Does hydroxychloroquine combat COVID-19? A timeline of evidence
Authors: Erisa Alia, Jane M. Grant-Kels
Journal: Journal of the American Academy of Dermatology (2020)

To the Editor: Chloroquine (CQ) and hydroxychloroquine (HCQ) garnered scientific attention in early February after publication of reports showing in vitro activity of CQ against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19.1Wang M. Cao R. Zhang L. et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.Cell Res. 2020; 30: 269-271Crossref PubMed Scopus (5040) Google Scholar On February 17, 2020, the State Council of China held a news conference indicating that chloroquine (CQ) had demonstrated efficacy in treating COVID-19–associated pneumonia in multicenter, nonrandomized, clinical trials.2Audio transcript of the news briefing held by the State Council of China on February 17, 2020 [in Chinese]. The National Health Commission of the People's Republic of China.http://www.nhc.gov.cn/xcs/yqfkdt/202002/f12a62d10c2a4 8c6895cedf2faea6e1f.shtmlDate accessed: February 18, 2020Google Scholar,3Gao J. Tian Z. Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.Biosci Trends. 2020; 14: 72-73Crossref PubMed Google Scholar This prompted multiple clinical trials in China (9 as of April 3, 2020).4Chinese Clinical Trial Registry (CHICTR). Available at: http://www.chictr.org.cn/searchprojen.aspx?title=hydroxychloroquine&officialname=&subjectid=&secondaryid=&applier=&studyleader=&ethicalcommitteesanction=&sponsor=&studyailment=&studyailmentcode=&studytype=0&studystage=0&studydesign=0&minstudyexecutetime=&maxstudyexecutetime=&recruitmentstatus=0&gender=0&agreetosign=&secsponsor=&regno=&regstatus=1008001&country=&province=&city=&institution=&institutionlevel=&measure=&intercode=&sourceofspends=&createyear=0&isuploadrf=&whetherpublic=&btngo=btn&verifycode=&page=1. Accessed April 3, 2020.Google Scholar Gao et al3Gao J. Tian Z. Yang X. Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.Biosci Trends. 2020; 14: 72-73Crossref PubMed Google Scholar treated >100 patients with CQ, reporting control in inhibiting the exacerbation of pneumonia, improved lung imaging findings, and shortened disease course, but detailed data underlying the claims have not yet been published. Hydroxychloroquine (HCQ), an analogue of CQ with fewer side effects, better safety profile, and less drug interactions, showed in vitro antiviral activity against SARS-CoV in the previous SARS outbreak.5Biot C. Daher W. Chavain N. et al.Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.J Med Chem. 2006; 49: 2845-2849Crossref PubMed Scopus (257) Google Scholar Yao et al6Yao X. Ye F. Zhang M. 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; ([Epub ahead of print])https://doi.org/10.1093/cid/ciaa237Crossref Scopus (1958) Google Scholar compared the in vitro anti–SARS-CoV-2 activity of both drugs, finding HCQ superior to CQ and recommending HCQ sulfate 400 mg twice daily on day 1, followed by 200 mg twice daily for the next 4 days to treat COVID-19. Similar in vitro results were reported by the Wuhan Institute of Virology.7Liu J. Cao R. Xu M. et al.Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.Cell Discov. 2020; 6: 16Crossref PubMed Scopus (1498) Google Scholar As the epicenter of COVID-19 shifted from China to Europe, Colson et al8Colson P. Rolain J.M. Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV-2.Int J Antimicrob Agents. 2020; 55: 105923Crossref PubMed Scopus (322) Google Scholar,9Colson P. Rolain J.M. Lagier J.C. Brouqui P. Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19.Int J Antimicrob Agents. 2020; ([Epub ahead of print])https://doi.org/10.1016/j.ijantimicag.2020.105932Crossref Scopus (662) Google Scholar recommended use of HCQ as a possible prophylaxis and curative treatment for COVID-19. Gautret et al10Gautret P. Lagier J.C. Parola P. 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; ([Epub ahead of print])https://doi.org/10.1016/j.ijantimicag.2020.105949Crossref PubMed Scopus (3763) Google Scholar were the first to report promising in vivo data of HCQ in a nonrandomized clinical trial. They used 200 mg of HCQ 3 times a day for 10 days, plus azithromycin if deemed necessary. A higher frequency of SARS-CoV-2 clearance was noticed after 6 days of treatment with HCQ alone or HCQ plus azithromycin vs the untreated control group (70% vs 12.5%; P < .001). Azithromycin added to HCQ was significantly more efficient for virus elimination. These findings were rapidly disseminated by the lay press and social media, leading to endorsement of HCQ by many government and institutional leaders, including President Trump, who referred to this as a "game changer." The demand for HCQ increased exponentially, leading to an overall shortage and making prescription refills challenging.11Mahase E. Covid-19: six million doses of hydroxychloroquine donated to US despite lack of evidence.BMJ. 2020; 368: m1166Crossref PubMed Scopus (32) Google Scholar,12Kim A.H.J. Sparks J.A. Liew J.W. et al.A rush to judgment? Rapid reporting and dissemination of results and its consequences regarding the use of hydroxychloroquine for COVID-19.Ann Intern Med. 2020; ([Epub ahead of print])https://doi.org/10.7326/M20-1223Crossref Scopus (164) Google Scholar On March 31, 2020, medRxiv.org published data of the first completed randomized clinical trial in Wuhan investigating the efficacy of HCQ in patients with COVID-19.13Chen Z. Hu J. Zhang Z. et al.Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.https://doi.org/10.1101/2020.03.22.20040758Date accessed: April 3, 2020Google Scholar The trial randomized 62 patients equally into 2 groups. The treatment group received oral HCQ 400 mg/d (200 mg twice daily) from day 1 to 5. Their article, currently under revision, reported a significant difference in the time to clinical recovery and radiologic findings between the groups (Table I).13Chen Z. Hu J. Zhang Z. et al.Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.https://doi.org/10.1101/2020.03.22.20040758Date accessed: April 3, 2020Google ScholarTable ISummary of the findings on the first randomized trial using hydroxychloroquine against COVID-1913Chen Z. Hu J. Zhang Z. et al.Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.https://doi.org/10.1101/2020.03.22.20040758Date accessed: April 3, 2020Google ScholarEnd pointsTreatment armControl armBody temperature recovery time, d∗Results are statistically significant.2.23.2Cough remission, d∗Results are statistically significant.23.1Chest computed tomography results improvement, %∗Results are statistically significant.,†Comparing results on day 0 and day 6.80.654.8∗ Results are statistically significant.† Comparing results on day 0 and day 6. Open table in a new tab To date, despite enough rationale to justify investigation into the efficacy and safety of HCQ in COVID-19 (Table II),14Zhou D. Dai S.M. Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.J Antimicrob Chemother. 2020; ([Epub ahead of print])https://doi.org/10.1093/jac/dkaa114Crossref Scopus (420) Google Scholar,15Devaux C.A. Rolain J.M. Colson P. Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?.Int J Antimicrob Agents. 2020; ([Epub ahead of print])https://doi.org/10.1016/j.ijantimicag.2020.105938Crossref Scopus (801) Google Scholar the evidence regarding its effect remains limited. HCQ has not yet received United States Food and Drug Administration approval for use against COVID-19, and further trials are needed to establish guidelines. If emerging data from ongoing trials establishes the efficacy of HCQ for prophylaxis and treatment of COVID-19, triage will be important to ensure that existing supplies are used appropriately.Table IISummary of the antiviral mechanism of action of chloroquine and hydroxychloroquine14Zhou D. Dai S.M. Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.J Antimicrob Chemother. 2020; ([Epub ahead of print])https://doi.org/10.1093/jac/dkaa114Crossref Scopus (420) Google Scholar,15Devaux C.A. Rolain J.M. Colson P. Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?.Int J Antimicrob Agents. 2020; ([Epub ahead of print])https://doi.org/10.1016/j.ijantimicag.2020.105938Crossref Scopus (801) Google ScholarMechanismEffectHalts the glycosylation of ACE2RReduces binding of spike protein of coronavirus to ACE2R on host cellIncreases the endosomal and lysosomal pHPrevents fusion of the virus with host cells and subsequent replicationPrevents antigen processing and MHC-II–mediated autoantigen presentation to T cellsReduces T-cell activation and expression of CD154 and other cytokines (IL-1, IL-6 and TNF-α)Disrupts the interaction of cytosolic viral DNA/RNA with TLRs and the nucleic acid sensor cGAS∗Hydroxychloroquine only.Halts transcription of proinflammatory genes attenuating the possibility of cytokine storm (type I interferons, IL-1, TNF-α)ACE2R, Angiotensin-converting enzyme 2 receptor; cGAS, cyclic guanosine monophosphate- adenosine monophosphate synthase; IL, interleukin; MHC, major histocompatibility complex; TLR, Toll-like receptor; TNF, tumor necrosis factor.∗ Hydroxychloroquine only. Open table in a new tab ACE2R, Angiotensin-converting enzyme 2 receptor; cGAS, cyclic guanosine monophosphate- adenosine monophosphate synthase; IL, interleukin; MHC, major histocompatibility complex; TLR, Toll-like receptor; TNF, tumor necrosis factor. Risks of hydroxychloroquine use for COVID-19 prophylaxisJournal of the American Academy of DermatologyVol. 83Issue 1PreviewTo the Editor: We were very pleased to read the article by Alia et al,1 "Does hydroxychloroquine combat COVID-19? A timeline of evidence." After thoroughly summarizing the literature studies on the efficacy and safety of hydroxychloroquine (HCQ), they rightly concluded that there is currently no robust evidence to support prescribing HCQ as a treatment or prophylaxis for COVID-19. As they mentioned, the United States President Donald Trump tweeted on March 21, 2020, that HCQ and azithromycin "taken together, have a real chance to be one of the biggest game changers in the history of medicine" and further urged that these drugs "be put in use IMMEDIATELY. Full-Text PDF