key: cord-0859446-nkaj9f51
authors: Ozer, Muhammet; Goksu, Suleyman Yasin; Conception, Reena; Ulker, Esad; Balderas, Rodolfo Magallanes; Mahdi, Mohammed; Manning, Zulfiya; To, Kim; Effendi, Muhammad; Anandakrishnan, Rajashree; Whitman, Marc; Gugnani, Manish
title: Effectiveness and safety of Ivermectin in COVID‐19 patients: A prospective study at a safety‐net hospital
date: 2021-11-29
journal: J Med Virol
DOI: 10.1002/jmv.27469
sha: d108b02e3fa760c8e4424e50f3798436947177db
doc_id: 859446
cord_uid: nkaj9f51

Ivermectin has been found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replication in vitro. It is unknown whether this inhibition of SARS‐CoV‐2 replication correlates with improved clinical outcomes. To assess the effectiveness and safety of ivermectin in hospitalized patients with COVID‐19. A total of 286 patients with COVID‐19 were included in the study. Univariate analysis of the primary mortality outcome and comparisons between treatment groups were determined. Logistic regression and propensity score matching (PSM) was used to adjust for confounders. Patients in the ivermectin group received 2 doses of Ivermectin at 200 μg/kg in addition to usual clinical care on hospital Days 1 and 3. The ivermectin group had a significantly higher length of hospital stay than the control group; however, this significance did not maintain on multivariable logistic regression analysis. The length of intensive care unit (ICU) stay and duration of mechanical ventilation were longer in the control group. However, a mortality benefit was not seen with ivermectin treatment before and after PSM (p values = 0.07 and 0.11, respectively). ICU admission, and intubation rate were not significantly different between the groups (p = 0.49, and p = 1.0, respectively). No differences were found between groups regarding the length of hospital stay, ICU admission, intubation rate, and in‐hospital mortality.

inhibiting the posttranslational processing of viral polyproteins.

Ivermectin may also be related to inhibiting nuclear transport. Previous studies reported that ivermectin inhibits IMPα/β1-mediated nuclear import of the N protein. 3, 4, 7, 8 Additionally, the SARS-CoV-2 accessory protein ORF6 has a potential role in the antiviral action of the STAT1 transcription factor by sequestering IMP α/β1 on the rough ER/Golgi membrane. 9 Overall, these findings increased the hope that ivermectin's nuclear transport inhibitory action might be effective against SARS-CoV-2. In efforts to combat the pandemic and in light of limited therapeutic options, ivermectin was utilized off-label early on for treatment of COVID-19 based upon in vitro studies.

To date, there is conflicting data on whether this inhibition of SARS-CoV-2 entry correlates with improved clinical outcomes. The concentrations tested in reported in-vitro assays are equivalent to more than 50-fold the normal C-max achieved with a standard single dose of ivermectin 200 μg/kg. The main concern is that standard doses of ivermectin show a lack of efficacy and tolerability in COVID-19 patients. 10 The most common reported side effects of ivermectin include elevation in transaminases, nausea, diarrhea, dizziness, decreased leukocyte count, allergic reactions, and ocular impairment. 11 Several studies have been conducted to investigate the clinical outcomes of patients with COVID-19 who received ivermectin treatment. Recent retrospective studies reported that ivermectin treatment in different dose modalities in hospitalized patients had lower mortality than those who did not receive ivermectin. 12, 13 There is a lack of randomized controlled trials to support the use of ivermectin in COVID-19 patients. More than a year after the start of the pandemic, a therapeutic medication that would limit the mortality and the course of infection is greatly needed. Therefore, the purpose of this prospective study is to assess the effectiveness and safety profile of ivermectin in addition to standard treatment in hospitalized patients with COVID-19. 

The primary endpoint was the comparison of clinical outcomes, measured by the rate of intubation, length of hospital stay, and mechanical ventilation duration. The secondary endpoint was drug safety outcomes (mainly neurological, cutaneous, GI, and ocular), the occurrence of the adverse events requiring discontinuation of the treatment, and clinical and laboratory improvement. The research question was framed before the data collection and database creation.

Venous blood samples for standard biochemistry analysis were collected on admission and during hospitalization based upon the patient's clinical conditions. The age-adjusted Charlson comorbidity index was calculated to assess the comorbidity burden. The severity of pulmonary involvement was evaluated at baseline data collection based on their initial oxygen requirements as nasal cannula up to 6 L, nonrebreather (NRB) Venturi mask or High flow, and mechanical ventilation.

Other variables evaluated as potential confounders were defined. Covariates that could be associated with the outcome was chosen based on clinical judgment and on previously published studies: age, sex, comorbidities assessed by Charlson comorbidity index, the severity of disease evaluated by FiO 2 requirement, white blood cell count (WBC), lymphocytes, platelets count, lactate dehydrogenase (LDH), D-dimer, procalcitonin, fibrinogen, C-reactive T A B L E 1 Baseline characteristics for Ivermectin and control groups before and after propensity score matching protein (CRP) on admission was considered as potential confounders

and was collected and included in the propensity score matching analysis. Data were collected via an electronic medical record system, and side effects were monitored by the investigator's daily examination.

Univariate analysis of the primary mortality outcome and comparisons between treatment groups were determined by the Student F I G U R E 1 Initial and peak oxygen requirement for ivermectin and control groups after propensity score matching. MV, mechanical ventilation; NRB, nonrebreather mask; NVM, noninvasive mechanical ventilation

We performed the propensity score matching analysis using the R software with the nearest-neighbor algorithm without replacement.

According to reporting guidelines on PS analysis, the PS method attempts to balance treated and nontreated groups to reduce confounding by indication in observational designs, thereby creating a quasi-randomized experiment. Propensity score-matched cohorts (1:1 matching ratio) were built. Each patient receiving the Ivermectin treatment was matched with a patient among those admitted at the same period and treated with standard care.

Statistical significance was established at p < 0.05. All reported p values were two-tailed. The results were analyzed using statistical software packages (SPSS 22.0, IBM; and R 3.5.1).

This study has no internal or external funders. No funders role in the design of the study; collection, analysis, or interpretation of the data;

or the decision to submit the article for publication. High flow (10%), and mechanical ventilation (5%) (Figure 1 ). The median lymphocyte count was higher in the control group (12 vs. 8, p = 0.002), while the median neutrophil count was higher in the ivermectin group (54.2 vs. 5.7, p < 0.001). Laboratory findings were summarized in Table 2 .

Ivermectin and control groups were well balanced after 1:1 propensity score matching adjusted by the age of diagnosis, gender, comorbidity T A B L E 2 Laboratory findings for ivermectin and control groups before and after propensity score matching 

In this prospective observational cohort study, we reported the effectiveness and safety of ivermectin in addition to standard treatment compared to standard therapy alone in hospitalized patients with laboratory-confirmed COVID-19 infection. Also, demographic, clinical, and laboratory findings, as well as treatment outcomes, were reported. In our population, we did not observe a significant association of a two doses modality of 200 μg/kg of ivermectin with improved survival before or after propensity score matching. In terms of the primary endpoints of our study, the ivermectin group had a significantly higher length of hospital stay than the control group;

however, this significance was not maintained on multivariable logistic regression analysis after adjustment for comorbidities and main confounders ( Table 3 ). The possible explanations could include delays in discharging patients to other facilities, including inpatient rehabilitation centers and skilled nursing facilities. Also, the ivermectin group had a significantly higher bacterial infection rate which can cause longer hospital stay in that group.

In particular, the length of ICU stay was longer in the control group compared to the ivermectin arm ( Figure 2A) . Similarly, Rajter et al. reported a trend of higher efficacy of ivermectin in patients who required higher inspired oxygen or ventilatory support. 12 On the other hand, we did not observe a significant difference in ICU admission, intubation rate, and duration of mechanical ventilation between the groups ( Figure 2B ). These findings were confirmed after multivariate adjustment for comorbidities and differences between groups and a propensity score-matched cohort (Table 3 ). In terms of laboratory findings of both groups, inflammatory, infectious and coagulation markers were well adjusted and there were no statistical differences between groups before and after propensity score matching except the median lymphocyte and neutrophil counts ( 

Our study did not find a difference in duration of hospitalization, intubation rate, or mortality when a two-dose ivermectin regimen was added to standard therapy of remdesivir, steroids, and anticoagulation for the treatment of COVID-19. Appropriately designed randomized clinical trials with higher doses of ivermectin should be conducted to validate the impact of Ivermectin in patients with COVID-19 infection.

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Analysis and/or interpretation: Muhammet Ozer

Other: Esad Ulker, Rodolfo Magallanes Balderas

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Effectiveness and safety of Ivermectin in COVID-19 patients: A prospective study at a safety-net hospital

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

http://orcid.org/0000-0002-9579-1372