key: cord-0074438-9ypttmqv authors: Taccone, Fabio Silvio; Hites, Maya; Dauby, Nicolas title: From hydroxychloroquine to ivermectin: how unproven “cures” can go viral date: 2022-02-03 journal: Clin Microbiol Infect DOI: 10.1016/j.cmi.2022.01.008 sha: 342654d0b7211dcfbb27e8ac5bc50a1cb1874522 doc_id: 74438 cord_uid: 9ypttmqv nan Since the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, various therapeutic agents have been repurposed to treat patients with coronavirus disease 2019 (COVID- 19) , and used empirically before adequate clinical studies were performed. One of the most controversial drugs in the very initial phase of the pandemic was hydroxychloroquine. This drug, which has been used to treat malaria, amebiasis and autoimmune diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis), had promising results on in vitro studies and observational studies (1), although cohorts were limited and there were significant methodological limitations. Over subsequent months, several randomized clinical trials reported that hydroxychloroquine, alone or in combination with azithromycin, was ineffective at preventing SARS-CoV-2 transmission, providing more rapid resolution of clinical symptoms or reducing hospital admissions and mortality in COVID-19 patients, and was associated with no improved mortality compared to placebo (2) (3) (4) (5) . Nevertheless, despite these consistent data, and the publication of the living World Health Organization (WHO) guidelines recommending against the use of hydroxychloroquine in COVID-19 (6), the "effectiveness" of this drug is still asserted by some, who are using social networks and the media to spread their beliefs (7, 8) . This (mis)information created doubt, angry debate, and even threats to hydroxychloroquine detractors. Arguments, such as "it was given too late" or "it was not administered at the right dose", "it is cheap and safe", or "it is unethical to perform a randomized trial and expose patients to placebo", have been used to explain the poor trial results during the fierce discussions that have occurred concerning hydroxychloroquine use in COVID-19. The drug is still administered in several countries where national leaders have supported its use (9, 10) . In a similar situation to that seen with hydroxychloroquine, ivermectin has been proposed as an interesting and potentially effective medication to treat COVID-19 patients. Ivermectin is an anti-parasitic molecule that showed potential anti-viral and antiinflammatory properties against SARS-CoV-2 in animal models (11) . However, the antiviral effects in in vitro and in vivo studies required serum and tissue drug concentrations that can only be obtained by administering daily doses significantly higher than for current antiparasitic regimens, with potentially toxic effects (12) . As with hydroxychloroquine, initial in vitro and observational studies suggested some outcome benefits with use of ivermectin in patients with COVID-19. Some randomized trials, limited by heterogeneity of populations J o u r n a l P r e -p r o o f receiving ivermectin, imbalanced allocation, selected doses and uncontrolled cointerventions, also reported some benefits with ivermectin in different populations of COVID-19 patients (13) . A systematic review, which initially suggested an improved survival rate with ivermectin treatment compared to placebo in COVID-19 patients (14), reanalyzed the available data by excluding studies at a high risk of bias (i.e. either retracted or considered potentially fraudulent) and reported no significant effect on survival or hospitalizations in favor of ivermectin. Other systematic reviews have also confirmed the low quality of published studies and the lack of any effectiveness of ivermectin on clinically relevant outcomes in COVID-19 patients (15, 16) . Although a large retrospective cohort of hospitalized COVID-19 patients in Florida suggested that those treated with ivermectin (n=173) had a significantly lower in-hospital mortality, even after adjustment for confounders and propensity matching analysis (13 vs. 25%), than untreated (n=107) patients (17) , those receiving the drug also more frequently received steroids (which can improve mortality in hospitalized COVID-19 patients requiring oxygen therapy) and were enrolled more recently (resulting in timing bias with possible improvement in medical knowledge and global patient care). A good-quality double-blind randomized trial conducted in Colombia assigned 400 patients with mild COVID-19 disease within the first 7 days of symptoms to receive ivermectin (300 μg/kg of body weight per day for 5 days) or placebo and reported a non-significant reduction of 2 days for symptom resolution but no effects of the drug on escalation of therapies or mortality (18) . In another randomized study conducted in Argentina, ivermectin had no significant effect on preventing hospitalization of patients with COVID-19 (19) . Taking all these data into consideration, the WHO guidelines recommended against the routine use of ivermectin in COVID-19 patients (4). However, adherence to these recommendations has again been hindered by social media's spread of incorrect The vicious progression of "anti-science", shedding doubts about vaccination and promoting treatments with unproven efficacy, such as hydroxychloroquine and ivermectin, has also shown that a firm condemnation by the scientific community is not sufficient. As such, scientists should attempt to vulgarize medical information in newspapers and social media and even accept debates on television with fake news and disinformation providers, explaining to audiences without medical knowledge and using non-polarized arguments how complex is the medical treatment of COVID-19. J o u r n a l P r e -p r o o f Hydroxychloroquine controversies: Clinical trials, epistemology, and the democratization of science Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: A randomized clinical trial Effect of hydroxychloroquine in hospitalized patients with Covid-19 Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials A living WHO guideline on drugs for covid-19 Stakes of Knowing the Truth: A Motivational Perspective on the Popularity of a Controversial Scientific Theory Hydroxychloroquine Controversies: Clinical Trials, Epistemology, and the Democratization of Science Sales of antibiotics and hydroxychloroquine in India during the COVID-19 epidemic: An interrupted time series analysis The regrettable story of the "Covid Kit" and the "Early Treatment of Covid-19" in Brazil Ivermectin reduces in vivo coronavirus infection in a mouse experimental model Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19 Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials Efficacy and safety of ivermectin for the treatment of COVID-19: A systematic review and meta-analysis Use of ivermectin Is associated with lower mortality in hospitalized patients with coronavirus disease 2019: The Ivermectin in COVID Nineteen Study Effect of ivermectin on time to resolution of symptoms among adults with mild COVID-19: A randomized clinical trial Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial Clinical and Scientific Rationale for the "MATH+" Hospital Treatment Protocol for COVID-19