key: cord-1011628-1ov3eydq
authors: Morgenstern, J.; Redondo, J. N.; Olavarria, A.; Rondon, I.; Roca, S.; De Leon, A.; Canela, J. M.; Tavares, J.; Minaya, M.; Lopez, O.; Castillo, A.; Placido, A. M.; Pena Cruz, R.; Merette, Y.; Toribio, M.; Francisco, J. A.
title: Retrospective cohort study of Ivermectin as a SARS-CoV-2 pre-exposure prophylaxis method in Healthcare Workers
date: 2021-04-17
journal: nan
DOI: 10.1101/2021.04.10.21255248
sha: 93cc80c04e2092d6886d43877415dd33cd345a3b
doc_id: 1011628
cord_uid: 1ov3eydq

This observational and retrospective cohort study, carried out in two medical centers, Centro Medico Bournigal (CMBO) in Puerto Plata and Centro Medico Punta Cana (CMPC) in Punta Cana, Dominican Republic, sought to determine whether Ivermectin, at a weekly oral (PO) dose of 0.2 mg/kg, is an effective pre-exposure prophylaxis (PrEP) method for the spread of Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2), in the healthcare workers. The study began on June 29, 2020 and ended on July 26, 2020, where 713 active healthcare personnel were included for the analysis, of which 326 adhered to a weekly prophylactic program with Ivermectin for Coronavirus Disease-19 (COVID-19), designed by Grupo Rescue task force, that runs both medical centers, and 387 healthcare personnel who did not adhere to the program were assigned to the control group. A SPSS Propensity Score Matching procedure was applied in a 1:1 ratio to homogeneously evaluate the groups that were made up of 271 participants each. In 28 days of follow-up, a significant protection of Ivermectin as a PrEP method of infection from SARS-CoV-2 was observed 1.8% compared to those who did not take it 6.2%, (p-value = 0.006) and a reduction of the risk of a positive Chain Reaction of Real-Time Polymerase Transcription (RT-PCR) COVID-19 test by 74% (HR 0.26, 95% CI [0.10,0.71]). These results support the use of weekly Ivermectin as a compassionate preventive method in the healthcare personnel.

There is a group of people who are highly exposed to the SARS-CoV-2 infection such as healthcare personnel. It would be very convenient to have a PrEP oral medication. Much more if one considers that vaccination against COVID-19, if we want to cover the largest percentage of the world population, will probably not be achieved before the year 2022.

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, started on June 29, 2020 and ending on July 26, 2020, followed up for 28 days, who were invited to a voluntary SARS-CoV-2 PrEP compassionate program using Ivermectin at a weekly PO dose of 0.2 mg/kg, that were given at the Office of Human Resources and were compared with a control group of healthcare personnel who did not receive Ivermectin, by their own will or there was a contraindication for its use.

Both the Ivermectin group and the control group followed strictly the preventive measures and the use of the Personal Protection Equipment (PPE) to avoid the SARS-CoV-2 infection, implemented since April 2020, well before the start of these study. The SARS-CoV-2 infected cases, were confirmed by a RT-PCR COVID-19 test.

The participants who adhered to the Ivermectin prophylaxis program and signed the informed consent and had a minimum age of 18 years old, 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 2 doses of Ivermectin during the 4 weeks of the study; 3. the difference in days between 2 doses was not greater than 14 days. They presented weekly to the Office of Human Resources, where they received the medication and the date of delivery of the Ivermectin was recorded.

The following healthcare personnel were excluded from the Ivermectin prophylaxis program: pregnant or suspected pregnant women; women breastfeeding; patients receiving coumarin anticoagulants; 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 and during the study did they take Ivermectin.

Those who had an RT-PCR COVID-19 positive, previous the start of the study, were excluded.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) To obtain the demographic data of the workers, they were extracted from the Sigma software in CMPC and an 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 that does not take care of patients (administrative, others).

The compilation of the 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 Office of Human Resources. 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 5 days. Those who required hospitalization received Ivermectin 0.3 mg/kg PO on days 1, 2, 6 and 7 plus Azithromycin 500 mg PO every 24 hours for 7 days. (1)

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 was included in the Propensity Score Matching process of the SPSS 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 was done in MariaDB 10. The statistical analysis was done with IBM SPSS and RStudio 4.0.4

Initially we had 943 candidate workers for the study, 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 study follow-up, 5 participants were lost, who resigned or were dismissed from their work, 2 in the Ivermectin group and 3 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 purposes of the study.

Finally, we had 713 participants, 326 in the Ivermectin group and 387 in the control group were considered for the preliminary analysis of this study. After the matching process with the Propensity Score, there were 271 members in each group for analysis ( Figure 1 ).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The 51.5% of the participants in the Ivermectin group took 4 doses; 40.4% took 3 doses; 6.7% took 2 doses; 1.4% of the participants managed to take a single dose and then reported a positive COVID-19 infection ( Figure 2 ).

There were no severe side effects reported from the use of Ivermectin. Only minor side effects such as dizziness (3.7%), headache (1.5%), stomachache (1.4%), pruritus (1.1%), nausea (1.1%) and diarrhea (0.7%).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The median time between doses was 7 days and the mean (average) was 7.2 days with a standard deviation of 1.03 ( Figure 3 ). 

Executing the Propensity Score Matching process using the gender, exposure and role variables, the groups were left without significant differences in the measured variables ( Table 1 ).

The mean age of the study was 35.19 years (+10.02). They were mostly female (79.0%).

Regarding the profession or role, physicians represent 10.3%, nurses 25.8%, medical assistants 11.6% and administrative personnel and others 52.2%. More than half of the personnel had medium and high exposure to COVID-19, 29.9% and 25.1% respectively (Table 1) .

Comorbidities were not included in the demographic data as the information was not complete in 8.1%. However, with the existing data, this variable did nor represent an imbalance between the Ivermectin group and the control group (chi-square homogeneity test p-value=0.890) and in the Cox regression it also did not show to be a variable that affects the main outcome (p-value= 0.851, HR=1.1, 95% CI [0.4, 2.9]).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2021. ; https://doi.org/10.1101/2021.04.10.21255248 doi: medRxiv preprint

The chi-square homogeneity test showed that PrEP with Ivermectin was associated with a statistically significant reduction in SARS-CoV-2 infection, with 1.8% versus 6.2% in the control group (p-value = 0.006). (Table 2) There was also seen no Covid-19 illness progression or complications which deserved hospital admission and mortality, in the Ivermectin group. In Control Group a 0.7% showed clinical complications that warranted hospitalization, but no death. When comparing both groups the difference was not statistically significant in deterioration that required hospitalization and or ICU (p-value =0.499) and in death (p-value =1.000) ( Table 2) . (Table 3) .

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted April 17, 2021. The first 4 days after starting the study, a slightly higher number of positive COVID-19 infections was seen in the control group compared to the Ivermectin group. Then from the 5th day on the number of positive COVID-19 infections is equal in both groups. At day 10, a difference between the two groups begins to be noticed, which increases over the course of the days until reaching day 28, where the protection of Ivermectin achieves significant statistics (p-value = 0.006). Between days 16 and 28 (12 days) the Ivermectin group did not present any contagion ( Figure  4 ).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Log-rank method for p-value (95% CI).

Ivermectin has 19 hours plasmatic half-life; also has an enterohepatic cycle and its active metabolites can remain in the patient blood for up to 72 hours. Its excretion is 99% hepatic and only 1% is excreted in the urine. If we give successive doses of Ivermectin on days 1, 4 and 7, the drug accumulation in blood is minimal (2, 3) . Ivermectin is very lipophilic and its concentration in some tissues are high; in the lungs active levels reach almost 3 times higher than in blood.

Kaplan-Meier risk analysis showed that the prevention with Ivermectin occurred after the second dose was received on day 8. This finding could suggest that to achieve a preventive dose of Ivermectin in the tissues, a second dose is needed ( Figure 4 ). This is consistent with the study results conducted in India, by Behera and colleagues, which evaluated 91 health workers exposed to patients with COVID-19, who received preventive Ivermectin at 0.3 mg/kg on days 1 and 4, and were followed for one month. They compared this group with another group of 67 health workers, that was not administered Ivermectin. A 73% decrease risk in COVID-19 infection was observed in the Ivermectin group versus the placebo group (OR = 0.26, 95% CI [0.14, 0.47]). COVID-19 infections in the group that received the 2 doses of Ivermectin were not severe in any case and there were no cases of death. They reported . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. a third group of 17 people who only took Ivermectin on day 1, in whom the preventive effect was not observed (4).

Chahla and colleagues, in Tucuman Argentina, conducted a 1:1 randomized controlled study in healthcare workers for 4 weeks with a 2-week follow-up after completion of the study. They compared a group that was administered PrEP with Ivermectin PO 12mg weekly plus Iota-Carrageenan 6 nasal sprays daily, versus a control group which did not receive any medication. In the "Ivermectin-Carrageenan" group, 4 out of the 117 participants (3.4%) were infected with COVID-19, and in the control group 25 out of the 117 participants (21.4%) were infected. The difference between the two groups was statistically significant (p-value <0.05). The odd ratio (OR) was 0.13, this value transformed into relative risk (RR) becomes 84% less risk of contagion of SARS-CoV-2 in the "Ivermectin-Carrageenan" group in comparison with the control group. In the Ivermectin group the 4 patients had a mild infection and in the control group, in 15 patients the infection was mild, in 7 moderate and in 3 severe (5).

In our study, the hazard ratio (HR) of 0.26 was achieved in the Ivermectin group, which translates into a 74% lower risk of contagion with SARS-CoV-2. This risk result is similar to Behera et al, but 10 points less that Chahla et al. study. This additional difference could be attributed to the use of Iota-Carrageenan.

In the present study, when comparing healthcare personnel who presented COVID-19 infection, the progression of the disease, the appearance of complications, the need for hospitalization and the occurrence of death, the difference between both groups was not statistically significant. These findings could be due to their average young age of 35 years, where patients tend to have fewer complications with COVID-19 infections and that the patients of both groups, were offered early treatment with Ivermectin, which diminishes the progression of SARS-CoV-2 infection, as seen in previous studies (1).

Since this is not a randomized study, it does not allow us to clear certain confounding factors, such as the fact that the Ivermectin group could be made up of healthcare personnel more concerned with prevention in general, including greater personal protection measures and more careful use of the PPE, reducing the risks of contracting SARS-CoV-2. To analyze this argument, we must follow up the same participants of the Ivermectin group ( Figure 5 ), who passed from the weekly dose to a monthly dose PO 0.4 mg/kg and were followed for 56 days (8 weeks). During these 56 days, most of the healthcare workers discontinued progressively the Ivermectin on their own will, for nonspecific reason ( Figure 6 ). When the Ivermectin group was compared to the control group, there was no statistically significant difference, regarding new cases of COVID-19 infections. This finding makes unlikely the former argument.

Another element that may raise doubts could be the possibility that some participants in the control group used Ivermectin on their own or another preventive drug, that would modify our results. We consider that this probability is very low, since the hospital management provided the medicine to the health personnel of both medical centers widely and free of charge.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 17, 2021. ; https://doi.org/10.1101/2021.04.10.21255248 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted April 17, 2021. ; https://doi.org/10.1101/2021.04.10.21255248 doi: medRxiv preprint

Limitations 1.The study was limited to 28 days, since in August 2020 the prevention scheme changed to a monthly dose of Ivermectin 0.4 mg/kg. 2.There was no RT-PCR test at the exit of this study

COVID-19, with a weekly oral dose of Ivermectin 0.2 mg/kg, was statistically significant in the exposed healthcare personnel, at the CMBO and CMPC, after 28 days of follow up, with only 1.8 % of the physicians and health collaborators, developing SARS-CoV-2 infection versus 6

Suggestions 1. The compassionate use of PrEP with Ivermectin 0.2 mg/kg PO per dose weekly

Pre-exposure prophylactic double-blind, controlled randomized studies with different protocols, in workers highly exposed to the SARS-CoV-2 infection, comparing Ivermectin with other possible preventive treatments

José Morgenstern Department of Infectious Diseases Adviser

The Use of Compassionate Ivermectin in the Management of Symptomatic Outpatients and Hospitalized Patients with Clinical Diagnosis of COVID-19 at the Centro Medico Bournigal and at the Centro Medico Punta Cana

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

Safety and pharmacokinetic profile of fixed dose of Ivermectin with innovative 18mg.tablet in healthy adult volunteers

Role of Ivermectin in the prevention of COVID-19 infection among healthcare workers in India

A randomized trial-intensive treatment based in Ivermectin and Iota-Carrageenan as pre-exposure prophylaxis for COVID-19 in healthcare agents

Ivermectin Pre-exposure prophylaxis in the transmission of the SARS-CoV-2 in healthcare workers. Retrospective, multicenter, cohort study. Morgenstern & Cols. Grupo Rescue-Dominican Republic

The authors want to acknowledge all Healthcare personnel involved in the successful management of the COVID-19 cases, their participation in this study and for their invaluable professional dedication and their permanent interest in collecting the data of the cases, in the matrix information technology of the institutions involved.

Authors have no conflict of interest to disclose with any material that is present in this manuscript. None have received any benefits or funding that could influence the results of this publication.

Authors acknowledge and thank Grupo Rescue National Network of Health Services, in Dominican Republic, for the financial support of this manuscript.