key: cord-0880772-q55my6yk
authors: Bernigaud, C.; Guillemot, D.; Ahmed‐Belkacem, A.; Grimaldi‐Bensouda, L.; Lespine, A.; Berry, F.; Softic, L.; Chenost, C.; Do‐Pham, G.; Giraudeau, B.; Fourati, S.; Chosidow, O.
title: Oral ivermectin for a scabies outbreak in a long‐term care facility: potential value in preventing COVID‐19 and associated mortality
date: 2021-03-01
journal: Br J Dermatol
DOI: 10.1111/bjd.19821
sha: ff22ecfe01cc8851bab28d3377dc156df966f4ad
doc_id: 880772
cord_uid: q55my6yk

To-date, COVID-19 pandemic affected >85 million persons worldwide with 14% severe and 5% critical, and a general population case-fatality rate of 1%. Age is the main risk factor for severe disease and death1 making the long-term-care facilities (LTCFs) residents particularly vulnerable.2 COVID-19 therapeutic agents remain sparce and ivermectin, an antiparasitic showed anti-SARS-CoV-2 activity in vitro.3 Moxidectin, another macrocyclic lactone, with a longer plasma half-life, could be considered too.

moxidectin on VeroE6-monkey kidney cells at increasing concentrations (range 0Á05-10 µmol L À1 ) by RNA quantification and immunofluorescence (with cell viability controlled at each step). We also performed a time-of-drug-addition assay.

Between 5 March and 15 May 2020, 69 LTCF-A residents (median age 90 years, interquartile range 84-94; 78% female) and 52 staff members received ivermectin ( Figure 1 ). Eleven persons presented confirmed or suspected COVID-19 (1Á4% declared in the ARS online database), with the first symptoms noticed on 11 March 2020 (Resident 1 on 19 March 2020). One resident (Resident 1) had a SARS-CoV-2-positive reversetranscriptase polymerase chain reaction. No hospitalizations and no deaths were noted. Forty-five 'matched' county-wide LTCFs were included as a reference sample (out of 177), housing 3062 residents (median age 86 years, interquartile range 87-89; 77Á3% female). Among them, a mean of 22Á6% (95% confidence interval 16Á3-28Á9) acquired declared COVID-19, with a lethality of 4Á9% (95% confidence interval 3Á2-6Á5).

The virological study confirmed important in vitro antiviral activity, with EC 50 values of 0Á14 AE 0Á02 µmol L À1 and 0Á48 AE 0Á08 µmol L À1 for ivermectin and moxidectin, respectively. The maximum inhibitions at 5 µmol L À1 were 55 000 and 19 000-fold, respectively, without affecting cell viability. The study also showed dose-dependently limited numbers of SARS-CoV-2-infected cells, and complete inhibition of SARS-CoV-2 infection at 2Á5 µmol L À1 . When ivermectin and moxidectin were added 3 h after infection (i.e. early during SARS-CoV-2 infection), no antiviral effect was seen (data not shown).

To control scabies, the entire LTCF-A population was given ivermectin, while at the same time a COVID-19 outbreak was declared. No ivermectin-exposed LTCF-A resident developed severe COVID-19 or died, while residents from control LTCFs showed higher COVID-19 rates. Usually, once COVID-19 enters an LTCFin any healthcare systemits rapid dissemination 5 is associated with a high risk of death. Ivermectin is an antiparasitic drug that is used to treat neglected tropical diseases such as onchocerciasis, helminthiases and scabies, and is evaluated at high doses for malaria control. It could have a protective role in COVID-19 within a therapeutic margin, 6 as supported by our optimized virological study. Other populations might have already benefited from ivermectin, as its use was associated with lower in-hospital mortality in a multihospital retrospective cohort study of 280 North American patients [ivermectin, n = 173 (15%) vs. no ivermectin, n = 107 (25Á2%), odds ratio 0Á52, 95% confidence interval 0Á29-0Á96; P = 0Á03]. 7 There are both epidemiological (i.e. the ecological nature of the data with probability of unmeasured confounding) and virological limitations of the available data, and difficulties in extrapolating in vitro antiviral effects against different coronaviruses to clinical efficacy. However, the plausibility is sufficient to carry out further studies to elucidate whether ivermectin (and moxidectin) is or is not an appropriate candidate for the prevention of COVID-19.

Acknowledgments: We would like to gratefully acknowledge all of the residents, healthcare workers and administrative staff of LTCF-A and their directors for agreeing to participate in this report, and providing their technical support. We acknowledge Margaut Petignier, ARS Ile-de-France, for assistance in generating COVID-19 and mortality rate data in Seine-et-Marne county, and all of the certified nurse assistants and administrative staff of the 45 LRCFs that agreed to share their demographic information. We thank Saskia Ingen-Housz-Oro, Franc ßoise Foulet, Audrey Colin and the nursing staff of the Dermatology Department, Henri-Mondor Hospital, Cr eteil, for their devoted patient care; Hayat Medjenah, Elie Guichard, Laetitia Gr egoire, the AGEPS pharmacists and the administrative staff of the Unit e de Recherche Clinique, Henri-Mondor Hospital, Cr eteil, for NCT02841215 RCT support; Franc ßoise Botterel and Jacques Guillot for their assistance supervising preliminary laboratory work; Selim Aractingi, Jean-Philippe Derenne, Ana€ ıs Farcet, Bruno Housset, Pascal del Giudice, Fatimata Ly and Sol ene Makdessi for discussions and thoughtful advice; Anne-Claude Cr emieux for the specific COVID-19 literature weekly review of APHP hospitals; and Janet Jacobson for editorial assistance.

C. Bernigaud iD , 1,2 D. Guillemot, 3,4,5 A. Ahmed-Belkacem, 6 L. Grimaldi-Bensouda, 3 Figure 1 Concomitant COVID-19 and ivermectin-treated scabies outbreak in a long-term care facility. The navy blue timeline represents COVID-19-dictated closure coinciding with onset of a scabies outbreak in long-term care facility A (LTCF-A), and the oral ivermectin (IVM) treatments for the scabies-infested patients (n = 4) and their contacts (n = 117), for a total of 121 IVM-treated individuals, according to NCT02841215 and current therapeutic recommendations on scabies. The bars below the timeline represent the different individuals with confirmed or suspected COVID-19 (LTCF-A residents and staff). Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) (RdRp gene, CT 36 and N gene, CT 34) detected Resident 1's COVID-19 (yellow bar).

Factors associated with COVID-19-related death using OpenSAFELY

Epidemiology of COVID-19 in a long-term care facility in King County, Washington

The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro

Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects

Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility

Ivermectin and COVID-19: a report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses

Use of ivermectin is associated with lower mortality in hospitalized patients with COVID-19 (ICON study)

Funding sources: The double-blind randomized controlled trial GALE-CRUSTED (NCT02841215) is funded by the French Ministry of Health (Programme Hospitalier de Recherche Clinique

act as unpaid scientific advisors for Medicines Development for Global Health. O.C. is the principal investigator of the RCT 'Dose-finding Study of Moxidectin for Treatment of Scabies' (NCT03905265). G.D-P. is the principal investigator, B.G. is the main statistician and O.C. is the scientific head of the RCT 'Efficacy Study Between Two Different Dosages of an Antiparasitic in Patients With