https://doi.org/10.5812/ijhls.107362

What Is Efficacy of Chloroquine/Hydroxychloroquine in Clinical Cure of SARS-CoV-2? Evidence from an Iranian Population

authors:

avatar Kiarash Ghazvini ORCID 1 , 2 , avatar Masoud Keikha ORCID 1 , 2 , 3 , *

Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Microbiology and Virology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
International Journal of Health and Life Sciences: Vol.7, issue 1; e107362
published online: October 11, 2020
article type: Letter
received: July 11, 2020
revised: September 12, 2020
accepted: September 29, 2020

how to cite: Ghazvini K, Keikha M. What Is Efficacy of Chloroquine/Hydroxychloroquine in Clinical Cure of SARS-CoV-2? Evidence from an Iranian Population. J Health Rep Technol. 2021;7(1):e107362. https://doi.org/10.5812/ijhls.107362.

Dear Editor,

Novel coronavirus which is known as sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerged in December 2019 from Wuhan, Hubei Province, China for the first time. The SARS-Cov 2 (The coronavirus disease 2019) is etiological cause of a viral sever pneumonia (1); however, The WHO is announced this disease as pandemic in 11th March 2020, due to its quickly spread and increasing number of COVID-19 patients throughout the worldwide (2, 3). There is an increasing number of people death related to COVID-19 which can be result from limitation in the efficient therapeutic options against COVID-19 (4). Introduction of efficient and safe therapeutic agents for COVID-19 is considered as one of the major global concern in this regard (5, 6). There is numerous treatment option for COVID-19 which are including teicoplanin, chloroquine/hydroxychloroquine, remdesivir, lopinavir/ritonavir, oseltamivir, umifenovir, ribavirin, favipiravir, IFN‐alpha, mycophenolic acid, corticosteroids, as well as, angiotensin‐converting enzyme 2 gene‐based peptides; although, there is remains a question that what is therapeutic agents has more virological and clinical efficacy without serious side-effects?? (7, 8).

The lopinavir/ritonavir was introduced as the first-line treatment of COVID-19; However, Cao et al. (9) were found that there are no beneficial findings for treatment of adults hospitalized with severe COVID‐19 with lopinavir/ritonavir regimens. In recently days, chloroquine (CQ) has introduced as potential option which can inhibits SARS-CoV 2 in vitro; Wang et al. (10), were showed that CQ has inhibitory effects against SARS‐CoV‐2 infected Vero‐E6 cell lines with EC50 = 1.13 µM concentration. Moreover, there are several documents about effects of CQ on increase of endosomal pH, dysregulation of glycosylation of angiotensin‐converting enzyme 2 (ACE2) receptors, reduction of pro-inflammatory cytokines, as well as, prohibition of cytokine storm initiation via increase of T regulatory subset (11-14). CQ is low-cost antimicrobial agents which is approved for prophylaxis of malaria, amebiasis and treatment of autoimmune diseases e.g. rheumatoid arthritis, systemic lupus erythematous, and, type 2 diabetes (7, 15, 16). Huang et al were conducted a randomized clinical trial in relation to efficacy of Chloroquine in treatment of 10 adult-cases with COVID-19; they are suggested that chloroquine has more beneficial effect compared to lopinavir‐ritonavir combination therapy (17). there are numerous clinical trials which conducted for evaluation of clinical efficacy of chloroquine as therapeutic agent against COVID-19 (7, 15). However, there is major concern about toxicity profile of chloroquine (18). Hydroxychloroquine (HCQ) is less-toxic CQ-derivative option which is emerged as therapeutic agent for SARS-CoV 2 by Yao et al. (19) (EC50 = 0.72µM against SARS‐CoV infected Vero cells); it has been estimated that loading dose of HCQ 400 mg BD is reliable for SARS‐CoV‐2 (Figure 1).

The proposed inhibitory strategies of chloroquine/hydroxychloroquine against SARS-CoV 2
The proposed inhibitory strategies of chloroquine/hydroxychloroquine against SARS-CoV 2
Figure 1.

The proposed inhibitory strategies of chloroquine/hydroxychloroquine against SARS-CoV 2

Iran, is developing countries which is located in Middle-East region, according to Iranian Ministry of health reports, there are more than 222,669 COVID-19 patients and 10,508 related-death. According to review of the literatures, Chloroquine is introduced as the first-line treatment of COVID-19 for Iranian patients (20). There is limited documents about efficacy of chloroquine in this country; the aim of present study was evaluating the clinical cure of chloroquine in an Iranian population.

We performed a computer-assisted literature search up to June 2020 to obtain total of available documents about efficacy of chloroquine in Iranian COVID-19 patients using search in several databases including PubMed, Scopus, Google Scholar, Cochrane, Embase, medRxiv, bioRxiv, Science Direct, CNKI, SID, IranMedex, Magiran, and, ISC by keywords according to MeSH keywords which consisting “COVID‐19”, “SARS-CoV 2”, “coronavirus disease 2019”, “chloroquine”, “hydroxychloroquine” and “Plaquenil”. We considered all available documents that published in both of English and Persian languages. The clinical efficacy and adverse event of chloroquine treatment in Iranian COVID-19 patients were assessed by Comprehensive Meta-Analysis (CMA) software version 2.2 (Biostat, Englewood, NJ, USA) using Event rate; heterogeneity were calculated using I2 index and Cochrane Q test (P < 0.05) In addition, the publication bias was also estimated via Beggs and Mazumdar rank and Egger’s regression model.

Overall, 5 articles (total participants = 345) were included in the present analysis (21-25). The majority portion of COVID-19 patients were treated by chloroquine, oseltamivir, and, lopinavir/ritonavir according to Iranian Ministry of health guidelines as well as some minor modifications (20, 24, 26). We estimated that clinical efficacy of chloroquine/hydroxychloroquine supplementation was 72.3% (65.3% - 78.4%); P value: 0.001; Q value: 0.96; I2: 0.00; P value: 0.81; Egger’s P value: 0.165; Begg’s P value: 0.308. whereas, adverse event rate e.g. symptom relapse, readmitted to the hospital, re-infection with SARS-CoV 2 and death was assessed about 32.8% (25.6% - 40.9%); P value: 0.001; Q value: 7.17; I2: 44.23; P value: 0.124; Egger’s P value: 0.45; Begges P value: 0.91. Its seems that chloroquine/hydroxychloroquine combination has beneficial results against SARS-CoV 2 among Iranian-COVID-19 patients; although we showed that adverse events of chloroquine/hydroxychloroquine was about 32.8%. But our analysis has several limitations such as (1) limit sample size; (2) low number studies; (3) lack of findings in relation to types of side-effects or reduction virological load, duration of cough, body temperature; and (4) lack of evidence for evaluation of CQ/HCQ efficacy compared with other therapeutically options (control/conventional/standard group). But efficacy of therapeutic options against COVID-19 should be monitored regularly to better patient management and increase of patient survival and prevention of mortality caused by SARS-CoV 2. It necessary to preform further investigation with more sample size.

Chloroquine has been emerged as treatment option of SARS-CoV 2 in several region of the world (15). The Taiwan CDC was announced that hydroxychloroquine is considered as therapeutically options against COVID-19 except in treatment of patients with allergy to HCQ and pregnant or breastfeeding females (15, 27). Moreover, Singh et al. (16), has been proposed that chloroquine/hydroxychloroquine is approved for COVID-19 in India. Recently, Iranian ministry of health was declaring chloroquine as low-cost antimicrobial drugs as the first-line of treatment of SARS-CoV 2 (26). Sarma et al. (28), were performed a meta-analysis to determine the efficacy of Hydroxychloroquine in virological and clinical cure of patients with COVID-19; they are showed that HCQ has preventive effects on radiological progression of lung disease and efficacy and safety of HCQ + azithromycin against COVID-19; however, Sarma et al. (28), were reported that HCQ have no effect on reduction of virological load. Shamshirian et al. (29), in recent meta-analysis were founded that controversial results, they are declared HCQ treatment with/without azithromycin for COVID-19 patients were not clinical benefits and associate with higher mortality rate (29). In General, there are limit documents in relation to evaluation of chloroquine/hydroxychloroquine efficacy in COVID-19; numerous registered clinical trials have not been completed and making conclusion about recommendation or rejection of chloroquine/hydroxychloroquine against COVID-19 is need to preform further investigations.

References

  • 1.

    Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;17(5):259-60. [PubMed ID: 32139904]. [PubMed Central ID: PMC7095524]. https://doi.org/10.1038/s41569-020-0360-5.

  • 2.

    Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. https://doi.org/10.1016/s0140-6736(20)30566-3.

  • 3.

    Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020;382(10):929-36. [PubMed ID: 32004427]. [PubMed Central ID: PMC7092802]. https://doi.org/10.1056/NEJMoa2001191.

  • 4.

    Ghaebi M, Osali A, Valizadeh H, Roshangar L, Ahmadi M. Vaccine development and therapeutic design for 2019-nCoV/SARS-CoV-2: Challenges and chances. J Cell Physiol. 2020;235(12):9098-109. [PubMed ID: 32557648]. [PubMed Central ID: PMC7323389]. https://doi.org/10.1002/jcp.29771.

  • 5.

    Hu TY, Frieman M, Wolfram J. Insights from nanomedicine into chloroquine efficacy against COVID-19. Nat Nanotechnol. 2020;15(4):247-9. [PubMed ID: 32203437]. [PubMed Central ID: PMC7094976]. https://doi.org/10.1038/s41565-020-0674-9.

  • 6.

    Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol. 2020;20(5):269-70. [PubMed ID: 32273594]. [PubMed Central ID: PMC7143200]. https://doi.org/10.1038/s41577-020-0308-3.

  • 7.

    Yousefi B, Valizadeh S, Ghaffari H, Vahedi A, Karbalaei M, Eslami M. A global treatments for coronaviruses including COVID-19. J Cell Physiol. 2020;235(12):9133-42. [PubMed ID: 32394467]. [PubMed Central ID: PMC7273044]. https://doi.org/10.1002/jcp.29785.

  • 8.

    Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60. [PubMed ID: 32147628]. https://doi.org/10.5582/ddt.2020.01012.

  • 9.

    Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-99. [PubMed ID: 32187464]. [PubMed Central ID: PMC7121492]. https://doi.org/10.1056/NEJMoa2001282.

  • 10.

    Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-71. [PubMed ID: 32020029]. [PubMed Central ID: PMC7054408]. https://doi.org/10.1038/s41422-020-0282-0.

  • 11.

    Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, et al. Drug targets for corona virus: A systematic review. Indian J Pharmacol. 2020;52(1):56-65. [PubMed ID: 32201449]. [PubMed Central ID: PMC7074424]. https://doi.org/10.4103/ijp.IJP_115_20.

  • 12.

    Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005;2(1):1.

  • 13.

    Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Res. 2020;177:104762. [PubMed ID: 32147496]. [PubMed Central ID: PMC7132364]. https://doi.org/10.1016/j.antiviral.2020.104762.

  • 14.

    Thome R, Moraes AS, Bombeiro AL, Farias Ados S, Francelin C, da Costa TA, et al. Chloroquine treatment enhances regulatory T cells and reduces the severity of experimental autoimmune encephalomyelitis. PLoS One. 2013;8(6). e65913. [PubMed ID: 23799062]. [PubMed Central ID: PMC3683039]. https://doi.org/10.1371/journal.pone.0065913.

  • 15.

    Jean SS, Lee PI, Hsueh PR. Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect. 2020;53(3):436-43. [PubMed ID: 32307245]. [PubMed Central ID: PMC7129535]. https://doi.org/10.1016/j.jmii.2020.03.034.

  • 16.

    Singh AK, Singh A, Shaikh A, Singh R, Misra A. Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes Metab Syndr. 2020;14(3):241-6. [PubMed ID: 32247211]. [PubMed Central ID: PMC7102587]. https://doi.org/10.1016/j.dsx.2020.03.011.

  • 17.

    Huang M, Tang T, Pang P, Li M, Ma R, Lu J, et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol. 2020;12(4):322-5. [PubMed ID: 32236562]. [PubMed Central ID: PMC7232130]. https://doi.org/10.1093/jmcb/mjaa014.

  • 18.

    Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020;57:279-83. [PubMed ID: 32173110]. [PubMed Central ID: PMC7270792]. https://doi.org/10.1016/j.jcrc.2020.03.005.

  • 19.

    Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020;71(15):732-9. [PubMed ID: 32150618]. [PubMed Central ID: PMC7108130]. https://doi.org/10.1093/cid/ciaa237.

  • 20.

    Karimi A, Rafiei Tabatabaei S, Rajabnejad M, Pourmoghaddas Z, Rahimi H, Armin S, et al. An Algorithmic Approach to Diagnosis and Treatment of Coronavirus Disease 2019 (COVID-19) in Children: Iranian Expert’s Consensus Statement. Arch Pediatr Infect Dis. 2020;8(2). https://doi.org/10.5812/pedinfect.102400.

  • 21.

    Ashraf MA, Shokouhi N, Shirali E, Davari-tanha F, Memar O, Kamalipour A, et al. COVID-19 in Iran, a comprehensive investigation from exposure to treatment outcomes. medRxiv. 2020. https://doi.org/10.21203/rs.3.rs-26339/v1.

  • 22.

    Eghbali A, Shokrollahi S, Mahdavi NS, Mahdavi SA, Dabbagh A. COVID-19 in pediatric patients: A case series. J Cell Mol Anesth. 2020;5(1):3-5.

  • 23.

    Azarkish M, Laleh Far V, Eslami M, Mollazadeh R. Transient complete heart block in a patient with critical COVID-19. Eur Heart J. 2020;41(22):2131. [PubMed ID: 32285920]. [PubMed Central ID: PMC7184360]. https://doi.org/10.1093/eurheartj/ehaa307.

  • 24.

    Jamaati H, Dastan F, Tabarsi P, Marjani M, Saffaei A, Hashemian S. A Fourteen-day Experience with Coronavirus Disease 2019 (COVID-19) Induced Acute Respiratory Distress Syndrome (ARDS): An Iranian Treatment Protocol. Iran J Pharm Res. 2020;19(1):31-6.

  • 25.

    Rahimzadeh G, Ekrami Noghabi M, Kadkhodaei Elyaderani F, Navaeifar MR, Enayati AA, Manafi Anari A, et al. COVID-19 Infection in Iranian Children: A Case Series of 9 Patients. J Pediatr Rev. 2020:139-44. https://doi.org/10.32598/jpr.8.2.139.

  • 26.

    Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (COVID-19): chloroquine or hydroxychloroquine. Int J Antimicrob Agents. 2020;55(4):105945. [PubMed ID: 32194152]. [PubMed Central ID: PMC7156117]. https://doi.org/10.1016/j.ijantimicag.2020.105945.

  • 27.

    Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020;56(1):105949. [PubMed ID: 32205204]. [PubMed Central ID: PMC7102549]. https://doi.org/10.1016/j.ijantimicag.2020.105949.

  • 28.

    Sarma P, Kaur H, Kumar H, Mahendru D, Avti P, Bhattacharyya A, et al. Virological and clinical cure in COVID-19 patients treated with hydroxychloroquine: A systematic review and meta-analysis. J Med Virol. 2020;92(7):776-85. [PubMed ID: 32297988]. [PubMed Central ID: PMC7262144]. https://doi.org/10.1002/jmv.25898.

  • 29.

    Shamshirian A, Hessami A, Heydari K, Alizadeh-Navaei R, Ebrahimzadeh MA, George WY, et al. Hydroxychloroquine Versus COVID-19: A Periodic Systematic Review and Meta-Analysis. MedRxiv. 2020.