More evidence for the liars and deniers and vaccine warriors
Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies
https://onlinelibrary.wiley.com/doi/full/10.1002/rmv.2265
Summary
Ivermectin is an FDA-approved drug for a parasitic disease that has broad antiviral activity. This study aims to analyse the efficacy of ivermectin in improving the Covid-19 outcomes. We systematically searched the PubMed, Europe PMC and ClinicalTrials.gov database using specific keywords related to our aims until 10th May 2021. All published randomized clinical trial studies on Covid-19 and ivermectin were retrieved. The quality of the study was assessed using Jadad scale assessment tool for clinical trial studies. Statistical analysis was done using Review Manager 5.4 software. A total of 19 studies with 2768 Covid-19 patients were included in this meta-analysis. This meta-analysis showed that ivermectin was associated with reduction in severity of Covid-19 (RR 0.43 [95% CI 0.23–0.81], p = 0.008), reduction of mortality (RR 0.31 [95% CI 0.15–0.62], p = 0.001), higher negative RT-PCR test results rate (RR 1.23 [95% CI 1.01–1.51], p = 0.04), shorter time to negative RT-PCR test results (mean difference [MD] −3.29 [95% CI −5.69, −0.89], p = 0.007), higher symptoms alleviations rate (RR 1.23 [95% CI 1.03−1.46], p = 0.02), shorter time to symptoms alleviations (MD −0.68 [95% CI −1.07, −0.29], p = 0.0007) and shorter time to hospital discharge (MD −2.66 [95% CI −4.49, −0.82], p = 0.004). Our study suggests that ivermectin may offer beneficial effects towards Covid-19 outcomes. More randomized clinical trial studies are still needed to confirm the results of our study.
DISCUSSION
According to our pooled analysis, ivermectin was discovered to have an association with a higher negative RT-PCR test results rate, shorter time to negative RT-PCR test results, higher symptoms alleviations rate, shorter time to symptoms alleviations, shorter time to hospital discharge and reduction in the severity and mortality from Covid-19. Our subgroup analysis also showed that the benefits of ivermectin therapy in reducing the severity and mortality outcomes from Covid-19 were more prominent when administered into mild to moderate patients, compared with in severe patients. On the other side, the benefits of ivermectin therapy in increasing negative RT-PCR test results rate, shortening time to negative RT-PCR test results, increasing symptoms alleviations rate and shortening time to symptoms alleviations were more apparent in severe patients when compared with in mild to moderate patients.
A few arguments might explain these findings. The sequestration of the SARS-CoV-2 viral nucleocapsid protein (NCP) into the host nucleus through the nuclear-pore-complex is a vital step in viral pathogenesis and defence against host immune response.48 Ivermectin can selectively inhibit the host importin α/β transporter protein which decreases translocation (shuttling) of SARS-CoV-2 NCP from the cytoplasm to the nucleus, alteration of NCP distribution will lead to viral propagation disruption and survival.23 The in vitro study by Caly et al.23 has proved that giving ivermectin in one dose was able to reduce the viral RNA load by 99.98% at 48 h and replication of an Australian isolate of SARS-CoV-2 in Vero/hSLAM cells by 5000-folds. Therefore, it has potent effects in altering disease progression and spread. These in vitro findings were further supported with the results from a double-blind, placebo-controlled, randomized clinical trial study, showing that patients who received ivermectin 400 μg/kg single dose have a lower median viral load at Day 4 (161,000 vs. 493,500 copies/ml) and Day 7 post-treatment (1018 vs. 23,550 copies/ml). The differences were found, rising from a threefold decrease on the fourth day to about 18-fold lower on the seventh day when compared with placebo.49 Second, the pathophysiologic process which underlies severe Covid-19 involves hyperinflammatory response and accumulation of cytokines, called a cytokine storm. A meta-analysis study has demonstrated that severe Covid-19 patients tend to produce higher cytokine levels such as interleukin-6 (IL-6), IL-8, IL-10 and tumour necrosis factor-α (TNF-α), in comparison to non-severe cases.50 On the other side, an anti-inflammatory effect was also demonstrated in ivermectin, both in vivo and in vitro studies. Ivermectin can reduce the IL-1, IL-6, TNF-α production and suppressing lipopolysaccharide-induced nuclear factor-kappa B translocation.51 The suppression of mucus due to hypersecretion in the respiratory tract, the reduction of immune cell recruitment, and a decrease in the production of cytokines and immunoglobulin E/immunoglobulin G1 in bronchoalveolar lavage of experimental mice, were found as a consequence of 2 mg/kg of ivermectin administration.52 These findings suggest that ivermectin has an anti-inflammatory effect on the lung tissue, besides at the systemic level, which might help to reduce the severity and prevent mortality from Covid-19.
This study has several limitations. First, significant heterogeneities were found on most of the outcomes of interests included in this study. This was probably caused by the difference in the given ivermectin doses and the medications used as a standard of care or placebo. Second, the total number of patients included in this study was relatively small because at this time, ivermectin is still considered as new repurposed drug for Covid-19 where early trials still show conflicting results and there is still no meta-analysis study to support its efficacy, therefore it may be difficult to collect the participants and receiving their consent to participate in the trials. Third, we include some pre-print studies to minimize the risk of publication bias; however, the authors have made exhaustive efforts to ensure that only sound studies were included, and we expect that most of those studies currently available in pre-print form will eventually be published and that we will identify them through ongoing electronic literature surveillances. We hope that this study can give further insight into the management of Covid-19 patients.
5 CONCLUSION
Our meta-analysis of randomized clinical trial studies indicates that ivermectin administration had an association with favourable outcomes of Covid-19, compromising of higher rate of negative RT-PCR test results, shorter time to negative RT-PCR test results, higher rate of symptoms alleviations, shorter time to symptoms alleviations, shorter time to hospital discharge, reduction in the severity and mortality rate from Covid-19. This study suggests that ivermectin may be the potential therapeutic agents for the managements of Covid-19 to give better outcomes for the patients. However, more randomized clinical trial studies are still necessary and encouraged to be done for confirming the results of our study. Finally, ivermectin should be considered as an essential drug for future Covid-19 therapy models.