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Interim Guidelines on Antiviral Therapy for COVID-19.

ABSTRACT: Since the first case was reported in Wuhan, Hubei Province, China on December 12, 2019, Coronavirus disease 2019 (COVID-19) has spread widely to other countries since January 2020. As of April 16, 2020, 10635 confirmed cases have been reported, with 230 deaths in Korea. COVID-19 patients may be asymptomatic or show various clinical manifestations, including acute symptoms such as fever, fatigue, sore throat; pneumonia presenting as acute respiratory distress syndrome; and multiple organ failure. As COVID-19 has such varied clinical manifestations and case fatality rates, no standard antiviral therapy regimen has been established other than supportive therapy. In the present guideline, we aim to introduce potentially helpful antiviral and other drug therapies based on in vivo and in vitro research and clinical experiences from many countries.

SUBMITTER: Kim SB

PROVIDER: S-EPMC7335642 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Interim Guidelines on Antiviral Therapy for COVID-19.

Kim Sun Bean SB Huh Kyungmin K Heo Jung Yeon JY Joo Eun Jeong EJ Kim Youn Jeong YJ Choi Won Suk WS Kim Yae Jean YJ Seo Yu Bin YB Yoon Young Kyung YK Ku Nam Su NS Jeong Su Jin SJ Kim Sung Han SH Peck Kyong Ran KR Yeom Joon Sup JS

Infection & chemotherapy 20200423 2

Since the first case was reported in Wuhan, Hubei Province, China on December 12, 2019, Coronavirus disease 2019 (COVID-19) has spread widely to other countries since January 2020. As of April 16, 2020, 10635 confirmed cases have been reported, with 230 deaths in Korea. COVID-19 patients may be asymptomatic or show various clinical manifestations, including acute symptoms such as fever, fatigue, sore throat; pneumonia presenting as acute respiratory distress syndrome; and multiple organ failure. ...[more]

PMID: 32342676

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Project description:BackgroundWorld Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).MethodsWe randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.ResultsAt 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.ConclusionsThese remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Project description:BackgroundBased on current evidence, recent guidelines of the National Institute of Health, USA indicated the use of remdesivir and dexamethasone for the treatment of COVID-19 patients with mild-moderate disease, not requiring high-flow oxygen. No therapeutic agent directed against the immunologic pathogenic mechanisms related to the cytokine release syndrome complicating the disease was indicated.ObjectivesThe purpose of this review was to assess the clinical impact of different therapies for COVID-19; thus, helping to identify the optimal management of the disease. To explain the rationale for the different therapeutic approaches, the characteristics of SARS-CoV-2, the pathogenesis of COVID-19, and the immune response triggered by SARS-CoV-2 infection were reported.MethodsThe efficacy assessment of the different treatments was performed by a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Available English language published articles including randomised controlled trials, open-label trials of antivirals and immune therapies extracted from Medline, Google Scholar, and MedRxiv databases were analysed. For inclusion, the primary end point of the trials had to be the efficacy as measured by the improvement of clinical features, or mortality, or the Intensive Care Unit Admission rate, or the discharge number. Case reports, paediatric studies, and studies without control group were excluded. The literature search was extended up to August 15, 2020.ResultsAfter the removal of duplicate articles, and the exclusion of studies not meeting the eligibility criteria, 2 trials of lopinavir/ritonavir, 1 of favipiravir, 3 of remdesivir, 1 of dexamethasone, 3 of hydroxychloroquine, 2 of colchicine, 6 of tocilizumab, 1 of sarilumab, 1 of siltuximab, 2 of anakinra, 3 of baricitinib, 1 of ruxolitinib, 1 of mavrilimumab, and 1 of itolizumab were suitable for the review. Among antivirals, only remdesivir significantly reduced the time to recovery, and mortality. Data for chloroquine and hydroxychloroquine were largely inconclusive. In a large trial, dexamethasone 6 mg/day reduced mortality by one-third. Trials of tocilizumab and sarilumab did not definitively demonstrate efficacy. Anakinra significantly reduced the mortality in 2 trials. Three retrospective trials on a cumulative number of 145 patients, reported the efficacy of baricitinib, with significant reduction of intensive care unit admission, and deaths. These results were recently confirmed by the ACTT-2 trial. Due to paucity of studies and to the small size clinical series, the results of other immune therapies were not conclusive.ConclusionsBeyond the supportive therapy, up to now the best therapeutic approach for COVID-19 may be a three-step combination therapy, including remdesivir 100 mg/day (200 mg loading dose on first day) in the first stage of the disease, and combined dexamethasone 6 mg/day plus baricitinib 4 mg/day to target the immune dysregulation triggered by the SARS-CoV-2 infection. The promising results of anakinra should be confirmed by the ongoing RCTs.

Project description:Favipiravir, a broad-spectrum RNA-dependent RNA polymerase inhibitor, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at significantly lower concentrations than the plasma trough levels achieved by the dosage adopted for influenza treatment and exhibits efficacy against coronavirus disease 2019 (COVID-19) pneumonia. Although high doses of favipiravir are required due to the molecule being a purine analog, its conversion into the active form in infected cells with active viral RNA synthesis enhances the antiviral specificity and selectivity as a chain terminator with lethal mutagenesis. Another characteristic feature is the lack of generation of favipiravir-resistant virus. COVID-19 pneumonia is caused by strong cell-mediated immunity against virus-infected cells, and the inflammatory response induced by adaptive immunity continues to peak for 3 to 5 days despite antiviral treatment. This has also been observed in herpes zoster (HZ) and cytomegalovirus (CMV) pneumonia. Inflammation due to an immune response may mask the effectiveness of favipiravir against COVID-19 pneumonia. Favipiravir significantly shortened the recovery time in patients with mild COVID-19 pneumonia by 3 days with the start of treatment by the 5th day of symptom onset. Since both CMV and COVID-19 pneumonia are caused by adaptive immunity and prevention of cytomegalovirus pneumonia is the standard treatment due to difficulties in treating refractory CMV pneumonia, COVID-19 pneumonia should be prevented with early treatment as well. In the present study, we have comprehensively reviewed the optimal antiviral therapy for COVID-19 based on clinical trials of favipiravir for the treatment of COVID-19 pneumonia and the concurrently established therapies for other viral infections, particularly HZ and CMV pneumonia. Optimally, antivirals should be administered immediately after COVID-19 diagnosis, similar to that after influenza diagnosis, to prevent COVID-19 pneumonia and complications resulting from microangiopathy.

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Interim Guidelines on Antiviral Therapy for COVID-19.

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Interim Guidelines on Antiviral Therapy for COVID-19.

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