Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers...

Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity score-matched Retrospective Cohort Study

Abstract

Background: Ivermectin is a drug that is active against coronavirus disease 19 (COVID-19) in previous studies. Healthcare personnel is highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Therefore, we decided to offer them ivermectin as pre-exposure prophylaxis (PrEP) method. Purpose: Primary outcome was to measure the number of healthcare workers with symptomatic SARS-CoV-2 infection and a positive reverse transcription-polymerase chain reaction (RT-PCR) COVID-19 test in the ivermectin group and the control group. The secondary outcome was to measure the number of sick healthcare workers with a positive RT-PCR COVID-19 test whose condition deteriorated and required hospitalization and/or an Intensive Care Unit (ICU), or who died, in the ivermectin group and the control group.


Material and methods:

This observational and retrospective cohort study was carried out in two medical centers, Centro Medico Bournigal (CMBO) in Puerto Plata and Centro Medico Punta Cana (CMPC) in Punta Cana, Dominican Republic. The study began on June 29, 2020, and ended on July 26, 2020. A Statistical Package for Social Sciences (SPSS) Propensity Score Matching procedure was applied in a 1:1 ratio to homogeneously evaluate 271 healthcare personnel that adhered to a PrEP program with ivermectin at a weekly oral (PO) dose of 0.2 mg/kg, and 271 healthcare personnel who did not adhere to the program were assigned as a control group. Results: In 28 days of follow-up, significant protection of ivermectin preventing the infection from SARS-CoV-2 was observed: 1.8% compared to those who did not take it (6.6%; p-value = 0.006), with a risk reduction of 74% (HR 0.26, 95% CI [0.10,0.71]). Conclusions: These results suggest that compassionate use of weekly ivermectin could be an option as a preventive method in healthcare workers and as an adjunct to immunizations, while further well-designed randomized controlled trials are developed to facilitate scientific consensus.




Introduction

Ivermectin, commonly used as an antiparasitic, has shown not only antiviral activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in-vitro but there are already studies of its viricidal action in humans. Peer-reviewed systematic reviews and meta-analyses also show a prophylactic effect The Grupo Rescue added its own pioneering experience in the use of ivermectin in the early treatment of coronavirus disease 2019 (COVID-19)-infected patients in the Dominican Republic at the beginning of the pandemic Healthcare personnel is highly exposed to SARS-CoV-2 infection. Therefore, it would be very wise and convenient to have pre-exposure prophylaxis (PrEP) oral medication at hand.

At a time of a wave of contagion with COVID-19 in the Dominican Republic, with several seriously infected in our healthcare personnel, we were forced to start with ivermectin as a PrEP method to try to reduce the incidence of the SARS-CoV-2 infection. This moved us several months later to collect the data to perform a retrospective observational cohort study and evaluate the results. The primary outcome measure of this study was the number of participants with symptomatic SARS-CoV-2 infection and a positive COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) test in the ivermectin group and the control group. The secondary outcome was the number of sick participants with a positive RT-PCR COVID-19 test, whose condition deteriorated and required hospitalization and/or an Intensive Care Unit (ICU), and the number of sick participants with a positive RT-PCR COVID-19 test who died in the ivermectin group and the control group. This article was previously posted to the medRxiv preprint server on 04/17/2021. Last version: 06/04/2021.

Materials & Methods

This study is an observational retrospective multicenter cohort conducted on active healthcare workers at the Centro Medico Bournigal (CMBO) and the Centro Medico Punta Cana (CMPC), Dominican Republic, following the suggested guidelines of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for reporting observational studies The study protocol is available at Clinicaltrials.gov, identifier NCT04832945. This study started on June 29, 2020, and ended on July 26, 2020, followed up for 28 days, in patients who were invited to a voluntary SARS-CoV-2 PrEP compassionate program using ivermectin at a weekly PO dose of 0.2 mg/kg, administered at the Human Resources Office. They were compared with a control group of healthcare personnel who did not receive ivermectin, either by their own will or because of contraindications in its use. Before the PrEP started it was submitted for consideration, comment, guidance, and approval to the Grupo Rescue Ethics Committee who issued approval ME-GRUR-328-2020.

Both the ivermectin group and the control group strictly followed the preventive measures and the use of personal protection equipment (PPE) to avoid SARS-CoV-2 infection, implemented since April 2020, well before the start of this study. The SARS-CoV-2 symptomatic infected cases were confirmed by an RT-PCR COVID-19 test. The participants who adhered to the ivermectin prophylaxis program had signed the informed consent, were a minimum age of 18 years old, and were included in the intervention group only if: 1. received the first dose of ivermectin during the first week of the study; 2. complied with a minimum of two doses of ivermectin during the four weeks of the study or one dose if RCT-PCR positive within 14 days of intake; 3. the difference in days between the two doses was no greater than 14 days. The participants had weekly presentations in the Human Resources Office, where the medication was orally administered, being recorded the date of the ivermectin delivery. The following healthcare personnel was excluded from the ivermectin prophylaxis program: pregnant or suspected pregnant women, women breastfeeding, patients receiving coumarin anticoagulants, and those allergic to ivermectin. The healthcare personnel who did not adhere to the program until July 26 were assigned to the control group and at no time before or during the study did they take ivermectin. To obtain the demographic data of the workers, they were extracted from the Sigma software in CMPC and internal development software in CMBO, from which the worker's code, date of birth, sex, and role or position were obtained. With this information, the Head of the Nursing Department assigned an exposure level, which was defined as follows: 1. High: personnel in direct contact with COVID-19 patients; 2. Medium: personnel who care for non-COVID-19 patients; 3. Low: personnel who do not take care of patients (administrative, others). The compilation of information from RT-PCR COVID-19 reports was done by consulting the Referencia Laboratorio Clínico system, located in Santo Domingo, Dominican Republic, who performed the analysis of the nasopharyngeal samples from both centers. Additionally, the healthcare personnel who gave an RT-PCR COVID-19 (+) during the study were registered in their respective files in the Human Resources Office. The records of both medical centers were consolidated into a single record by the Head of the Nursing Department, individualizing the worker, date of report, and outcome (hospitalization and/or death).

Those participants in the study who tested positive for COVID-19 were treated as outpatients and followed by their respective medical center with ivermectin 0.4 mg/Kg PO one dose and azithromycin 500 mg PO every 24 hours for five days. Those who required hospitalization received ivermectin 0.3 mg/kg PO on days one, two, six, and seven-plus azithromycin 500 mg PO every 24 hours for seven days.

Statistical analysis

To determine the degree of balance of the cohorts and to adjust the possible confounders of the study, a chi-square homogeneity test was performed. Those variables that obtained a p-value < 0.1 test were included in the Propensity Score Matching (PSM) process of the Statistical Package for Social Sciences (SPSS; IBM Corp., Armonk, NY, USA) software, in which a 1:1 match was performed with a tolerance of 0.05 to obtain homogeneous cohorts. These variables were gender, exposure, and role.

After performing the matching, a chi-square test and a Kaplan-Meier hazard curve were performed with the positive COVID-19 test results of the healthcare personnel. Thereafter a Cox regression was performed to compare the effect of the study variables on the primary outcome, which was a positive COVID-19 test. The validation and creation of the cohorts were done in MariaDB 10 (mariadb.org). The statistical analysis was done with SPSS and RStudio 1.4 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Initially, 943 candidates were selected for the study, from which 43 were excluded for having a positive COVID-19 RT-PCR report before the start of the study. The ivermectin group was made up of 510 healthcare personnel and the control group was made up of 390 participants. In total, 182 healthcare workers who did not comply with the ivermectin doses described in the inclusion criteria were excluded from the ivermectin group. In the follow-up study, five participants were lost who resigned or were dismissed from their work, two in the ivermectin group and three in the control group. This equates to a 0.6% loss of the follow-up for the ivermectin group and 0.77% for the control group. As it is less than 5%, it is not considered relevant for the study.

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