207 EDITORIAL New and Emerging Therapeutic Agents for the Management of SARS-Cov-2 Coronavirus Infection COVID-19 Sayed Subhan Bukhari, Shaun H Livsey COVID-19 emerged as a new severe acute respiratory illness in Wuhan, China in December 2019 and rapidly spread worldwide to become a global 1 pandemic. Although the figures keep changing on daily basis, by the end of October 2020, over 44 million people have been diagnosed with COVID-19 worldwide, according to World Health Organization. The pandemic has claimed more than a million human lives so far and resurgence in the number of new cases and continued growth in some countries has threatened both high and low-resource countries alike. In January 2020, the virus responsible for the Coronavirus Infectious Disease 2019 (abbreviated as COVID19) was isolated and its RNA genome 2,3 sequenced and shared globally online. From complete genome sequencing it transpired that the cause of the severe acute respiratory illness that became known as COVID-19 is in fact a novel coronavirus, named SARS-CoV-2. Since then every so often new information about the virus and the new infection is emerging and history is constantly being rewritten. Subsequent phylogenetic analysis of the viral genome sequence suggests that SARS-CoV-2 originated in animals, probably bats, and was transmitted to other animals before crossing the human species barrier at the Huanan wet market in 4,5,6 Wuhan City. The search for specific therapeutic drugs to effectively treat COVID-19 commenced as early as the discovery of the virus itself. However, with many studies carried out independently in small numbers of patients, there is a risk that such trials may lack s u f f i c i e n t s t a t i s t i c a l p o w e r f o r c l i n i c a l recommendations. In this editorial, we will describe selected agents which are under investigation in large scale studies and which are more likely to produce robust outcome data for the efficacy and safety of these agents in the management of COVID- 19. These studies include the World Health Organisation (WHO) SOLIDARITY study and the 7,8 French Discovery study. WHO Study, “SOLIDARITY” This is an international clinical trial to help find out an effective treatment for COVID-19 which was launched by the World Health Organization (WHO) and partners. It is one of the largest international randomised trials for COVID-19 treatments, enrolling almost 12, 000 patients in 500 hospital sites in over 30 countries. This study is evaluating the effect of drugs on 3 important outcomes in COVID-19 patients: mortality, need for assisted ventilation and 7,8 duration of hospital stay. The study compares treatment options against standard of care to assess their relative effectiveness against COVID-19. By enrolling patients in multiple countries, the Solidarity Trial aims to evaluate whether any of the drugs improve survival or reduce the need for ventilation or reduce the duration of hospital stay. The trial is open to adding other drugs based on emerging new evidence. However, until such time as there is sufficient evidence, WHO cautions physicians and medical associations against re co m m e n d i n g o r a d m i n i ste r i n g u n p rove n treatments to patients with COVID-19 or people self- medicating with such agents. WHO guidance on compassionate use can be found on the following l i n k : h t t p s : / / w w w . w h o . i n t / n e w s - ro o m /co m m e nta r i e s / d eta i l /o ff - l a b e l - u s e - o f - medicines-for-covid-19. The Solidarity Trial published interim results in October 2020 which indicate that all four treatments evaluated (remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon) had little or no effect on overall mortality, initiation of ventilation and duration of hospital stay in hospitalised patients. This study is considering evaluating other Correspondence: Prof. Sayed Subhan Bukhari Consultant in Infection Medicine Training Programme Director, Honorary Clinical Professor University Hospitals of Leicester NHS Trust, Leicester, United Kingdom E-mail: sayed.bukhari@uhl-tr.nhs.uk Received: October 30, 2020; Accepted: November 16, 2020 University Hospitals of Leicester NHS Trust, Leicester, United Kingdom h as b een ceased sin ce Ju n e 29, 2020) + Lopinavir/Ritonavir plus interferon ß-1a versus SoC (this treatment arm has been ceased since June 29, 2020) + Hydroxychloroquine (this treatment arm has been ceased since May 24, 2020). The primary objective of the study is to evaluate the clinical efficacy and safety of different investigational therapeutic options relative to the control arm in patients hospitalised with COVID-19, the primary endpoint is subject clinical status (on a 7-point ordinal scale) at day 15. The secondary objectives of the study are to evaluate: 1) the clinical efficacy of different investigational therapeutic agents through 28 days of follow-up as compared to the control arm as assessed by clinical severity (7-point ordinal scale, national early warning score, oxygenation, mechanical ventilation), hospitalisation, mortality through 28 days of follow-up, in-hospital mortality and 90-day mortality, 2) the safety of different investigational therapeutic options through 28 days of follow-up as compared to the control arm as assessed by the cumulative incidence of serious adverse events (SAEs), the cumulative incidence of Grade 3 and 4 adverse events (AEs), the discontinuation or temporary suspension of antiviral drugs for any reason, and the changes in white blood cell count, haemoglobin, platelets, creatinine, blood electrolytes, prothrombin time and international normalised ratio (INR), glucose, total bilirubin, alanine aminotransferase (ALT), and aspartate 7,8 aminotransferase (AST) over time. Other agents that have shown potential for the treatment of earlier coronavirus infections SARS and MERS are also being evaluated on the basis that the viruses share structural similarities with SARS-CoV-2. These include novel agents in development and antivirals currently in use for other indications. In addition, several studies have evaluated potential 9,10,11 treatments in vitro. A number of these therapies appear to have been introduced in China but are not well reported in English language scientific literature. China, as the country with the longest experience of managing COVID-19, is likely to have valuable expertise to share with the rest of the world. Following is a summary of various agents under investigation for the treatment of COVID-19 that 7,8 have shown some promise. 1. Chloroquine/hydroxychloroquine: This drug treatments, to continue the search for effective COVID-19 therapies. So far, only corticosteroids have been proven effective against severe and 7,8 critical COVID-19 infection. In July 2020, WHO accepted the recommendation from the Solidarity Trial's International Steering Committee to discontinue the trial's hydroxychloroquine and lopinavir/ritonavir arms. The International Steering Committee formulated the recommendation in light of the evidence for hydroxychloroquine vs standard-of-care and for lopinavir/ritonavir vs standard-of-care from the Solidarity Trial interim results, and from a review of the evidence from all trials presented at the 1-2 July 2020 WHO Summit on COVID-19 research and innovation. These interim trial results demonstrated that hydroxychloroquine and lopinavir/ritonavir produce little or no reduction in the mortality of hospitalised COVID-19 patients when compared to standard of care. Consequently, Solidarity Trial investigators interrupted the trials with immediate effect. It is noteworthy that this decision applies only to the conduct of the Solidarity Trial in hospitalised patients and does not affect the possible evaluation in other studies of hydroxychloroquine or lopinavir/ritonavir in non-hospitalised patients or as pre- or post- exposure prophylaxis for COVID-19. French Study, “Discovery” France is co-ordinating the Discovery trial to compare the same drugs with standard care in a network of 3,200 patients in Belgium, France, Germany, Luxembourg, the Netherlands, Spain, Sweden and the UK. This will be randomised but 7,8 non-blinded and will assess outcomes at 15 days. This study is a multi-centre, adaptive, randomised, open clinical trial of the safety and efficacy of treatments of COVID-19 in hospitalised adults. The study is a multi-centre and multi-country trial that will be conducted in various sites in Europe. Adult patient (≥18 year-old) hospitalised for COVID-19 with SpO2 ≤ 94% on room air OR acute respiratory failure requiring supplemental oxygen or ventilatory support are randomised between 4 treatment arms, each to be given in addition to the usual standard of care (SoC) in the participating hospital: SoC alone v e r s u s S o C + R e m d e s i v i r v e r s u s S o C + Lopinavir/Ritonavir versus SoC (this treatment arm 208 JIIMC 2020 Vol. 15, No.4 8 and cytokine storm. 6. Fav i p i rav i r + i nte r fe ro n a l p h a : I n t h i s combination, favipiravir blocks viral RNA synthesis and interferon alpha stimulates innate antiviral response. This combination is being 10 studied in a number of trials in China. 7. Fa v i p i r a v i r + b a l o x a v i r m a r b o x i l : T h i s combination of two antiviral agents blocks viral RNA synthesis. The U.S. Food and Drug Administration has approved baloxavir marboxil for the treatment of acute uncomplicated influenza (flu) in patients 12 years of age and older who have been symptomatic for no more than 48 hours. Now it is being studied against 11 COVID19 in combination with favipiravir. 8. Ribavirin + interferon alpha+ Lopinavir/ritonavir: This is a triple therapy combination of antiviral agents. Ribavirin inhibits the activity of the enzyme RNA dependent RNA polymerase, due to its resemblance to building blocks of the RNA molecules. It may inhibit replication of SARS- CoV-2. Lopinavir/ritonavir combination is viral protease inhibitors which may also inhibit SARS-CoV-2 virus and thus reduce adverse outcomes of COVID-19 infection. Interferon alpha stimulates innate antiviral response. Triple therapy is recommended by National Health Commission of the People's Republic of China as per Guidelines for diagnosis and treatment of novel coronavirus pneumonia 2020 (Trial Version 17 5). A trial claiming to show efficacy with hydroxy- chloroquine plus azithromycin received wide 12 coverage in the lay media. This study had important methodological deficiencies and its conclusions have 18 been disputed by expert reviewers. In addition, this combination is associated with an increased risk of QT interval prolongation which may turn out to be fatal in some high risk patients. Another controlled trial indicated that the combined viral protease inhibitor formulation of lopinavir/ritonavir is 13 ineffective. However, an uncontrolled trial of remdesivir which has in vitro activity against SARS-CoV-2, demonstrated improvement in 36 of 53 (68%) COVID-19 patients who were severely ill and who had oxygen saturation at ≤94% or were receiving 14 oxygen support. More recently, a randomised impairs release of virus after cell entry and blocks virus binding to cell receptor. It modulates immune response. The Food and Drug Administration (FDA) has given emergency use authorisation in the USA, however, the UK Medicine and Healthcare products Regulatory Agency (MHRA) states that it should only be used within a clinical trial. It is being investigated in t h e W H O S O L I DA R I T Y s t u d y. H yd rox y - chloroquine is the preferred choice as it is associated with fewer adverse effects than chloroquine. 2. H y d r o x y c h l o r o q u i n e + a z i t h r o m y c i n : Hydroxychloroquine impairs release of virus after cell entry and block virus binding to cell receptor. It modulates immune response. A z i t h ro my c i n p o s s e s s e s p o s s i b l e a n t i - inflammatory action and it prevents secondary bacterial infection. One trial suggests reduction in viral nasopharyngeal carriage at 6 days in 20 patients as compared with unmatched untreated cohort, with azithromycin reinforcing 12 the effect of hydroxychloroquine. 3. Lopinavir/ritonavir: These agents are viral protease inhibitors. The use of this combination may inhibit SARS-CoV-2 virus and thus reduce adverse outcomes of infection. A randomised controlled trial including 200 patients, suggested 13 no benefit so far. Another trial is now underway in combination with a steroid, dexamethasone. Lopinavir/ritonavir combination is also being investigated in the WHO SOLIDARITY study. 4. Remdesivir: This drug blocks viral RNA synthesis. It has a broad-spectrum of activity against many coronaviruses. It was given emergency use authorisation by the FDA in the USA. Clinical 14,15,16 trials have reported preliminary results. Data from a study called Adaptive COVID-19 Treatment Trial (ACTT) indicates beneficial effect on reduction of time to recovery. Remdesivir is included in the WHO SOLIDARITY study. 5. Tocilizumab: This agent blocks interleukin-6 signalling which may inhibit the cytokine release in cytokine storm during severe COVID-19 infection. 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Comparative effectiveness and safety of ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha and ribavirin plus lopinavir/ritonavir plus interferon-alpha in in patients with mild to moderate novel coronavirus JIIMC 2020 Vol. 15, No.4 211