key: cord-333200-yka7wfbi authors: Dhampalwar, Swapnil; Saigal, Sanjiv; Soin, Arvinder title: Treatment armamentarium of COVID-19: Evolving strategies & evidence so far date: 2020-07-16 journal: J Clin Exp Hepatol DOI: 10.1016/j.jceh.2020.07.001 sha: doc_id: 333200 cord_uid: yka7wfbi The outbreak of SARS-CoV-2 started in Hubei province of China in December 2019 and rapidly spread all over the world. It has infected more than 7 million people worldwide and has pushed half of the world in a state of lockdown. There is an urgent unmet need of interventions both for prevention & treatment of this disease and more than 500 clinical trials are ongoing in this regard. At present, no study with robust methodology have clearly demonstrated benefits of Hydroxycholoquine for treatment, pre-exposure prophylaxis in healthcare workers or post exposure prophylaxis in COVID-19. Remdesivir has been shown to have modest benefits in moderate to severe disease, if administered early. Given the rapid pace of clinical information and discoveries, it is important for clinicians to be up to date with the latest, evidence-based treatment options available for this novel disease. Keeping up with this current pace of information, we review the clinical studies of different therapeutic options available to treat SARS-CoV-2. In New coronaviruses appear to infect humans periodically due to their wide distribution, zoonotic reservoirs, genetic diversity with frameshift genetic recombination, and increased human-animal interface activities. SARS-CoV-2 belongs to Betacoronavirus genus which includes Bat SARS- (DPP4). SARS-CoV-2 has lower Case fatality rate (around 3%) and higher transmissibility (basic reproduction number R 0 2-2.5) as compared to SARS-CoV (9.5% and 1.7-1.9, respectively) and MERS-CoV (34.4% and 0.7, respectively). (6) SARS-CoV-2 is an enveloped, non-segmented, positive sense, single stranded RNA virus. It has 4 structural proteins including Spike (S) glycoprotein, envelope (E) glycoprotein, membrane (M) glycoprotein, nucleocapsid (N) protein and several other non-structural proteins. It is essential to understand the lifecycle of the virus and pathogenesis as it offers insights into potential therapeutic targets. The process of cellular entry of virus starts by attachment of S protein with Angiotensin Converting Enzyme 2 (ACE-2) receptor on host cells (i.e. pneumocytes). Attachment occurs via binding domain of S protein to ACE-2 which is followed by fusion of viral membrane to host cell. After fusion, Type 2 transmembrane serine protease Table 1 . There is no approved treatment for SARS-CoV-2 at present and the current guidance is from Table 2) . Seventy patients who were intubated, died, or discharged within 24 hours of admission and were excluded from analysis. Primary end point was respiratory failure which was a composite of intubation or death. In patients who died after intubation, primary end point was defined as time of intubation. Patients treated with HCQ had severe disease at baseline. Overall, 346 patients (25.1%) had a primary end-point event. In unadjusted analysis, patients in HCQ arm had more primary end point events. However, propensity matched analysis showed no significant difference. (20) Since, these studies with CQ & HCQ have different therapeutic regimens, heterogenous study population, unequal arms to compare, ill-defined outcomes, and non-reproducible results; further randomized trials are needed before recommending the routine use of HCQ in mild COVID-19. Recently, a large multinational registry analysis failed to show benefits of HCQ in COVID-19, which was later retracted because of inconsistencies in dataset and the analysis that was (Table 3) . Approximately 31% patients of total 199, were on mechanical ventilation at baseline. Authors found no significant difference in viral loads over time or viral loads as per disease severity. Also, there was no significant difference in clinical outcomes and mortality in patients treated with LPV/RTV versus standard of care. Median time to clinical improvement was shorter by 1 day in LPV/RTV arm. Overall mortality was 22%. There was possible benefit of early intervention in a post hoc subgroup analysis. Patients who were treated within 12 days of symptom onset, had a trend towards reduced mortality.(23) Remdesivir is a nucleotide analogue and RNA polymerase inhibitor with in vitro activity against There is no approved treatment of SARS-CoV-2 at present. With elucidation of viral genome, combination of newer drugs with proven activity at different stages (like polypeptide synthetase inhibitors, replicase inhibitors) of SARS-CoV-2 lifecycle and disease pathogenesis may pave the way for viral elimination. With the available evidence so far, HCQ may be used as prophylaxis in high risk individuals with unproven benefits. No recommendation regarding use of HCQ in treating COVID-19 can be made at present. Since Favipiravir and Lopinavir-ritonavir did not provide significant benefits in viral clearance or clinical improvement in severe disease, further randomized trials are necessary before recommending these drugs in clinical practice. Remdesivir improves clinical outcomes when given early during moderate to severe disease and should be strongly considered. Tocilizumab has been found useful in patients with cytokine storm & elevated IL-6 levels. Convalescent plasma transfusion can be used as rescue therapy in critically ill COVID-19 pneumonia as a part of clinical trials. A suggested algorithm would be to categorize patients into low risk & high-risk group at presentation. Remdesivir +/-Tocilizumab should be used early in the disease course, before multi-organ dysfunction sets in. Convalescent plasma can be used as rescue therapy in patients with multi-organ dysfunction. Further multicenter randomized trials are necessary for proving the benefit of these available, repurposed drugs until newer drugs are available. COVID-19 Dashboard by the Center for Systems Science and Engineering Department of Health and Human Services COVID-19, SARS and MERS: are they closely related? 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Engineering Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab