key: cord-255208-rbko9ecz
authors: Stevens, Ryan W.; Rivera, Christina G.; Saleh, Omar Abu
title: Time to Treat: Applying Lessons Learned from Other Viral Syndromes to SARS-CoV-2
date: 2020-10-12
journal: Mayo Clin Proc Innov Qual Outcomes
DOI: 10.1016/j.mayocpiqo.2020.09.010
sha: 
doc_id: 255208
cord_uid: rbko9ecz

In many different infectious syndromes, most notably several viral conditions, time to therapy initiation from symptom onset has been identified as a critical component contributing to the success of therapy. With regards to COVID-19, several therapeutic antivirals, both repurposed and novel, have been evaluated for overall safety and efficacy. As the literature related to these therapies has expanded over the last several months, a wide array of trial designs, time to therapy initiation thresholds, and clinical outcomes with regards to time to initiation have been reported. Herein we describe the potential impact of time to therapy initiation on outcomes in patients with COVID-19 and detail the existing data surrounding this topic in relation to remdesivir, convalescent plasma, lopinavir/ritonavir, and hydroxychloroquine.

Since the beginning of the COVID-19 pandemic, the medical community has engaged in an ongoing search for safe and effective therapy for SARS-CoV-2 infection. This has been guided by the current understanding of viral attachment, replication, and subsequent immune hyper-stimulation observed during coronavirus infection. 1 The current schema for clinical interventions includes supportive care, direct antiviral therapies, and immune modulation strategies targeting the cytokine release syndrome.

Multiple therapeutic agents, both novel and repurposed, are approved under emergency use authorizations or under investigation, with early front-runners in the United States being remdesivir, convalescent plasma therapy (CPT), hydroxychloroquine, and lopinavir/ritonavir (LPV/r). A bulk of published COVID-19 literature to date has consisted of small observational studies, early reports of larger-scale retrospective data, and few randomized, controlled clinical trials. Given the frequency of methodologic limitations to much of the available evidence, careful interpretation and application of this data has been required by healthcare practitioners worldwide. A key observation from the available data is patient groups with more rapid antiviral intervention generally experience better outcomes.

The median time to therapy from the onset of symptoms in most interventional studies is more than seven days, with some greater than ten days. This is largely driven by trial design that targeted hospitalized patients with hypoxia and requirement of respiratory support. Thereby, antiviral intervention was often delayed until after respiratory decompensation was observed indicating that patients may have passed from the acute viral phase into the hyper-inflammatory phase of the illness.

With few exceptions, time until initiation of therapy was not explored as an independent variable in outcomes analyses. When time to therapy was incorporated into statistical analysis, patients designated J o u r n a l P r e -p r o o f 5 -Stevens in "early therapy" groups still often had prolonged (i.e. 7-12 days) time to therapy initiation or the analysis did not account for the time since symptom onset until presentation.

Data from other respiratory viral infections, such as influenza, suggest greatest benefit of antiviral therapy when given earlier during infection. 2 Targeting a viral replication earlier during the illness is anticipated to influence the immune response and temper the progression to severe disease. In theory this may also hold true for SARS-CoV-2, where earlier initiation of antiviral therapy during the early postexposure, minimally symptomatic phase, being likely to result in the greatest possible clinical benefit in the form of shortening the duration of illness, viral shedding, modulating the immune response, and subsequent prevention of hospitalization. The natural progression of the COVID-19 clinical course allows for a window of time between symptom onset and subsequent progression into the pulmonic and hyper-inflammatory phase, which usually takes place around seven days. 3 An early initiation approach may be particularly impactful in those patients with multiple risk factors for severe illness, and, beyond individual patients, benefits may be seen in the dynamics of transmission in the community. Current evidence, albeit limited, appears to support this theory. For example, a study from China demonstrated that patients who received treatment within 6 days of symptom onset demonstrated shorter times to viral clearance as compared to those who received later therapy initiation. Interpretation of this data remains difficult given the selected endpoints and the fact that patients in the study received various antiviral treatments, the primary of which (i.e. arbidol) is not widely available. 4 Studies involving applicable individual therapies should be closely scrutinized for time to effective therapy.

J o u r n a l P r e -p r o o f

A randomized, placebo-controlled trial by Wang et al. evaluated the efficacy of remdesivir in patients with COVID-19. 5 In this study the median time to therapy initiation from symptom onset was 10 days (IQR 9-12). Time to therapy initiation from hospital admission was not reported. Mortality at 28 days was numerically higher in the placebo group compared to the early treatment group (≤10 days); however, this did not reach statistical significance.There was numerically higher mortality in the late treatment group (>10 days) as compared to placebo, also not reaching statistical significance. 5 In the subsequent randomized clinical trial by Beigel et al., median time to therapy initiation from symptom onset was 9 days (IQR 6-12) and time to therapy initiation following hospitalization was not reported.

They reported no difference in recovery rate between the early (≤10 days from symptom onset to treatment) versus late treatment (>10 days from symptom onset to treatment) groups. 6 Another clinical trial compared a five-day versus ten-day course of therapy with remdesivir for the treatment of severe COVID-19. 7 The median time to therapy initiation from symptom onset was 8 days (IQR 5-11) and 9 days (IQR 6-12) in the 5 and 10 day groups, respectively. Discharge rates were 62% among patients who had symptoms for <10 days before receiving the first dose of therapy as compared to 49% in those who had symptoms for≥10 days. 7 A randomized, controlled trial compared 5 and 10-day courses of remdesivir to standard of care for the treatment of moderate COVID-19. 8 They demonstrated that 5-day courses, but not 10-day course, were associated with improved clinical status on day 11. They did not compare outcomes by symptom duration prior to initiation, and both the 5-day and 10-day patients had symptoms for a median of 8 days prior to therapy, whereas standard of care patients had symptoms for a median of 9 days prior to randomization. 8 identified 5 studies, all uncontrolled, with a total of 27 patients. The time to therapy from symptom onset ranged from 6 to 50 days. 14 Also, a small uncontrolled study of 25 patients receiving CPT had a median time from symptom onset to transfusion of 10 days (IQR 7.5-12.5) and hospitalization to transfusion of 2 day (IQR 2-4). 15 In one randomized trial to date, patients were administered CPT in addition to standard of care. 16 onset. 17 They showed that early initiation (<12 days from symptom onset) resulted in a numerically lower mortality rate as compared to standard of care, though this did not reach statistical significance.

The time between therapy initiation and hospital admission was not reported. 17 A multicenter, prospective, open-label, randomized trial, comparing LPV/r monotherapy to LPV/r combined with interferon beta-1b and ribavirin, had a median duration between therapy initiation and symptom onset of 4 days (IQR 3-8) in the monotherapy group and 5 days (IQR 4-7) in the combination therapy group. 18 They demonstrated positive impact on virologic outcomes with combination therapy (median time from enrollment to negative nasopharyngeal swab of 7 days combination therapy vs. 12 days control (p = 0.001)) and clinical recovery (median time to national early warning score (NEWS2) of zero of 4 days combination therapy vs. 8 days control (p <0.0001)). This finding was most pronounced in patients that received treatment within less than seven days from symptom onset. Notably, early intervention was part of this trial design as they required patients in the intervention group to have initiated therapy within 48 hours of hospitalization. 18 

When evaluating the literature pertaining to the efficacy of therapeutic agents in COVID-19 clinicians should carefully consider the time to initiation of therapy. Available evidence would seem to suggest that, similar to evidence from other viral illnesses, when a benefit is observed it is generally optimized with initiation of therapy earlier in the course of illness. Careful attention to the time to therapy initiation metrics employed in various studies will serve to further inform interpretation of the literature, as time to initiation may be reported from symptom onset, diagnosis, or study enrollment.

We acknowledge the multiple challenges with early initiation of antiviral therapy, especially within the context of currently available agents and our understanding of their application to patient care. These include the need for intravenous access (i.e. remdesivir), potential toxicities and drug-drug interactions, and considerations related to appropriate allocation of resources, especially in the context of high J o u r n a l P r e -p r o o f 10 -Stevens patient volumes. Beyond improved understanding of the efficacy of antiviral therapies, development of a validated risk prediction tool to identify patients at high risk for disease progression and aid with selection of those who may most benefit from early initiation of therapy would be ideal. We encourage clinicians to carefully consider time to initiation of antiviral therapy from symptoms onset when evaluating and applying emerging literature surrounding the treatment of COVID-19. Furthermore, until a SARS-CoV-2 vaccine is available, in order to optimize the available pharmacologic tools in battling the current pandemic, we advocate for researchers and clinicians alike to aim to shorten the time from the onset of symptoms until antiviral initiation, particularly in patients at high risk for disease progression.

Author contribution: All authors contributed to the literature review, manuscript drafting, and content review.

Funding: Mayo Clinic Midwest Pharmacy Research Committee providing funding for the manuscript publication fee.

All authors have no conflicts of interest to disclose.

Research and development on therapeutics agents and vaccines for COVID-19 and related coronavirus diseases

Efficacy and safety of oseltamivir in treatment of acute influenza: a randomized controlled trial

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

COVID-19 patients benefit from early antiviral treatment: a comparative, retrospective study

Remdesivir in adults with severe COVID-19: a randomized, doubleblind, placebo-controlled, multicenter trial

Remdesivir for the treatment of Covid-19 -preliminary report

Remdesivir for 5 or 10 days in patients with severe COVID-19

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

Compassionate use of remdesivir for patients with severe Covid-19

Compassionate remdesivir treatment of severe COVID-19 pneumonia in intensive care unite (ICU) and non-ICU patients: clinical outcome and differences in post-treatment hospitalization status

Profile of immunoglobulin G and IgM antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: Initial three-month experience

Use of convalescent plasma therapy in SARS patients in Hong Kong

Convalescent plasma transfusion for the treatment of COVID-19: a systematic review

Treatment of COVID-19 patients with convalescent plasma

Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: a randomized clinical trial

A Trial of lopinavir-ritonavir in adults hospitalized with severe covid-19

Triple combination of interferon beta-1b, lopinavir/ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomized, phase 2 trial

Lopinavir/ritonavir and interferon combination therapy may help shorten the duration of viral shedding in patients with COVID-19: a retrospective study in two designated hospitals in Anhui

Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open-label, randomised controlled trial

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label, non-randomized clinical trial

Clinical efficacy of hydroxychloroquine in patients with COVID-19 pneumonia who require oxygen: observational comparative study using routine care data

A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19