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Does hydroxychloroquine combat COVID-19? A timeline of evidence

Published:April 10, 2020DOI:https://doi.org/10.1016/j.jaad.2020.04.031
      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.
      • Wang M.
      • Cao R.
      • Zhang L.
      • et al.
      Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
      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.
      Audio 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.
      ,
      • Gao J.
      • Tian Z.
      • Yang X.
      Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
      This prompted multiple clinical trials in China (9 as of April 3, 2020). Gao et al
      • Gao J.
      • Tian Z.
      • Yang X.
      Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
      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.
      • Biot C.
      • Daher W.
      • Chavain N.
      • et al.
      Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.
      Yao et al
      • Yao 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).
      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.
      • Liu J.
      • Cao R.
      • Xu M.
      • et al.
      Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro.
      As the epicenter of COVID-19 shifted from China to Europe, Colson et al
      • Colson P.
      • Rolain J.M.
      • Raoult D.
      Chloroquine for the 2019 novel coronavirus SARS-CoV-2.
      ,
      • Colson P.
      • Rolain J.M.
      • Lagier J.C.
      • Brouqui P.
      • Raoult D.
      Chloroquine and hydroxychloroquine as available weapons to fight COVID-19.
      recommended use of HCQ as a possible prophylaxis and curative treatment for COVID-19.
      Gautret et al
      • Gautret 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.
      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.
      • Mahase E.
      Covid-19: six million doses of hydroxychloroquine donated to US despite lack of evidence.
      ,
      • Kim 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.
      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.
      • Chen Z.
      • Hu J.
      • Zhang Z.
      • et al.
      Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.
      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).
      • Chen Z.
      • Hu J.
      • Zhang Z.
      • et al.
      Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.
      Table ISummary of the findings on the first randomized trial using hydroxychloroquine against COVID-19
      • Chen Z.
      • Hu J.
      • Zhang Z.
      • et al.
      Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial.
      End pointsTreatment armControl arm
      Body temperature recovery time, d
      Results are statistically significant.
      2.23.2
      Cough remission, d
      Results are statistically significant.
      23.1
      Chest 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.
      To date, despite enough rationale to justify investigation into the efficacy and safety of HCQ in COVID-19 (Table II),
      • Zhou D.
      • Dai S.M.
      • Tong Q.
      COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.
      ,
      • Devaux 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?.
      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 hydroxychloroquine
      • Zhou D.
      • Dai S.M.
      • Tong Q.
      COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression.
      ,
      • Devaux 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?.
      MechanismEffect
      Halts the glycosylation of ACE2RReduces binding of spike protein of coronavirus to ACE2R on host cell
      Increases the endosomal and lysosomal pHPrevents fusion of the virus with host cells and subsequent replication
      Prevents 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.

      References

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        Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro.
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        Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies.
        Biosci Trends. 2020; 14: 72-73
      2. Chinese 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.

        • Biot C.
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        Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities.
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      Linked Article

      • Risks of hydroxychloroquine use for COVID-19 prophylaxis
        Journal of the American Academy of DermatologyVol. 83Issue 1
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          To 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.
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