Effectiveness of dolutegravir in moderate severity COVID-19 patients: A single-center, randomized, double-blind, placebo-controlled trial
Hamideh Abbaspour Kasgari, Siavash Moradi, Ahmad Alikhani, Nasim Ahmadian
BioImpacts, doi:10.34172/bi.29952
Introduction: Drug repurposing as a low-cost, time-saving, and often less risky strategy has been attractive for the treatment of coronavirus disease 2019 (COVID-19) during the pandemic. This trial aimed to evaluate the effectiveness of dolutegravir, an HIV-1 integrase inhibitor, in admitted patients with moderate COVID-19. Methods: This study was a randomized, double-blind, placebo-controlled clinical trial assessing the efficacy of dolutegravir in adults admitted to a hospital in Ghaemshahr, Mazandaran Province, Iran. Patients aged 18-80 years with early symptoms of moderate COVID-19, which was confirmed based on reverse transcription polymerase chain reaction (RT-PCR) and/or chest computed tomography (CT) scan, were considered to be included in this study. Patients were randomly assigned in a 1:1 ratio to receive 50 mg dolutegravir plus the standard treatment regimen or the same value of placebo plus the standard treatment regimen, daily for 7 days. The standard treatment regimen was remdesivir 200 mg on day 1 followed by 100 mg for five days or until discharge. The primary endpoint was recovery 10 days after the beginning of the study. Results: Between August 22 and October 23, 2021, of 120 patients who were enrolled, 93 patients were randomly assigned to receive 50 mg dolutegravir (n = 46) or the placebo regimen (n = 47). No significant difference was observed between the two intervention groups based on the obtained results including frequency of respiratory modes during the first five days of admission, respiratory rate, and O 2 saturation during six time periods.
Conclusion: The results showed that in adult patients admitted to the hospital with moderate COVID-19, treatment with dolutegravir was not associated with improvement in clinical recovery. Larger randomized trials are required to provide more robust evidence about the effectiveness of dolutegravir.
Competing Interests The authors declare that there is no conflict of interest.
Ethical Statement The
References
Aghaali, Kolifarhood, Nikbakht, Saadati, Nazari, Estimation of the serial interval and basic reproduction number of COVID-19 in Qom, Iran, and three other countries: A data-driven analysis in the early phase of the outbreak, Transbound Emerg Dis,
doi:10.1111/tbed.13656Amin, Banerjee, Ghosh, Gayen, Jha, Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors, Bioorg Med Chem,
doi:10.1016/j.bmc.2020.115860Baig, Khaleeq, Ali, Syeda, Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms, ACS Chem Neurosci,
doi:10.1021/acschemneuro.0c00122Bakowski, Beutler, Wolff, Kirkpatrick, Chen et al., Drug repurposing screens identify chemical entities for the development of COVID-19 interventions, Nat Commun,
doi:10.1038/s41467-021-23328-0Behera, Mahapatra, Tripathy, Pati, Drug repurposing for identification of potential inhibitors against SARS-CoV-2 spike receptor-binding domain: An in silico approach, J Biomol Struct Dyn,
doi:10.4103/ijmr.IJMR_1132_20Chakraborty, Sharma, Bhattacharya, Lee, A detailed overview of immune escape, antibody escape, partial vaccine escape of SARS-CoV-2 and their emerging variants with escape mutations, Front Immunol,
doi:10.3389/fimmu.2022.801522Chen, Liu, Guo, Emerging coronaviruses: genome structure, replication, and pathogenesis, J Med Virol,
doi:10.1002/jmv.25681Dastan, Saffaei, Haseli, Marjani, Moniri et al., Promising effects of tocilizumab in COVID-19: a noncontrolled, prospective clinical trial, Int Immunopharmacol,
doi:10.1016/j.intimp.2020.106869Delgado, Duro, Rogers, Tkatchenko, Pandit et al., Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor, Proteins,
doi:10.1002/prot.26086Drożdżal, Rosik, Lechowicz, Machaj, Kotfis et al., FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy, Drug Resist Updat,
doi:10.1016/j.drup.2020.100719Duan, Liu, Li, Zhang, Yu et al., Effectiveness of convalescent plasma therapy in severe COVID-19 patients, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.2004168117Fattahi, Mohseni, Jalalvand, Moghadam, Ghaziasadi et al., SARS-CoV-2 outbreak in Iran: The dynamics of the epidemic and evidence on two independent introductions, Transbound Emerg Dis,
doi:10.1111/tbed.14104Finsterer, Neurological side effects of SARS-CoV-2 vaccinations, Acta Neurol Scand,
doi:10.1111/ane.13550Galindez, Matschinske, Rose, Sadegh, Salgado-Albarrán et al., Lessons from the COVID-19 pandemic for advancing computational drug repurposing strategies, Nat Comput Sci,
doi:10.1038/s43588-020-00007-6Gao, Yan, Huang, Liu, Zhao et al., Structure of the RNA-dependent RNA polymerase from COVID-19 virus, Science,
doi:10.1126/science.abb7498Garrepalli, Gudipati, Kapavarapu, Ravindhranath, Pal, Synthesis and characterization of two known and one new impurities of dolutegravir: In silico evaluation of certain intermediates against SARS CoV-2 O-ribose methyltransferase (OMTase), Journal of Molecular Structure,
doi:10.1016/j.molstruc.2022.133992Gysi, Valle, Zitnik, Ameli, Gan et al., Network medicine framework for identifying drug-repurposing opportunities for COVID-19, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.2025581118Indu, Rameshkumar, Arunagirinathan, Al-Dhabi, Arasu et al., Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNAdependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach, J Infect Public Health,
doi:10.1016/j.jiph.2020.10.015Kalantari, Fard, Maleki, Taher, Yassin et al., Comparing the effectiveness of Atazanavir/Ritonavir/ Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/ Hydroxychloroquine treatment regimens in COVID-19 patients, J Med Virol,
doi:10.1002/jmv.27195Lan, Ge, Yu, Shan, Zhou et al., Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor, Nature,
doi:10.1038/s41586-020-2180-5Lee, Chong, Sukumaran, Nimmanpipug, Letchumanan et al., Computational screening and identifying binding interaction of anti-viral and anti-malarial drugs: Toward the potential cure for SARS-CoV-2, Progress in Drug Discovery & Biomedical Science,
doi:10.36877/pddbs.a0000065Llibre, Hung, Brinson, Castelli, Girard et al., Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies, Lancet,
doi:10.1016/S0140-6736(17)33095-7Lu, Zhao, Li, Niu, Yang et al., Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding, Lancet,
doi:10.1016/S0140-6736(20)30251-8Macchiagodena, Pagliai, Procacci, Identification of potential binders of the main protease 3CLpro of the COVID-19 via structure-based ligand design and molecular modeling, Chemical Physics Letters,
doi:10.1016/j.cplett.2020.137489Menachery, Schäfer, Burnum-Johnson, Mitchell, Eisfeld et al., MERS-CoV and H5N1 influenza virus antagonize antigen presentation by altering the epigenetic landscape, Proc Natl Acad Sci U S A,
doi:10.1073/pnas.1706928115Mohamed, Yazdanpanah, Saghazadeh, Rezaei, Computational drug discovery and repurposing for the treatment of COVID-19: a systematic review, Bioorg Chem,
doi:10.1016/j.bioorg.2020.104490Murugan, Kumar, Jeyakanthan, Srivastava, Searching for target-specific and multi-targeting organics for Covid-19 in the Drugbank database with a double scoring approach, Sci Rep,
doi:10.1038/s41598-020-75762-7Oprea, Bauman, Bologa, Buranda, Chigaev et al., Drug repurposing from an academic perspective, Drug Discovery Today: Therapeutic Strategies,
doi:10.1016/j.ddstr.2011.10.002Osterholzer, Goldman, Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection, Clin Infect Dis,
doi:10.1093/cid/ciu221Poustchi, Darvishian, Mohammadi, Shayanrad, Delavari et al., SARS-CoV-2 antibody seroprevalence in the general population and high-risk occupational groups across 18 cities in Iran: a population-based cross-sectional study, Lancet Infect Dis,
doi:10.1016/S1473-3099(20)30858-6Pushpakom, Iorio, Eyers, Escott, Hopper et al., Drug repurposing: progress, challenges and recommendations, Nat Rev Drug Discov,
doi:10.1038/nrd.2018.168Rathbun, Lockhart, Miller, Liedtke, Dolutegravir, a second-generation integrase inhibitor for the treatment of HIV-1 infection, Ann Pharmacother,
doi:10.1177/1060028013513558Rhee, Grant, Tzou, Barrow, Harrigan et al., A systematic review of the genetic mechanisms of dolutegravir resistance, J Antimicrob Chemother,
doi:10.1093/jac/dkz256Rudrapal, Khairnar, Jadhav, Drug repurposing (DR): an emerging approach in drug discovery. drug repurposinghypothesis, molecular aspects and therapeutic applications IntechOpen, Intech Open Publications,
doi:10.5772/intechopen.93193Sahraei, Shabani, Shokouhi, Saffaei, Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine, Int J Antimicrob Agents
Simmons, Wentzel, Mobarak, Eslami, Sadeghi et al., Sofosbuvir/daclatasvir regimens for the treatment of COVID-19: an individual patient data meta-analysis, J Antimicrob Chemother,
doi:10.1093/jac/dkaa418Walmsley, Antela, Clumeck, Duiculescu, Gutiérrez, Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection, N Engl J Med,
doi:10.1056/NEJMoa1215541Wang, Guan, COVID-19 drug repurposing: a review of computational screening methods, clinical trials, and protein interaction assays, Med Res Rev,
doi:10.1002/med.21728Wang, Guo, Liu, Wang, Rao et al., Endocytosis of the receptor-binding domain of SARS-CoV spike protein together with virus receptor ACE2, Virus Res,
doi:10.1016/j.virusres.2008.03.004Wang, Xu, Wang, Hong, Zhang et al., Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM, Nat Commun,
doi:10.1038/s41467-021-27350-0Wrapp, Wang, Corbett, Goldsmith, Hsieh et al., Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation, Science,
doi:10.1126/science.abb2507Xia, Zhang, Wang, Wang, Yang et al., Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial, Lancet Infect Dis,
doi:10.1016/S1473-3099(20)30831-8Xue, Li, Xie, Wang, Review of drug repositioning approaches and resources, Int J Biol Sci,
doi:10.7150/ijbs.24612Ye, Xu, Rong, Xu, Liu et al., Delivery of infection from asymptomatic carriers of COVID-19 in a familial cluster, International Journal of Infectious Diseases,
doi:10.1016/j.ijid.2020.03.042Ying, Ebrahimi, Keivan, Khoshnam, Salahi et al., miRNAs; a novel strategy for the treatment of COVID-19, Cell Biol Int,
doi:10.1002/cbin.11653Yu, Chen, Lan, Shen, Li, Computational screening of antagonists against the SARS-CoV-2 (COVID-19) coronavirus by molecular docking, Int J Antimicrob Agents,
doi:10.1016/j.ijantimicag.2020.106012Zheng, Shao, Chen, Zhang, Wang et al., Realworld effectiveness of COVID-19 vaccines: a literature review and meta-analysis, Int J Infect Dis,
doi:10.1016/j.ijid.2021.11.009DOI record:
{
"DOI": "10.34172/bi.29952",
"ISSN": [
"2228-5652",
"2228-5660"
],
"URL": "http://dx.doi.org/10.34172/bi.29952",
"abstract": "<jats:p>Introduction: Drug repurposing as a low-cost, time-saving, and often less risky strategy has been attractive for the treatment of coronavirus disease 2019 (COVID-19) during the pandemic. This trial aimed to evaluate the effectiveness of dolutegravir, an HIV-1 integrase inhibitor, in admitted patients with moderate COVID-19. Methods: This study was a randomized, double-blind, placebo-controlled clinical trial assessing the efficacy of dolutegravir in adults admitted to a hospital in Ghaemshahr, Mazandaran Province, Iran. Patients aged 18-80 years with early symptoms of moderate COVID-19, which was confirmed based on reverse transcription polymerase chain reaction (RT-PCR) and/or chest computed tomography (CT) scan, were considered to be included in this study. Patients were randomly assigned in a 1:1 ratio to receive 50 mg dolutegravir plus the standard treatment regimen or the same value of placebo plus the standard treatment regimen, daily for 7 days. The standard treatment regimen was remdesivir 200 mg on day 1 followed by 100 mg for five days or until discharge. The primary endpoint was recovery 10 days after the beginning of the study. Results: Between August 22 and October 23, 2021, of 120 patients who were enrolled, 93 patients were randomly assigned to receive 50 mg dolutegravir (n = 46) or the placebo regimen (n = 47). No significant difference was observed between the two intervention groups based on the obtained results including frequency of respiratory modes during the first five days of admission, respiratory rate, and O2 saturation during six time periods. Conclusion: The results showed that in adult patients admitted to the hospital with moderate COVID-19, treatment with dolutegravir was not associated with improvement in clinical recovery. Larger randomized trials are required to provide more robust evidence about the effectiveness of dolutegravir.</jats:p>",
"assertion": [
{
"label": "Journal Owner",
"name": "journal_owner",
"value": "Tabriz University of Medical Sciences"
},
{
"label": "Journal Publisher",
"name": "journal_publisher",
"value": "Tabriz University of Medical Sciences"
},
{
"group": {
"label": "Publication History",
"name": "publication_history"
},
"label": "Received",
"name": "received",
"order": 1,
"value": "2023-06-25"
},
{
"group": {
"label": "Publication History",
"name": "publication_history"
},
"label": "Accepted",
"name": "accepted",
"order": 2,
"value": "2024-02-06"
},
{
"group": {
"label": "Publication History",
"name": "publication_history"
},
"label": "Published",
"name": "published",
"order": 3,
"value": "2024-06-26"
}
],
"author": [
{
"ORCID": "https://orcid.org/0000-0002-6441-139X",
"affiliation": [
{
"name": "Department of Clinical Pharmacy, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran"
}
],
"authenticated-orcid": true,
"family": "Abbaspour Kasgari",
"given": "Hamideh",
"sequence": "first"
},
{
"ORCID": "https://orcid.org/0000-0002-0222-9920",
"affiliation": [
{
"name": "Education Development Center, Mazandaran University of Medical Sciences, Sari, Iran"
}
],
"authenticated-orcid": true,
"family": "Moradi",
"given": "Siavash",
"sequence": "additional"
},
{
"affiliation": [
{
"name": "Antimicrobial Resistance Research Center, Mazandaran University of Medical Sciences, Sari, Iran"
}
],
"family": "Alikhani",
"given": "Ahmad",
"sequence": "additional"
},
{
"ORCID": "https://orcid.org/0000-0002-0404-5949",
"affiliation": [
{
"name": "Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran"
},
{
"name": "Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Sari, Iran"
}
],
"authenticated-orcid": true,
"family": "Ahmadian",
"given": "Nasim",
"sequence": "additional"
}
],
"container-title": "BioImpacts",
"container-title-short": "Bioimpacts",
"content-domain": {
"crossmark-restriction": false,
"domain": [
"bi.tbzmed.ac.ir"
]
},
"created": {
"date-parts": [
[
2024,
8,
19
]
],
"date-time": "2024-08-19T08:22:10Z",
"timestamp": 1724055730000
},
"deposited": {
"date-parts": [
[
2024,
8,
19
]
],
"date-time": "2024-08-19T08:22:12Z",
"timestamp": 1724055732000
},
"indexed": {
"date-parts": [
[
2025,
2,
21
]
],
"date-time": "2025-02-21T21:45:57Z",
"timestamp": 1740174357604,
"version": "3.37.3"
},
"is-referenced-by-count": 0,
"issued": {
"date-parts": [
[
2024,
6,
26
]
]
},
"language": "en",
"link": [
{
"URL": "https://bi.tbzmed.ac.ir/Inpress/bi-29952.pdf",
"content-type": "application/pdf",
"content-version": "vor",
"intended-application": "text-mining"
},
{
"URL": "https://bi.tbzmed.ac.ir/Inpress/bi-29952.pdf",
"content-type": "unspecified",
"content-version": "vor",
"intended-application": "similarity-checking"
}
],
"member": "20123",
"original-title": [],
"prefix": "10.34172",
"published": {
"date-parts": [
[
2024,
6,
26
]
]
},
"published-online": {
"date-parts": [
[
2024,
6,
26
]
]
},
"publisher": "Maad Rayan Publishing Company",
"reference-count": 0,
"references-count": 0,
"relation": {},
"resource": {
"primary": {
"URL": "https://bi.tbzmed.ac.ir/Inpress/bi-29952"
}
},
"score": 1,
"short-title": [],
"source": "Crossref",
"subject": [],
"subtitle": [],
"title": "Effectiveness of dolutegravir in moderate severity COVID-19 patients: A single-center, randomized, double-blind, placebo-controlled trial",
"type": "journal-article",
"update-policy": "https://doi.org/10.34172/crossmark_policy"
}
