tag:theconversation.com,2011:/us/topics/chloroquine-84429/articlesChloroquine – The Conversation2021-12-10T05:46:41Ztag:theconversation.com,2011:article/1727002021-12-10T05:46:41Z2021-12-10T05:46:41ZThe warning lights are on for malaria medicines in Africa<figure><img src="https://images.theconversation.com/files/436076/original/file-20211207-136652-kzthjf.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Medicines, insecticides and nets may deliver short-term anti-malaria goals.
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p><em>Reports of sporadic resistance to modern malaria drugs have begun appearing in recent years, and are now confirmed in <a href="https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00142-0/fulltext">Rwanda</a> and <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2101746">Uganda</a>. The Conversation Africa’s Ina Skosana asked infectious diseases experts Deus Ishengoma and Fredros Okumu to explain this development and what the implications are.</em></p>
<h2>What is drug resistant malaria and how did it come about?</h2>
<p>Resistance occurs when the effectiveness of a drug is reduced and it no longer provides a full cure against the targeted infection. It usually starts with only a few mutated parasites that survive treatments in an area. But it can spread rapidly because these resistant parasites continue to reproduce, while the susceptible ones are killed by the treatments. </p>
<p>For example, <a href="https://www.ncbi.nlm.nih.gov/books/NBK2616/">chloroquine</a> was once considered to be the magic bullet against malaria. But malaria parasites evolved to survive it. The resistance spread in the 1980s and 1990s. It took more than 20 years of gradual failure before African governments and the World Health Organisation (WHO) agreed to change the guidelines and stop using chloroquine.</p>
<p>One reason for this was that the alternative medicines, notably artemisinin combination therapy (ACTs), were way <a href="https://pubmed.ncbi.nlm.nih.gov/16098946/">too expensive and out of reach</a> for most patients in the low-income countries</p>
<p>The other alternative drug at the time, sulfadoxine-pyrimethamine, was also showing <a href="https://academic.oup.com/trstmh/article-abstract/103/Supplement_1/S11/1908160">signs of failure</a>. </p>
<p>The methods for diagnosing malaria were less accurate and not always available back then. So children with fever were commonly treated as if they had malaria. This situation <a href="https://academic.oup.com/trstmh/article-abstract/103/4/333/1917327">required a low-cost</a> and widely available medicine, even if imperfect. </p>
<p>An even bigger problem was the lack of real-time data on the extent, impact and magnitude of drug resistance. The delayed appreciation of drug resistance caused an unnecessarily <a href="https://www.ncbi.nlm.nih.gov/books/NBK2616/">large number</a> of severe malaria cases and preventable deaths across Africa in the late 1990s and early 2000s.</p>
<p>The WHO then recommended the use of artemisinin combination therapy (ACTs). These are cocktails, in which the most important ingredients are derivatives of artemisinin, a plant extract first synthesized in 1972 by the Chinese chemist, Tu Youyou, who later won the <a href="https://www.nobelprize.org/prizes/medicine/2015/tu/facts/">Nobel Prize in Physiology and Medicine in 2015</a>. Because the ACTs are mixtures, it is difficult for malaria parasites to resist them.</p>
<p>Soon after the introduction of ACTs, reports of resistance to artemisinins started to emerge. These were initially in <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa0808859">south-east Asia</a>.</p>
<p>Since 2006, the WHO has been advising countries not to use single drugs (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1463909/">especially any artemisinin drug on its own</a>). Instead, countries should use mostly combination therapies.</p>
<p>Unfortunately, for management of severe malaria, there are still no alternatives, so the recommended options still consist of only one active ingredient instead of mixtures. Examples are <a href="https://www.mmv.org/access/products-projects/injectable-artesunate-treatment-severe-malaria">artesunate injections</a> or the <a href="https://www.mmv.org/access/products-projects/artesunate-rectal-capsules-pre-referral-intervention-children-severe">rectal artesunate</a> capsules recommended for low income remote settings to buy families time and save lives of babies before reaching appropriate care.</p>
<p>These single drug options are the ones most threatened by the emerging resistance to front-line treatments for severe malaria in Africa. Moreover, <a href="https://www.medrxiv.org/content/10.1101/2021.09.24.21263966v1">new evidence</a> now suggests that rectal artesunate capsules may actually not reduce malaria deaths unless the underlying health systems are sufficiently strong. Therefore, new options are even more urgently required here. </p>
<h2>What do recent developments signal?</h2>
<p>In Africa, most malaria-infected people who receive treatment in good time are fully cured and suffer no long-term effects. However, a minority can be unresponsive to standard treatments. Scientists and health practitioners are increasingly concerned that the situation may worsen in the years to come.</p>
<p><a href="https://www.sanger.ac.uk/external_person/djimde-abdoulaye/">Professor Abdoulaye Djimde</a> is the director of the Malaria Research and Training Centre at the University of Bamako in Mali. He was among the experts who first demonstrated (in 2001) how certain genetic changes in malaria parasites were linked to resistance against chloroquine. We <a href="https://www.youtube.com/watch?v=YJQee6MSPTQ">recently asked him</a> about the evidence for resistance to artemisinins in Africa. He thought deeply for moments before stating sadly that “the lights are yellow”. By this he meant that front-line drugs remain largely effective, but the likelihood of widespread failure is growing fast. </p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/YJQee6MSPTQ?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Malaria Meds: a MasterClass with Profs. Timothy Wells, Pierre Hugo, George Jagoe & Abdoulaye Djimde.</span></figcaption>
</figure>
<p>Efforts to develop new medicines have gained momentum, but no new drugs are expected in the market for at least several years. </p>
<p>The good news is that resistance to artemisinins has not spread widely in Africa. A recent <a href="https://www.sciencedirect.com/science/article/pii/S2211320721000282">review</a> by a consortium of African scientists concluded that African malaria parasites already have the genetic changes potentially associated with resistance to artemisinins. But the frequency of these changes is still very low. Surveillance of these genetic elements must be ramped up and performance of drug treatments closely monitored. </p>
<p>It matters because of the scale of the potential problem. There are <a href="https://www.who.int/news-room/fact-sheets/detail/malaria">241 million malaria cases</a> resulting in <a href="https://www.who.int/news-room/fact-sheets/detail/malaria">627,000 deaths</a> annually – even without widespread drug resistance in Africa, where nearly all these deaths occur. </p>
<h2>What needs to happen?</h2>
<p>First, we must recognise the urgency of this situation and develop a plan. In a recent conversation, <a href="https://www.who.int/about/people/biography/pedro-alonso">Prof. Pedro Alonso</a>, the director of the WHO Global Malaria Programme, reminded us that the drug resistance in Africa is emerging independently of the situation in south-east Asia, and we should not wait until complete <a href="https://www.who.int/initiatives/mekong-malaria-elimination-programme">failure</a> emerges in Africa. </p>
<p>Prof. Alonso also recommended the following four measures. </p>
<ul>
<li><p>Accelerate research and development for alternative medicines and other tools to control malaria. </p></li>
<li><p>Maintain healthy markets to attract more manufacturers to produce malaria medicines. </p></li>
<li><p>Continuously improve the quality of care for malaria patients and reduce the use of single medicines also known as monotherapies. </p></li>
<li><p>Enhance surveillance to track drug resistance within and across borders. </p></li>
</ul>
<p>There are <a href="https://www.cdc.gov/malaria/malaria_worldwide/reduction/dx_rdt.html">now low-cost rapid diagnostics</a> for detecting malaria even in rural settings. There are also far better scientific methods for monitoring performance and <a href="https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwip2PDT0af0AhUFp3IEHdh8B6sQFnoECAsQAQ&url=https%3A%2F%2Fapps.who.int%2Firis%2Fhandle%2F10665%2F43914&usg=AOvVaw0Ktmohkc3iTigQk0q2-Hb7">safety of malaria medicines</a>.</p>
<p>More importantly, <a href="https://www.who.int/malaria/mpac/mpac-october2019-session7-report-consultation-on-genomics.pdf">molecular surveillance</a> allows us to detect the resistance signals in circulating malaria parasites long before the medicines begin failing. This way, public health authorities and drug developers can stay ahead of the game, by adjusting treatment guidelines.</p>
<p>One example is a <a href="https://mesamalaria.org/mesa-track/molecular-surveillance-malaria-parasite-populations-and-antimalarial-drug-resistance">programme</a> we recently established in Tanzania to track genetic changes in the circulating malaria parasites and how these parasites respond to current treatments.</p>
<p>Countries must endeavour to prevent as many cases as possible and <a href="https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-risk">limit</a> the likelihood of severe malaria. </p>
<p>The <a href="https://www.who.int/groups/malaria-policy-advisory-group/about">WHO Malaria Policy Advisory Group</a> has emphasised the need to intensify investigations into artemisinin resistance in Africa and urged the <a href="https://www.who.int/teams/global-malaria-programme">Global Malaria Programme</a> to consider what to do if partner drugs become less effective.</p>
<p>Beyond this, we must learn from history and from recent trends. Most importantly, we all need a honest reflection of what it will really take to eliminate malaria. The overriding lesson is that problems such as resistance are merely <a href="https://dash.harvard.edu/bitstream/handle/1/37369526/WG3-1.%20Rethinking%20Malaria%20Control%20and%20Elimination%20in%20Africa_Okumu%20et%20al.pdf?sequence=10&isAllowed=y">symptoms of greater challenges</a>. Medicines, insecticides and nets may deliver short-term anti-malaria goals. But sustainable progress towards elimination requires more <a href="https://www.project-syndicate.org/commentary/malaria-prevention-mosquito-nets-not-enough-by-fredros-okumu-2019-04">holistic approaches</a>.</p><img src="https://counter.theconversation.com/content/172700/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Fredros Okumu is mosquito biologist and public health expert. He is director of science at Ifakara Health Institute in Tanzania, a Senior Fellow of Aspen Institute New Voices Fellow and a World Economic Forum Young Global Leader. <a href="https://twitter.com/Fredros_Inc">https://twitter.com/Fredros_Inc</a>. He is a member of the WHO Malaria Policy Advisory Group and reports having received research funding from the Bill and Melinda Gates Foundation and the Wellcome Trust, among others
</span></em></p><p class="fine-print"><em><span>Dr. Deus S. Ishengoma is Principal Research Scientist at the National Institute for Medical Research (NIMR), Tanzania. He is a public health expert working on genomic surveillance of malaria and on new ways to improve case management.
Dr. Ishengoma receives funding from Bill & Melinda Gates Foundation, the World Health Organization, US President’s Malaria Initiative and the US National Institute of Health.
</span></em></p>Treatments for uncomplicated malaria remain mostly robust. But the arsenal against severe malaria and deaths is rapidly weakening. New options are urgently required.Fredros Okumu, Director of Science, Ifakara Health InstituteDeus Ishengoma, Principal Research Scientist, National Institute for Medical Research (NIMR)Licensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1684492021-10-14T12:15:17Z2021-10-14T12:15:17ZIvermectin is a Nobel Prize-winning wonder drug – but not for COVID-19<figure><img src="https://images.theconversation.com/files/425990/original/file-20211012-15-lephma.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1024%2C680&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">While ivermectin was originally used to treat river blindness, it has also been repurposed to treat other human parasitic infections.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/christophe-koffi-a-nurse-mamadou-kone-gives-medecine-news-photo/83038610">ISSOUF SANOGO/AFP via Getty Images</a></span></figcaption></figure><p>Ivermectin is an over 30-year-old <a href="https://doi.org/10.1038/ja.2017.11">wonder drug</a> that treats life- and sight-threatening parasitic infections. Its lasting influence on global health has been so profound that two of the key researchers in its discovery and development won the <a href="https://www.nobelprize.org/prizes/medicine/2015/summary/">Nobel Prize in 2015</a>.</p>
<p>I’ve been an <a href="https://pharmacy.uconn.edu/person/jeffrey-aeschlimann/">infectious disease pharmacist</a> for over 25 years. I’ve also managed patients who delayed proper treatment for their severe COVID-19 infections because they thought ivermectin could cure them.</p>
<p>Although ivermectin has been a game-changer for people with certain infectious diseases, it isn’t going to save patients from COVID-19 infection. In fact, it could cost them their lives.</p>
<p>Let me tell you a short story about the history of ivermectin. </p>
<h2>Developing ivermectin for animal use</h2>
<p>Ivermectin was first identified in the 1970s during a <a href="https://dx.doi.org/10.2183%2Fpjab.87.13">veterinary drug screening project</a> at Merck Pharmaceuticals. Researchers focused on discovering chemicals that could potentially treat parasitic infections in animals. Common parasites include nematodes, such as flatworms and roundworms, and arthropods, such as fleas and lice. All of these infectious organisms are quite different from viruses. </p>
<p>Merck partnered with the Kitasato Institute, a medical research facility in Japan. Satoshi Omura and his team isolated a group of chemicals called avermectin from bacteria found in a <a href="https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/ivermectin-mectizan.html">single soil sample near a Japanese golf course</a>. To my knowledge, avermectin has yet to be found in any other soil sample in the world.</p>
<p>Research on avermectin continued for approximately five years. Soon, Merck and the Kitasato Institute developed a <a href="https://web.stanford.edu/group/parasites/ParaSites2005/Ivermectin/History.htm">less toxic form</a> they named ivermectin. It was approved in 1981 for commercial use in veterinary medicine for <a href="https://doi.org/10.1016/j.pt.2017.02.004">parasitic infections in livestock and domestic pets</a> with the brand name Ivomec.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Hand holding a blister packet of ivermectin." src="https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=390&fit=crop&dpr=1 600w, https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=390&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=390&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=490&fit=crop&dpr=1 754w, https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=490&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/426002/original/file-20211012-19-kpglc8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=490&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The chemical compounds that make up ivermectin were first discovered in bacteria found in the soil of a Japanese golf course.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/communityeyehealth/5637492224">Pak Sang Lee/flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span>
</figcaption>
</figure>
<h2>Developing ivermectin for human use</h2>
<p><a href="https://doi.org/10.1002/anie.201601492">Early experiments</a> by William Campbell and his team from Merck discovered that the drug also worked against a human parasite that causes an infection called river blindness.</p>
<p><a href="https://www.cdc.gov/dpdx/onchocerciasis/index.html">River blindness, also known as onchocerciasis</a>, is the <a href="https://www.neglecteddiseases.gov/usaid-targeted-diseases/onchocerciasis/">second leading cause</a> of preventable blindness in the world. It is transmitted to humans from blackflies carrying the parasitic worm <em>Onchocerca volvulus</em> and occurs predominantly in Africa. </p>
<p>Ivermectin underwent trials to treat river blindness in 1982 and was approved in 1987. It has since been <a href="https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/ivermectin-mectizan.html">distributed free of charge</a> through the Mectizan Donation Program to dozens of countries. Thanks to ivermectin, river blindness has been <a href="https://www.paho.org/en/topics/onchocerciasis-river-blindness">essentially eliminated in 11 Latin American countries</a>, preventing approximately <a href="https://doi.org/10.1371/journal.pmed.0030371">600,000 cases of blindness</a>.</p>
<p>These two decades of extensive work to discover, develop and distribute ivermectin helped to significantly reduce human suffering from river blindness. It’s these efforts that were recognized by the <a href="https://www.nobelprize.org/prizes/medicine/2015/summary/">2015 Nobel Prize in Physiology or Medicine</a>, awarded to both William Campbell and Satoshi Omura for their leadership on this groundbreaking research.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Satoshi Omura and William Campbell." src="https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=469&fit=crop&dpr=1 600w, https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=469&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=469&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=590&fit=crop&dpr=1 754w, https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=590&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/425821/original/file-20211011-19-11vhjl4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=590&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Satoshi Omura and William Campbell were awarded the 2015 Nobel Prize in Physiology or Medicine for their research on ivermectin.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:Satoshi_%C5%8Cmura_5107-2015.jpg">Bengt Nyman/Wikimedia Commons</a></span>
</figcaption>
</figure>
<h2>Repurposing drugs for other uses</h2>
<p>Infectious disease researchers frequently attempt to <a href="https://doi.org/10.1038/s41564-019-0357-1">repurpose antimicrobials and other medications</a> to treat infections. Drug repurposing is attractive because the approval process can happen more quickly and at a lower cost since nearly all of the basic research has already been completed.</p>
<p>In the years since it was approved to treat river blindness, ivermectin was also shown to be highly effective against other parasitic infections. This includes <a href="https://www.cdc.gov/dpdx/strongyloidiasis/index.html">strongyloidiasis</a>, an intestinal roundworm infection that affects an estimated <a href="https://www.cdc.gov/dpdx/strongyloidiasis/index.html">30 to 100 million people worldwide</a>.</p>
<p>Another example is amphotericin B, originally approved to treat human <a href="https://doi.org/10.1007/s40121-020-00382-7">yeast and mold infections</a>. Researchers discovered it can also be an effective treatment for severe forms of <a href="https://www.cdc.gov/parasites/leishmaniasis/health_professionals/index.html">leishmaniasis</a>, a parasitic infection prevalent in tropical and subtropical countries. </p>
<p>Likewise, doxycycline is an antibiotic used for a wide variety of human bacterial infections such as <a href="https://doi.org/10.1097/00007691-198206000-00001">pneumonia and Lyme disease</a>. It was later found to also be <a href="https://dx.doi.org/10.4269%2Fajtmh.2011.10-0285">highly effective</a> in preventing and treating <a href="https://www.cdc.gov/malaria/travelers/drugs.html">malaria</a>.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Microscopic image of strongyloides stercoralis in human stool" src="https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/425988/original/file-20211012-23-12ftlpa.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Ivermectin has been used to treat strongyloidiasis, an intestinal infection that can be life-threatening for the immunocompromised.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/strongyloides-stercoralis-or-threadworm-in-human-royalty-free-image/1186707060">jarun011/iStock via Getty Images Plus</a></span>
</figcaption>
</figure>
<h2>Repurposing drugs for COVID-19</h2>
<p>Not every attempt at repurposing a drug works as hoped, however.</p>
<p>At the start of the pandemic, scientists and doctors tried to find <a href="https://theconversation.com/we-found-and-tested-47-old-drugs-that-might-treat-the-coronavirus-results-show-promising-leads-and-a-whole-new-way-to-fight-covid-19-136789">inexpensive medications to repurpose</a> for the treatment and prevention of COVID-19. Chloroquine and hydroxychloroquine were two of those drugs. They were chosen because of possible antiviral effects documented in <a href="https://doi.org/10.1038/s41422-020-0282-0">laboratory studies</a> and limited <a href="https://doi.org/10.5582/bst.2020.01047">anecdotal case reports</a> from the first COVID-19 outbreaks in China. However, <a href="https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/chloroquine-or-hydroxychloroquine-and-or-azithromycin/clinical-data/">large clinical studies</a> of these drugs to treat COVID-19 did not translate to any meaningful benefits. This was partly due to the <a href="https://doi.org/10.1001/jamacardio.2020.1834">serious toxic effects</a> patients experienced before the drugs reached a high enough dose to inhibit or kill the virus.</p>
<p>Unfortunately, <a href="https://doi.org/10.1038/d41586-020-01165-3">lessons from these failed attempts</a> have not been applied to ivermectin. The false hope around using ivermectin to treat COVID-19 originated from an <a href="https://doi.org/10.1016/j.antiviral.2020.104787">April 2020 laboratory study</a> in Australia. Although the results from this study were <a href="https://www.bbc.com/news/health-58170809">widely circulated</a>, <a href="https://twitter.com/AeschlimannJeff/status/1246837139687514112">I immediately had serious doubts</a>. The concentration of ivermectin they tested was 20 to 2,000 times higher than the standard dosages used to treat human parasitic infections. Indeed, many other pharmaceutical experts <a href="https://doi.org/10.1111/bcp.14476">confirmed</a> my <a href="https://doi.org/10.1080/13102818.2020.1775118">initial</a> <a href="https://dx.doi.org/10.1016%2Fj.antiviral.2020.104805">concerns</a> within a month of the paper’s publication. Such high concentrations of the drug could be significantly toxic.</p>
<p>Another commonly cited paper on ivermectin’s purported effects against COVID-19 was <a href="https://doi.org/10.21203/rs.3.rs-100956/v4">withdrawn in July 2021</a> after scientists <a href="https://doi.org/10.1038/d41586-021-02081-w">found serious flaws</a> with the study. These flaws ranged from incorrect statistical analyses to discrepancies between collected data and published results to duplicated patient records and the inclusion of study subjects who died before even entering the study. Even more concerning, <a href="https://gidmk.medium.com/is-ivermectin-for-covid-19-based-on-fraudulent-research-part-2-a4475523b4e4">at least two</a> other <a href="https://gidmk.medium.com/is-ivermectin-for-covid-19-based-on-fraudulent-research-part-3-5066aa6819b3">oft-cited studies</a> have raised significant concerns about <a href="https://kylesheldrick.blogspot.com/2021/08/data-from-cadegiani-et-al-contains.html">scientific fraud</a>.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1422135837416849409"}"></div></p>
<p>At the time of this writing, two <a href="http://doi.org/10.1001/jama.2021.3071">large randomized</a> <a href="https://doi.org/10.1186/s12879-021-06348-5">clinical trials</a> both showed no significant benefit from the use of ivermectin for COVID-19. Reputable national and international health care organizations, including the <a href="https://www.who.int/news-room/feature-stories/detail/who-advises-that-ivermectin-only-be-used-to-treat-covid-19-within-clinical-trials">World Health Organization</a>, the <a href="https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19">Centers for Disease Control and Prevention</a>, the <a href="https://www.covid19treatmentguidelines.nih.gov/therapies/antiviral-therapy/ivermectin/">National Institutes of Health</a>, the <a href="https://www.fda.gov/consumers/consumer-updates/why-you-should-not-use-ivermectin-treat-or-prevent-covid-19">Food and Drug Administration</a> and the <a href="https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/">Infectious Diseases Society of America</a>, unanimously recommend against the use of ivermectin to prevent or treat COVID-19 unless in the context of a clinical trial.</p>
<h2>Consequences of using ivermectin for COVID-19</h2>
<p>Unfortunately, many <a href="https://time.com/6092368/americas-frontline-doctors-covid-19-misinformation/">organizations with dubious intentions</a> have continued to promote unsubstantiated use of invermectin for COVID-19. This has led to a dramatic rise in <a href="https://emergency.cdc.gov/han/2021/han00449.asp">ivermectin prescriptions</a> and a <a href="https://emergency.cdc.gov/han/2021/han00449.asp">flood of calls</a> to U.S. poison control centers for <a href="https://www.dshs.texas.gov/HealthAdvisory-20210826.aspx">ivermectin overdoses</a>. Many calls were due to ingestion of large amounts of veterinary products containing ivermectin – two <a href="https://www.kiro7.com/news/trending/coronavirus-2-deaths-linked-ivermectin-new-mexico-officials-say/5SZ55BRSFRDGTLJZ7ODKGZP6XI/">deaths linked to ivermectin overdose</a> were reported in September 2021.</p>
<p>Ivermectin, when used correctly, has prevented millions of potentially fatal and debilitating infectious diseases. It’s meant to be prescribed only to treat infections caused by parasites. It’s not meant to be prescribed by parasites looking to <a href="https://theintercept.com/2021/09/28/covid-telehealth-hydroxychloroquine-ivermectin-hacked/">extract money</a> from <a href="https://www.businessinsider.com/americas-frontline-doctors-sells-disproven-covid-drugs-2021-9">desperate people</a> during a pandemic. It’s my sincere hope that this unfortunate and tragic chapter in the otherwise incredible story of a lifesaving medication will come to a quick end.</p>
<p><em>Article updated to indicate that the brand name for veterinary ivermectin is Ivomec</em></p>
<p>[<em>Like what you’ve read? Want more?</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=likethis">Sign up for The Conversation’s daily newsletter</a>.]</p><img src="https://counter.theconversation.com/content/168449/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jeffrey R. Aeschlimann has received funding from the NIH for collaborative research projects focusing on bacterial antibiotic resistance. </span></em></p>Ivermectin has been a lifesaving drug for people with parasitic infections like river blindness and strongyloidiasis. But taking it for COVID-19 may result in the opposite effect.Jeffrey R. Aeschlimann, Associate Professor of Pharmacy, University of ConnecticutLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1432342020-07-23T18:29:07Z2020-07-23T18:29:07ZWhy hydroxychloroquine and chloroquine don’t block coronavirus infection of human lung cells<figure><img src="https://images.theconversation.com/files/348997/original/file-20200722-24-1448fpn.jpg?ixlib=rb-1.1.0&rect=0%2C25%2C4168%2C2735&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chloroquine is an antimalarial drug originally developed in 1934; it doesn't block coronavirus infection in humans. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/chloroquine-medicine-pills-royalty-free-image/1215181871?adppopup=true">Brasil2 / Getty Images</a></span></figcaption></figure><p><em>The Research Brief is a short take about interesting academic work.</em> </p>
<h2>The big idea</h2>
<p><a href="https://doi.org/10.1038/s41586-020-2575-3">A paper came out in Nature</a> on July 22 that further underscores earlier studies that show that neither the malaria drug hydroxychloroquine nor chloroquine prevents SARS-CoV-2 – the virus that causes COVID-19 – from replicating in lung cells. </p>
<p>Most Americans probably remember that hydroxychloroquine became the focus of numerous clinical trials following the president’s statement that <a href="https://www.nytimes.com/2020/03/19/health/coronavirus-drugs-chloroquine.html">it could be a “game changer.”</a> At the time, he appeared to base this statement on anecdotal stories, as well as <a href="https://theconversation.com/hydroxychloroquine-for-covid-19-a-new-review-of-several-studies-shows-flaws-in-research-and-no-benefit-137869">a few early and very limited studies</a> that hydroxychloroquine seemed to help patients with COVID-19 recover.</p>
<p>Many in the antiviral field, including <a href="https://chemistry.umbc.edu/seley-radtke-lab/">myself</a>, questioned the validity of both, and in fact, one of the papers was later <a href="https://www.the-scientist.com/news-opinion/journal-publisher-concerned-over-hydroxychloroquine-study-67405">disparaged by the scientific society and the editor of the journal</a> that published it.</p>
<p>Since then, HQC has had a bumpy ride. It was <a href="https://www.buzzfeednews.com/article/zahrahirji/fda-eua-hydroxychloroquine-chloroquine">initially approved by the FDA</a> for emergency use. The FDA <a href="https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-chloroquine-and">then quickly reversed</a> its decision when <a href="https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or">numerous reports of deaths caused by heart arrhythmias emerged</a>. That news brought many clinical trials to a halt. Regardless, some scientists continued to study it in hopes of finding a cure for this deadly virus. </p>
<h2>How the work was done</h2>
<p><a href="https://doi.org/10.1038/s41586-020-2575-3">The new study</a> was carried out by scientists in Germany who tested HCQ on a collection of different cell types to figure out why this drug doesn’t prevent the virus from infecting humans. </p>
<p>Their findings clearly show that that HQC can block the coronavirus from infecting kidney cells from the African green monkey. But it does not inhibit the virus in human lung cells – the primary site of infection for the SARS-CoV-2 virus. </p>
<p>In order for the virus to enter a cell, it can do so by two mechanisms - one, when the <a href="https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928">SARS-CoV-2 spike protein attaches to the ACE2 receptor</a> and inserts its genetic material into the cell. In the second mechanism, the virus is absorbed into some special compartments in cells called endosomes. </p>
<p>Depending on the cell type, some, like kidney cells, need an enzyme called cathepsin L for the virus to successfully infect them. In lung cells, however, an enzyme called TMPRSS2 (on the cell surface) is necessary. Cathepsin L requires an acidic environment to function and allow the virus to infect the cell, while TMPRSS2 does not. </p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p>
<p>In the green monkey kidney cells, both hydroxychloroquine and chloroquine decrease the acidity, which then disables the cathepsin L enzyme, blocking the virus from infecting the monkey cells. In human lung cells, which have very low levels of cathepsin L enzyme, the virus uses the enzyme TMPRSS2 to enter the cell. But because that enzyme is not controlled by acidity, neither HCQ and CQ can block the SARS-CoV-2 from infecting the lungs or stop the virus from replicating. </p>
<h2>Why it matters</h2>
<p>This matters for several reasons. One, much time and money has been spent studying a drug that many scientists said from the very beginning was not going to be effective in killing the virus.</p>
<p>The second reason is that the studies that have reported antiviral activity for hydroxychloroquine were not in epithelial lung cells. Thus, their results are not relevant to properly studying SARS-CoV-2 infections in humans. </p>
<h2>What’s next?</h2>
<p>As scientists proceed with investigating new drugs as well as trying to <a href="https://theconversation.com/covid-19-treatment-might-already-exist-in-old-drugs-were-using-pieces-of-the-coronavirus-itself-to-find-them-133701">repurpose old ones</a>, like hydroxychloroquine, it is critical that researchers take the time to think about their study design. </p>
<p>In short, those of us involved in antiviral drug development should all take a lesson from this study. It is important not only to focus our efforts on pursuing drugs that will directly shut down viral replication, but also to study the virus in the primary site of infection.</p><img src="https://counter.theconversation.com/content/143234/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Katherine Seley-Radtke receives funding from the National Institutes of Health and the National Institutes of Allergies and Infectious Diseases. </span></em></p>A new study not only shows that the malarial drug chloroquine doesn’t block SARS-CoV-2 from infecting lung cells, but also explains why.Katherine Seley-Radtke, Professor of Chemistry and Biochemistry and President-Elect of the International Society for Antiviral Research, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1401562020-07-09T12:13:52Z2020-07-09T12:13:52ZWhen Trump pushed hydroxychloroquine to treat COVID-19, hundreds of thousands of prescriptions followed despite little evidence that it worked<figure><img src="https://images.theconversation.com/files/346160/original/file-20200707-26-imzchz.jpg?ixlib=rb-1.1.0&rect=0%2C68%2C4587%2C2977&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">As public figures and some in the media touted hydroxychloroquine, prescriptions skyrocketed. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/white-pills-spilling-out-of-prescription-bottle-royalty-free-image/1161234835?adppopup=true&uiloc=thumbnail_same_series_adp&uiloc=thumbnail_same_series_adp"> Grace Cary / Moment via Getty Images</a></span></figcaption></figure><p>In late March and early April, <a href="https://www.huffpost.com/entry/trump-fauci-coronavirus-hloroquine-azithromycin_n_5e768e4fc5b6eab77949660d">President Trump repeatedly proclaimed that hydroxychloroquine</a> could prevent or treat COVID-19. Within days, the number of prescriptions for the drug skyrocketed even though evidence it could safely prevent or treat the disease was at the time very weak. </p>
<p>A casual remark by a president who is not in any way a medical expert somehow led thousands of U.S. physicians to write prescriptions for a drug that had never before been used to treat a viral illness. What could be happening here? </p>
<p>As a <a href="https://health.ucdavis.edu/team/internalmedicine/373/richard-kravitz---health-policy---internal-medicine-sacramento">general internist</a> at the University of California, Davis health center, I have seen thousands of patients in both inpatient and outpatient settings. As a researcher, I have focused on how <a href="https://scholar.google.com/citations?user=u8ZMXTMAAAAJ&hl=en&oi=ao">patients influence what physicians do</a>, and consequently, I often find myself asking how the larger world influences what patients think. </p>
<p>Through my research, I’ve found that the process of prescribing medication is more complicated than most people realize. In the real world, it’s a mix of the current state of medical knowledge and a negotiation between what the patient wants or asks for and the habits and beliefs of the physician. It is a human experience, and can be influenced by things like advertising, media and even politics. </p>
<p>I think the hydroxychloroquine situation perfectly illustrates how much the outside world shapes patients’ views of their own health care. It also shows how, particularly when the science is uncertain, patients’ views strongly affect what their doctors do.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/346161/original/file-20200707-194418-1qu50y5.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">President Trump has repeatedly and consistently touted the effectiveness of hydroxychloroquine despite shaky scientific evidence at best, even going so far as to announce that he was taking it as a preventative measure against the coronavirus.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Virus-Outbreak-Trump/3357c55019e6411687156a1db305332c/22/0">AP Photo/Evan Vucci</a></span>
</figcaption>
</figure>
<h2>The hydroxychloroquine boom</h2>
<p>On March 21 President Trump touted hydroxychloroquine – and its biochemical cousin, chloroquine – as <a href="https://thehill.com/homenews/administration/488796-trump-steps-up-effort-to-tout-malaria-drug-as-coronavirus-game">potential “game changers”</a> in the battle against COVID-19. Two months later, he announced on national television that he had been <a href="https://thehill.com/homenews/administration/498375-trump-says-hes-been-taking-hydroxychloroquine">taking the drug himself</a> as a preventative treatment.</p>
<p>During the 10-week period between Feb. 17 and April 27 doctors wrote approximately <a href="https://dx.doi.org/10.1001/jama.2020.9184">483,000 more prescriptions for hydroxychloroquine</a> than in the same time period in 2019. The week after President Trump mentioned the drug during a press conference, prescriptions were up more than <a href="https://dx.doi.org/10.1001/jama.2020.9184">200% compared to the previous year</a>. The vast majority of excess prescriptions were written between March 14 and April 4, but as news spread about shortages of the drug and the lack of evidence to support its use, prescribing returned quickly to normal. </p>
<p>Research now shows that this once-promising drug likely <a href="https://theconversation.com/hydroxychloroquine-for-covid-19-a-new-review-of-several-studies-shows-flaws-in-research-and-no-benefit-137869">isn’t effective for preventing or treating COVID 19</a>, but the damage was already done. Hundreds of thousands of Americans unnecessarily took medicine that <a href="https://www.who.int/publications/m/item/targeted-update-safety-and-efficacy-of-hydroxychloroquine-or-chloroquine-for-treatment-of-covid-19">can have dangerous side effects</a>. Additionally, many people with an actual medical need to take hydroxychloroquine – like those living with lupus and related autoimmune diseases – found themselves <a href="https://www.washingtonpost.com/business/2020/03/20/hospitals-doctors-are-wiping-out-supplies-an-unproven-coronavirus-treatment/">unable to obtain the drugs they needed</a>.</p>
<p>What explains the sharp rise, and equally precipitous fall, of hydroxychloroquine prescriptions?</p>
<h2>Amplification of shaky science</h2>
<p>The hydroxychloroquine story is in part connected to the way information about prescription drugs in the United States is produced and disseminated. This process greatly influences what the public thinks about drugs. </p>
<p>First, the clinical research supporting the use of hydroxychloroquine for COVID-19 was <a href="https://theconversation.com/hydroxychloroquine-for-covid-19-a-new-review-of-several-studies-shows-flaws-in-research-and-no-benefit-137869">shaky from the start</a>. The initial studies were very small, and likely because of the pressure from the pandemic, the research was <a href="https://theconversation.com/coronavirus-research-done-too-fast-is-testing-publishing-safeguards-bad-science-is-getting-through-134653">rushed through the usual safeguards like peer review</a>.</p>
<p>[<em>Get facts about coronavirus and the latest research.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=coronavirus-facts">Sign up for The Conversation’s newsletter.</a>]</p>
<p>Second, influential individuals and organizations played on the public’s perceptions. President Trump was certainly a factor, but media outlets – notably <a href="https://www.foxnews.com/opinion/sean-hannity-gov-cuomo-stop-denying-new-yorkers-hydroxychloroquine">Fox News</a> and <a href="https://nypost.com/2020/04/02/hydroxychloroquine-most-effective-coronavirus-treatment-poll/">the New York Post</a> oversold the apparent benefits and downplayed the ample uncertainty surrounding the treatment at the time. Even The New York Times may have inadvertently contributed to the <a href="https://www.nytimes.com/2020/04/01/health/hydroxychloroquine-coronavirus-malaria.html">initial prescribing stampede</a> by covering the science before it was peer–reviewed, even though they clearly stated the shortcomings of the research.</p>
<p>The truth is that researchers, academic institutions, medical journals and the media all face powerful incentives to portray the latest research findings as more earthshaking than they actually are. Under normal circumstances, numerous mechanisms exist to blunt some of the worst overhyping and many sources of medical information do their best to be accurate in what they report. But in the midst of a pandemic, the urgency of the moment can overwhelm these defenses and good intentions. Bad science can be spread far and wide by normally credible sources.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/346162/original/file-20200707-194405-hv9un6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Why were doctors prescribing hydroxychloroquine to patients when the science was still so shaky?</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/female-doctor-talking-to-patient-royalty-free-image/532726150?adppopup=true">LWA-Dann Tardif / Stone via Getty Images</a></span>
</figcaption>
</figure>
<h2>From public interest to actual prescriptions</h2>
<p>It would be one thing if patients could get unproven medications like hydroxychloroquine for COVID-19 on their own. But physicians are supposed to be the guardians at the gate of medicine. Why were doctors writing prescriptions for a drug to fight COVID-19 without evidence that it worked?</p>
<p>Some physicians were likely overeager early adopters. Additionally, some hospitals – including my own at the University of California, Davis – made hydroxychloroquine available to COVID-19-positive inpatients during the early days of the epidemic. However, early adopters constitute a low percentage of all prescribers - generally <a href="https://www.jstor.org/stable/3768086">less than 10% according to one study</a> – and cumulative U.S. hospitalizations through April 25 totaled <a href="https://gis.cdc.gov/grasp/covidnet/COVID19_3.html">no more than 150,000</a>. With almost a half million extra prescriptions filled over that time, these explanations cannot fully explain the surge.</p>
<p>Substantial research, including my own, shows that when patients ask for drugs by name, <a href="https://dx.doi.org/10.1001/jama.293.16.1995">doctors will frequently prescribe them</a>. A reasonable hypothesis is that many of the excess hydroxychloroquine prescriptions filled in the weeks after President Trump’s remarks resulted from patients asking about or explicitly requesting hydroxychloroquine from their primary care physicians.</p>
<p>Over a decade ago, my colleagues and I ran an experiment where we sent actors pretending to have symptoms of depression to see physicians. Some of the actors explicitly asked for drugs while others did not. The results were striking. Patients requesting antidepressants were more than <a href="https://dx.doi.org/10.1001/jama.293.16.1995">twice as likely to receive them</a>, regardless of whether their symptoms warranted the drugs or not.</p>
<p>These results should not be overinterpreted - we would not have found the same results in a study where patients with broken bones asked for chemotherapy, for example. But much of medical practice occurs in the gray zone of limited evidence. It is these gray areas where <a href="https://doi.org/10.1136/bmj.324.7332.278">media and advertising most influence patients</a>, who in turn influence physicians. With research on treatments for COVID-19 coming out at an incredible rate, the health effects of the virus still largely a mystery and people’s lives on the line, the gray zone for COVID-19 treatments is massive.</p>
<p>In the case of hydroxychloroquine, the combination of shaky science, loud public proponents like the president and the influence patients have on physicians likely resulted in close to half a million prescriptions before the public health benefits and risks were adequately understood.</p>
<p>Research on hydroxychloroquine has accumulated, and now most experts agree that <a href="https://theconversation.com/hydroxychloroquine-for-covid-19-a-new-review-of-several-studies-shows-flaws-in-research-and-no-benefit-137869">it likely isn’t effective</a> as a COVID-19 treatment – with some studies even suggesting that it <a href="http://dx.doi.org/10.1016/j.medj.2020.06.001">may be harmful</a>. But new drugs and treatments to fight this deadly virus are going to continue to emerge in the coming months and years. The media, politicians, doctors and patients must all maintain a critical stance and acknowledge the influence they have on each other.</p>
<p>Waiting for solid evidence in the form of randomized studies takes patience. But the alternative is to wander into a therapeutic fog where potential harms lurk alongside potential benefits. This is never a good idea, and it is especially dangerous now.</p><img src="https://counter.theconversation.com/content/140156/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Richard L. Kravitz received funding from the National Institutes of Health.</span></em></p>When news reports tout a drug, people get interested, even if the benefits are unproven. Patient hopes, requests and demands can easily turn into real prescriptions in their doctor’s office.Richard L. Kravitz, Professor of Health Policy and Internal Medicine, University of California, DavisLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1415132020-07-01T12:30:14Z2020-07-01T12:30:14ZWhich drugs and therapies are proven to work, and which ones don’t, for COVID-19?<figure><img src="https://images.theconversation.com/files/344835/original/file-20200630-103673-pcawdc.jpg?ixlib=rb-1.1.0&rect=0%2C10%2C6679%2C4426&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">We are slowly figuring out which drugs and therapies are effective against the new coronavirus.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/china-wuhan-smartphone-with-aliepress-logo-with-royalty-free-image/1203497795?adppopup=true&uiloc=thumbnail_similar_images_adp">Anton Petrus / Getty Images</a></span></figcaption></figure><p><em>Leer <a href="https://theconversation.com/que-medicamentos-y-tratamientos-se-ha-demostrado-que-funcionan-y-cuales-no-para-la-covid-19-143395">en español</a></em></p>
<p><a href="https://uvahealth.com/findadoctor/profile/william-petri">I am a physician and a scientist</a> at the University of Virginia. I care for patients and conduct research to find better ways to diagnose and treat infectious diseases, including COVID-19. Here I’m sharing what is known about which treatments work, and which don’t, for the new coronavirus infection. </p>
<p>Keep in mind that this field of medicine is rapidly evolving as our understanding of the SARS-CoV-2 virus improves. So what I am writing today may change within days or weeks.</p>
<p>Below are the treatments that have been tried and for which we have the best knowledge.</p>
<h2>Hydroxychloroquine or chloroquine – no evidence they work</h2>
<p>There are <a href="http://doi.org/10.1126/science.abd2496">three randomized controlled trials</a> of hydroxychloroquine, all of which have failed to prove or disprove a beneficial or harmful effect on COVID-19 clinical course or clearance of virus. Given this current lack of evidence, these drugs, which normally are used to treat arthritis, should <a href="https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/#toc-5">only be used within the context of a controlled clinical trial.</a> </p>
<h2>Lopinavir/ritonavir – not helpful</h2>
<p>The drug Lopinavir is an inhibitor of an enzyme called HIV protease which is involved in the production of viral particles. Protease inhibitors for HIV were revolutionary, leading to our current ability to effectively treat HIV. Lopinavir also can inhibit enzymes that perform similar functions as the HIV protease in the <a href="https://www.niaid.nih.gov/diseases-conditions/covid-19">SARS and MERS coronaviruses</a>. Ritonavir increases the level of Lopinavir in the blood so the lopinavir/ritonavir combination was tested in a randomized controlled clinical trial for COVID-19. </p>
<p>Unfortunately, there was no impact on the levels of virus in the throat or duration of viral shedding, nor did patients’ clinical course or survival change. There therefore is <a href="http://doi.org/10.1056/NEJMoa2001282">no role for lopinavir/ritonavir in the treatment of COVID-19.</a></p>
<h2>Steroids – yes for almost all COVID-19 patients</h2>
<p>When a synthetic steroid hormone, called dexamethasone, was given to patients with COVID-19 the drug decreased <a href="https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1">28-day mortality by 17% and hastened hospital discharge</a>. </p>
<p>This work was performed in a <a href="http://www.ox.ac.uk/news/2020-06-16-low-cost-dexamethasone-reduces-death-one-third-hospitalised-patients-severe">randomized and controlled clinical trial</a> of over 6,000 patients, and while not replicated in another study or yet peer reviewed, is certainly enough evidence to recommend its use. </p>
<h2>Tocilizumab – too early to judge</h2>
<p>Tocilizumab is an <a href="https://theconversation.com/antibody-injections-could-fight-covid-19-infections-an-infectious-disease-expert-explains-the-prospects-139444">antibody</a>, that blocks a protein, called IL-6 receptor, from binding IL-6 and triggering inflammation. Levels of IL-6 are higher in many patients with COVID-19, and the immune system in general seems to be hyperactivated in those with the most severe disease. This leads many physicians and physicians to think that inhibiting the IL-6 receptor might protect patients from severe disease. </p>
<p>Tocilizumab is currently FDA approved for the treatment of rheumatoid arthritis and several other collagen-vascular diseases and for “<a href="https://theconversation.com/blocking-the-deadly-cytokine-storm-is-a-vital-weapon-for-treating-covid-19-137690">cytokine storm</a>” – a harmful overreaction of the immune system – that can be caused by certain types of cancer therapy and COVID-19.</p>
<p><a href="https://doi.org/10.1016/S2665-9913(20)30173-9">A retrospective observational study</a> found that COVID-19 patients treated with tocilizumab had a lower risk of mechanical ventilation and death. But we lack a randomized controlled clinical trial so there is no way to ascertain if this apparent improvement was due to tocilizumab or from the imprecise nature of retrospective studies.</p>
<h2>Convalescent plasma – too early to judge</h2>
<p>Convalescent plasma, the liquid derived from blood after removing the white and red blood cells, contains antibodies from previous infections that the plasma donor had. This plasma has been used to prevent infectious diseases including pneumonia, tetanus, diphtheria, mumps and chickenpox for over a century. It is thought to benefit patients because antibodies from the plasma of survivors bind to and inactivate pathogens or their toxins of patients. Convalescent plasma has now been used in thousands of COVID-19 patients. </p>
<p>However, the only randomized clinical trial was small and included just 103 patients who received convalescent plasma 14 days after they became ill. There was <a href="http://doi.org/10.1001/jama.2020.10044">no difference in the time to clinical improvement or mortality</a> between those who did and did not receive treatment. The encouraging news was that there was a significant decrease in virus levels detected by PCR. </p>
<p>It is therefore too early to tell if this will be beneficial and controlled clinical trials are needed.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/344915/original/file-20200630-103636-1os1g3t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A nurse is collecting convalescent plasma from a recovered COVID-19 patient to help the healing process of other COVID-19 patients in Indonesia.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/nurse-were-conducting-the-process-of-taking-a-plasma-news-photo/1223515838?adppopup=true&uiloc=thumbnail_more_search_results_adp">Budiono,/ Sijori images/Barcroft Media via Getty Images</a></span>
</figcaption>
</figure>
<h2>Remdesivir – yes, decreases hospital stay</h2>
<p><a href="https://theconversation.com/remdesivir-explained-what-makes-this-drug-work-against-viruses-137751">Remdesivir is a drug that inhibits the coronavirus enzyme</a> that makes copies of the viral RNA genome. It acts by causing premature stoppage or termination of the copying and ultimately blocks the virus from replicating.</p>
<p>Remdesivir treatment, especially for patients who required supplemental oxygen before they were placed on a ventilator <a href="http://doi.org/10.1056/NEJMoa2007764">reduced mortality and shortened the average recovery time</a> from 15 to 11 days. </p>
<h2>ACE inhibitors and ARBs – keep taking them</h2>
<p>There was a concern that drugs called <a href="https://www.webmd.com/heart-disease/guide/medicine-ace-inhibitors#:%7E:text=Angiotensin%2Dconverting%20enzyme%20(ACE),to%20lower%20your%20heart's%20workload.">ACE inhibitors</a> or angiotensin receptor blockers (ARBs), which are used to treat high blood pressure and heart failure, could increase levels of the ACE2 proteins, the receptor <a href="https://theconversation.com/what-is-the-ace2-receptor-how-is-it-connected-to-coronavirus-and-why-might-it-be-key-to-treating-covid-19-the-experts-explain-136928">for SARS-CoV-2,</a> on the surface of cells in the body. This would, physicians hypothesized, allow more entry points for the virus to infect cells and would therefore boost the severity of new coronavirus infections.</p>
<p>However, there is no evidence that this is the case. The American Heart Association, the Heart Failure Society of America and the American College of Cardiology all recommend that patients continue to take these medications during the pandemic as they are <a href="https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19">beneficial in the treatment of high blood pressure and heart failure</a>. </p>
<p>We have made amazing progress in the treatment of COVID-19. Two therapies – steroids and Remdesivir – have already been shown to help. Those who benefit from these treatments owe thanks to patients who volunteered to participate in controlled clinical trials, and the physicians and pharmaceutical companies that lead them. </p>
<p>[<em>Deep knowledge, daily.</em> <a href="https://theconversation.com/us/newsletters/the-daily-3?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=deepknowledge">Sign up for The Conversation’s newsletter</a>.]</p><img src="https://counter.theconversation.com/content/141513/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>William Petri receives funding from the NIH and the Gates Foundation.</span></em></p>During the last six months, news reports have mentioned dozens of drugs that may be effective against the new coronavirus. Here we lay out the evidence and reveal which ones are proven to work. Or not.William Petri, Professor of Medicine, University of VirginiaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1391532020-06-07T08:41:19Z2020-06-07T08:41:19ZWhy it’s vital to look beyond the hype about repurposed malaria drugs<figure><img src="https://images.theconversation.com/files/337959/original/file-20200527-20219-1ncjwns.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The World Health Organisation has suspended the use of hydroxychloroquine in a global drug trial.</span> <span class="attribution"><span class="source">George Frey/AFP via Getty Images</span></span></figcaption></figure><p>There are many examples in history of drugs that have been <a href="https://www.tandfonline.com/doi/full/10.1080/17460441.2020.1704729">repurposed</a> for different diseases. One such drug is chloroquine, which was and is still used for malarial treatment. It has been repurposed as an anti-inflammatory, anti-diabetic and, most recently, as an anti-viral drug. </p>
<p>Chloroquine was first produced in 1934, and <a href="https://blogs.sciencemag.org/pipeline/archives/2020/03/20/chloroquine-past-and-present">widely distributed</a> to soldiers who were training or stationed in malaria hot spots during World War II. By 1945, the drug became the <a href="https://www.astmh.org/ASTMH/media/Documents/Presidential%20Addresses/1962-G-Robert-Coatney.pdf">standard recommendation</a> for malaria treatment by the World Health Organisation (WHO). </p>
<p>The wide distribution of chloroquine led to the <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052376/">observation</a> that the drug improved rashes and arthritis in soldiers. Not long after, it was prescribed to <a href="https://www.elsevier.com/books/dubois-lupus-erythematosus-and-related-syndromes/wallace/978-1-4377-1893-5">lupus and arthritis</a> patients globally. </p>
<p>But these patients also suffered from blurry vision, gastrointestinal problems and weakened muscles. To decrease the side-effects of chloroquine, hydroxychloroquine, which is identical to chloroquine with the exception of one chemical group, was produced in <a href="https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=reportsSearch.process&rptName=1&reportSelectMonth=4&reportSelectYear=1955&nav">1955</a> and has been used since. </p>
<p>Observational studies in arthritis and lupus patients who received chloroquine or hydroxychloroquine over a long time period suggested that these patients were less likely to develop <a href="https://jamanetwork.com/journals/jama/fullarticle/207908">type 2 diabetes</a>, and a new role for these drugs as a potential anti-diabetic treatment emerged in <a href="https://diabetes.diabetesjournals.org/content/33/12/1133.long">1984</a>.</p>
<p>But reports have also <a href="https://www.sciencedirect.com/science/article/abs/pii/S1473309907701871">suggested</a> that high doses of chloroquine and hydroxychloroquine can be harmful to the heart. We set out to <a href="https://link.springer.com/article/10.1007/s10557-018-06847-9">investigate</a> this and found that there were indeed cardiovascular effects which might outweigh the drug’s advantages. This risk needs to be considered carefully, especially when researchers are looking for quick solutions to urgent health problems.</p>
<h2>Anti-diabetic</h2>
<p>To understand how hydroxychloroquine works against diabetes, it’s necessary to know something about the human body’s response to food.</p>
<p>Insulin resistance develops when there is a surplus of nutrients present in the diet (for example in obesity) over long time periods. The excess glucose present in the blood stimulates a continuous release of insulin. Cells throughout the body become desensitised to the extra glucose and insulin. They decrease their uptake of both, which influences cell behaviour. </p>
<p>In type 2 diabetes, the body can’t produce any insulin in response to the extra glucose. Hydroxychloroquine stimulates the body to produce more insulin and keep it in the blood for longer by protecting it from being broken down. This gives the cells more time to take up both insulin and glucose. </p>
<p>But this does not come cheap. Hydroxychloroquine can also lower blood pressure, cause an irregular heartbeat and further decrease already low blood sugar levels. All of these are serious side effects.</p>
<p>The advantages and disadvantages of chloroquine and hydroxychloroquine as repurposed drugs have led to a debate in <a href="https://www.tandfonline.com/doi/abs/10.3109/08923973.2013.780078">scientific literature</a> about its use and dosages. </p>
<p>Our study <a href="https://link.springer.com/article/10.1007/s10557-018-06847-9">investigated</a> the effect of different chloroquine concentrations on the rat heart. We found that a single low dose of chloroquine is enough to significantly decrease heart rate and function. Long-term treatment with low doses of chloroquine worsened heart function in healthy and obese rats and did not improve glucose uptake in the obese animals.</p>
<p>Overall, our study concluded that the side effects of chloroquine on the heart, after as little as a single low dose, outweigh any therapeutic advantages that the drug might have for diabetic patients, especially when there are more effective and less toxic anti-diabetic drugs available.</p>
<p>There have been reports of <a href="http://www.jrheum.org/content/39/5/1099.long">heart complications</a> in patients with diabetes, arthritis, <a href="https://journals.sagepub.com/doi/full/10.1177/2048872612471215?casa_token=tCzcx5PRxGUAAAAA%3A0Jsrk4nQVHEi23QvVCGMkpeSvsVYs4piljrU6cCTVTG4cTm8xf9CsgxdlmsYgbBsJ3YDMzqqoYcI">lupus</a> and <a href="https://academic.oup.com/jac/article/70/6/1608/728687">malaria</a> treated with chloroquine or hydroxychloroquine. This has been blamed, partly, on the drug’s ability to stop the cellular recycling machinery from working. This also prevents insulin from being degraded and can result in a buildup of toxic byproducts. </p>
<p>Both chloroquine and hydroxychloroquine accumulate in cells over time. It’s <a href="https://www.tandfonline.com/doi/full/10.3109/08923973.2013.780078">believed</a> that this accumulation leads to some of the side effects observed after prolonged use or very high doses. Both drugs are still widely prescribed for arthritis, lupus and malaria, but patients are <a href="https://www.onlinecjc.ca/article/S0828-282X(14)01284-7/fulltext">advised</a> to undergo annual electrocardiograms.</p>
<h2>From anti-malarial to anti-viral</h2>
<p>Recently, chloroquine and hydroxychloroquine have come to the fore in the search for a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/">treatment</a> for COVID-19. This is because the drugs were shown to prevent viruses from multiplying inside a cell under laboratory conditions.</p>
<p>They were tested against <a href="https://retrovirology.biomedcentral.com/articles/10.1186/s12977-015-0178-0">HIV</a> and the <a href="https://europepmc.org/article/med/15351731">human coronavirus</a> that caused the severe acute respiratory syndrome outbreak of 2002-2003. But these studies were mainly done in laboratories and rarely tested in patients. </p>
<p>A recent <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/">study</a> (20 patients) in France found that hydroxychloroquine lowered the viral load of SARS-CoV-2, the virus that causes COVID-19. The study did not report any side-effects, but has been widely <a href="https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25898">criticised</a> for design flaws in the methodology. This was followed by a <a href="https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v2">larger study</a> in Brazil where 81 patients were treated with either low or high doses of chloroquine. Within three days of the study, several of the patients developed an irregular heartbeat (arrhythmia). After six days, 11 patients had died. The high dose arm of the study was stopped, citing a 25% increased risk of developing arrhythmia. </p>
<p>The WHO recently <a href="https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---25-may-2020">suspended the use</a> of hydroxychloroquine in a global drug trial. This followed the publication of a <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext">study</a> that showed no benefits from the use of chloroquine or hydroxychloroquine for COVID-19, and suggested that the drugs might actually be harmful. But data from this study and <a href="https://www.nejm.org/doi/full/10.1056/NEJMc2021225">others</a> by the authors could not be independently verified, and have been <a href="https://www.thelancet.com/lancet/article/s0140673620313246">retracted</a>. </p>
<h2>Way forward</h2>
<p>At this stage, the scientific community <a href="https://www.nature.com/articles/d41586-020-01165-3">warns</a> that the <a href="https://www.sciencemag.org/news/2020/04/antimalarials-widely-used-against-covid-19-heighten-risk-cardiac-arrest-how-can-doctors">hype</a> around chloroquine and hydroxychloroquine could derail the search for more effective treatments. There is an urgent need to develop effective treatments against COVID-19. But there are also many pitfalls in small, uncontrolled <a href="https://www.nature.com/articles/d41586-020-01391-9">drug trials</a>, and the accelerated pace at which data is published. </p>
<p>If these drugs are prescribed for COVID-19, it should be done with extreme caution and a detailed risk assessment of the patient. The Food and Drug Administration in the US has <a href="https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or">warned</a> against the use of chloroquine and hydroxychloroquine outside of a clinical setting or drug trial. </p>
<p>In the hope of finding a cure for COVID-19, it is easy to get lost in the hype and rapid publication of data. For now, chloroquine and hydroxychloroquine should be handled with caution, at least until more information from robust and peer-reviewed studies is available about its effect on the hearts of compromised COVID-19 patients.</p><img src="https://counter.theconversation.com/content/139153/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Marguerite Blignaut does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>In the hope of finding a cure for COVID-19, it is easy to get lost in the hype. But chloroquine and hydroxychloroquine should for now be set aside.Marguerite Blignaut, Postdoctoral research fellow, Stellenbosch UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1393092020-05-29T02:05:27Z2020-05-29T02:05:27ZCould taking hydroxychloroquine for coronavirus be more harmful than helpful?<figure><img src="https://images.theconversation.com/files/337900/original/file-20200527-20229-1imk34p.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C7951%2C5304&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><span class="source">Shutterstock</span></span></figcaption></figure><p><em><strong>UPDATE</strong>: Since this Research Check was published, The Lancet has <a href="https://www.thelancet.com/lancet/article/s0140673620313246">retracted</a> the study it published (and which is evaluated in this article), explaining that three of the study’s authors said they “can no longer vouch for the veracity of the primary data sources” and were unable to independently audit the data.</em></p>
<p><em>The journal previously issued an <a href="https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31290-3.pdf">expression of concern</a> over the study, referring to “serious scientific questions” over the provenance of the data. The World Health Organisation has also announced it will <a href="https://www.statnews.com/2020/06/03/who-resuming-hydroxychloroquine-study-for-covid-19/">resume</a> its trial of hydroxychloroquine for COVID-19, after temporarily suspending it in response to the Lancet study.</em></p>
<hr>
<p><em>In response to the initial expression of concern, Andrew McLachlan, lead author of this Research Check, <a href="https://www.scimex.org/newsfeed/expert-reaction-who-restarts-hydroxychloroquine-trials-after-study-data-raises-concerns">told the Australian Science Media Centre</a>:</em> </p>
<p><em>“The study used data from an international registry curated by a US company including 96,000 people with COVID-19, 671 hospitals across 6 continents. People treated with hydroxychloroquine or chloroquine had a higher death rate. This was a surprising and controversial finding (hydroxychloroquine has been used safely for malaria and autoimmune diseases for decades). On the back of these results a number of trials investigating hydroxychloroquine in COVID-19, including a WHO trial, were suspended, after a reassessment of the possible harms from hydroxychloroquine. Subsequently, many commentators and groups called into question the veracity of the registry data in the Lancet study, how it was collected, and aspects of the analysis. While the authors published a clarification, it failed to address major issues.</em></p>
<p><em>"The study itself (and most commentators) concluded that high-quality randomised controlled trials of hydroxychloroquine in COVID-19 were needed – especially to clarify possible harms and establish which COVID-19 patients would benefit. Many considered suspending ongoing clinical trials involving hydroxychloroquine in COVID-19 as premature. All the ongoing randomised controlled trials involve careful screening and monitoring of well-known adverse effects (on heart rhythm and eye toxicity). The numerous trials should continue; they can be conducted safely and when complete will answer the important question of whether hydroxychloroquine is a safe and effective drug to treat or prevent COVID-19 in the global pandemic.”</em></p>
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<p>A <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext">paper published in The Lancet</a> has cast fresh controversy on the use of the malaria drug hydroxychloroquine as a potential treatment for COVID-19. </p>
<p>The study’s authors reported they were “unable to confirm a benefit” of using the drug, while also finding COVID-19 patients in hospital treated with hydroxychloroquine were more likely to die or suffer life-threatening heart rhythm complications.</p>
<p>The publication prompted the World Health Organisation to <a href="https://www.abc.net.au/news/2020-05-26/who-pauses-trial-of-hydroxychloroquine-for-coronavirus-patients/12285652">suspend its testing of hydroxychloroquine to treat COVID-19</a>, while a <a href="https://www.ascot-trial.edu.au/blogs/news/statement-on-the-status-of-australasian-covid-19-trial-ascot">similar Australian trial</a> has paused recruitment.</p>
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Read more:
<a href="https://theconversation.com/donald-trump-is-taking-hydroxychloroquine-to-ward-off-covid-19-is-that-wise-139031">Donald Trump is taking hydroxychloroquine to ward off COVID-19. Is that wise?</a>
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<h2>A bit of background</h2>
<p>Hydroxychloroquine has been used since the 1940s to treat malaria, but has been making headlines as a <a href="https://www.nps.org.au/media/hydroxychloroquine-and-covid-19">potential treatment for COVID-19</a>. US President Donald Trump recently declared <a href="https://theconversation.com/donald-trump-is-taking-hydroxychloroquine-to-ward-off-covid-19-is-that-wise-139031">he was taking it daily</a>, while Australian businessman and politician Clive Palmer <a href="https://www.sbs.com.au/news/the-feed/clive-palmer-has-bought-30-million-doses-of-an-anti-malaria-drug-to-fight-covid-19-but-experts-warn-this-may-not-be-the-cure-all">pledged to create a national stockpile</a> of the drug.</p>
<p>The drug alters the human immune system (it’s an <a href="https://www.nps.org.au/hcq-and-covid-19">immunomodulator, not an immunosuppressant</a>) and has an important role in helping people with rheumatoid arthritis and lupus. </p>
<p>It does have a range of serious <a href="https://www.tga.gov.au/alert/new-restrictions-prescribing-hydroxychloroquine-covid-19">possible side-effects</a>, including eye damage and altered heart rhythm, which require monitoring. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/338096/original/file-20200528-20229-1lfsj4s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">We don’t know the patients in this study died because they took hydroxychloroquine.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
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<p><a href="https://www.nature.com/articles/s41421-020-0156-0">Laboratory studies</a> suggest hydroxychloroquine may disrupt replication of the SARS-CoV-2 virus that causes COVID-19. It’s also possible hydroxychloroquine could reduce “<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161506/">cytokine storm</a>” – the catastrophic immune system overreaction that happens in some people with severe COVID-19.</p>
<p>A huge global effort is underway to investigate whether hydroxychloroquine is safe and effective for preventing or treating COVID-19, especially to improve recovery and reduce the risk of death. Previous studies have been inconclusive as they were anecdotal, observational or small randomised trials. </p>
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<em>
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Read more:
<a href="https://theconversation.com/in-the-fight-against-coronavirus-antivirals-are-as-important-as-a-vaccine-heres-where-the-science-is-up-to-133926">In the fight against coronavirus, antivirals are as important as a vaccine. Here's where the science is up to</a>
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<p>Doubts about hydroxychloroquine’s effectiveness have been increasing, with a large observational study from New York <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2012410">showing it had no benefit</a> in treating people with COVID-19.</p>
<p>The new <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext">Lancet study</a>, published last week, has found it could increase the risk of death among COVID-19 patients in hospital. But there’s more to the story. </p>
<h2>What did the new study do?</h2>
<p>The <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31180-6/fulltext">Lancet study</a> collected real-world data on more than 96,000 hospitalised patients with COVID-19 from more than 600 hospitals across six continents. </p>
<p>About 15,000 patients were treated with hydroxychloroquine (or a closely related drug, chloroquine) alone or in combination with an antibiotic.</p>
<p>Using a global registry the researchers investigated the safety of these treatments. They looked at whether people died in hospital, as well as the risk of developing life-threatening heart rhythm problems (called ventricular arrhythmias).</p>
<h2>What did the study find?</h2>
<p>Treatment with hydroxychloroquine was associated with increased rates of death in people with COVID-19, even after the researchers adjusted for other factors (age, other health conditions, suppressed immune system, smoking, and severity of the COVID-19 infection) that might increase the risk of death. </p>
<p>About 18% of people who received hydroxychloroquine died in hospital, compared with 9% of people with COVID-19 who did not receive these treatments. The risk of death was even higher (24%) in people receiving hydroxychloroquine in combination with either of the antibiotics azithromycin or clarithromycin.</p>
<p>Hydroxychloroquine (6%) and chloroquine (4%) treatment was also associated with more cases of dangerous heart rhythm problems when compared with untreated people with COVID-19 (0.3%).</p>
<p>Any evidence of benefit, while not the focus of this study, was unclear.</p>
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Read more:
<a href="https://theconversation.com/why-are-there-so-many-drugs-to-kill-bacteria-but-so-few-to-tackle-viruses-137480">Why are there so many drugs to kill bacteria, but so few to tackle viruses?</a>
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<h2>How can we interpret the results?</h2>
<p>This was an observational study, so it can only explore the association between treatments and death – rather than telling us hydroxychloroquine <em>caused</em> these patients to die.</p>
<p>It is <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31174-0/fulltext">unclear</a> why the death rate for patients treated with hydroxychloroquine and chloroquine was double that of those who weren’t, as the cause of death was not reported in this study.</p>
<p>Importantly, the study cannot account for all the factors that might contribute to death in these hospitalised patients and how these factors interact with each other. However, the researchers did a good job of “<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3144483/">matching</a>” the characteristics of people who were receiving hydroxychloroquine with those who were not receiving the drug, which makes the results more reliable. </p>
<p>But there may still be other factors, or medicines, that contributed to these findings. So there remains uncertainly about whether hydroxychloroquine causes, or even contributes to, the death of people with COVID-19. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/338100/original/file-20200528-20245-ml466p.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">While the Lancet study has seen some hydroxychloroquine trials halted, others are continuing under careful monitoring.</span>
<span class="attribution"><span class="source">Shutterstock</span></span>
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<p>Further, it was not possible to have careful control over the hydroxychloroquine dose people received – or other medicines people might be taking such as antivirals or other medicines for heart conditions (which potentially interact in sick hospitalised patients). </p>
<p>The average dose of hydroxychloroquine in this study was at the upper end of the regular recommended dose range for rheumatoid arthritis and lupus. But the wide range of hydroxychloroquine (and chloroquine) doses in this study makes interpretation of the findings difficult, especially when we know <a href="https://www1.racgp.org.au/ajgp/coronavirus/hydroxychloroquine-use-during-the-covid-19-pandemi">harmful effects</a> are associated with larger doses.</p>
<h2>Broader implications</h2>
<p>This study provides important information about the safety of hydroxychloroquine in treating vulnerable people with COVID-19 receiving hospital care.</p>
<p>While the implications for using hydroxychloroquine to treat COVID-19 in the community or for prevention of COVID-19 remain unclear, if nothing else this study highlights the need to carefully monitor people receiving the drug. </p>
<p>Some hydroxychloroquine trials are continuing, such as the very large <a href="https://www.recoverytrial.net/for-site-staff/site-staff/#alert">RECOVERY trial</a> in the UK. </p>
<p>This new information must be considered when balancing harm and potential benefit of these trials and will likely result in renewed safety monitoring.</p>
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Read more:
<a href="https://theconversation.com/coronavirus-scientists-promoting-chloroquine-and-remdesivir-are-acting-like-sports-rivals-138051">Coronavirus: scientists promoting chloroquine and remdesivir are acting like sports rivals</a>
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<p>We’ll need to see results from <a href="https://www.mja.com.au/journal/2020/clinical-trials-prevention-and-treatment-coronavirus-disease-2019-covid-19-current">ongoing</a> high-quality randomised controlled trials to truly know if hydroxychloroquine is effective and safe in treating or preventing COVID-19. </p>
<p>Further questions about what dose should be used, and which patients will benefit most, are topics under active investigation. </p>
<p>You <a href="https://www.tga.gov.au/alert/new-restrictions-prescribing-hydroxychloroquine-covid-19">should not take hydroxychloroquine</a> for COVID-19 unless you’re part of a clinical trial. <strong>– Andrew McLachlan and Ric Day</strong></p>
<h2>Blind peer review</h2>
<p><em>This review was written before further questions were raised about the Lancet study. See update below.</em></p>
<p>This is a fair and reasonable review of the Lancet paper, its relationship to previous studies, and its impact on ongoing clinical trials. </p>
<p>As stated in the review the Lancet article adds to the body of knowledge, including recent substantial studies in the <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2012410">New England Journal of Medicine</a> and the <a href="https://www.bmj.com/content/369/bmj.m1849">British Medical Journal</a>, that hydroxychloroquine is without significant effect in treatment trials. </p>
<p>The high death rate is concerning but not unprecedented, given that a clinical trial in Brazil was <a href="https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2765499">halted</a> because of adverse effects on the heart. However, recent <a href="https://www.theguardian.com/science/2020/may/28/questions-raised-over-hydroxychloroquine-study-which-caused-who-to-halt-trials-for-covid-19?CMP=share_btn_tw">media reports</a> suggest the data may have to be revised due to <a href="https://statmodeling.stat.columbia.edu/2020/05/25/hydroxychloroquine-update/">misclassification</a> of the participating hospitals. <strong>– Ian Musgrave</strong></p>
<p><em><strong>UPDATE</strong>: Ian Musgrave has provided the following comments (with thanks to the <a href="https://www.smc.org.au/">Australian Science Media Centre</a>) in response to The Lancet’s earlier expression of concern about the study:</em></p>
<p><em>“The news of the WHO restarting clinical trials ironically comes as another study was <a href="https://www.nejm.org/doi/pdf/10.1056/NEJMoa2016638">published in the New England Journal of Medicine</a> which showed no effect of hydroxychloroquine as pre-exposure prophylaxis for COVID-19. The decision by the WHO to pause trials was appropriate at the time, and the decision to reopen after careful review is also appropriate.</em></p>
<p><em>"Even if we completely discount the Lancet studies, there is still significant evidence of lack of efficacy and potential harm that restarting clinical trials should be done carefully. And clinical trials are still needed. The rapid pace of the COVID-19 outbreak means the early data we collect may be misleading or incomplete. While hydroxychloroquine has been given undue attention (and its potential harms minimised) there may still be some benefit to its judicious use. The Lancet case shows us that the scientific community must remain vigilant even with results we agree with and that data transparency and data sharing are even more important when we need to make good conclusions quickly in uncertain times.”</em></p>
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<p><em>Research Checks interrogate newly published studies and how they’re reported in the media. The analysis is undertaken by one or more academics not involved with the study, and reviewed by another, to make sure it’s accurate.</em></p><img src="https://counter.theconversation.com/content/139309/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Andrew McLachlan receives research funding from the NHMRC, research scholarship funding from GSK for a PhD student under his supervision and has previously received (and disclosed) in kind research support from Pfizer and GSK for investigator initiated research projects. Andrew serves and is paid as an expert on Australian government committees related to medicines regulation and anti-doping.</span></em></p><p class="fine-print"><em><span>IIan Musgrave has previously received funding from the National Health and Medical Research Council to study adverse reactions to herbal medicines and has previously been funded by the Australian Research Council to study potential natural product treatments for Alzheimer's disease. He has collaborated with SA water on studies of cyanobacterial toxins and their implication for drinking water quality. He has no funding from nor shares in any companies that have financial interests in COVID-19 therapies. He is a member of Friends of Science in Medicine.</span></em></p><p class="fine-print"><em><span>Ric Day does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>People taking hydroxychloroquine for coronavirus may be more likely to die, according to new research. But that doesn’t mean the drug is killing them.Andrew McLachlan, Head of School and Dean of Pharmacy, University of SydneyRic Day, Professor of Clinical Pharmacology, UNSW SydneyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1390312020-05-21T06:47:25Z2020-05-21T06:47:25ZDonald Trump is taking hydroxychloroquine to ward off COVID-19. Is that wise?<p>The White House’s confirmation that US President Donald Trump has been <a href="https://www.theguardian.com/us-news/2020/may/19/trump-hydroxychloroquine-covid-19-white-house">taking hydroxychloroquine every day for the past two weeks</a>, with his doctor’s blessing, has reignited the controversy over the drug. It has long been used against malaria but has not been approved for COVID-19.</p>
<p>Trump said he has “<a href="https://www.abc.net.au/news/2020-05-19/donald-trump-hydroxychloroquine-coronavirus-health-warnings/12261652">heard a lot of good stories</a>” about hydroxychloroquine, and incorrectly claimed there is no evidence of harmful side-effects from taking it. His <a href="https://twitter.com/realDonaldTrump/status/1241367239900778501?s=20">previous claims in March</a> that the drug could be a “game changer” in the pandemic prompted many people, including <a href="https://www.medreach.com.au/wp-content/uploads/2020/05/The-Age-Digital-Edition-Saturday-May-2-2020-Palmer-Hydroxychloroquine.pdf">Australian businessman and politician Clive Palmer</a>, to suggest stockpiling and distribution of the drug to the public. </p>
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<p>But the dangers of acting on false or incomplete health information were underlined by the <a href="https://edition.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html">death of an Arizona man</a> in March after inappropriate consumption of the related drug chloroquine. It’s important to know the real science behind the touted health benefits.</p>
<h2>How do these medicines work?</h2>
<p>Hydroxychloroquine is an analogue of chloroquine, meaning both compounds have similar chemical structures and a similar mode of action against malaria. Both medications are administered orally and have common side-effects such as nausea, diarrhoea and muscle weakness. However, hydroxychloroquine is <a href="https://www.amjmed.com/article/0002-9343(83)91265-2/pdf">less toxic</a>, probably because it is easier for the body to metabolise.</p>
<p>Chloroquine and hydroxychloroquine are <a href="https://apps.who.int/iris/bitstream/handle/10665/325771/WHO-MVP-EMP-IAU-2019.06-eng.pdf?ua=1">listed by the World Health Organisation as an essential medicine</a>. Both drugs have been used to treat malaria for more than 70 years, and hydroxychloroquine has also proved effective against auto-immune diseases such as <a href="https://link.springer.com/article/10.1007/s10787-015-0239-y">systemic lupus erythematosus and rheumatoid arthritis</a>. The US Food and Drug Administration has approved both <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/083082s050lbl.pdf">chloroquine</a> and <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/009768Orig1s051lbl.pdf">hydroxychloroquine</a> for treating malaria, but not for COVID-19.</p>
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<strong>
Read more:
<a href="https://theconversation.com/in-the-rush-to-innovate-for-covid-19-drugs-sound-science-is-still-essential-134638">In the rush to innovate for COVID-19 drugs, sound science is still essential</a>
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<p>We don’t know exactly how these drugs work to combat the malaria parasite. But we know chloroquine disrupts the parasite’s digestive enzymes by <a href="https://jcs.biologists.org/content/119/6/1016.short">altering the pH inside the parasite cell</a>, presumably effectively starving it to death.</p>
<p>Malaria parasites and coronaviruses are very different organisms. So how can the same drugs work against both? In lab studies, chloroquine <a href="https://link.springer.com/article/10.1186/1743-422X-2-69">hinders replication of the SARS coronavirus</a>, apparently by changing the pH inside particular parts of human cells where the virus replicates. </p>
<p>This offers a glimmer of hope that these pH changes inside cells could hold the key to thwarting such different types of pathogens. </p>
<h2>Is it OK to repurpose drugs like this?</h2>
<p>Existing drugs can be extremely valuable in an emergency like a pandemic, because we already know the maximum dose and any potential toxic side-effects. This gives us a useful basis on which to consider using them for a new purpose. Chloroquine is also <a href="http://viruseradication.com/journal-details/Minimum_costs_to_manufacture_new_treatments_for_COVID-19/">cheap to manufacture</a>, and has already been widely used in humans. </p>
<p>But we shouldn’t be complacent. There are significant gaps in our understanding of the biology of SARS-CoV-2, which causes COVID-19, because it is a brand new virus. There is a <a href="https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkaa114/5810487">20% genetic difference</a> between SARS-CoV-2 and the previous SARS coronavirus, meaning we should not assume a drug shown to act against SARS will automatically work for SARS-CoV-2. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/336619/original/file-20200521-102657-11qokxg.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Widely used, but with common side effects.</span>
<span class="attribution"><span class="source">Gary L. Hider/Shutterstock</span></span>
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<p>Even in its primary use against malaria, long-term chloroquine exposure can lead to increased risks such as <a href="https://link.springer.com/article/10.1007%2Fs12016-015-8469-8">vision impairment</a> and <a href="https://link.springer.com/article/10.1007%2Fs40264-018-0689-4">cardiac arrest</a>. Hydroxychloroquine offers a safer treatment plan with reduced tablet dosages and lessened side-effects. But considering their potentially lethal cardiovascular side-effects, these drugs are especially detrimental to those who are overweight or have pre-existing heart conditions. Despite the urgent need to confront COVID-19, we need to tread carefully when using existing medicines in new ways. </p>
<p>Any medication that has not been thoroughly tested for the disease in question can have seriously toxic side-effects. What’s more, different diseases may require different doses of the same drug. So we would need to ensure any dose that can protect against SARS-CoV-2 would actually be safe to take.</p>
<h2>The evidence so far</h2>
<p>Although many clinical trials are under way, there is still not enough evidence chloroquine and hydroxychloroquine will be useful against COVID-19. The few trials completed and published so far, despite claiming positive outcomes, have been either <a href="https://pubmed.ncbi.nlm.nih.gov/32205204/">small and poorly controlled</a> or <a href="https://pubmed.ncbi.nlm.nih.gov/32074550/">lacking in detail</a>.</p>
<p>A <a href="https://www.bmj.com/content/369/bmj.m1849.full">recent hydroxychloroquine trial in China</a> showed no significant benefits for COVID-19 patients’ recovery rate. A <a href="https://www.bmj.com/content/369/bmj.m1844">French hydroxychloroquine trial</a> was similarly discouraging, with eight patients prematurely discontinuing the treatment after heart complications. </p>
<p>The fascination with chloroquine and hydroxychloroquine has also adversely affected other drug trials. Clinical trials of other possible COVID-19 treatments, including HIV drugs and antidepressants, have seen <a href="https://www.nature.com/articles/d41586-020-01165-3">reduced enrolments</a>. Needless to say, in a pandemic we should not be putting all our eggs in one basket.</p>
<p>Then there is the issue of <a href="https://www.cbsnews.com/news/coronavirus-treatment-drug-hydroxychloroquine-doctor-prescription-family-friends/">chloroquine hoarding</a>, which not only encourages dangerous self-medication, but also puts malaria patients at greater risk. With malaria transmission season looming in some countries, the anticipated shortage of chloroquine and hydroxychloroquine will severely impact current malaria control efforts.</p>
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Read more:
<a href="https://theconversation.com/coronavirus-scientists-promoting-chloroquine-and-remdesivir-are-acting-like-sports-rivals-138051">Coronavirus: scientists promoting chloroquine and remdesivir are acting like sports rivals</a>
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<p>Overall, despite their tantalising promise as antiviral drugs, there isn’t enough evidence chloroquine and hydroxychloroquine are safe and suitable to use against COVID-19. The current preliminary data need to be backed up by multiple properly designed clinical trials that monitor patients for prolonged periods. </p>
<p>During a pandemic there is immense pressure to find drugs that will work. But despite Trump’s desperation for a miracle cure, the risks of undue haste are severe.</p>
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<p><em>This article was coauthored by Liana Theodoridis, an Honours student in Microbiology at La Trobe University.</em></p><img src="https://counter.theconversation.com/content/139031/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Teresa Carvalho receives funding from the Centre for Invasive Species Solutions, Defense Science Institute, Victoria State Government. </span></em></p>The US president has reignited controversy over the use of malaria drugs to guard against COVID-19. But there is little reliable evidence so far that this tactic is safe or effective.Teresa G. Carvalho, Senior Lecturer in Microbiology, La Trobe UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1353522020-04-16T12:14:15Z2020-04-16T12:14:15ZCoronavirus treatments: what drugs might work against COVID-19?<p>As the <a href="https://theconversation.com/coronavirus-where-do-new-viruses-come-from-136105">COVID-19 pandemic</a> continues to spread across the world, killing thousands and bringing economies to their knees, doctors, scientists and governments are on the lookout for safe and effective treatments to help those who are sick. And yet a large issue with COVID-19 is that there is, as yet, no cure.</p>
<p>Though there are treatments that can alleviate the symptoms – such as difficulty breathing – they do not address the underlying cause: the virus. The idea is that treating the symptoms will help prolong a patient’s life and buy time for their own <a href="https://theconversation.com/regular-exercise-has-long-term-benefits-for-immunity-its-important-to-stay-active-135836">immune systems</a> to kick in and remove the infection.</p>
<p>While research into related coronaviruses over the last few decades has brought some <a href="https://theconversation.com/drug-companies-should-drop-their-patents-and-collaborate-to-fight-coronavirus-135241">promising looking drugs</a>, only large <a href="https://theconversation.com/covid-19-treatment-might-already-exist-in-old-drugs-were-using-pieces-of-the-coronavirus-itself-to-find-them-133701">clinical trials</a> on patients with COVID-19 will be able to reveal precisely whether these interventions are safe and effective. Unfortunately, these kinds of large trials take time to carry out, but they are ongoing.</p>
<p>The <a href="https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments">World Heath Organization</a> (WHO) announced it has helped to launch four “mega trials” against COVID-19 and there are countless more smaller ones coordinated in countries worldwide. </p>
<p>The WHO-backed trials are focusing on drugs that are thought to directly block SARS-CoV-2 – the virus strain that causes coronavirus COVID-19 – from replicating inside our lungs. Below are some of the main drugs these trials are looking at.</p>
<h2>Remdesivir</h2>
<p>This is an intravenous antiviral drug that was developed to block infection with related coronaviruses and even Ebola, and is one of the drugs the WHO is helping to investigate. </p>
<p><a href="https://www.nature.com/articles/s41422-020-0282-0">Remdisivir</a> has already been shown to work against SARS-CoV-2 in cells in a dish in a lab as well as in mice infected with the virus. Remdesivir specifically targets key viral proteins involved in making new copies of the virus and prevents them from working. </p>
<p>Remdesivir has already been used in some COVID-19 <a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2007016">patients in the US</a> and appears safe, but large trials are needed to really know if this is the case. </p>
<h2>Lopinavir/ritonavir</h2>
<p>This is a drug combination used against viruses like HIV. It works in a similar way to remdesivir by blocking key viral proteins called “proteases”. </p>
<p><a href="https://www.nejm.org/doi/full/10.1056/NEJMoa2001282">Lopinavir/ritonavir</a> has also been shown to be effective against SARS-CoV-2 in lab cells as well as in mice and is being tested alongside an antiviral drug called interferon beta. This is currently used to treat Multiple sclerosis and can enhance the natural defences of the body’s cells against COVID-19.</p>
<h2>Chloroquine and hydroxychloroquine</h2>
<p>Both of <a href="https://theconversation.com/chloroquine-and-hydroxychloroquine-no-proof-these-anti-malarial-drugs-prevent-novel-coronavirus-in-humans-134703">these drugs</a> are currently used to treat malaria and the autoimmune disease lupus. <a href="https://theconversation.com/could-chloroquine-treat-coronavirus-5-questions-answered-about-a-promising-problematic-and-unproven-use-for-an-antimalarial-drug-134511">Chloroquine</a> has been tested against lots of different infections because in the lab it can block viruses – including SARS-CoV-2 - from getting inside cells placed in a dish and so prevent infection. </p>
<p>Outside the lab, chloroquine has not been demonstrated to have a profound effect at preventing disease and there is limited evidence so far that it can work for COVID-19, despite receiving <a href="https://www.sciencemag.org/news/2020/03/insane-many-scientists-lament-trump-s-embrace-risky-malaria-drugs-coronavirus">a lot of hype from President Donald Trump</a>. But again, large trials are needed and the WHO is supporting these. </p>
<p>Caution should be observed with chloroquine as it can have significant side effects in certain people and may even block the immune response – the desired result in lupus treatment.</p>
<h2>Two other options</h2>
<p>The above potential treatments all work by blocking some key element of the virus infection machinery using small molecules. Two other kinds of treatments are also being explored in trials that work in a different way. </p>
<p>The first is <a href="https://www.jci.org/articles/view/138003">passive immunisation</a> which is the transfer – or transfusion – of potential protective antibodies from someone who has been infected and recovered from COVID-19 to someone who is at high-risk or is suffering from a SARS-CoV-2 infection. </p>
<p>This so-called “<a href="https://www.jci.org/articles/view/138003">convalescent sera</a>” (which is a purified blood product from someone who has recovered from COVID-19) can block SARS-CoV-2 in cells in a dish in the lab and has the potential to help develop treatments. Passive immunisation for COVID-19 is being tested in trials across the world and so far results seem to <a href="https://jamanetwork.com/journals/jama/fullarticle/2763983">suggest it is safe to use</a>. </p>
<p>Another kind of possible treatment works by blocking parts of our own immune system that are likely overreacting to SARS-CoV-2 infection and <a href="https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30628-0/fulltext">contributing to the damage in our lungs</a>. </p>
<p>In the limited studies that have been conducted on COVID-19, it seems that in some severe cases our immune response goes into overdrive without being able to clear the infection and this can increase the severity of the disease. When this happens, high levels of inflammation is found in the lungs. </p>
<p>Potential treatments that look at blocking the immune components linked to this severity <a href="https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30092-8/fulltext">have begun</a>. That said, extreme caution must be taken when manipulating the immune response during an infection as in the absence of other therapies we rely on our immune response to limit the virus replicating.</p>
<p>So although specific treatments for COVID-19 are not yet available, drugs are being tested and clinical trials and starting to yield results. This, combined with the further knowledge that scientists are gaining about SARS-CoV-2 will help massively until a vaccine becomes available.</p>
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<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=140&fit=crop&dpr=1 600w, https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=140&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=140&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=176&fit=crop&dpr=1 754w, https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=176&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/301912/original/file-20191115-66957-gxdqkd.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=176&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<p><em>Get the latest news and analysis, direct from the experts in your inbox, every day. Join hundreds of thousands who trust experts by <strong><a href="http://theconversation.com/newsletter?utm_source=TCUK&utm_medium=linkback&utm_campaign=TCNewsletter&utm_content=newsletterA">subscribing to our newsletter</a></strong>.</em></p><img src="https://counter.theconversation.com/content/135352/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Connor Bamford receives funding from the Wellcome Trust.</span></em></p>Coronavirus drug trials are underway – a virologist explains what the treatment options may be.Connor G G Bamford, Research Fellow, Virology, Queen's University BelfastLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1346382020-04-08T12:13:38Z2020-04-08T12:13:38ZIn the rush to innovate for COVID-19 drugs, sound science is still essential<figure><img src="https://images.theconversation.com/files/325881/original/file-20200406-110267-1281ry5.jpg?ixlib=rb-1.1.0&rect=65%2C90%2C5398%2C3432&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Employees work on the production line of chloroquine phosphate, resumed after a 15-year break, in a pharmaceutical company in Nantong city in east China's Jiangsu province Thursday, Feb. 27, 2020. </span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/employees-work-on-the-production-line-of-chloroquine-news-photo/1203673365?adppopup=true">Feature China/Barcroft Media via Getty Images</a></span></figcaption></figure><p><a href="https://www.statnews.com/2020/04/06/trump-hydroxychloroquine-fact-check/">Hydroxychloroquine and chloroquine</a> have been at the center of debate in recent weeks over which drugs should be used to treat COVID-19. Neither product has strong evidence to support use for this purpose, and small studies reported to date have either had significant flaws or failed to demonstrate effect. </p>
<p>Nonetheless, the president can’t seem to stop <a href="https://www.nytimes.com/2020/04/06/us/politics/coronavirus-trump-malaria-drug.html">pushing them</a>, arguing that patients have nothing to lose. As physicians, bioethicists and drug law experts, we have a responsibility to inject caution here. As public officials and scientists rush to innovate, no one should overlook the critical role of strong regulatory protections in supporting our ability to actually figure out which drugs work against COVID-19. Weakening commitment to science and evidence during this crisis truly would be “<a href="https://twitter.com/realDonaldTrump/status/1241935285916782593">a cure worse</a>” than the disease. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=384&fit=crop&dpr=1 600w, https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=384&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=384&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=483&fit=crop&dpr=1 754w, https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=483&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/325443/original/file-20200404-74216-1totpj9.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=483&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">The FDA is on the lookout for fraudulent products that claim to cure COVID-19.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/the-outside-of-the-food-and-drug-administration-news-photo/496532228?adppopup=true">Getty Images / Al Drago / CQ Roll Call</a></span>
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<h2>FDA’s emergency use authorization</h2>
<p>There are no Food and Drug Administration-approved drugs to treat COVID-19, and no product has strong data to support its use against this disease. Nonetheless, on March 28, the FDA issued an <a href="https://www.fda.gov/media/136534/download">emergency use authorization</a> (EUA) for certain hydroxychloroquine sulfate and chloroquine phosphate products donated to the strategic national stockpile by various pharmaceutical companies. The EUA was granted exclusively to the Biomedical Advanced Research and Development Authority (BARDA), allowing it to distribute these stockpiled drugs to local public health authorities for the unapproved use of treating hospitalized COVID-19 patients unable to participate in clinical trials. </p>
<p>An <a href="https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/emergency-use-authorization">EUA</a> is not the same as the FDA’s traditional marketing approval. To be approved under normal rules, drugs must be shown safe and effective for their intended use. An EUA, in contrast, is a temporary authorization granted in the face of a public health emergency, based only on a determination that a product “may” be effective and that its likely benefits outweigh its likely risks. This EUA was supported only by “limited in-vitro and anecdotal clinical data in case series” – with no acknowledgment of contrary data or <a href="https://jamanetwork.com/journals/jama/fullarticle/2763802">significant safety concerns</a>. Overall, it’s sown even further confusion about the promise and uncertainties of these drugs. </p>
<h2>Off-label use</h2>
<p>An EUA is <a href="https://www.youtube.com/watch?v=4Bve0hBt1qg&feature=youtu.be">not the only way</a> that COVID-19 patients may access hydroxychloroquine and chloroquine. A physician is generally free to prescribe approved drugs for unapproved uses as part of their authority to practice medicine. This is referred to as “off-label” use. Because several hydroxychloroquine and chloroquine products have been FDA-approved for malaria, lupus and rheumatoid arthritis, they’re eligible for off-label use against COVID-19. </p>
<p>Following President Trump’s comments that these drugs could be a potential “<a href="https://abcnews.go.com/Politics/fauci-throws-cold-water-trumps-declaration-malaria-drug/story?id=69716324">game changer</a>,” attention and prescriptions sky-rocketed, despite caution from experts. Some physicians <a href="https://www.nytimes.com/2020/03/24/business/doctors-buying-coronavirus-drugs.html">stockpiled the drugs for personal use</a>, and several hospitals have adopted hydroxychloroquine as COVID-19 standard of care. Although there have been efforts to help protect supply for those patients needing the drug for their proven indications, some of these patients have been told they may have to <a href="https://www.buzzfeednews.com/article/tanyachen/kaiser-permanente-lupus-chloroquine">go without</a>.</p>
<p>It is <a href="https://annals.org/aim/fullarticle/2764199/use-hydroxychloroquine-chloroquine-during-covid-19-pandemic-what-every-clinician?fbclid=IwAR2H4Iv_4yXUEQZIC8EiB437guq3B_R6o9VfB9ltA6bUfpmFBVgz3-Ww1dA">too soon to say</a> whether chloroquine products work for COVID-19, since the <a href="https://annals.org/aim/fullarticle/2764065/rush-judgment-rapid-reporting-dissemination-results-its-consequences-regarding-use">few clinical studies</a> are small and lack randomization or carefully matched control groups. Severe side effects have caused <a href="https://www.newsweek.com/swedish-hospitals-chloroquine-covid-19-side-effects-1496368?fbclid=IwAR0Bwnsd9czDSJkgMug0wWcozXBVorouU5mklHfYZ4bM4KcqP-fOnfkLWfk">some hospitals</a> to stop using them altogether.</p>
<p>There is a great need for rigorously conducted clinical trials on these products and their possible effectiveness in fighting COVID-19. But if physicians continue prescribing them off-label, without regard for appropriate testing, we’ll be left with anecdotes, not evidence. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/325445/original/file-20200404-74235-1gxu50j.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A box of hydroxychloroquine, marketed under the name of Plaquenil, in a Paris pharmacy.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/news-photo/pharmacy-employee-wearing-a-protective-mask-shows-a-box-of-news-photo/1215113294?adppopup=true">Getty Images / Chesnot</a></span>
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<h2>Expanded access to new drugs</h2>
<p>There are other drugs with some potential to combat COVID-19, but that have not yet been approved for any use and therefore may not be prescribed off-label. These drugs are currently under investigation in clinical trials around the U.S. and the globe. For seriously ill patients, the FDA has <a href="https://www.fda.gov/news-events/public-health-focus/expanded-access">a pathway</a> known as “expanded access” (sometimes called “compassionate use”) by which patients may be dosed with unapproved drugs for treatment use, if they are unable to enroll in a clinical trial. This eligibility restriction is critical because it ensures that patients cannot secure access by opting out of the trials designed to produce the evidence needed to confidently assess a product’s safety and efficacy. </p>
<p>Drug maker Gilead has emphasized this approach with its investigational antiviral drug remdesivir. Even as it opens its <a href="https://www.gilead.com/stories/articles/an-open-letter-from-our-chairman-and-ceo">expanded access program</a> through a wider pathway, the company <a href="https://www.gilead.com/purpose/advancing-global-health/covid-19/emergency-access-to-remdesivir-outside-of-clinical-trials">has explained</a> that participation in clinical trials will be the primary mode of patient access. </p>
<h2>Focus on science</h2>
<p>Pragmatism is needed to collect data in real time, as patients are also in desperate need of treatment. That’s precisely the approach taken by the World Health Organization in its <a href="https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarity-clinical-trial-for-covid-19-treatments">mega trial</a> of four potential treatments for COVID-19, including remdesivir and chloroquine products, with over 70 countries participating. The trial is aptly named SOLIDARITY, and it is designed to minimize the burden on physicians and patients, while allowing random assignment and collection of systematic, anonymous data.</p>
<p>We simply have to stop guessing about what’s going to work for patients battling COVID-19. Patients today and tomorrow need a commitment from politicians, policymakers, companies and physicians to prioritize science and <a href="https://jamanetwork.com/journals/jama/fullarticle/2763802">rigorous study</a>. Off-label use and expanded access may be reasonable options for patients when there is no clinical trial available, but if there is, we have to prioritize enrollment.</p>
<p>The FDA has demonstrated its willingness to help speed trials and facilitate the collection of data. But its regulatory standards must not be short-circuited and its flexibility must be used judiciously. Federal policy in this area should be driven by scientific expertise, not false hope, hunches or short-sighted political demands.</p>
<p>[<em>Get facts about coronavirus and the latest research.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=upper-coronavirus-facts">Sign up for The Conversation’s newsletter.</a>]</p><img src="https://counter.theconversation.com/content/134638/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christopher Robertson is author of Exposed: Why Our Health Insurance is Incomplete and What Can Be Done About It (2019 Harvard University Press). He is affiliated faculty with the Petrie Flom Center for Health Care Policy, Bioethics and Biotechnology at Harvard, and a reporter for the Health Law Monitoring Committee of the Uniform Law Commission. He is part of the NYU Working Group on Compassionate Use and Preapproval Access, an academic group focused on access to investigational medicines. </span></em></p><p class="fine-print"><em><span>Alison Bateman-House is co-Chair of the NYU Working Group on Compassionate Use and Preapproval Access, an academic group focused on access to investigational medicines, and has testified before Congress about this topic. In 2020, the FDA paid for her travel expenses to speak about access to investigational medicines at a Center for Biologics Evaluation and Research public meeting. Bateman-House administers a NYU program that provides advice about access to investigational medicines to Janssen Pharmaceuticals, a part of Johnson & Johnson. She receives no pay for this work, but her employer, the Division of Medical Ethics, receives money from Johnson & Johnson to run the program.
</span></em></p><p class="fine-print"><em><span>Holly Fernandez Lynch receives funding from the Greenwall Foundation as a Faculty Scholar. She is a member of the NYU Working Group on Compassionate Use and Preapproval Access. </span></em></p><p class="fine-print"><em><span>Keith Joiner is Professor of Medicine, Economics and Health Promotion Sciences at the University of Arizona. He teaches health economics in the Eller College of Management at the University of Arizona. He is an Infectious Disease specialist with prior funding from the National Institutes of Health and the Burroughs Wellcome Fund for basic science research on a variety of infectious diseases, including malaria.
</span></em></p>To battle the coronavirus, strong regulatory protection from the FDA is essential.Christopher Robertson, Professor of Law, Boston UniversityAlison Bateman-House, Research Assistant Professor, Division of Medical Ethics, New York UniversityHolly Fernandez Lynch, Assistant Professor of Medical Ethics, University of PennsylvaniaKeith Joiner, Professor of Medicine, Economics and Health Promotions Science, University of ArizonaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1354842020-04-03T12:40:54Z2020-04-03T12:40:54ZA small trial finds that hydroxychloroquine is not effective for treating coronavirus<figure><img src="https://images.theconversation.com/files/325047/original/file-20200402-74863-1r24p09.jpg?ixlib=rb-1.1.0&rect=218%2C311%2C4708%2C3404&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A trial of an anti-malaria drug in France found different results from a similar study last month.</span> <span class="attribution"><span class="source">Liliboas / Getty Images</span></span></figcaption></figure><p>On Saturday the <a href="https://www.hhs.gov/about/news/2020/03/29/hhs-accepts-donations-of-medicine-to-strategic-national-stockpile-as-possible-treatments-for-covid-19-patients.html">Food and Drug Administration approved the use of two antimalarial drugs</a>, hydroxychloroquine and a related medication, chloroquine, for emergency use to treat COVID-19. The drugs were touted by <a href="https://theconversation.com/could-chloroquine-treat-coronavirus-5-questions-answered-about-a-promising-problematic-and-unproven-use-for-an-antimalarial-drug-134511">President Trump as a “game changer”</a> for COVID-19. </p>
<p>However, <a href="https://doi.org/10.1016/j.medmal.2020.03.006">a study just published</a> in a French medical journal provides new evidence that hydroxychloroquine does not appear to help the immune system clear the coronavirus from the body. The study comes on the heels of two others - one in France and <a href="https://www.nytimes.com/2020/04/01/health/hydroxychloroquine-coronavirus-malaria.html">one in China</a> - that reported some benefits in the combination of hydroxychloroquine and azithromycin for COVID-19 patients who didn’t have severe symptoms of the virus.</p>
<p><a href="https://chemistry.umbc.edu/seley-radtke-lab/">I am a medicinal chemist</a> who has specialized in discovery and development of antiviral drugs for the past 30 years, and I have been actively working on coronaviruses for the past seven. I am among a number of researchers who are concerned that this drug has been given too much of a high priority before there is enough evidence to show it is indeed effective. </p>
<p>There are already other clinical studies that showed it is <a href="http://www.zjujournals.com/med/EN/10.3785/j.issn.1008-9292.2020.03.03">not effective against COVID-19</a> <a href="http://doi.org/10.3390/v10050268">as well</a> <a href="https://doi.org/10.1371/journal.pntd.0000785">as</a> <a href="http://doi.org/10.1016/S1473-3099(11)70065-2">several other</a> <a href="http://doi.org/10.1001/jama.2012.6936">viruses</a>. And, more importantly, it can have dangerous side effects, as well as giving people false hope. The latter has led to widespread shortages of hydroxychloroquine for patients who need it to treat malaria, lupus and rheumatoid arthritis, the indications for which it was originally approved. </p>
<p>The idea that the combination of hydroxychloroquine with an antibiotic drug, azithromycin, was effective against COVID-19 gained more attention after a study published on March 17. This study described a trial of 80 patients carried out by <a href="https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf">Philippe Gautret in Marseille, France</a>. Although some of their results appeared to be encouraging, it should also be noted that most of their patients only had mild symptoms. Furthermore, 85% of the patients didn’t even have a fever – one of the major telltale symptoms of the virus, thus suggesting that these patients likely would have naturally cleared the virus without any intervention.</p>
<p><a href="https://doi.org/10.1101/2020.03.22.20040758">In another study, posted on medRxiv</a>, which has not yet been peer-reviewed, Chinese scientists from Renmin Hospital of Wuhan University, in Wuhan, China, gave hydroxychloroquine to patients with only mild infections who were free of medical issues, similar to the Gautret study. The results showed that the 31 patients who received the drug showed a lessening of their symptoms 24 hours earlier than patients in the control group. In addition, pneumonia symptoms improved in 25 of the 31 patients versus 17 of 31 in the control group. As noted in several of the comments associated with the manuscript, there are issues related to the translation of the paper, thus clouding interpretations of some of the results. The paper also appears to focus more on pneumonia than COVID-19. However, these issues may be cleared up or addressed once the paper finishes the peer-review process. </p>
<p>But two other studies have conflicting results.</p>
<p>A second French group, led by Jean-Michel Molina, has now tested the hydroxychloroquine-azithromycin combination treatment in 11 patients at the Hôpital Saint-Louis in Paris, France, and their <a href="https://doi.org/10.1016/j.medmal.2020.03.006">results were strikingly different</a>. </p>
<p>Like the Marseille study, the Molina trial was also a small pilot study. Molina and colleagues used the same dosing regimen as Gautret. In contrast, however, to the Gautret study, eight of the 11 patients had underlying health conditions, and 10 of 11 had fevers and were quite ill at the time the dosing began. </p>
<p>These Paris researchers found that after five to six days of treatment with hydroxychloroquine (600 mg per day for 10 days) and azithromycin (500 mg on day 1 and 250 mg on days 2 to 5), eight of the 10 patients still tested positive for COVID-19. Of these 10 patients, one patient died, two were transferred to the ICU and another had to be removed from the treatment due to serious complications. </p>
<p>In addition, <a href="http://www.zjujournals.com/med/EN/10.3785/j.issn.1008-9292.2020.03.03">a similar study in China</a> also showed no difference in viral clearance after seven days either with or without the hydroxychloroquine with the patients in the trial. This supports Molina’s findings. </p>
<p>Thus, despite the recent approval of this drug for use against COVID-19, questions remain as to the efficacy of this treatment. As Molina and colleagues note: “Ongoing randomized clinical trials with hydroxychloroquine should provide a definitive answer regarding the alleged efficacy of this combination and will assess its safety.”</p>
<p>[<em>You need to understand the coronavirus pandemic, and we can help.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=upper-coronavirus-help">Read The Conversation’s newsletter</a>.]</p><img src="https://counter.theconversation.com/content/135484/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Katherine Seley-Radtke receives funding for her research from the National Institutes of Health and the National Institute of Allergies and Infectious Diseases. </span></em></p>The president promoted the combination of hydroxychloroquine and an antibiotic for treating COVID-19. But a new study suggests it provides no benefits.Katherine Seley-Radtke, Professor of Chemistry and Biochemistry and President-Elect of the International Society for Antiviral Research, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1349472020-03-31T10:47:34Z2020-03-31T10:47:34ZNo, cinchona bark is not a cure for coronavirus<p>Posts touting the curative effects of cinchona, or fever tree, bark have recently been circulating on social networks such as Instagram and Facebook. These posts promise a “natural” source of the prescription-only drug chloroquine. </p>
<p>Chloroquine and hydroxychloroquine are currently being researched as potential treatments for COVID-19. The public has paid increased attention to these drugs since US President Donald Trump mentioned “promising” results in a <a href="https://factba.se/transcript/donald-trump-remarks-fema-governors-teleconference-march-19-2020">speech on March 19 2020</a>. As the drug is not available over the counter and is in relatively short supply, there is an interest in alternative sources, and the bark of the cinchona tree is being advertised as one.</p>
<p>Hydroxychloroquine and chloroquine are antimalarial drugs. (Although, despite nearly a century of use, scientists still don’t fully understand how their antimalarial properties work.) They are also prescribed for lupus and rheumatoid arthritis. </p>
<p>Most people would not have heard of these drugs, though, if it hadn’t been for recent news reports about research which suggests they may inhibit the ability of the novel coronavirus to infect cells. However, some have <a href="https://theconversation.com/could-chloroquine-treat-coronavirus-5-questions-answered-about-a-promising-problematic-and-unproven-use-for-an-antimalarial-drug-134511">expressed concern</a> about the quality of the trials and the statements made by Trump. More worrying are reports of people self-medicating, <a href="https://www.washingtonpost.com/gdpr-consent/?next_url=https%3a%2f%2fwww.washingtonpost.com%2fnation%2f2020%2f03%2f24%2fcoronavirus-chloroquine-poisoning-death%2f">with one couple taking a fishtank cleaner</a>, containing chloroquine phosphate, resulting in the death of one and the hospitalisation of the other. </p>
<p>There has also been a rise in demand for chloroquine, which has meant some patients have been unable to access their <a href="https://www.theguardian.com/world/2020/mar/27/vital-drug-people-lupus-coronavirus-covid-19-link-hydroxychloroquine">regular prescriptions</a>. </p>
<p>False links are now being made between another source of antimalarial compounds, cinchona bark, as a natural or alternative source of chloroquine or hydroxychloroquine. As quinine from cinchona bark is an ingredient in tonic water (in very low amounts), there have been rumours that it could also protect against SARS-CoV-2 – the virus that causes COVID-19.</p>
<h2>Cinchona, quinine and chloroquine</h2>
<p>Since its <a href="https://academic.oup.com/jhmas/article-lookup/doi/10.1093/jhmas/jrw004">discovery in the 17th century</a>, the bark of the Andean cinchona tree and its chemical constituents, known as quinoline alkaloids (quinine, quinidine, cinchonine and cinchonidine), provided the only treatment for malaria for over 300 years. In 1934, scientists developed the first synthetic antimalarial, later known as <a href="https://blogs.sciencemag.org/pipeline/archives/2020/03/20/chloroquine-past-and-present?fbclid=IwAR3_DIyv-VW_fguO-VzV95hJzS9KrbDvkrym0_Ud_u17QtDBdvC7lGzTjCw">chloroquine</a>. Although chloroquine was inspired by the antimalarial activity of quinine, its chemical structure (and pharmacological properties) are quite different from the natural compounds found in cinchona bark.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=278&fit=crop&dpr=1 600w, https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=278&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=278&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=349&fit=crop&dpr=1 754w, https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=349&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/323728/original/file-20200328-146695-19jgpfc.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=349&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The different chemical structures of quinine and chloroquine.</span>
<span class="attribution"><span class="source">Cassandra Quave, Emory University. Author provided (No reuse).</span></span>
</figcaption>
</figure>
<p>To date, there is no laboratory or clinical evidence that quinine or any other cinchona bark compounds exhibit activity against COVID-19. Also, not everything that is natural is safe. Cinchona and quinine are toxic and can cause <a href="https://www.sciencedirect.com/science/article/abs/pii/S1357303915003205">serious side-effects</a> known as “cinchonism” which can include hearing and vision loss, breathing issues, and heart and kidney issues. It can also lead to a coma. </p>
<p>While quinine pills were once sold over the counter in the US to treat night leg cramps, they were <a href="https://www.webmd.com/pain-management/news/20061212/fda-dont-use-quinine-leg-cramps">pulled from the market by the Food and Drug Administration</a> in 2006 after serious side effects and death were reported.</p>
<h2>Pandemic profiteering</h2>
<p>History is <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2762764/">full of examples</a> of people profiting from the public’s panic and fear during unstable times. The European Union law enforcement agency has already seized <a href="https://www.europol.europa.eu/newsroom/news/rise-of-fake-%E2%80%98corona-cures%E2%80%99-revealed-in-global-counterfeit-medicine-operation">48,000 packages</a> of potentially dangerous pharmaceuticals, including unauthorised chloroquine, as well as fake masks and bogus coronavirus cures. </p>
<p>The benefits, if any, of chloroquine or hydroxychloroquine for treating COVID-19 are still not fully understood. Cinchona bark does not contain either of these compounds, and the alkaloids in the bark bear no relation to them. Likewise, there is no evidence of cinchona being able to prevent or treat COVID-19. </p>
<p>Cinchona is highly toxic and self-medication with it or any other unproven cures should be avoided. Protect your health and don’t waste money funding unethical people and companies profiteering off fear in these uncertain times.</p><img src="https://counter.theconversation.com/content/134947/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Kim Walker receives funding from Techne National Productivity Investment Fund (NPIF), part of the Arts and Humanities Research Council (AHRC). </span></em></p><p class="fine-print"><em><span>Cassandra Quave receives funding from the United States National Institutes of Health (NIH), National Center for Complementary and Integrative Health (NCCIH) and the National Institute of Allergy and Infectious Diseases (NIAID). The content is solely the responsibility of the authors and does not necessarily reflect the official view of NCCIH, NIAID or NIH.</span></em></p><p class="fine-print"><em><span>Nataly Olivia A. Canales receives funding from the European Union's Horizon 2020 research and innovation programme under H2020 MSCA-ITN-ETN grant agreement No 765000 Plant.ID.</span></em></p>Cinchona bark, the flavouring in tonic water, is not a natural source of chloroquine.Kim Walker, PhD Candidate, Economic Botany Collection, Royal Botanic Gardens, Kew, Royal Holloway University of LondonCassandra Quave, Assistant Professor of Dermatology and Human Health; Herbarium Curator, Emory UniversityNataly Olivia A Canales, PhD Fellow in Evolutionary Genomics, Natural History Museum of Denmark, University of CopenhagenLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1347032020-03-26T12:43:34Z2020-03-26T12:43:34ZChloroquine and hydroxychloroquine: no proof these anti-malarial drugs prevent novel coronavirus in humans<figure><img src="https://images.theconversation.com/files/323232/original/file-20200326-132969-jxpmul.jpg?ixlib=rb-1.1.0&rect=46%2C23%2C5156%2C3403&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Chloroquine is an anti-malarial drug.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/doctor-holding-chloroquine-phosphate-drug-1671796519">baranq/ Shutterstock</a></span></figcaption></figure><p>There’s worrying news around the world of people self-medicating at home with the drugs chloroquine and hydroxychloroquine to treat COVID-19. There’s since been reports of <a href="https://edition.cnn.com/2020/03/23/africa/chloroquine-trump-nigeria-intl/index.html">chloroquine poisoning</a> and even <a href="https://edition.cnn.com/2020/03/23/health/arizona-coronavirus-chloroquine-death/index.html">death</a> after taking the drug. Scientists <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/">first reported</a> chloroquine’s potential against coronaviruses after the <a href="https://www.who.int/ith/diseases/sars/en/">Sars epidemic in 2003</a>.</p>
<p>Part of the recent confusion seems to have followed US president Donald Trump’s <a href="https://twitter.com/realdonaldtrump/status/1241367239900778501">announcement on Twitter</a> that implied hydroxychloroquine and another drug (the antibiotic <a href="https://www.nhs.uk/medicines/azithromycin/">azithromycin</a>) taken together could treat novel coronavirus. The US Food and Drug Administration <a href="https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-facilitate-development-treatments">released a statement</a> in response, saying they’re still looking into whether chloroquine can treat people with mild to moderate symptoms of COVID-19. Neither of these drugs have <a href="https://www.bbc.co.uk/news/51980731">been approved</a> in the US to treat COVID-19. Tests are still being conducted elsewhere, <a href="https://www.who.int/blueprint/priority-diseases/key-action/RD-Blueprint-expert-group-on-CQ-call-Mar-13-2020.pdf">including in China</a>, to see whether they can help treat patients admitted to hospital with COVID-19. </p>
<p><a href="https://www.nhs.uk/conditions/malaria/treatment/">Chloroquine</a> has been around for more than 80 years. It was developed as an antimalarial drug but is now also used to treat conditions including <a href="https://www.ncbi.nlm.nih.gov/pubmed/6678200">rheumatoid arthritis</a> and <a href="https://ard.bmj.com/content/78/6/736">systemic and discoid lupus erythematosus</a> (lupus). It was produced to provide another treatment option to <a href="https://www.britannica.com/science/quinine">quinine</a>, an older antimalarial drug, which came from the bark of cinchona trees. </p>
<p><a href="https://bnf.nice.org.uk/drug/hydroxychloroquine-sulfate.html#indicationsAndDoses">Hydroxychloroquine</a>, which has <a href="https://link.springer.com/article/10.1007%2Fs12016-010-8243-x">been around since 1955</a>, is similar to chloroquine but <a href="https://www.sciencedirect.com/science/article/abs/pii/0002934383912652">less toxic</a>. But it does have some <a href="https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/009768s041lbl.pdf">side effects</a>, including stomach problems and long-term problems for the eyes. Like chloroquine, hydroxychloroquine is used to treat rheumatoid arthritis and lupus, and is also <a href="http://www.bad.org.uk/shared/get-file.ashx?id=92&itemtype=document">used for managing sun allergies</a>.</p>
<p>Chloroquine has been <a href="https://www.who.int/ith/diseases/malaria/en/">used to treat malaria</a> for many years, but it <a href="https://www.who.int/malaria/publications/mct_workingpaper.pdf">stopped</a> <a href="https://apps.who.int/iris/bitstream/handle/10665/44449/9789241500470_eng.pdf?sequence=1">working</a> against malaria caused by the <em>Plasmodium Falciparum</em> parasite which is <a href="https://apps.who.int/medicinedocs/en/d/Jh2922e/2.5.html">common in sub-Saharan Africa</a>. Despite this, chloroquine is still available to buy in Nigeria where people have starting taking it for COVID-19 – <a href="https://www.theglobeandmail.com/world/article-at-least-two-cases-of-chloroquine-poisoning-in-nigeria-after-trump/">leading to reports</a> of <a href="https://twitter.com/gboyegaakosile/status/1240968351280697344?ref_src=twsrc%5Etfw%7Ctwcamp%5Etweetembed%7Ctwterm%5E1240968351280697344&ref_url=https%3A%2F%2Fwww.cnn.com%2F2020%2F03%2F23%2Fafrica%2Fchloroquine-trump-nigeria-intl%2Findex.html">accidental poisonings</a>. </p>
<p>The seriousness of the problem has led the Nigeria Centre for Disease Control to <a href="https://twitter.com/NCDCgov/status/1241006420419641345">announce on Twitter</a> that chloroquine is not approved for COVID-19 and that self-medicating with the drug will cause harm – and could lead to death.</p>
<p>Chloroquine is <a href="https://www.who.int/docs/default-source/coronaviruse/transcripts/who-audio-emergencies-coronavirus-full-press-conference-20feb2020-final.pdf?sfvrsn=3295d775_0">not yet proven</a> to work against COVID-19, though news reports originating in <a href="http://www.xinhuanet.com/english/2020-02/17/c_138792545.htm">China</a> have speculated otherwise. <a href="https://www.sciencedirect.com/science/article/pii/S0166354220301145?via%3Dihub">Scientists</a> have asked <a href="https://www.jstage.jst.go.jp/article/bst/14/1/14_2020.01047/_article">Chinese researchers</a> to share details of their findings. </p>
<p>But <a href="https://www.msn.com/en-za/news/other/chloroquine-found-effective-against-coronavirus-cures-12552-patients-in-china/ar-BB10cWjT">theories about chloroquine</a> and COVID-19 have <a href="https://www.wired.com/story/an-old-malaria-drug-may-fight-covid-19-and-silicon-valleys-into-it/">spread around the world</a>, despite a lack of hard evidence about the value of chloroquine in preventing or treating COVID-19. Although chloroquine has been used for more than 80 years, it’s still <a href="https://pubchem.ncbi.nlm.nih.gov/compound/chloroquine#section=Acute-Effects&fullscreen=true">far from safe</a> if used without medical advice. </p>
<p>First, it’s really easy to get the dose of chloroquine wrong and end up with too much of it in the body if taken without medical advice. <a href="https://journals.sagepub.com/doi/full/10.1345/aph.1C311">Too much</a> <a href="https://pmj.bmj.com/content/postgradmedj/67/789/678.full.pdf">chloroquine</a> is <a href="https://apps.who.int/iris/bitstream/handle/10665/65773/WHO_MAL_79.906.pdf?sequence=1&isAllowed=y">poisonous</a>. Symptoms of chloroquine poisoning include feeling sick or having a stomachache, vomiting, feeling sleepy and body shakes. Without urgent medical care, your breathing and heart can stop, or you could slip into a coma. <a href="https://apps.who.int/iris/bitstream/handle/10665/65773/WHO_MAL_79.906.pdf?sequence=1&isAllowed=y">Patients can die</a> very quickly from chloroquine poisoning – <a href="http://www.annals.edu.sg/pdf/40VolNo6Jun2011/V40N6p296.pdf">within a few hours</a>.</p>
<p>Second, it takes the body a really long time to flush all of the chloroquine out. Even if you take the correct dose of chloroquine, the build up of it in the body over many years might still cause damage. For example, chloroquine is especially <a href="https://www.ncbi.nlm.nih.gov/pubmed/3964626">harmful to the eyes</a> and can cause vision loss with long-term use. No one should take it without having <a href="https://www.ncbi.nlm.nih.gov/books/NBK537086/">regular eye checks</a>.</p>
<h2>Ongoing research</h2>
<p>The science around chloroquine and COVID-19 is so far inconclusive. Chloroquine and hydroxychoroquine have been <a href="https://www.nature.com/articles/s41421-020-0156-0">tested against</a> the <a href="https://www.nature.com/articles/s41422-020-0282-0">novel coronavirus</a> both <a href="https://www.sciencedirect.com/science/article/pii/S0924857920300881?via%3Dihub">in the lab</a>, and <a href="https://www.sciencedirect.com/science/article/pii/S0924857920300996?via%3Dihub">in patients</a>. But <a href="https://www.who.int/blueprint/priority-diseases/key-action/RD-Blueprint-expert-group-on-CQ-call-Mar-13-2020.pdf">none of the studies</a> so far show convincing evidence that chloroquine or hydroxychloroquine work against COVID-19. </p>
<p>For example, the patient study claiming <a href="https://www.sciencedirect.com/science/article/pii/S0924857920300996?via%3Dihub">hydroxychloroquine is effective in COVID-19</a> didn’t use a control group. This means we don’t know if the results would have been any different without giving hydroxychloroquine. For now, the <a href="https://sccm.org/getattachment/Disaster/SSC-COVID19-Critical-Care-Guidelines.pdf?lang=en-US&_zs=ugFQi1&_zl=j1cc6">US Society of Critical Care Medicines</a> has said there isn’t sufficient evidence to recommend the use of chloroquine or hydroxychloroquine in critically ill adults with COVID-19.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/323235/original/file-20200326-132995-vpmpko.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">There isn’t enough evidence yet into the use of either drug to treat COVID-19.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/hydroxychloroquine-chloroquine-pills-generic-plaquenil-on-1680633361">David Shao/ Shutterstock</a></span>
</figcaption>
</figure>
<p>This doesn’t mean chloroquine is no longer being <a href="https://www.gov.uk/government/news/chloroquine-and-hydroxychloroquine-not-licensed-for-coronavirus-covid-19-treatment">explored in patient trials</a> though. There are <a href="https://www.who.int/ictrp/network/primary/en/">numerous ongoing studies</a> looking at the effect of different drugs on the virus, including chloroquine and hydroxychloroquine. <a href="https://infectioncontrol.ucsfmedicalcenter.org/sites/g/files/tkssra4681/f/UCSF%20Adult%20COVID%20draft%20management%20guidelines.pdf">Some hospitals are also publishing guidelines</a> for their staff which include the use of both drugs in treating patients with COVID-19 and lower respiratory tract infections. But from a scientific angle, there’s still reason to be cautious until <a href="https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html">these trials</a> are <a href="https://clinicaltrials.gov/ct2/show/NCT04303299?cond=COVID&draw=2&rank=1">finished</a>, and the results are known.</p>
<p>Because of the media attention on these prescription drugs, chloroquine and hydroxychloroquine are <a href="https://www.modernhealthcare.com/supply-chain/chloroquine-short-supply-hospitals-buy-bulk">now in short supply</a> for <a href="https://www.pharmacytimes.com/news/shortage-of-malaria-treatment-with-possibilities-for-covid-19-treatment">patients who need them</a> to treat their rheumatoid arthritis and lupus. Even more worryingly are <a href="https://twitter.com/DRxKatherine/status/1241816884166578176">reports on Twitter</a> and <a href="https://www.theguardian.com/world/2020/mar/25/australian-doctors-warned-off-after-prescribing-potentially-deadly-covid-19-trial-drug-to-themselves">in the media</a> that <a href="https://twitter.com/jessicashorty14/status/1241828448944787456">healthcare workers are self-prescribing</a> them to their own friends and family. This hoarding of medicines for personal use has been <a href="https://www.npr.org/sections/health-shots/2020/03/23/820228658/why-hoarding-of-hydroxychloroquine-needs-to-stop?t=1585004392184&t=1585035328209">called out</a> by <a href="https://www.reuters.com/article/us-health-coronavirus-usa-pharmacies/states-work-to-limit-prescriptions-of-potential-coronavirus-drugs-idUSKBN2190XC">state pharmacy boards</a> in the US.</p>
<p>If either chloroquine or hydroxychloroquine is found to be useful for COVID-19, it would need to be given by doctors monitoring patients closely to make sure the dose is right to avoid patient harm. Getting these drugs in a hospital setting under the care of doctors is quite different to deciding to buy and use them at home without supervision.</p>
<p>No one should be <a href="https://www.gov.uk/government/news/chloroquine-and-hydroxychloroquine-not-licensed-for-coronavirus-covid-19-treatment?utm_source=e9b36c55-1a1f-4fb8-8215-bb1bf1f82cdd&utm_medium=email&utm_campaign=govuk-notifications&utm_content=immediate&dm_i=EQ,6T08E,1STHU,R8RWK,1">self-treating with chloroquine or hydroxychloroquine</a> for COVID-19 as there is currently no proof they can cure the infection – and accidental harm is more likely if they are used in this way.</p><img src="https://counter.theconversation.com/content/134703/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Parastou Donyai does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Taking these drugs to treat COVID-19 without medical advice has caused poisonings and death.Parastou Donyai, Professor and Director of Pharmacy Practice, University of ReadingLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1345112020-03-25T15:50:31Z2020-03-25T15:50:31ZCould chloroquine treat coronavirus? 5 questions answered about a promising, problematic and unproven use for an antimalarial drug<figure><img src="https://images.theconversation.com/files/322670/original/file-20200324-155683-1a7ap98.jpg?ixlib=rb-1.1.0&rect=36%2C44%2C4857%2C3199&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An employee in Nantong, China, checks the production of chloroquine phosphate, an old drug for the treatment of malaria. </span> <span class="attribution"><span class="source">Feature China/Barcroft Media via Getty Images</span></span></figcaption></figure><p><a href="https://www.npr.org/sections/coronavirus-live-updates/2020/03/24/820512107/man-dies-woman-hospitalized-after-taking-form-of-chloroquine-to-prevent-covid-19">An Arizona man died</a>, and his wife was hospitalized, after taking a form of chloroquine, which <a href="https://abcnews.go.com/Politics/fauci-throws-cold-water-trumps-declaration-malaria-drug/story?id=69716324">President Trump has touted as an effective treatment for COVID-19</a>. The couple decided to self-medicate with chloroquine phosphate, which they had on hand to kill parasites in their fish, after hearing the <a href="https://www.nytimes.com/2020/03/19/health/coronavirus-drugs-chloroquine.html">president describe the drug as a “game changer.”</a> </p>
<p>Dr. Anthony Fauci, head of NIH’s National Institute for Allergies and Infectious Diseases, quickly corrected the statement, explaining that <a href="https://www.nytimes.com/aponline/2020/03/19/us/politics/ap-us-virus-outbreak-trump-fact-check.html">Trump’s comments</a> were based on anecdotes and not a controlled clinical trial. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=302&fit=crop&dpr=1 600w, https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=302&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=302&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=380&fit=crop&dpr=1 754w, https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=380&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/322764/original/file-20200325-194438-171frsu.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=380&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Donald Trump’s Twitter feed.</span>
<span class="attribution"><span class="source">@realDonaldTrump</span></span>
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<p><a href="https://chemistry.umbc.edu/faculty/katherine-seley-radtke/">I am a medicinal chemist</a> who specializes in discovery and development of antiviral drugs, and I have been actively working on coronaviruses for seven years. </p>
<p>However, because I am a scientist and I deal in facts and evidence-based medicine, I am concerned about the sweeping statements the president has been making regarding the use of chloroquine or the closely related hydroxychloroquine, both antimalarial drugs, as cures for COVID-19. So let’s examine the facts.</p>
<h2>What are chloroquine and hydroxychloroquine?</h2>
<p>These are both FDA-approved antimalarial drugs that have been in use for many years. Chloroquine was originally developed in 1934 at the pharmaceutical company Bayer and used in World War II to prevent malaria.</p>
<p>Although the FDA has not approved its use for these conditions, both <a href="https://blogs.sciencemag.org/pipeline/archives/2020/03/20/chloroquine-past-and-present">chloroquine and hydroxychloroquine are also used</a> to treat rheumatoid arthritis and lupus. </p>
<h2>What triggered talk that this drug might work?</h2>
<p>After the initial outbreak of MERS in 2012, scientists conducted random screens of thousands of approved drugs to identify one that might block MERS infection. <a href="https://doi.org/10.1038/d41573-020-00016-0">Several drugs, including chloroquine</a>, showed the ability to <a href="https://doi.org/10.1186/1743-422X-2-69">block coronaviruses</a> from infecting cells in vitro. But these drugs were not extensively pursued because ultimately they did not show enough activity to be considered further. </p>
<p>When the new coronavirus appeared, many drugs that had shown some initial promise against the related coronaviruses MERS and SARS were at the top of the list as worthy of further evaluation as possible treatments. </p>
<p>So the science is real, and a number of <a href="http://doi.org/10.1016/j.jcrc.2020.03.005">labs around the world are now investigating these drugs</a> and testing them in clinical trials in the U.S., <a href="http://doi.org/10.1016/j.ijantimicag.2020.105949">France</a> <a href="http://www.chictr.org.cn/showprojen.aspx?proj=49145">and China</a>. But so far, there is no consensus about whether the drugs are safe and effective for treating COVID-19, as it is still very early in the testing process. </p>
<h2>Why would antimalarial drugs work on a virus?</h2>
<p>It is still unclear how the chloroquines (or any antimalarial drug) would work against COVID-19, which is a virus. <a href="https://www.niaid.nih.gov/diseases-conditions/malaria">Malaria is caused by <em>Plasmodium</em> parasites</a> that are spread by mosquitoes, whereas <a href="https://www.niaid.nih.gov/diseases-conditions/covid-19">COVID-19 is caused by the SARS-CoV-2 virus</a>.</p>
<p>Viral infections and parasitic infections are very different, and so scientists wouldn’t expect what works for one to work for the other. It has been suggested that the chloroquines can change the <a href="https://doi.org/10.1016/j.ijantimicag.2020.105938">acidity at the surface of the cell</a>, thereby preventing the virus from infecting it. </p>
<p>It’s also possible chloroquines help <a href="https://doi.org/10.1016/j.ijantimicag.2020.105938">activate the immune response</a>. <a href="http://doi.org/10.1016/j.ijantimicag.2020.105949">One study that was just published</a> tested hydroxychloroquine in combination with an antibacterial drug (azithromycin), which worked better to stop the spread of the infection than hydroxychloroquine alone. However it’s only one preliminary study that was done on a limited test group.</p>
<h2>Do other drugs show promise?</h2>
<p>To my knowledge, no other antimalarial drugs have shown any meaningful activity against treating coronaviruses. However, another potential drug has risen to the forefront. Remdesivir, developed by Gilead Pharmaceuticals, seems to be highly effective at preventing viruses – including <a href="http://doi.org/10.1074/jbc.AC120.013056">coronaviruses such as SARS and MERS</a>, and <a href="https://doi.org/10.3390/v11040326">filoviruses such as Ebola</a> – from replicating. </p>
<p>In late February the <a href="https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins">National Institute for Allergy and Infectious Diseases launched</a> a clinical trial for Remdesivir. And this month <a href="https://www.gilead.com/news-and-press/press-room/press-releases/2020/2/gilead-sciences-initiates-two-phase-3-studies-of-investigational-antiviral-remdesivir-for-the-treatment-of-covid-19">Gilead launched two phase III trials</a> of the drug in medical centers in Asia.</p>
<h2>Should I start taking them to ward off coronavirus?</h2>
<p>Absolutely not. Chloroquine and hydroxychloroquine have not been appropriately evaluated in controlled studies, not to mention that they have numerous and, in some cases, very <a href="https://www.mayoclinic.org/drugs-supplements/chloroquine-oral-route/side-effects/drg-20062834?p=1">deadly side effects</a>.</p>
<p>No one should take a drug that has not been proven to be safe and effective for a disease or condition for which it is not approved. There are just so many issues that can arise, from side effects to serious toxicity and death due to possible interactions with other medications and other underlying health conditions.</p>
<p>So until these or any drugs have been shown to be effective against SARS-CoV-2 in clinical trials and have been approved by the FDA, no one should be self-medicating.</p>
<p>[<em>You need to understand the coronavirus pandemic, and we can help.</em> <a href="https://theconversation.com/us/newsletters?utm_source=TCUS&utm_medium=inline-link&utm_campaign=newsletter-text&utm_content=upper-coronavirus-help">Read our newsletter</a>.]</p><img src="https://counter.theconversation.com/content/134511/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Katherine Seley-Radtke has previously consulted for Gilead Pharmaceuticals. She is also involved in many other aspects of the antiviral field, including serving on numerous funding agency grant review panels dealing with antiviral, antibactieral, antiparasitic and antifungal research. In addition, I have received funding from the National Institutes of Health for antiviral research related projects. </span></em></p>A medicinal chemist addresses questions about chloroquine and hydroxychloroquine: what it is, whether it is effective against COVID-19 and whether it can treat and/or prevent this disease.Katherine Seley-Radtke, Professor of Chemistry and Biochemistry and President-Elect of the International Society for Antiviral Research, University of Maryland, Baltimore CountyLicensed as Creative Commons – attribution, no derivatives.