in the late 1950s as an anti-inflammatory and has been used to treat RA and other inflammatory conditions [@doi:10.1021/ja01545a061; @doi:10.1001/jama.1960.03030070009002], including allergies and asthma [@url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=537b424a-3e07-4c81-978c-1ad99014032a]. Steroids such as dexamethasone are widely available and affordable, and they are often used to treat community-acquired pneumonia [@doi:10.1038/s41392-020-0127-9]. A clinical trial that began in 2012 recently reported that dexamethasone may improve outcomes for patients with ARDS [@doi:10/ggpxzc]. -However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [@doi:10/ggks86]; however, these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [@doi:10/ggq356]. +However, a meta-analysis of a small amount of available data about dexamethasone as a treatment for SARS suggested that it may, in fact, be associated with patient harm [@doi:10/ggks86]; these findings may have been biased by the fact that all of the studies examined were observational and a large number of inconclusive studies were not included [@doi:10/ggq356]. Dexamethasone works as an anti-inflammatory agent by binding to glucocorticoid receptors with higher affinity than endogenous cortisol [@doi:10.1016/B978-0-323-48110-6.00034-X]. In order to understand how dexamethasone reduces inflammation, it is necessary to consider the stress response broadly. @@ -557,12 +563,12 @@ Additionally, dexamethasone is a widely available and affordable medication, rai The results of the RECOVERY trial's analysis of dexamethasone suggest that this therapeutic is effective primarily in patients who had been experiencing symptoms for at least seven days and patients who were not breathing independently [@doi:10.1056/NEJMoa2021436]. A meta-analysis that evaluated the results of the RECOVERY trial alongside trials of other corticosteroids, such as hydrocortisone, similarly concluded that corticosteroids may be beneficial to patients with severe COVID-19 who are receiving oxygen supplementation [@doi:10.1053/j.jvca.2020.11.057]. -Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS). +Thus, it seems likely that dexamethasone is useful for treating inflammation associated with immunopathy or cytokine release syndrome (CRS), which is a condition caused by detrimental overactivation of the immune system [@individual-pathogenesis]. In fact, corticosteroids such as dexamethasone are sometimes used to treat CRS [@doi:10.1182/blood-2014-05-552729]. It is not surprising that administration of an immunosuppressant would be most beneficial when the immune system was dysregulated towards inflammation. However, it is also unsurprising that care must be taken in administering an immunosuppressant to patients fighting a viral infection. In particular, the concern has been raised that treatment with dexamethasone might increase patient susceptibility to concurrent (e.g., nosocomial) infections [@doi:10.23812/20-EDITORIAL_1-5]. -Additionally, the drug could potentially slow viral clearance and inhibit patients' ability to develop antibodies to SARS-CoV-2 [@doi:10.23812/20-EDITORIAL_1-5; @doi:10/ggks86], and the lack of data about viral clearance has been put forward as a major limitation of the RECOVERY trial [@doi:10/ftk4]. +Additionally, the drug could potentially slow viral clearance and inhibit patients' ability to develop antibodies to SARS-CoV-2 [@doi:10.23812/20-EDITORIAL_1-5; @doi:10/ggks86], with the lack of data about viral clearance being put forward as a major limitation of the RECOVERY trial [@doi:10/ftk4]. Furthermore, dexamethasone has been associated with side effects that include psychosis, glucocorticoid-induced diabetes, and avascular necrosis [@doi:10/ggks86], and the RECOVERY trial did not report outcomes with enough detail to be able to determine whether they observed similar complications. The effects of dexamethasone have also been found to differ among populations, especially in high-income versus middle- or low-income countries [@doi:10/gg42kx]. However, since the RECOVERY trial's results were released, strategies have been proposed for administering dexamethasone alongside more targeted treatments to minimize the likelihood of negative side effects [@doi:10.23812/20-EDITORIAL_1-5]. @@ -585,7 +591,8 @@ As a result, biologics are another possible avenue through which the pharmacolog TCZ is a receptor antibody that was developed to manage chronic inflammation caused by the continuous synthesis of the cytokine IL-6 [@doi:10.1101/cshperspect.a016295]. IL-6 is a pro-inflammatory cytokine belonging to the interleukin family, which is comprised by immune system regulators that are primarily responsible for immune cell differentiation. -Often used to treat conditions such as RA [@doi:10.1101/cshperspect.a016295], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease. +Often used to treat conditions such as RA [@doi:10.1101/cshperspect.a016295], TCZ has become a pharmaceutical of interest for the treatment of COVID-19 because of the role IL-6 plays in this disease. +It has also been approved to treat CRS caused by CAR-T treatments [@url:https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2e5365ff-cb2a-4b16-b2c7-e35c6bf2de13]. While secretion of IL-6 can be associated with chronic conditions, it is a key player in the innate immune response and is secreted by macrophages in response to the detection of pathogen-associated molecular patterns and damage-associated molecular patterns [@doi:10.1101/cshperspect.a016295]. An analysis of 191 in-patients at two Wuhan hospitals revealed that blood concentrations of IL-6 differed between patients who did and did not recover from COVID-19. Patients who ultimately deceased had higher IL-6 levels at admission than those who recovered [@doi:10/ggnxb3]. @@ -606,7 +613,7 @@ Both classical and trans-signaling can occur through three independent pathways: These signaling pathways are involved in a variety of different functions, including cell type differentiation, immunoglobulin synthesis, and cellular survival signaling pathways, respectively [@doi:10.3389/fimmu.2016.00604]. The ultimate result of the IL-6 cascade is to direct transcriptional activity of various promoters of pro-inflammatory cytokines, such as IL-1, TFN, and even IL-6 itself, through the activity of NF-κB [@doi:10.3389/fimmu.2016.00604]. IL-6 synthesis is tightly regulated both transcriptionally and post-transcriptionally, and it has been shown that viral proteins can enhance transcription of the IL-6 gene by strengthening the DNA-binding activity between several transcription factors and IL-6 gene-cis-regulatory elements [@doi:10.2492/inflammregen.33.054]. -Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS and CSS. +Therefore, drugs inhibiting the binding of IL-6 to IL-6Rα or sIL-6Rα are of interest for combating the hyperactive inflammatory response characteristic of CRS/CSS. TCZ is a humanized monoclonal antibody that binds both to the insoluble and soluble receptor of IL-6, providing de facto inhibition of the IL-6 immune cascade. Tocilizumab is being administered either as an intervention or as concomitant medication in {{ebm_tocilizumab_ct}} interventional COVID-19 clinical trials (Figure @fig:ebm-trials). @@ -615,11 +622,11 @@ Therefore, no conclusions can be drawn about its efficacy for the treatment of C However, early interest in TCZ as a possible treatment for COVID-19 emerged from a very small retrospective study in China that examined 20 patients with severe symptoms in early February 2020 and reported rapid improvement in symptoms following treatment with TCZ [@doi:10.1073/pnas.2005615117]. Subsequently, a number of retrospective studies have been conducted in several countries. Many studies use a retrospective, observational design, where they compare outcomes for COVID-19 patients who received TCZ to those who did not over a set period of time. -For example, one of the largest retrospective, observational analysis released to date [@doi:10/d2pk] compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC. +For example, one of the largest retrospective, observational analyses released to date [@doi:10/d2pk], consisting of 1351 patients admitted to several care centers in Italy, compared the rates at which patients who received TCZ deceased or progressed to invasive medical ventilation over a 14-day period compared to patients receiving only SOC. Under this definition, SOC could include other drugs such as HCQ, azithromycin, lopinavir-ritonavir or darunavir-cobicistat, or heparin. While this study was not randomized, a subset of patients who were eligible to receive TCZ were unable to obtain it due to shortages; however, these groups were not directly compared in the analysis. -After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, _p_ = 0.020), although analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients). -They reported particular benefits for patients whose PaO~2~/FiO~2~ ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold. +After adjusting for variables such as age, sex, and SOFA (sequential organ failure assessment) score, they found that patients treated with TCZ were less likely to progress to invasive medical ventilation and/or death (adjusted HR = 0.61, CI 0.40-0.92, _p_ = 0.020); analysis of death and ventilation separately suggests that this effect may have been driven by differences in the death rate (20% of control versus 7% of TCZ-treated patients). +The study reported particular benefits for patients whose PaO~2~/FiO~2~ ratio, also known as the Horowitz Index for Lung Function, fell below a 150 mm Hg threshold. They found no differences between groups administered subcutaneous versus intravenous TCZ. Another retrospective observational analysis of interest examined the charts of patients at a hospital in Connecticut, USA where 64% of all 239 COVID-19 patients in the study period were administered TCZ based on assignment by a standardized algorithm [@doi:10.1016/j.chest.2020.06.006]. @@ -633,12 +640,12 @@ Therefore, patients who would have been eligible for TCZ prior to this arbitrary Despite this design, demographic factors did not appear to be consistent between the two groups, and the average age of the control group was older than the TCZ group. The control group also had a higher percentage of males and a higher incidence of comorbidities such as diabetes and heart disease. All the same, the multivariate HR, which adjusted for these clinical and demographic factors, found a significant difference between survival in the two groups (HR=0.035, CI=0.004-0.347, _p_ = 0.004). -They reported improvement of survival outcomes after the addition of TCZ to their SOC regime, with 11 of 23 patients (47.8%) admitted prior to March 13th dying compared to 2 of 62 (3.2%) admitted afterwards. +The study reported improvement of survival outcomes after the addition of TCZ to the SOC regime, with 11 of 23 patients (47.8%) admitted prior to March 13th dying compared to 2 of 62 (3.2%) admitted afterwards (HR=0.035; 95% CI, 0.004 to 0.347; _p_ = 0.004). They also reported a reduced progression to mechanical ventilation in the TCZ group. However, this study also holds a significant limitation: the time delay between the two groups means that knowledge about how to treat the disease likely improved over this timeframe as well. All the same, the results of these observational retrospective studies provide support for TCZ as a pharmaceutical of interest for follow-up in clinical trials. -In addition to the retrospective observational studies, other analysis have utilized a retrospective case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19. +Other retrospective analyses have utilized a case-control design to match pairs of patients with similar baseline characteristics, only one of whom received TCZ for COVID-19. In one such study, TCZ was significantly associated with a reduced risk of progression to ICU admission or death [@doi:10.1016/j.medmal.2020.05.001]. This study examined only 20 patients treated with TCZ (all but one of the patients treated with TCZ in the hospital during the study period) and compared them to 25 patients receiving SOC. For the combined primary endpoint of death and/or ICU admission, only 25% of patients receiving TCZ progressed to an endpoint compared to 72% in the SOC group (_p_ = 0.002, presumably based on a chi-square test based on the information provided in the text). @@ -646,15 +653,16 @@ When the two endpoints were examined separately, progression to invasive medical In contrast, a study that compared 96 patients treated with TCZ to 97 patients treated with SOC only in New York City found that differences in mortality did not differ between the two groups, but that this difference did become significant when intubated patients were excluded from the analysis [@doi:10.1093/qjmed/hcaa206]. Taken together, these findings suggest that future clinical trials of TCZ may want to include intubation as an endpoint. However, these studies should be approached with caution, not only because of the small number of patients enrolled and the retrospective design, but also because they performed a large number of statistical tests and did not account for multiple hypothesis testing. -These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS and CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections. +In general, caution must be exercised when interpreting subgroup analyses after a primary combined endpoint analysis. +These last findings highlight the need to search for a balance between impairing a harmful immune response, such as the one generated during CRS/CSS, and preventing the worsening of the clinical picture of the patients by potential new viral infections. Though data about TCZ for COVID-19 is still only just emerging, some meta-analyses and systematic reviews have investigated the available data. One meta-analysis [@doi:10.2139/ssrn.3642653] evaluated 19 studies published or released as preprints prior to July 1, 2020 and found that the overall trends were supportive of the frequent conclusion that TCZ does improve survivorship, with a significant HR of 0.41 (_p_ < 0.001). This trend improved when they excluded studies that administered a steroid alongside TCZ, with a significant HR of 0.04 (_p_ < 0.001). They also found some evidence for reduced invasive ventilation or ICU admission, but only when excluding all studies except a small number whose estimates were adjusted for the possible bias introduced by the challenges of stringency during the enrollment process. -A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of 0.453 (95% CI 0.376–0.547, _p_ < 0.001), suggesting possible benefits associated with TCZ treatment [@doi:10.7717/peerj.10322]. -Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same biases in publication. -A second systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias [@doi:10.1016/j.pulmoe.2020.07.003]. +A systematic analysis of sixteen case-control studies of TCZ estimated an odds ratio of mortality of 0.453 (95% CI 0.376–0.547, _p_ < 0.001), suggesting possible benefits associated with TCZ treatment [@doi:10.7717/peerj.10322]. +Although these estimates are similar, it is important to note that they are drawing from the same literature and are therefore likely to be affected by the same potential biases in publication. +A different systematic review of studies investigating TCZ treatment for COVID-19 analyzed 31 studies that had been published or released as pre-prints and reported that none carried a low risk of bias [@doi:10.1016/j.pulmoe.2020.07.003]. Therefore, the present evidence is not likely to be sufficient for conclusions about the efficacy of TCZ. Additionally, there are possible risks associated with the administration of TCZ for COVID-19. @@ -662,14 +670,14 @@ TCZ has been used for over a decade to treat RA [@doi:10.1177/1759720X18798462], However, TCZ may increase the risk of developing infections [@doi:10.1177/1759720X18798462], and RA patients with chronic hepatitis B infections had a high risk of hepatitis B virus reactivation when TCZ was administered in combination with other RA drugs [@doi:10.1111/1756-185X.13010]. As a result, TCZ is contraindicated in patients with active infections such as tuberculosis [@doi:10.1186/s12967-020-02339-3]. Previous studies have investigated, with varying results, a possible increased risk of infection in RA patients administered TCZ [@doi:10.1093/rheumatology/keq343; @doi:10.1136/annrheumdis-2018-214367], although another study reported that the incidence rate of infections was higher in clinical practice RA patients treated with TCZ than in the rates reported by clinical trials [@doi:10.1093/rheumatology/ker223]. -In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group [@doi:10/d2pk]. +In the investigation of 544 Italian COVID-19 patients, the group treated with TCZ was found to be more likely to develop secondary infections, with 24% compared to 4% in the control group (_p_ < 0.0001) [@doi:10/d2pk]. Reactivation of hepatitis B and herpes simplex virus 1 was also reported in a small number of patients in this study, all of whom were receiving TCZ. A July 2020 case report described negative outcomes of two COVID-19 patients after receiving TCZ, including one death; however, both patients were intubated and had entered septic shock prior to receiving TCZ [@doi:10.1016/j.chest.2020.04.024], likely indicating a severe level of cytokine production. Additionally, D-dimer and sIL2R levels were reported by one study to increase in patients treated with TCZ, which raised concerns because of the potential association between elevated D-dimer levels and thrombosis and between sIL2R and diseases where T-cell regulation is compromised [@doi:10.1016/j.chest.2020.06.006]. An increased risk of bacterial infection was also identified in a systematic review of the literature, based on the unadjusted estimates reported [@doi:10.2139/ssrn.3642653]. TCZ administration to COVID-19 patients is not without risks, may introduce additional risk of developing secondary infections, and should be approached especially cautiously for patients who have latent viral infections. -In summary, approximately 25% of coronavirus patients develop ARDS, which is caused by an excessive early response of the immune system which can be a component of CRS [@doi:10.1016/j.chest.2020.06.006] and CSS [@doi:10.1186/s12967-020-02339-3]. +In summary, approximately 33% of hospitalized COVID-19 patients develop ARDS [@doi:10.1186/s13054-020-03240-7], which is caused by an excessive early response of the immune system which can be a component of CRS/CSS [@doi:10.1016/j.chest.2020.06.006; @doi:10.1186/s12967-020-02339-3]. This overwhelming inflammation is triggered by IL-6. TCZ is an inhibitor of IL-6 and therefore may neutralize the inflammatory pathway that leads to the cytokine storm. While the mechanism suggests TCZ could be beneficial for the treatment of COVID-19 patients experiencing excessive immune activity, no randomized controlled trials are available assessing its effect. @@ -685,7 +693,7 @@ Clinical trials that are in progress are likely to provide additional insight in Monoclonal antibodies have revolutionized the way we treat human diseases. They have become some of the best-selling drugs in the pharmaceutical market in recent years [@doi:10.1186/s12929-019-0592-z]. There are currently 79 FDA approved mAbs on the market, including antibodies for viral infections (e.g. Ibalizumab for HIV and Palivizumab for RSV) [@doi:10.1186/s12929-019-0592-z; @doi:10.1146/annurev-immunol-032712-095916]. -Virus-specific nAbs commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [@doi:10.3389/fmicb.2017.02323; @doi:10.1080/21645515.2017.1337614]. +Virus-specific nAbs commonly target viral surface glycoproteins or host structures, thereby inhibiting viral entry through receptor binding interference [@doi:10.3389/fmicb.2017.02323; @doi:10.1080/21645515.2017.1337614]. This section discusses current efforts in developing nAbs against SARS-CoV-2 and how expertise gained from previous approaches for MERS-CoV and SARS-CoV-1 may benefit antibody development. ##### Spike (S) Neutralizing Antibody @@ -703,7 +711,7 @@ Although targeting of the host cell enzyme ACE2 shows efficacy in inhibiting SAR This concern underlies the rationale for developing nAbs against the S glycoprotein, disrupting its interaction with ACE2 and other potential entry points and thereby inhibiting viral entry. The first human nAb against SARS-CoV-2 targeting the S glycoproteins was developed using hybridoma technology [@doi:10.1101/2020.03.11.987958], where antibody-producing B-cells developed by mice can be inserted into myeloma cells to produce a hybrid cell line (the hybridoma) that is grown in culture. -The 47D11 clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2 by a mechanism that is different from receptor binding interference. +The 47D11 antibody clone was able to cross-neutralize SARS-CoV-1 and SARS-CoV-2 by a mechanism that is different from receptor binding interference. The exact mechanism of how this clone neutralizes SARS-CoV-2 and inhibits infection _in vitro_ remains unknown, but a potential mechanism might be antibody-induced destabilization of the membrane prefusion structure [@doi:10.1101/2020.03.11.987958; @doi:10.1016/j.cell.2018.12.028]. The ability of this antibody to prevent infection at a feasible dose needs to be validated _in vivo_, especially since _in vitro_ neutralization effects have been shown to not be reflective of _in vivo_ efficacy [@doi:10.1128/JVI.01603-17]. Only a week later, a different group successfully isolated multiple nAbs targeting the RBD of the S glycoprotein from blood samples taken from COVID-19 patients in China [@doi:10.1101/2020.03.21.990770]. @@ -741,7 +749,7 @@ In July, a press release from Synairgen stated that SNG001 reduced progression t These results were subsequently published in November 2020 [@doi:10/ghjzm4]. The study reports that the participants were assigned at a ratio of 1:1 to receive either SNG001 or a placebo that lacked the active compound, by inhalation for up to 14 days. The primary outcome they assessed was the change in patients' score on the WHO Ordinal Scale for Clinical Improvement (OSCI) at trial day 15 or 16. -SNG001 was associated with an odds ratio (OR) of 2.32 (95% CI 1.07 – 5.04, _p_ = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, _p_ = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16. +SNG001 was associated with an odds ratio of improvement on the OSCI scale of 2.32 (95% CI 1.07 – 5.04, _p_ = 0.033) in the intention-to-treat analysis and 2.80 (95% CI 1.21 – 6.52, _p_ = 0.017) in the per-protocol analysis, corresponding to significant improvement in the SNG001 group on the OSCI at day 15/16. Some of the secondary endpoints analyzed also showed differences: at day 28, the OR for clinical improvement on the OSCI was 3.15 (95% CI 1.39 – 7.14, _p_ = 0.006), and the odds of recovery at day 15/16 and at day 28 were also significant between the two groups. Thus, this study suggested that IFN-𝛽1 administered via SNG001 may improve clinical outcomes. @@ -769,7 +777,7 @@ As more evidence becomes available, the potential for existing and novel therapi **Mechanism of Action for Potential Therapeutics** Potential therapeutics currently being studied can target the SARS-CoV-2 virus or modify the host environment through many different mechanisms. Here, the relationship between the virus and several therapeutics described above are visualized. -](images/N001-LifeCyclePlusDrugs.png){#fig:therapeutics secno=1} +](images/N001-LifeCyclePlusDrugs.png){#fig:therapeutics secno=1} Insights into the pathogenesis of and immune response to SARS-CoV-2 (see [@individual-pathogenesis]) have also guided the identification of potential prophylactics and therapeutics. As cases have become better characterized, it has become evident that many patients experience an initial immune response to the virus that is typically characterized by fever, cough, dyspnea, and related symptoms. @@ -782,7 +790,7 @@ The potential for other drugs, such as tocilizumab, to reduce recovery time rema One additional concern is that the presentation of COVID-19 appears to be heterogeneous across the lifespan. Many adult cases, especially in younger adults, present with mild symptoms or even asymptomatically, while others, especially in older adults, can be severe or fatal. -In children, the SARS-CoV-2 virus can present as two distinct diseases, COVID-19 or MIS-C. +In children, the SARS-CoV-2 viral infection can present either as a respiratory illness comparable to COVID-19 or as an inflammatory condition, known as multisystem inflammatory syndrome in children, for which presentation is similar to Kawasaki Disease [@doi:10.1038/s41390-020-1053-9]. The therapeutics and prophylactics discussed here were primarily tested in adults, and additional research is needed to identify therapeutics that address the symptoms characteristic of pediatric COVID-19 and MIS-C cases. #### Potential Avenues of Interest for Therapeutic Development @@ -835,7 +843,7 @@ While still nascent, work in this area is promising. Over the longer term, this approach and others may lead to the development of novel therapeutics specifically for COVID-19 and SARS-CoV-2. -#### Conclusions +#### Conclusions Due to the large number of clinical trials currently under examination (Figure @fig:ebm-trials), not all candidates are examined here. Instead, this review seeks to provide an overview of the range of mechanisms that have been explored and to examine some prominent candidates in the context of the pathogenesis of and immune response to SARS-CoV-2.