COVID-19 therapies: where do we stand?

By Sarah Thomas

The development of a vaccine against COVID-19 is being pursued at an unprecedented pace. Nevertheless, the release date for a vaccine is a topic of ongoing speculation. Thus, it remains a priority to determine appropriate therapies for the treatment of COVID-19. Throughout the pandemic, many drugs have been repurposed to determine their therapeutic value for COVID-19. 

Hydroxychloroquine (HCQ) is arguably the COVID-19 therapy that has received the most publicity, with some (including the US president) referring to the drug as a “game changer”. HCQ, a more soluble and less toxic metabolite of the anti-malarial chloroquine (CQ), has previously shown promise as an antiviral. Two of the methods by which HCQ has been postulated to be helpful are via reduction in ACE2 (Angiotensin-Converting Enzyme 2)-mediated viral internalization(Devaux et al., 2020), and via interference with lysosome-endosome interactions leading to viral release in the cell(Savarino et al., 2003, Golden et al., 2015, Vincent et al., 2005).

However, HCQ has not proven the miracle drug it was initially touted to be. Over the course of several months, multiple studies have investigated the potential benefits of HCQ in treating COVID-19, with disappointing results. In March, HCQ was removed from the RECOVERY study, an adaptive randomized controlled trial (RCT) out of Oxford, with the principal investigators citing “no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19”(Horby and Landray, 2020). The vast majority of the literature at present is consistent with this conclusion, though there are a few notable exceptions. 

Another therapy which has received some attention is azithromycin (AZ). A macrolide traditionally used as an antibacterial, AZ has shown promise in treatment of viral infections, both for prevention of secondary bacterial infections and also for specific antiviral activity. Some studies have indicated AZ may be linked to increased virus-induced production of interferons, which work to inhibit viral replication(Gielen et al., 2010, Menzel et al., 2016). AZ may also interfere with endocytic virus internalization, as demonstrated with influenza virus A(H1N1)(Tran et al., 2019). Indeed, the viral-load reduction observed with AZ treatment is consistent across multiple investigations(Schogler et al., 2015, Gielen et al., 2010, Menzel et al., 2016, Min and Jang, 2012). 

However, as with HCQ, the initial promise of AZ as a therapy for COVID-19 has not held up in human trials. Several studies have reported no benefit when patients were treated with AZ, and given the numerous, well-cited risks associated with the drug, attention has largely shifted elsewhere(Sarma et al., 2020, Simpson et al., 2020). 

The corticosteroid dexamethasone is another drug involved in modulation of the immune system. The RECOVERY trial – the very same trial that concluded HCQ was an ineffective treatment – recently reported that dexamethasone was an effective therapy for treatment of severe COVID-19(Horby et al., 2020). Since steroids’ immunosuppression is undesirable in the initial phases of infection, but desirable in some high-acuity cases in which over-exuberant immune response damages lung tissue, dexamethasone therapy is reserved for patients with significant disease(Johnson and Vinetz, 2020). Unlike other coronaviruses, if a patient develops severe respiratory complications of COVID-19, this tends to occur at least a week after initial symptoms when viral load is already waning. Therefore, dexamethasone’s risk-to-benefit is unfavorable in the early stages of COVID-19, but favorable in those with advanced respiratory involvement(Horby et al., 2020). Thus, while dexamethasone shows promise as a therapy for severe cases of the disease, it by no means is a panacea for COVID-19.  

Convalescent plasma is a therapy that has a history as a last resort for diseases including Severe Acute Respiratory Syndrome (SARS) and Ebola(Chen et al., 2020). The concept is rooted in the idea that the antibodies against the virus in question are present in the plasma of those who have contracted and recovered from the disease. The plasma of these recovered individuals is then injected into those who are currently infected, in an effort to provoke an immune response. 

Unfortunately, the use of convalescent plasma to treat COVID-19 has not been entirely effective. In one review of the literature updated in July, the authors remained sceptical of the benefits of the treatment and wary of the lack of evidence or discussion around its potential risks(Piechotta et al., 2020). With the current evidence base primarily consisting of small studies with notable methodological limitations, e.g. not randomized, it is difficult to ascertain the efficacy of convalescent plasma as a therapy for COVID-19. 

Antivirals such as remdesivir are thought to have potential as therapies for COVID-19. Developed as a treatment for Ebola, remdesivir targets viral RNA production, thus reducing viral load and potentially reducing the severity and transmissibility of the disease(Crosby et al., 2020). Remdesivir has been previously associated with reduced viral replication of SARS-CoV-2’s predecessors, SARS-CoV-1 and MERS-CoV (Middle East Respiratory Syndrome), thus it remains of interest despite the current paucity of data. At present, there are several studies investigating the potential use of remdesivir as a therapy for COVID-19 in multiple countries, including the US and Singapore. 

In conclusion, despite the range of therapies that have been investigated as potentially beneficial against COVID-19 infection, a reliably effective treatment remains elusive. Even if a vaccine is developed, it may not be as effective against COVID-19 as hoped, particularly given speculation that it may be possible to be re-infected with the virus. Finding a treatment for COVID-19 remains essential, independent of the search for a vaccine. We can only hope that ongoing trials shed further light on pharmacologic management of COVID-19.

References

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