Outpatient regimens to reduce COVID-19 hospitalisations: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background. Antiviral therapy has a greater impact when provided early in the disease to outpatients, potentially preventing hospitalization and subsequent deaths, while reducing healthcare system pressure. Controversies persist about the best treatment option for COVID-19 outpatients at risk of disease progression to hospital. No head-to-head RCT has been conducted to compare the three major modalities in current use-oral/intravenous antivirals, monoclonal antibodies and COVID-19 convalescent plasma (CCP). Methods. We assembled data from March 2020 to April 2022 from published outpatient RCTs examining authorized COVID-19 therapies with hospitalization as the major endpoint, and that also assessed mortality, symptom resolution, underlying risk factors for progression, timing and dose of the intervention in relationship to evolving variants of concern (VOC). Findings. CCP, monoclonal antibodies and oral antivirals each had comparable efficacy converging to 80% hospital risk reduction dependent on the dose and the timing of the intervention. Most RCTs targeted populations with at least one risk factor for severe COVID-19. Control group hospitalizations were less than 10% in 16 of 20 RCTs. Amongst the effective two CCP trials, monoclonals and three antiviral small molecules, deaths were reduced by 90% from 44 total in combined control arm to 4 in intervention arms. The overall risk of bias was deemed low for nine studies and some concerns for eight. The I2 statistic heterogeneity amongst the outpatient trials with endpoint hospitalization is 73% (p- < 0.01). Interpretation. The emerging resistance of Omicron BA.2 and related sublineages (XE, BA.2.12.1, BA.4, and BA.5) to monoclonal antibodies suggests a pressing need to reevaluate CCP (nowadays largely available from vaccinees with high neutralizing antibody levels) for COVID19 outpatients at risk of disease progression, especially in settings with constrained medical resources. Funding. This study was funded by the US Department of Defense, in collaboration with the Defense Health Agency and NIH.

The impact of sphingosine-1-phosphate receptor modulators on COVID-19 and SARS-CoV-2 vaccination

“…Whilst vaccination issues have become evident due to the COVID-19 pandemic, annual vaccinations such as with the current influenza vaccines, mean that this element of S1P and S1PR biology will remain an issue. Therefore, ways to improve/optimize vaccination responses will be beneficial ( Sullivan et al, 2022 *). Although, repeated boosting can increase the titres of SARS-CoV-2 specific-antibodies in some people ( Tallantyre et al, 2022a , Milo et al, 2022 , Capuano et al, 2022 , Achtnichts et al, 2022 ), uninterrupted S1PR modulator treatment is currently often associated with a blunted vaccination response ( Pitzalis et al, 2021 , Tallantyre et al, 2022a , Louapre et al, 2022 *), ( Meyer-Arndt et al, 2022 , Akgün et al, 2022 *), ( Scn et al, 2022 ).…”

Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients—An Open-Label Phase II Clinical Trial

“…This study suggests that CCP may be as effective as other antibody-based and small-chemical antivirals [ 81 ], especially if given early in the disease course and with a high titer of antibodies. CCP can be helpful in selected patients with COVID-19, and further studies are needed to identify the subset of patients that would most benefit from it and to elucidate the optimal dose.…”

Synergism of interferon-beta with antiviral drugs against SARS-CoV-2 variants

“…1.1.529,BA.1) variant took over from Delta, which keeps evolving into further subvariants such as BA. 2, BA.2.12.1, BA.3, BA.4, and BA.5 [Kawaoka et al, 2022;Sullivan et al, 2022]. SARS-CoV-2 evolution is at least in part driven by the selection pressure induced by previous infections and vaccinations.…”

“…The original Wuhan strain, was replaced by the Alpha variant (B.1.1.7), which was later replaced by the Beta and P.1 variants in some parts of the world, before the Delta became the dominant variant [Forchette et al, 2021]. Most recently, the Omicron (B.1.1.529, BA.1) variant took over from Delta, which keeps evolving into further subvariants such as BA.2, BA.2.12.1, BA.3, BA.4, and BA.5 [Kawaoka et al, 2022; Sullivan et al, 2022].…”