Abstract
The novel coronavirus, SARS-CoV-2, which causes the illness COVID-19, has spread across 213 countries and devastated millions of lives. SARS-CoV-2 is a betacoronavirus which enters the host respiratory cell via the ACE2 receptor and uses the host cell mechanisms to reproduce. There are currently no treatments for COVID-19 but the Solidarity trial conducted by the World Health Organisation and the RECOVERY and PRINCIPLE trials conducted by the University of Oxford are testing potential treatments. Remdesivir is an antiviral drug that prevents the replication of the virus. When looking at conducted trials, the benefits of remdesivir are undetermined but more trials would be useful to validate the results. Lopinavir/ritonavir are antiviral protease inhibitors. Multiple trials have been held to test the efficiency of this drug combination against the standard care. Overall, there have been no benefits of using lopinavir/ritonavir. Chloroquine and hydroxychloroquine both mediate the innate immune response, by changing the pH of endosomes, thus interfering with the viral life cycle. However, recent results from the RECOVERY trial stated that there was no overall benefit to the 28-day mortality endpoint and hydroxychloroquine has been removed from the trial. Cytokine storms and exaggerated immune responses are common within severe COVID-19 patients. This can lead to acute lung injury and acute respiratory distress syndrome. Anti-inflammatory drugs could reduce the cytokine storm and regulate the immune system, but could increase the risk of a secondary infection. Decisions need to be made before the administration of successful drugs to evaluate the potential risks and benefits. This article explores the current drugs which are being tested and evaluates both the effectiveness of the trials as well as the mechanisms by which the drugs treats COVID-19.
Introduction
In December of 2019, the novel betacoronavirus SARS-CoV-2 was first discovered in Wuhan, China. This virus has had damaging effects across the globe, infecting 8,574,434 people and killing 458,526 as of June 18th, 2020 (Worldometer, 2020).
Coronaviruses have been identified as human pathogens since the 1960s. There have been multiple betacoronavirus outbreaks such as the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). SARS-CoV-1 appeared in Guangdong, China, in November of 2002, infecting approximately 8000 humans and causing 774 deaths. In 2012, MERS-CoV was first found in Saudi Arabia, with 2494 confirmed cases and 858 deaths reported (Lu et al., 2020). In a study completed by Lu et al., SARS-CoV-2 and SARS-CoV-1 have genomic sequence similarity of 79% and are, therefore, closely related. They are both members of the subgenus Sarbecovirus but SARS-CoV-2 is more closely related to two bat-derived strains (bat-SL-CoVXC45 and bat-SL-CoVZXC21) (Lu et al., 2020). SARS-CoV, MERS-CoV and SARS-CoV-2 are all beta-coronaviruses which are said to be derived from bats but another animal may act as an intermediate host before being transmitted to humans, the terminal host. Although the intermediate species for SARS-CoV-2 is not confirmed, pangolins, snakes and turtles could be possible culprits (Javis, 2020; Lui et al., 2020).
SARS-CoV-2 is an RNA virus which attacks the respiratory system and enters the body through inhaled water droplets. The virus is covered in attachment glycoproteins which bind to the ACE2 receptor on host cell membranes (Patel, 2020). It enters the cell and uses the host cell’s replication mechanism to produce more structural viral proteins and enzymes, resulting in more virions (infected form of a virus outside the host cell). There are currently three known proteins, encoded for by the viral RNA, which remain inside the host cell and each has a specific function. One inhibits the host cell from signalling to the immune system, one makes the host cell release newly created virions and the other aids in resistance to the host cell’s innate immune response (Patel, 2020). Infected cells produce huge numbers of SARS-CoV-2 virions, eventually becoming overwhelmed and burst. This releases the new virions that can spread and further infect more healthy cells and kills the infected host cell, causing COVID-19. If an infection sufficiently damages the lungs, gaseous exchange cannot take place and oxygen cannot be delivered around the body, resulting in mechanical ventilation being required.
Despite the identification of the genomic structure for SARS-CoV-2, there are currently no vaccines and many trials are still taking place to find out which treatment is the most effective. The medication and current drug trials taking place will be discussed and evaluated.
Discussion
Current Clinical Trials:
The World Health Organization (WHO) is currently holding a clinical trial called “Solidarity”. Adults across the globe that have tested positive for COVID-19 are eligible to take part. However, the Solidarity trial must check that none of the patients are false positives for COVID-19 because this could compromise the validity of the results. Participating hospitals randomly allocate each patient to one of five different treatments including remdesivir, chloroquine and hydroxychloroquine, lopinavir and/or ritonavir, ritonavir and interferon beta-1a. All are compared to standard care. From June 17 the hydroxychloroquine and chloroquine arm of the trial has been removed due to results indicating that hydroxychloroquine does not reduce mortality.
WHO designed the trial to reduce the time to completion by 80% compared to a standard randomised clinical trial which would take years to design and conduct (World Health Organization, 2020). Due to the reduction in time, a small sample size could mean there is not a complete representation of the effects on the population, due to varying genetics, and therefore reduces the accuracy of the results. To overcome this, WHO is recruiting patients worldwide to be a part of the trial. If the trial is completed faster, the long term effects of these drugs cannot be thoroughly explored. Furthermore, many resources may be redirected at the Solidarity trial to help with its early completion, hindering other research or trials WHO is currently conducting. However, multiple manufacturers are donating resources to provide access to thousands of treatment courses as well as collaborating to ensure affordability and availability to effective and successful treatments. Although there are concerns, if a treatment is found quickly, lives could be saved.
Similarly, the University of Oxford has been holding clinical trials to also find an effective treatment for COVID-19. The first being the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial. Like the Solidarity trial, adults which have been tested positive with COVID-19 are randomly allocated to a treatment, which have all been recommended by an expert panel who advise England’s Chief Medical Officer. The possible treatments include lopinavir-ritonavir, a low dose of dexamethasone, hydroxychloroquine, azithromycin and tocilizumab. Only results regarding dexamethasone and hydroxychloroquine have been published as of yet and are discussed later in the article (University of Oxford, 2020).
Another trial held by the University of Oxford is the Platform Randomised trial of Interventions against COVID-19 in older people (PRINCIPLE) trial. The purpose of this trial is to test pre-existing drugs to observe if they slow or stop the progression of COVID-19 and prevent the need for hospital admission of older patients, who are most at risk of developing complications. Over 500 GP practices are recruiting people with and without underlying health problems (University of Oxford, 2020). The first phase includes a 7-day course of hydroxychloroquine and the antibiotic azithromycin will be added later on in the course. For approximately the first month of the trial, participants will be closely monitored and health record notes will be reviewed for up to three months to determine any long-term effects of COVID-19 (University of Oxford, 2020). Whether three months is long enough to fully assess the long-term effects of COVID-19 treatments is questionable since there are still gaps in the knowledge of SARS-CoV-2. Therefore, only monitoring the patients for up to three months seems unreasonable in fully analysing the true effect of COVID-19 and treatments on underlying health conditions. Some drugs being tested, such as hydroxychloroquine and lopinavir/ritonavir, have links with abnormal heart rhythms (Ogbru, 2020; Soto, 2020). Therefore, discovering to what extent these drugs cause these side effects will enable physicians to make an informed decision about whether the risks outweigh the benefits, since prescribing these drugs in the trial could have damaging effects to the patient’s health. As a result, risks with each treatment are made clear to the consenting participants of the trial prior . The RECOVERY and Solidarity trial do not include patients with underlying health conditions so research in this area is useful. Drugs such as lopinavir and ritonavir, which have links to increasing cholesterol and worsening diabetes (Ogbru, 2020), should also be monitored as these risks can have serious effects on a patient\’s health. Both cardiovascular disease and diabetes are common health conditions in the UK and therefore a proportion of the patients in the PRINCIPLE trial may have one or both conditions. Therefore, this needs to be taken into account while treating COVID-19.
Possible treatments:
Remdesivir
Remdesivir is an antiviral drug that prevents the production of viral RNA. It has previously been shown to reduce viral replication against the Ebola virus (EBOV) and demonstrated antiviral properties against MERS and SARS (Eastman and Ross, 2020). Remdesivir closely resembles the base adenine and, therefore, the RNA-dependent RNA polymerase, utilised by SARS-CoV-2, may insert a remdesivir molecule instead into the RNA strand. This prevents the polymerase from replicating the viral RNA further (Hogan, 2020; Shi and Lai, 2005).
Whether the drug is beneficial to patients with COVID-19 is yet to be determined. A recent placebo-controlled trial in Hubei, China, tested adults with laboratory-confirmed SARS-CoV-2 in 10 hospitals and, unfortunately, remdesivir was not associated with a difference in the time to clinical improvement. Patients who have had symptoms for up to 12 days, an oxygen saturation lower than 94% and with radiologically confirmed pneumonia, are classed with severe COVID-19. 237 severe COVID-19 patients were enrolled in the trial; 158 were randomly allocated remdesivir and 78 were given a placebo. Patients who received remdesivir had a faster clinical improvement compared to patients who received the placebo but the results, however, were statistically insignificant (Wang and Zhang, 2020). This indicates that remdesivir could help treat patients with an early onset of symptoms and prevent a patient’s condition becoming severe or critical. More testing should take place to gather a clear conclusion about whether remdesivir is an effective treatment, including the possibility of side effects and long-term effects. A larger sample size and more variables, such as gender, age and medical history, would make the results more accurate. Patients in a specific age bracket with similar medical backgrounds were tested initially but including a variety of age groups would demonstrate whether the effectiveness of remdesivir is dependent on age, concluding that more trials should take place.
Although the outcome of remdesivir in the Hubei trial is not completely favourable, a trial known as the Adaptive COVID-19 Treatment Trial (ACTT), in the United States, indicated that remdesivir resulted in an accelerated recovery from COVID-19 (National Institute of Health, 2020). The randomised trial involved 1063 patients and it was discovered that patients who were administered with remdesivir had a 31% faster recovery time. Additionally, the mortality rates for these patients were 3.6% lower than those individuals taking the placebo (National Institute of Health, 2020). Due to the larger sample size of the trial, the results gathered are more reliable than the Hubei trial. Therefore, remdesivir could be a successful drug for treating patients with mild symptoms, but also preventing patients from developing more severe symptoms. However, only looking at the time to recovery may not show a true representation of remdesivir effects. The gender, health history and lifestyles of the participants on the trial were not mentioned, which could mean that the results may not be purely affected by remdesivir. Despite this, the overall results of the trial are positive. Since the outcome of this trial contradicts the results seen in the Hubei trial, more trials and testing should be conducted to confirm the true effect of remdesivir.
Lopinavir and Ritonavir
The combination of lopinavir and ritonavir (Kaletra) is a treatment for, HIV-1 by acting as a protease inhibitor (Chandwani and Shuter, 2008). SARS-CoV-2 is an RNA virus, therefore can be destroyed in a similar way to HIV, making lopinavir/ritonavir a potential treatment. Lopinavir blocks the action of 3-chymotrypsin-like protease processing viral RNA in the host cell. This leads to the inhibition of structural proteins and enzymes production needed for cell wall and capsid formation in new virions. HIV protease inhibitors target a C2-symmetric pocket, which is not present in the 3-chymotrypsin-like protease in SARS-CoV-2, therefore making the use of HIV protease inhibitors to treat this virus questionable (Doward and Gbinigie, 2020). Lopinavir will quickly undergo first-pass metabolism in the liver by cytochrome P450 3A (CYP3A4 and CYP3A5) enzymes. When co-administered with ritonavir, the CYP3A4 isotype is inhibited, resulting in an increased concentration of active lopinavir (increased half-life) (Chandwani and Shuter, 2008; Doward and Gbinigie, 2020). However, the side effects of Kaletra include nausea and abdominal pain. Protease inhibitors, specifically, are associated with increased cholesterol, worsening of diabetes, and abnormal heart rhythms (Ogbru, 2020). However, this risk could be reduced by decreasing the dosage given to patients. Lopinavir/ritonavir combination should not be administered to patients with pre-existing heart problems or diabetes until thorough research has been completed.
Cao et al. conducted a randomised trial where 199 patients were enrolled, of which 99 were given the lopinavir/ritonavir combination and 100 were just given standard care (support therapy and oxygen). The mortality rate after 28 days was similar between the treatments, with standard care only being 5.8% higher, and 13 patients (13.8%) stopped the treatment early due to adverse events (Cao and Wang, 2020).
An exploratory, random trial, called ELACOI, conducted by Li et al., assessed the efficiency of lopinavir/ritonavir in 86 patients. Similar trends were observed to Cao et al., concluding that lopinavir/ritonavir presented little benefit to improve the clinical outcome for patients compared with supportive care. This study, however, has not been peer-reviewed yet so the reliability and results need to be evaluated (Li and Xie, 2020). The sample size in both trials could be increased to create more valid and reliable results with great significance, as well as using a double-blind placebo to show the true effectiveness of the drugs. The reliability of both trials is debatable therefore a final assumption can not be made from these trials alone.
Interferon beta-1a
Interferon-beta-1a is a type of cytokine cause the activation and transcription of interferon-stimulated genes (ISGs), which are largely involved in regulating inflammation, signalling and immunomodulation (Sallard and Lescure, 2020). They are produced by the host cell through an antiviral response during infection. ISGs interfere with viral replication and stimulate the adaptive immune response by activating antiviral proteins, such as cytotoxic T lymphocytes, natural killer cells and macrophages (Sallard and Lescure, 2020; Shen and Yang, 2020).
A clinical trial in Hong Kong investigated the use of interferon-beta in 127 COVID-19 patients seven days after symptom onset. 86 patients were prescribed a combination of interferon-beta, lopinavir, ritonavir and ribavirin (an antiviral drug) and 41 were given a control of lopinavir and ritonavir. The primary objective from this was a negative nasopharyngeal swab (to collect nasal secretions from the back of the throat and nose) for SARS-CoV-2 and secondary to this the length of time until symptoms are alleviated (Yukon Communicable Disease Control, 2015; Shalhoub, 2020). The combination of drugs compared to the control decreased the time to get a negative swab by 5 days and the time until symptom resolution by 4 days (Shalhoub, 2020).
The analysis of these results showed a significant improvement to patients who were enrolled; however, there were no fatalities in the trial, suggesting that all patients included had relatively mild symptoms. As a result, the effectiveness of interferon-beta still needs to be investigated as a treatment for more severe symptoms. The data gathered in the trial is reliable because the sample size had almost an equal distribution in gender, with 54% being male. Also, participants ranged in age with the sample having a median age of 52. However, the primary endpoint records a negative swab test, therefore there are concerns about the recording of false negatives. Previous trials assessing the efficiency of interferon-beta have been observational or retrospective, therefore a trial with this perspective adds value to the growing evidence on treatments by eliminating limitations that retrospective studies have.
Hydroxychloroquine and Chloroquine
The mechanisms behind hydroxychloroquine and chloroquine are not fully understood but these drugs change the pH in endosomes, which is essential to prevent cell membrane fusion and, ultimately, viral entry, transport and post-entry events. This is done by interfering with the glycosylation of cellular SARS-CoV-2 receptors (Singh and Shaikh, 2020). However, the use of either can have serious side effects such as abnormal heart rhythms and may interfere with the antibiotic azithromycin, another compound w being tested in combination with hydroxychloroquine as an inflammatory drug, which means the risks to the participant must be evaluated thoroughly (Soto, 2020).
Recent results from the RECOVERY trial indicated that hydroxychloroquine and chloroquine have no overall beneficial effect in treating COVID-19. A total of 1542 patients were allocated hydroxychloroquine randomly and the results were compared with those from 3132 patients allocated standard care alone. There was no significant difference in the mortality rate between the two after 28 days. Therefore, the chief investigators of the RECOVERY trial decided to remove hydroxychloroquine from the trial (University of Oxford, 2020).
Anti-Inflammatory Drugs
In severe cases of COVID-19, exaggerated immune and inflammatory response can result in acute lung injuries and acute respiratory distress syndrome. An inflammatory cytokine storm (the uncontrolled release of cytokines activating more immune cells which leads to hyperinflammation) is common within patients and can result in lymphocytopenia (Zhang and Zhao, 2020). This is a disease characterised by low levels of white blood cells in the blood, but it could also be due to lymphocytes being attacked by the virus itself. However, it is most likely caused because of the cytokine storm due to it being a common symptom among severe COVID-19 patients (Zhang and Zhao, 2020).
Both dexamethasone and tocilizumab are anti-inflammatory drugs which could help treat the cytokine storm by preventing white blood cells to the site of infection.
A retrospective study conducted by Wei Haiming et al. observed the efficiency of tocilizumab (IL-6 receptor inhibitor) in severe or critical COVID-19 patients and the results were said to be successful, but yet to be published (Zhang and Zhao, 2020). The drug was given alongside the lopinavir/ritonavir combination to 20 patients. Within a few days, fevers returned to normal, 75% had improved oxygenation and 52.6% of patients had normal lymphocyte levels in the body, indicating that the cytokine storm had been alleviated. However, the main concern with anti-inflammatory treatments is that it weakens the immune system so much that there is a high risk of secondary infection, by delaying the elimination of the virus (Zhang and Zhao, 2020). Furthermore, the small sample size does not show a true representation of the infected population. A larger sample size including an equal distribution of gender and age would create more reliable results. Investigating the long-term effects of the treatment is also necessary, such as the risk of a secondary infection. Knowing this information is vital in predicting the number and rate of infection in the future.
Results from the RECOVERY trial concluded that dexamethasone is an effective drug in treating severe COVID-19 patients on ventilators or who are receiving oxygen. Six-milligram doses of dexamethasone were randomly allocated to 2104 patients whereas 4321 patients received standard care. Deaths of ventilated patients dropped by one third (University of Oxford, 2020). Dexamethasone reduced the deaths by one fifth in patients receiving just oxygen. These results are very promising because dexamethasone is inexpensive, relatively accessible and can be immediately used across the world to save lives. The results from both trials show that anti-inflammatory drugs are a promising treatment for severe COVID-19 patients and could help thousands of lives recover.
Conclusion
During a pandemic where there are no current treatments, there is a race to find the most effective and safest option. The only drug to be approved across all three trials is dexamethasone in the RECOVERY trial. This drug, however, can only be used to treat severe COVID-19 patients. Therefore, a drug for mild COVID-19 symptoms needs to be discovered. With drugs like chloroquine and other anti-inflammatory drugs, a decision needs to be made about whether the potential benefits of the treatment outweigh the risks. The negative results for the RECOVERY trial concerning hydroxychloroquine and the insignificant positive results regarding lopinavir and ritonavir demonstrate that it will take time before one will be authorised for production and administration.
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About the Author
Stephanie has a passion in medicine and her curiosity has taken her through many different areas in the subject. She has a keen interest in genetics and neurology but she aspires to work in paediatrics in the future. As well as medicine, music is also a passion in her life. She plays the piano, cello and sings. She likes to combine the two and look into how music can affect your wellbeing.