key: cord-0726130-wixd647g authors: Ahmed, Sabeena; Khan, Wasif Ali title: A Five-day Course of Ivermectin may Reduce the Duration of COVID-19 Illness date: 2021-07-26 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.07.050 sha: c347266efea01df6403527af5d7e882880c33210 doc_id: 726130 cord_uid: wixd647g nan This pilot study was performed to evaluate the rapidity of viral clearance and safety of a 5-day course of ivermectin or a single-dose of ivermectin + a 5-day course of doxycycline in the treatment of mild COVID-19 in adults. The letter states that any significant antiviral activity is unlikely to achieve the dose used in our study and the resultant plasma concentration of the administered ivermectin. In response to the letter we intend to make few comments. We agree with Shukla and Misra, that in vitro studies showed antiviral activities of ivermectin in such a high plasma concentration which cannot be achieved through therapeutic dose in vivo. In this connection, firstly, we like to state that in vitro and in vivo studies of same drug may differ in various aspects. Viruses are known to have high rates of replication and therefore, one day dose of ivermectin, is unlikely to have sufficient effect since half life is around 20 hours (2) . To maintain an effective concentration of ivermectin in the body we decided to give ivermectin single dose for 5 days. The highest dose of ivermectin that we have used in our study is 12 mg (200 µg/kg) once daily for 5 consecutive days which showed significantly shorter time of viral clearance. Virological clearance was earlier in the 5-day ivermectin treatment arm when compared to the placebo group (9.7 days vs 12.7 days; p = 0.02), but this was not the case for the ivermectin + doxycycline arm (11.5 days; p = 0.27). Similar to this, clinical trial with the 3-day once daily dose of 400 µg/kg oral ivermectin on dengue patients has been proved to be safe and accelerated clearance of nonstructural protein 1 of dengue virus (3) . In response to Shukla and others' comment on other retrospective studies that showed no improvement in microbiological and virological clearance, we like to state that pooled analysis of 6 studies of ivermectin on COVID-19, which includes our studies showed that ivermectin administration significantly shortened the time to negative COVID -19 RT-PCR results (p = 0.007) (4). Besides, we like to state that ivermectin is a multifaced medication with anti-viral as well as anti-inflamatory and anticancerous properties. Studies of ivermectin have reported potential immunemodulatory functions of the drug, which have been hypothesized to be beneficial for COVID-19 infection (5) (6) (7) . We cannot rule out the effect of immunomodulatory function of ivermectin that could be present in vivo and play synergistic role with antiviral properties of the medicine. At last, we agree with the WHO recommendation that Shukla and others mentioned in their letter. As mentioned in the 'Discussion' section, we also think that a larger randomized controlled clinical trial of ivermectin treatment is warranted to validate these important findings. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness The pharmacokinetics and interactions of ivermectin in humans--a mini-review Ivermectin Accelerates Circulating Nonstructural Protein 1 (NS1) Clearance in Adult Dengue Patients: A Combined Phase 2/3 Randomized Double-blinded Placebo Controlled Trial Ivermectin and outcomes from Covid-19 pneumonia: A systematic review and meta-analysis of randomized clinical trial studies Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway Ivermectin may be a clinically useful antiinflammatory agent for late-stage COVID-19