A randomized controlled trial of combined ivermectin and zinc sulfate versus combined hydroxychloroquine, darunavir/ritonavir, and zinc sulfate among adult patients with asymptomatic or mild coronavirus-19 infection
Prof. Yupin Yupin Suputtamongkol, Sireethorn Nimitvilai, Ussanee Poolvivatchaikarn, Dechatorn Rassamekulthana, Nuttawut Rongkiettechakorn, Anek Mungaomklang, Susan Assanasaen, Ekkarat Wongsawat, Chompunuch Boonarkart, Waritta Sawaengdee
Journal of Global Infectious Diseases, doi:10.4103/jgid.jgid_281_21
IntRoductIon The outbreak of coronavirus-19 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused an ongoing burden on health-care systems worldwide. Both the asymptomatic and symptomatic patients had similar viral loads. Published data showed that the transmission from asymptomatic or mild infection is very high. [1, 2] The administration of an effective oral antiviral therapy would be useful for transmission blocking or reducing onward transmission by these population. In addition, early treatment of these patients may prevent progression to severe COVID-19. However, an effective treatment option is not yet available for SARS-CoV-2 infection. Ivermectin is a safe and widely used antiparasitic drug with known in vitro efficacy against several single-strain RNA viruses, including SARS-CoV-2. [3] Ivermectin has been Introduction: Ivermectin, hydroxychloroquine (HQ), and darunavir/ritonavir are widely prescribed as an oral treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection despite their uncertainty of clinical benefit. The objective is to determine the safety and the efficacies of two treatment regimens against SARS-CoV-2 infection. Methods: We conducted an open-labeled, randomized, controlled trial to compare the efficacy between a 3-day course of once-daily high-dose oral ivermectin plus zinc sulfate (Group A) and a combination of HQ, darunavir/ritonavir, and zinc sulfate (HQ + antiretroviral, Group B) for 5 days in asymptomatic or mild SARS-CoV-2 infection. The study period was between December 2020 and April 2021. Results: Overall, 113 patients were randomized and analyzed (57 patients in Group A and 56 patients in Group B). The median duration to achieve the virological outcome of either undetected or cycle threshold (Ct) for N gene of SARS-CoV-2 by real-time polymerase chain reaction was 6 days (95% confidence interval [CI] 5.3-6.7) versus 7 days (95% CI: 5.4-8.6) in Group A and Group B, respectively (P = 0.419) in the modified intention-to-treat population. All patients were discharged from hospital quarantine as planned. Two patients in Group A and one patient in Group B were considered clinically worsening and received 10 days of favipiravir treatment. There was no serious adverse event found in both groups. Conclusion: We demonstrated that both treatment regimens were safe, but both treatment regimens had no virological or clinical benefit. Based on this result and current data, there is no supporting evidence for the clinical benefit of ivermectin for coronavirus-19.
Research quality and ethics statement The authors followed applicable EQUATOR Network (http:// www.equator-network.org/) guidelines during this research project. This study was approved by the appropriate Institutional Review Board of all study sites, the Council of Architecture (COA 323/2563), and (COA 002/2021). The trial was registered with ClinicalTrials.gov (NCT02045069).
Conflicts of interest There are no conflicts of interest.
References
Araujo, Machado, Amgarten, Malta, De Araujo et al., SARS-CoV-2 isolation from the first reported patients in Brazil and establishment of a coordinated task network, Mem Inst Oswaldo Cruz
Baek, Lee, Yoon, Sohn, Cho et al., Duration of culturable SARS-CoV-2 within different specimens among mild and severe COVID-19 patients: A longitudinal study, J Infect
Bakadia, He, Souho, Lamboni, Ullah et al., Prevention and treatment of COVID-19: Focus on interferons, chloroquine/hydroxychloroquine, azithromycin, and vaccine, Biomed Pharmacother
Caly, Druce, Catton, Jans, Wagstaff, The FDAapproved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res
Carlucci, Ahuja, Petrilli, Rajagopalan, Jones et al., Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients, J Med Microbiol
Elgarzzar, Eltaweel, Youssef, Hany, Hafes et al., Efficacy and safety of ivermectin for treatment and prophylaxis of COVID-19 pandemic, Res Sq,
doi:10.21203/rs.3rs-100956/v3Fleiss, Tytun, Ury, A simple approximation for calculating sample sizes for comparing independent proportions, Biometrics
Hill, Garratt, Levi, Falconer, Ellis et al., Erratum: Expression of concern: "Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection, Open Forum Infect Dis
Hill, Garratt, Levi, Falconer, Ellis et al., Metaanalysis of randomized trials of ivermectin to treat SARS-CoV-2 infection, Open Forum Infect Dis
Jefferson, Spencer, Brassey, Heneghan, Viral cultures for COVID-19 infectious potential assessment -A systematic review, Clin Infect Dis
Kinobe, Owens, A systematic review of experimental evidence for antiviral effects of ivermectin and an in silico analysis of ivermectin's possible mode of action against SARS-CoV-2, Fundam Clin Pharmacol
Momekov, Momekova, Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: Antiviral levels are not likely attainable with known dosing regimens, Biotechnol Biotechnol Equip
Osborne, Davies, Lane, Evans, Denyer et al., Lopinavir-ritonavir in the treatment of COVID-19: A dynamic systematic benefit-risk assessment, Drug Saf
Rabaan, Tirupathi, Sule, Aldali, Mutair et al., Viral dynamics and real-time RT-PCR Ct values correlation with disease severity in COVID-19, Diagnostics
Reis, Silva, Silva, Thabane, Milagres et al., Effect of Early Treatment with Ivermectin among Patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2115869Samaha, Mouawia, Fawaz, Hassan, Salami et al., Effects of a single dose of ivermectin on viral and clinical outcomes in asymptomatic SARS-CoV-2 infected subjects: A pilot clinical trial in Lebanon, Viruses
Singanayagam, Patel, Charlett, Bernal, Saliba et al., Duration of infectiousness and correlation with RT-PCR cycle threshold values in cases of COVID-19, England, January to, Euro Surveill
Suputtamongkol, Avirutnan, Mairiang, Angkasekwinai, Niwattayakul et al., Ivermectin accelerates circulating nonstructural protein 1 (NS1) clearance in adult dengue patients: A combined phase 2/3 randomized double-blinded placebo controlled trial, Clin Infect Dis
Tang, Cao, Han, Wang, Chen et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomised controlled trial, BMJ
Terry, Anderson, Scherman, Mcalister, Perera et al., Development of a SARS-CoV-2 nucleocapsid specific monoclonal antibody, Virology
Vallejos, Zoni, Bangher, Villamandos, Bobadilla et al., Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial, BMC Infect Dis
Velthuis, Van Den Worm, Sims, Baric, Snijder et al., Zn2+ inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture, PLoS Pathog
Yap, Tan, Chan, Tee, Kamarulzaman et al., An overview of the genetic variations of the SARS-CoV-2 genomes isolated in Southeast Asian countries, J Microbiol Biotechnol
Yu, Bafadhel, Dorward, Hayward, Saville et al., Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): A randomised, controlled, open-label, adaptive platform trial, Lancet
Zou, Ruan, Huang, Liang, Huang et al., SARS-CoV-2 viral load in upper respiratory specimens of infected patients, N Engl J Med
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"unstructured": "National Institutes of Health. Ivermectin. Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ivermectin/. [Last updated on 2021 Feb]."
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