Safety and Efficacy of Ivermectin and Doxycycline Monotherapy and in Combination in the Treatment of COVID-19: A Scoping Review

Abstract

Introduction and Objective Ivermectin (IVM) and doxycycline (DOXY) have demonstrated in-vitro activity against SARS-CoV-2, and have a reasonable safety profile. The objective of this systematic review was to explore the evidence in the literature on the safety and efficacy of their use as monotherapy and combination therapy in COVID-19 management. Methods After prospectively registering the study protocol with the Open Science Framework, we searched PubMed, Google Scholar, clinicaltrials.gov, various pre-print servers and reference lists for relevant records published until 16 February, 2021 using appropriate search strategies. Baseline features and data pertaining to efficacy and safety outcomes were extracted separately for IVM monotherapy, DOXY monotherapy, and IVM + DOXY combination therapy. Methodological quality was assessed based on the study design. Results Out of 200 articles screened, 19 studies (six retrospective cohort studies, seven randomised controlled trials, five non-randomised trials, one case series) with 8754 unique patients with multiple stages of COVID-19 were included; four were pre-prints and one was an unpublished clinicaltrials.gov document. The comparator was standard care and ‘hydroxychloroquine + azithromycin’ in seven and three studies respectively, and two studies were placebo controlled; six studies did not have a comparator. IVM monotherapy, DOXY monotherapy and IVM + DOXY were explored in eight, five and five studies, respectively; one study compared IVM monotherapy and IVM + DOXY with placebo. While all studies described efficacy, the safety profile was described in only six studies. Efficacy outcomes were mixed with some studies concluding in favour of the intervention and some studies displaying no significant benefit; barring one study that described 9/183 patients with erosive esophagitis and non-ulcer dyspepsia with IVM + DOXY (without causality assessment details), there were no new safety signals of concern with any of the three interventions considered. The quality of studies varied widely, with five studies having a ‘good’ methodological quality. Conclusions Evidence is not sufficiently strong to either promote or refute the efficacy of IVM, DOXY, or their combination in COVID-19 management. Systematic Review Protocol Registration Details Open Science Framework: https://osf.io/n7r2j . Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01066-y.

COVID-19 treatment in children

“…[ 49 ] Similarly, a number of studies from developing countries have suggested the efficacy of ivermectin and doxycycline, especially in 2021. [ 50 51 52 ] For this reason, few recent articles mentioned the use of ivermectin and doxycycline in children, but the universal use of this medication is still controversial. We could not find much data for use of casirivimab/imdevimab in children <12 years, as it is yet to be FDA approved.…”

“…They concluded that the evidence was not strong enough to either promote or refute their efficacy in COVID-19 management. [ 50 ]…”

Perspectives on Antiviral Drugs Development in the Treatment of COVID-19

“…It has many advantages, including the simplification of authorization procedures and the speed of being placed on the market at much lower costs (Jourdan et al, 2020). The most affordable alternative method for discovering the treatment of COVID-19 is the repositioning of existing drugs that are potentially active against SARS-CoV-2 (Akilesh et al, 2021;Bhowmick et al, 2021;Gatti and De Ponti, 2021).…”

“…These drugs are supposed to work upon different elements in the disease pathophysiology, and these correspond to two primary therapeutic classifications: drugs that inhibit the viral activity (e.g., favipiravir, remdesivir, azithromycin, lopinavir-ritonavir, hydroxychloroquine) and drugs that modulate the antiviral immune reaction in the host (e.g., corticosteroids, interferons, tocilizumab). Along with these, other agents have been investigated in the management of COVID-19: ivermectin -an antiparasitic agent, and doxycycline -a broad-spectrum tetracycline antibiotic (Bhowmick et al, 2021). In a trial reported by the ISRCTN Registry and ClinicalTrials.gov, WHO specialists used four known antiviral drugs that could potentially affect mortality for patients with COVID-19.…”

Editorial: From Pathogenic Infections to Inflammation and Disease - the Tumultuous Road of the ‘Cytokine Storm’

“…So far, there is no effective antiviral therapy to treat for SARS-CoV-2 infection and COVID-19. Although along the whole COVID-19 pandemic numerous reports have been published describing the potential use of attractive drugs such as ivermectin, doxycycline, hydroxychloroquine, azithromycin, and remdesivir (Yates et al, 2020;Mcfee, 2020;Bhowmick et al, 2021), yet there is controversial of using any of these attractive drug candidates either as monotherapy or in combination. This work by Tan et al penlights their potential use for the treatment of COVID-19 giving new insights into the generation of more effective drug combinations or new formulations against viral infections.…”