Thursday, March 19, 2020

Hydroxychloroquine and azithromycin as a treatment of COVID-19

Philippe Gautret, Jean-Christophe Lagier,  Philippe Parola,  Van Thuan Hoang, Line Meddeb, Morgane Mailhe,, Barbara Doudier,, Johan Courjone, Valérie Giordanengoh, Vera Esteves Vieira, Hervé Tissot Dupont,  Stéphane Honoréi, Philippe Colson,  Eric Chabrière, Bernard La Scola,  Jean-Marc Rolain, Philippe Brouqui, Didier Raoult.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial


Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and
reported to be efficient in Chinese COV-19 patients. We evaluate the role of
hydroxychloroquine on respiratory viral loads.

Patients and methods
French Confirmed COVID-19 patients were included in a single arm protocol from early
March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in
nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical
presentation, azithromycin was added to the treatment. Untreated patients from another center
and cases refusing the protocol were included as negative controls. Presence and absence of
virus at Day6-post inclusion was considered the end point.

Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight
had lower respiratory tract infection symptoms. 
Twenty cases were treated in this study and showed a significant reduction of the viral
carriage at D6-post inclusion compared to controls, and much lower average carrying duration
than reported of untreated patients in the literature. Azithromycin added to
hydroxychloroquine was significantly more efficient for virus elimination.

Despite its small sample size our survey shows that hydroxychloroquine treatment is
significantly associated with viral load reduction/disappearance in COVID-19 patients and its
effect is reinforced by azithromycin.


  1. Could the old generic malaria drug hydroxychloroquine (Plaquenil, Sanofi-Aventis, among others), which is also used for the treatment of rheumatic disease, be an essential treatment for COVID-19?

    This hypothesis, put forward by some, including Professor Didier Raoult of the IHU Méditerranée Infection in Marseille, was dismissed by other eminent infectious disease specialists and dismissed as fake news recently by the Ministry of Health.

    Yet it resurfaced yesterday with the presentation on YouTube by Prof Raoult of positive results in a non-randomised, unblinded trial of 24 patients.

    This follows encouraging in vitro results obtained by a Chinese team led by Xueting Yao, from Peking University Third Hospital, Beijing, China, which were published online by the journal Clinical Infectious Diseases on March 9th. However, the data were deemed insufficient by the infection community to recommend the compound as a treatment. Moreover, chloroquine is not listed among the four treatments studied as part of the recently launched European clinical trial piloted by Inserm, which includes 3200 severe hospitalised patients, including 800 French patients.

    Chloroquine was ruled out due to the risk of interactions with other medications for common comorbidities in infected patients, and because of possible adverse effects in patients undergoing resuscitation.

    The European Union Clinical Trials Register shows that the Marseille study was accepted on 5th March by the National Medicines Safety Agency (ANSM). It could include up to 25 COVID-19 positive patients, comprising five aged 12–17 years, 10 aged 18–64 years, and 10 more aged 65 years or over.

    While the data have not yet been published, and should therefore be interpreted with caution, this non-randomised, unblinded study showed a strong reduction in viral load with hydroxychloroquine.

    After 6 days, the percentage of patients testing positive for COVID-19 who received hydroxychloroquine fell to 25% versus 90% for those who did not receive the treatment (a group of untreated COVID-19 patients from Nice and Avignon).(continued)

  2. (continued)In addition, comparing untreated patients, those receiving hydroxychloroquine and those given hydroxychloroquine plus the antibiotic azithromycin, the results showed there was "a spectacular reduction in the number of positive cases" with the combination therapy, said Prof Raoult.

    At 6 days, among patients given combination therapy, the percentage of cases still carrying SRAS-CoV-2 was no more than 5%.

    Azithromycin was added because it is known to be effective against complications from bacterial lung disease but also because it has been shown to be effective in the laboratory against a large number of viruses, the infectious disease specialist explained.

    "Everyone who died from COVID-19 were still carriers of coronavirus. To no longer have the virus changes the prognosis," Prof Raoult said.

    More detailed results of the study have been submitted for publication in the International Journal of Antimicrobial Agents.

    The announcement of positive results from this small study split medical opinion.

    Professor Gilles Pialoux, an infectious disease specialist at Tenon Hospital, was cautious in his response. He told Medscape's French Edition: "The idea is interesting but we need large, randomised, controlled trials. We should not communicate this kind of information on YouTube, it is not meaningful.

    "Don’t forget, this compound has not been included in Inserm’s trial because there are more interesting avenues, such as remdesivir or Kaletra [lopinavir/ritonavir]. We must be careful not to repeat the story with cyclosporin in HIV."

    Christian Perronne, head of infectious diseases, University Hospital Raymond Poincaré, Garches, Paris, was more enthusiastic.

    "I really believe in hydroxychloroquine. It is a drug I find rather fascinating, that has been used for decades. There have been positive results in an in vitro study and a preliminary Chinese study in 100 patients which showed that hydroxychloroquine reduced the viral load, the symptoms lasted for less time, and they are not as severe. This could reduce the number of carriers, which I find interesting from an epidemiological perspective. (continued)

  3. (continued)"I think from an ethical point of view, we should suggest it to all patients with severe disease who are hospitalised, under surveillance and on short treatment, paying attention to drug interactions, especially with drugs that prolong the QT interval. Afterwards, in terms of adverse effects, at increased doses, it is possible that patients will have pain or fever, but it seems that the treatment is effective at lower doses, according to the Chinese data. In any case, the adverse effects of this compound are not dangerous."

    On the adverse effects, Professor Thomas Papo, from Bichat Hospital, the University of Paris, confirmed via email: "Hydroxychloroquine (Plaquenil, which is not chloroquine), vaunted by Didier Raoult as an anti-viral, has been used for decades in tens of thousands of patients, for several decades, so we have a huge follow-up and lots of data. This drug is remarkably well tolerated and we give it to all patients with lupus (for example), including in pregnant women. The main complication (retinal toxicity) is rare and does not last beyond 5 years of continuous use."

    Hydroxychloroquine Tested in Other Hospitals

    At the end of Tuesday’s Council of Ministers, Sibeth Ndiaye, a government spokesperson, discussed the results published by Prof Raoult. "The clinical trial in Marseille is a promising start; we are extending it because science requires the experience to be validated and repeated several times to be able to say whether or not it works," she warned. Other tests will be carried out at Lille Hospital to confirm, or not, Prof Raoult’s results.

    Chloroquine is currently being examined in a number of clinical studies in China and elsewhere, and some in France have also decided to suggest it following Prof Raoult’s findings.

    This is the case for Dr Alexandre Bleibtreu, an internal medicine specialist at Pitié Salpêtrière Hospital, Paris, who was initially not persuaded by the in vitro data but has changed his opinion after having seen the results of the study carried out by Didier Raoult.

    Contacted by CheckNews, the on-demand journalism service from Liberation, he explained that the compound was now used in almost all (approximately 50) hospitalised patients in their service, except those who refuse it or who have contraindications.

    "I heard about the results, which changed my mind. We followed the Marseille protocol, and there are surely others who will use it. It is not the most obvious treatment; it works in vitro but we didn’t have data in vivo.

  4. Finally, there are some potentially very interesting results from France on hydroxychloroquine. That compound (and chloroquine itself) have been the subject of much interest, and these are the first trial data that I’ve seen. A number of things need to be said up front: first of all, this was a small trial. Second, it was open-label. Third, there were significant patient drop-outs in the treatment group, making the sample even smaller. Under normal circumstances, to be honest, I would be looking askance at this, but (1) these ain’t normal circumstances and (2) the effect size seen in this work may be significant.

    In summary, 26 patients were enrolled in the treatment group, with 16 controls. Six patients dropped out of the treatment group: 3 went to the ICU, one dropped out due to nausea, one left the hospital (apparently recovered?) and one died. No one left the control group. There were 15 male and 21 female patients. 6 of them were asymptomatic, 22 had upper respiratory symptoms, and 8 had lower respiratory tract symptoms (all of those had confirmed pneumonia by imaging).

    The treatment group got 200mg of hydroxychloroquine sulfate three times a day, and six of those patients were also given 500mg azithromycin in addition. The paper says that this was the deal with possible bacterial superinfection, and the lead author also makes mention of possible antiviral effects of the compound. I hadn’t heard of these – azithromycin is, of course, more famous as an antibacterial – but there seems to be a pretty established literature on this, although the mechanism doesn’t seem to be well worked out.

    The results are shown at right[figure at link]. As you can see, there appears to be an effect of hydroxychloroquine (although I would like to see some error bars), and a notably stronger effect (down to zero virus as measured by nasal swab) of the hydroxychloroquine – azithromycin combination. That’s the result that’s getting the attention, and justifiably so.

    I would expect this to start some larger trials, and that looks completely justified. This by itself is not enough to recommend that people start using this combination – again, it’s a very small trial and open-label at that. But it points the way to something larger and more controlled. These are two inexpensive generic drugs with a long history of use in humans; if they can be repurposed in this manner we need to know as soon as possible. Chloroquine and hydroxychloroquine both can have notable side effects, but this is not a long course of treatment, either. Let’s see if this is real!

  5. Hydroxychloroquine and chloroquine are oral prescription drugs that have been used for treatment of malaria and certain inflammatory conditions. Chloroquine has been used for malaria treatment and chemoprophylaxis, and hydroxychloroquine is used for treatment of rheumatoid arthritis, systemic lupus erythematosus and porphyria cutanea tarda. Both drugs have in-vitro activity against SARS-CoV, SARS-CoV-2, and other coronaviruses, with hydroxychloroquine having relatively higher potency against SARS-CoV-2. A study in China reported that chloroquine treatment of COVID-19 patients had clinical and virologic benefit versus a comparison group, and chloroquine was added as a recommended antiviral for treatment of COVID-19 in China. Based upon limited in-vitro and anecdotal data, chloroquine or hydroxychloroquine are currently recommended for treatment of hospitalized COVID-19 patients in several countries. Both chloroquine and hydroxychloroquine have known safety profiles with the main concerns being cardiotoxicity (prolonged QT syndrome) with prolonged use in patients with hepatic or renal dysfunction and immunosuppression but have been reportedly well-tolerated in COVID-19 patients.

    Due to higher in-vitro activity against SARS-CoV-2 and its wider availability in the United States compared with chloroquine, hydroxychloroquine has been administered to hospitalized COVID-19 patients on an uncontrolled basis in multiple countries, including in the United States. One small study reported that hydroxychloroquine alone or in combination with azithromycin reduced detection of SARS-CoV-2 RNA in upper respiratory tract specimens compared with a non-randomized control group but did not assess clinical benefit. Hydroxychloroquine and azithromycin are associated with QT prolongation and caution is advised when considering these drugs in patients with chronic medical conditions (e.g. renal failure, hepatic disease) or who are receiving medications that might interact to cause arrythmias.

    Hydroxychloroquine is currently under investigation in clinical trials for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection, and treatment of patients with mild, moderate, and severe COVID-19. In the United States, several clinical trials of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection are planned or will be enrolling soon. More information on trials can be found at: icon.

    There are no currently available data from Randomized Clinical Trials (RCTs) to inform clinical guidance on the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection. Although optimal dosing and duration of hydroxychloroquine for treatment of COVID-19 are unknown, some U.S. clinicians have reported anecdotally different hydroxychloroquine dosing such as: 400mg BID on day one, then daily for 5 days; 400 mg BID on day one, then 200mg BID for 4 days; 600 mg BID on day one, then 400mg daily on days 2-5.

  6. Chinese researchers showed in lab cell culture tests that hydroxychloroquine can slow infections from the virus behind Covid-19, SARS-CoV-2, blocking it from entering cells. Some doctors in China and South Korea have also used it to treat patients. And a recent study by researchers in France found that the drug was “efficient” in clearing upper airways from the virus in three to six days in most patients. That timing is important because an untreated infected person can transmit the virus for 20 days or more, even without showing symptoms. So it’s important to shrink the amount of time a person carries the virus in order to limit its spread.

    “Such results are promising and open the possibility of an international strategy to decisionmakers to fight this emerging viral infection in real-time even if other strategies and research including vaccine development could be also effective, but only in the future,” the French researchers wrote. “We therefore recommend that COVID-19 patients be treated with hydroxychloroquine and azithromycin to cure their infection and to limit the transmission of the virus to other people in order to curb the spread of COVID-19 in the world.”

    But the researchers only looked at 36 patients and only 26 actually received hydroxychloroquine in the study — a tiny sample size. Hydroxychloroquine can also have side effects like headaches, dizziness, and diarrhea, so it’s not something that doctors can blanketly prescribe. And the study wasn’t blinded, meaning the patients knew what they were getting, nor was it randomized. That limits the scientific merit of the study.

    That said, there are plans for wider testing. At least six clinical trials for hydroxychloroquine are recruiting patients or in planning stages around the world. In the meantime, health officials are scrambling to get enough Covid-19 tests and to build up the capacity to care for a looming surge in patients.

  7. Gov. Andrew Cuomo announced Saturday that the U.S. Food and Drug Administration will send 10,000 doses of azithromycin and hydroxychloroquine to New York. Azithromycin is an antibiotic and hydroxychloroquine is used to treat malaria.

    Cuomo spoke to President Donald Trump on Friday and expressed interest in conducting trials in New York.

    "There is a theory that the drug treatment could be helpful," Cuomo said. "We have people who are in serious condition and (state Health Commissioner Dr. Howard Zucker) feels comfortable, as well as a number of other health professionals, that in a situation where a person is in dire circumstance, try what you can."...

    New York will play a role in determining whether the combination of the antibiotic and anti-malaria drugs can be effective in treating the coronavirus. The state has the most confirmed cases of COVID-19 in the U.S. — 10,356, as of Saturday — and 1,603 people are hospitalized after contracting the virus.

    The drug trials will be part of other New York efforts to identify treatments and vaccines for the coronavirus. Cuomo said researchers are working on a possible antibody therapy and vaccines. Regeneron, a New York-based company, is also working on a drug to treat COVID-19 that could be available soon for clinical trials.

    Cuomo exempted Regeneron from his executive order requiring businesses to keep 100% of their workforce at home.

    "They could possibly have a really significant achievement for us," he said.

  8. Malaria drugs are showing "promising" initial results as a potential coronavirus treatment, a toxicologist and economic researcher said Saturday.

    Appearing on "Fox & Friends Weekend," Dr. Chris Martenson said the experimental drugs -- including hydroxychloroquine and azithromycin -- were made available on Thursday by the Food and Drug Administration.

    Although chloroquine has a "spotty past" and is unsafe at certain levels, Martenson noted that at the levels used in studies, the drug seems to "be reasonably safe" and works by allowing zinc to stop viruses from replicating.

    In addition, azithromycin could potentially stop secondary infections in damaged lungs, he said.

    Martenson, however, warned there are plenty of unknowns.

    "Unfortunately, we don't know a lot yet about how this is really going to behave in the patient population because the studies in question just involved a couple of dozen people," he said.

    Martenson, a futurist and co-founder of, said that while a small number of patients saw viral loads going down, long-term effects have yet to be revealed.

    "What we don't know yet is how much better are these patients actually fairing from a long-term outcome?" he said."And let's be clear about this: This is not a cure. We don't know if it works on a preventative basis yet. But what this does is it seems to give a better outcome once in the clinic."

    In the next couple of weeks, Martenson told the "Fox & Friends" hosts there would be expanded trials with the malaria drugs.

    "We are going to want to test this against all sorts of different patient populations, different co-morbidities. We are going to want to track the safety of profiles very, very carefully," he said. "So, in essence, we are going to be running basically live clinical trials on this at this point in time. And there, we are looking for both efficacy and safety, and we need to be really tracking very carefully what the outcomes are."

    Caveats aside, Martenson added: "This is the most promising thing I have seen so far."

  9. Dr Zev Zelenko MD, a prominent doctor who has treated hundreds of Kiryas Joel patients for COVID-19, recently made a video addressed to President Trump.

    In the video, Dr Zelenko claims to have a groundbreaking solution on how to curb the virus.

    Watch the video below for the details.[video at link]

  10. Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and
    hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020 Mar 4:105932. doi:10.1016/j.ijantimicag.2020.105932. [Epub ahead of print]

    A movement to reposition drugs has been initiated in recent years. In this strategy, it is important to use drugs that have been proven to be harmless and whose pharmacokinetics and optimal dosage are well known. In the current episode of novel coronavirus (SARS-CoV-2) emergence, we find a spectacular example of possible repositioning of drugs, particularly chloroquine. We had 20 years ago proposed to systematically test chloroquine in viral infections because it had been shown to be effective in vitro against a broad range of viruses. This drug has multiple activities, one of which is to alkalise the phagolysosome, which hampers the low-pH-dependent steps of viral replication, including fusion and uncoating. Other mechanisms of antiviral activity are poorly explained .

    At the time of the severe acute respiratory syndrome (SARS)-associated coronavirus epidemic in 2003, several molecules were tested to assess their effectiveness against this virus. Among these, teicoplanin, an antistaphylococcal agent, had proven efficacy in vitro, and this was also the case for chloroquine, at a 50% effective concentration (EC50) of approximatively 8 µM, and when added to the cell culture either before of after exposure to the virus. These findings ended up being forgotten because of the disappearance of SARS for reasons that are neither clear nor explained. The novel coronavirus currently isolated in China has been, with staggering speed, evaluated regarding its sensitivity to already used drugs. Thus, the new antiviral drug remdesivir as well as chloroquine, at an EC50 of 1.1 µM, were found to be effective in preventing replication of this virus. Chloroquine is perhaps one of the most prescribed drugs in the world. As a matter of fact, all Europeans visiting malaria-endemic geographic areas for decades received chloroquine prophylaxis and continued it for 2 months after their return. In addition, local residents took chloroquine continuously, and treatment of malaria has long been based on this drug. In addition, hydroxychloroquine has been used for decades at much higher doses (up to 600 mg/day) to treat autoimmune diseases. It is difficult to find a product that currently has a better established safety profile than chloroquine. Furthermore, its cost is negligible. Hence, its possible use both in prophylaxis in people exposed to the novel coronavirus and as a curative treatment will probably be promptly evaluated by our Chinese colleagues. If clinical data confirm the biological results, the novel coronavirus-associated disease will have become one of the simplest and cheapest to treat and prevent among infectious respiratory diseases.

    Funding: This work was supported by the French Government under the ‘Investments for the Future’ program managed by the National Agency for Research (ANR) [Méditerranée-Infection 10-IAHU-03]. The funding sources had no role in the preparation, review or approval of the manuscript.

  11. Margaret Novins talked to me on her cellphone from a hospital bed at CentraState Medical Center in Freehold, N.J.

    She had been ill since March 8, toughing it out through fatigue, a cough and fevers that brought on vicious chills for five evenings straight.

    Finally, on March 15, she went to an urgent care center and, on March 16, to an emergency room. The attending there called it “conversational dyspnea.”

    “I couldn’t breathe,” she said.

    Novins, who shared her lab tests and medication list, got her diagnosis March 19. Next to the entry for SARS-CoV-2 were the words “Detected Critical.” She had the coronavirus, or COVID-19.

    To that point, Novins had been a pneumonia patient for three days, treated mainly with antibiotics. But within an hour, a new drug was added to her med list: hydroxychloroquine, a decades-old malaria-turned-autoimmune drug, also called by its brand name Plaquenil. President Trump is touting the drug, some say overselling it, as the possible answer to the COVID-19 crisis.

    Novins’ responded to the treatment. She was better, though surely not well, the next day.

    “The fever,” which was still spiking when she was on other meds, “is now gone, which is fantastic,” she said on Saturday March 21, coughing at times but able to speak.

    A 53-year-old nurse who described herself as a nonsmoker with no medical issues, Novins spoke to me from the hospital that had cared for some of the seven members of a family ravaged by COVID; two adult brothers, a sister and their mother died from the infection.

    “The doctor insisted the pharmacy get it to me the minute we got the positive,” she said of hydroxychloroquine. “It seemed like their go-to right away.”

    There are other anecdotal successes like Novins’, including one in which end-of-life discussions for an older parent had been broached — until Plaquenil apparently kicked in. In that case, the family had to plead for, rather than being offered, the drug.

    Anecdotes are surely not science, which for now is limited and new.

    Trump is basing his optimism mostly on one small study from Marseilles, France, that, combined with laboratory findings, has prompted ongoing trials in France and the United States. The just-released French study reported that 70 percent of hydroxychloroquine-treated patients, or 14 of 20, were negative for the virus at day 6, as were all six patients who were treated with hydroxychloroquine and the antibiotic azithromycin (which Novins also received). But the study was small – 20 treated patients and 16 controls – and had other serious limitations.

    Of concern, six patients dropped out and were not considered in the reported efficacy rates. Three went to intensive care; one died; one left the hospital testing negative, and one opted out due to nausea.(continued)

  12. (continued)Two scientists at major university centers reviewed the French trial for me. They agreed, separately, that while the study is preliminary, small, and not without flaws, its findings were strong enough, given the drugs’ known safety records, to guide treatment decisions in a crisis.

    “Despite the limitations of this study, in the absence of any effective treatment, in this urgent situation, this Plaquenil and Azithromycin combination therapy should be given to patients with COVID-19 as a treatment option,” Ying Zhang, a professor of microbiology at Johns Hopkins Bloomberg School of Public Health, wrote in an email. “For now, there is no time to wait.”

    Working against the study, in Zhang’s view: It was not a randomized trial, which would avoid bias; the sample size was small, and the treatment and followup duration was too short. The findings are nonetheless “potentially interesting and justified,” he wrote.

    Brian Fallon, a research scientist and clinical trials investigator at the Columbia University Irving Medical Center, agreed on the study’s overall merit despite the patients who dropped out. After analyzing the data and counting all six dropouts as treatment failures, he said the overall rate of improvement was still statistically significant for the entire group, though not for the hydroxychloroquine group alone.

    He too had reservations, in particular that the combination therapy group was very small, six patients, and that high doses of the two drugs together carry “serious risk of cardiac arrhythmias.” Physicians must be warned of this, he suggested.

    Nonetheless, he wrote in an email, “Given the life and death situation of hospitalized patients with COVID-19 and the possibility that hydroxychloroquine plus azithromycin may be helpful, it was valuable and ethical for the authors to report these promising, preliminary results.”

    Others agreed. Lorraine Johnson, who has published on the use of collected data to improve health care outcomes, said, “It is important right now to take the gloves off clinicians and give them access to all available tools; patients are dying and can’t wait for clinical trials.”

    At the same time, she and Zhang, who has published on treatments for difficult infections like tuberculosis and Lyme disease, said a database should be set up to track patients, like Margaret Novins, in order to document drug performance. “I would recommend real-time online posting of treatment evaluation results of the Plaquenil+Azithromycin at multi-center sites across the US and the Globe,” Zhang wrote. “Someone has to coordinate this online registry and resources.” He added that other treatments should be included.

    Supply issues raised

    In a 1982 drug bulletin, the FDA encouraged so-called off-label use of approved drugs: “Valid new uses for drugs already on the market are often first discovered through serendipitous observations and therapeutic innovations, subsequently confirmed by well-planned and executed clinical investigations.”

    In the real world, however, a rush to put a relatively safe approved drug to a vastly expanded new use may reduce supplies for others who need it, including lupus, rheumatoid arthritis and Lyme disease sufferers.

    Kenneth Farber, president of the Lupus Research Alliance, said there were shortages of Plaquenil throughout the United States and especially in New York and California. (continued)

  13. (continued)Asked about supplies, a spokesperson for CVS Health, T.J. Crawford, said the drug-store chain has an “adequate supply on-hand” of hydroxychloroquine but supply of a related drug, chloroquine, “is tight across the marketplace.”

    Jane Marke, a New York City psychiatrist who takes Plaquenil for Lyme disease, said she had trouble getting her prescription filled at several city chains. After reading the French study, she understands why. “It is really possible that this is a major breakthrough,” she said, envisioning a time when a good test could pick up early infections and the drug would stop the epidemic in its tracks.

    In that vein, the University of Minnesota is organizing a trial to treat 1,500 people with hydroxychloroquine who were exposed to the virus from infected family members or as healthcare workers but are not yet ill. The study relied on laboratory experiments in China that found hydroxychloroquine inhibited the infection.

    “If effective, this may become a worldwide standard of care for helping prevent disease in other healthcare workers and people exposed,” Dr. David Boulware, a U of M professor of medicine, said in announcing the study.

    A key advantage of an off-patent generic drug like hydroxychloroquine: “A five-day treatment course would cost approximately $12,” Boulware said.

    Novins, meantime, is expecting to leave the hospital in a day or two. As a nurse for a medical equipment company, she believes she contracted the infection not from a patient but while conducting a day-long training session.

    Nonetheless, she said in a text, “I feel fortunate.”

    “From my notes it is clear that my fevers and horrible chills I fought hard from 3/8-3/18 turned the corner the day I started Plaquenil 3/19,” she wrote.

    While she said COVID is a “violent illness,” Novins never was in intensive care or on a respirator. The French study offers a mere glint of hope for more serious cases too. Of five patients with lower respiratory infection, four turned negative by day 6, three of them on both drugs.

    In the meantime, scientists said larger, more rigorous studies must be launched to answer questions of efficacy, dosing, duration, and potential adverse drug interactions — for this and other COVID treatments.

  14. Hope has emerged around two anti-malaria drugs: chloroquine, discovered in 1934, and a derivative of it called hydroxychloroquine that is thought to have less severe side effects. Both have shown promise in preventing SARS-CoV-2 from infecting cells in the laboratory. And a small and preliminary clinical trial of hydroxychloroquine in France circulated widely and stirred excitement on social media (including from the president) — though its findings were hardly definitive about whether the drug would benefit coronavirus patients. New York Governor Andrew Cuomo said Sunday that a study of the drug will start Tuesday.

    The fact that these drugs have already been cleared by the FDA for use against other diseases — they’re prescribed by doctors not just for malaria but also rheumatoid arthritis and lupus — has added momentum to the argument they should be quickly made available for Covid-19; their side effects, which include heart and nerve damage and suicidal thoughts, are well-understood and, given the current circumstances, manageable, supporters argue. Doctors can already prescribe them off-label.

    At a Thursday news briefing, Trump trumpeted that chloroquine had shown “very, very encouraging early results” and said “we’re going to be able to make that drug available almost immediately.” Minutes later, FDA Commissioner Stephen Hahn, an oncologist, clarified that the drug would be available “in the setting of a clinical trial — a large, pragmatic clinical trial — to actually gather that information and answer the question that needs to be answered and — asked and answered.”

    Friday, the President said, “It may work, it may not work. I feel good about it. That’s all it is. Just a feeling.” At the same press conference, Anthony Fauci, a physician who heads the NIAID and a veteran of outbreaks going back to HIV, emphasized the need for a methodical clinical trial…

    The study Trump and others have touted was anything but randomized. Instead, Covid-19 patients were treated with either hydroxychloroquine or the combination of hydroxychloroquine and azithromycin, an antibiotic also known as Zithromax, at a hospital in Marseille, France. They were compared to coronavirus patients at hospitals in Marseille, Nice, Avignon, and Briançon who didn’t receive these drugs.

    The study doesn’t show that patients lived longer or were more likely to recover, but instead shows that the amount of virus in the blood was reduced much faster in the patients who took hydroxychloroquine and even faster in the six patients who took the combination of hydroxychloroquine and azithromycin.

    That result is encouraging, but for patients who are not gravely ill, it doesn’t tell how to weigh the side effects of hydroxychloroquine against the potential benefits. That’s the reason for a clinical study like the one starting in New York.

    But for doctors on the front lines, particularly in New York City, where hospitals are becoming overwhelmed and where there are many patients on ventilators, the drugs could be an immediate option. As Cuomo put it in a press conference Friday, “where a person is in dire circumstance, [you] try what you can.”

    Reports about the potential of hydroxychloroquine as a potential treatment for Covid-19 have been circulating among New York City emergency physicians for more than a week, and some patients are reportedly getting the hydroxychloroquine/azithromycin combination. (Perhaps as a result, there are shortages cropping up for patients with lupus and other diseases who need the drug.) The University of California, San Francisco, and the University of Washington both recommend hydroxycholoroquine for very sick Covid-19 patients…

    For drug development, getting results so soon is blindingly fast. For doctors on the ground and patients who are struggling to breathe, it is agonizingly slow.

  15. A Florida man hospitalized with the novel coronavirus claims an anti-malarial drug — one that President Trump has said is being tested as a possible treatment option but has not yet been approved — saved his life.

    Rio Giardinieri, 52, told Fox 11 that he experienced a fever for five days, back pain, headache, cough, and tiredness after attending a work-related conference in New York. After returning home, he claims he was diagnosed with COVID-19 and pneumonia at Joe DiMaggio Children's Hospital in South Florida. He was reportedly hospitalized in the facility’s intensive care unit for more than a week, at which point he says his symptoms had not alleviated.

    “I was at the point where I was barely able to speak and breathing was very challenging. I really thought my end was there. I had been through nine days of solid pain and for me, the end was there. So I made some calls to say in my own way goodbye to my friends and family,” Giardinieri said.

    The man then claims a friend told him about a possible treatment option, an anti-malarial drug known as hydroxychloroquine.

    The same drug has also been used to treat auto-immune diseases like lupus, according to the New York Post. Some researchers in France recently issued a statement detailing how a combination of the anti-malarial medication and antibiotics could be a vital weapon in the battle against the coronavirus. Trump has also touted the drug as a possible treatment, saying last week that he has pushed the U.S. Food and Drug Administration (FDA) to test hydroxychloroquine and chloroquine, a similar drug, as possible treatment options. However, such use has yet to be approved by the federal agency.

    An infectious disease doctor treating Giardinieri “gave me all the reasons why I would probably not want to try it because there are no trials, there’s no testing, it was not something that was approved.”

    But, Giardinieri recalled, “I said, ‘look I don’t know if I’m going to make it until the morning,’ because at that point I really thought I was coming to the end because I couldn’t breathe anymore.”

    Giardinieri said he then received the medication, during which time he felt like his heart was “beating out of his chest” and still experienced difficulty breathing.

    The man claimed he was then given Benadryl and other drugs and later woke up like “nothing ever happened.” He now claims that his fever has dissipated and he is no longer in pain. He also told Fox 11 he is able to breathe more normally again. The episodes he experienced after being administered hydroxychloroquine were likely his body fighting off the infection rather than an adverse reaction to the medication itself, doctors reportedly told him.

    “To me, there was no doubt in mind that I wouldn’t make it until morning,” Giardinieri said, noting he received the medication on Saturday and hopes to be able to leave the hospital in five days. “So to me, the drug saved my life.”

  16. Coronavirus: Hydroxychloroquine, TRUTHS and LIES

  17. A lot of attention has shifted to the malaria drug hydroxychloroquine for treatment of COVID-19, the disease caused by the novel coronavirus. This was largely based on a study published in 2005 that found that chloroquine prevented the replication of the SARS-CoV-1 virus that caused SARS in laboratory studies.

    In the midst of the China outbreak, production of the drug was ramped up for use in treatment. President Trump has touted it as a “game-changer,” while drug and public health experts have been more conservative in their praise, saying that the drugs, chloroquine and hydroxychloroquine, have not been approved as treatments for COVID-19 and that for the most part, their effectiveness for treating COVID-19 are largely anecdotal. However, because the drugs are approved for malaria, lupus and rheumatoid arthritis, physicians have broad latitude for using them “off-label” for COVID-19.

    At least three big drug companies, Mylan, Novartis and Teva Pharmaceutical have agreed to increase production of hydroxychloroquine, with plans to donate literally tens of millions of doses of the drug hoping it can be used to treat COVID-19. On March 17, the University of Minnesota initiated a clinical trial of hydroxychloroquine for treatment of COVID-19.

    French researchers have published an article in the International Journal of Antimicrobial Agents describing the potential use of a combination of hydroxychloroquine and the antibiotic azithromycin, which is better known as Z-Pak. The U.S. Food and Drug Administration (FDA) is also evaluating the drugs but have not yet made recommendations.

    IHU-Mediterranee Infection in Marseille, France, stated, “A treatment with the hydroxychloroquine combination (200 mg X 3 per days for 10 days) + Azithromycin (500 mg on the 1st day then 250 mg per day for 5 more days), as part of the precautions for use of this association (including an electrocardiogram on D0 and D2). In cases of severe pneumonia, a broad-spectrum antibiotic is also used. We believe that it is not ethical that this association should not be systematically included in therapeutic trials concerning the treatment of COVID-19 infection in France.”

    The French study, which is very small, “showed a significant reduction of the viral carriage” after six days of treatment and “much lower average carrying duration” compared to patients receiving other treatment. Six patients in the trial were asymptomatic and 22 had upper respiratory tract infection symptoms. Eight patients had lower respiratory tract infections. Twenty cases were treated in the study, with untreated patients acting as negative controls.

    Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, is taking a more cautious, scientific approach. “As the Commissioner of FDA and the president mentioned yesterday, we’re trying to strike a balance between making something with the potential of an effect available to the American people, at the same time that we do it under the auspices of a protocol that would give us information to determine if it’s truly safe and truly effective,” he said in a Friday, March 20 press conference. “But the information that you’re referring to specifically is anecdotal, it was not done in a controlled clinical trial. So you really can’t make any definitive statement about it.”

    Chloroquine is an effective drug for malaria, lupus and chronic rheumatoid arthritis, but it has significant side effects, including gastrointestinal distress and potential permanent vision damage. It can also be deadly at a relatively low dose. A Wuhan Institute of Virology study indicated it can be fatal in adults at twice the daily recommended amount, which is only one gram. It is, of course, even more dangerous for children.(continued)

  18. (continued)According to China’s Ministry of Sciences and Technology, which ran trials of chloroquine in about 130 patients, the drug decreased the severity of COVID-19 and increased the speed of viral clearance.

    Azithromycin is a widely-used antibiotic for bacterial infections. Side effects include upset stomach, diarrhea, nausea, vomiting or abdominal pain. Less common but serious side effects include hearing damage or deafness, drooping eyelids and blurred vision, difficulty swallowing or speaking, muscle weakness, and liver damage. It is contraindicated for people allergic to azithromycin and other antibiotics, including erythromycin, clarithromycin, telithromycin. It is also contraindicated in people with liver and kidney disease.

    While production of these drugs increases, physicians will likely use the combination and others to treat COVID-19 under hospital conditions, if they can acquire enough doses of them. Individuals hoarding them will make that more difficult and people using them without physician supervision run serious risks of side effects and potential overdoses.

  19. In Maricopa County, Ariz., a couple in their 60s watched politicians and news anchors on TV tout chloroquine, an anti-malaria drug that has shown the ability to disrupt some viruses but that has not yet been proved effective against the novel coronavirus.

    That pharmaceutical name matched the label on a bottle of chemicals they used to clean their koi pond, NBC News reported. The fish tank solvent that treats aquatic parasites contains the same active ingredient as the drug, but in a different form that can poison people.

    “I saw it sitting on the back shelf and thought, ‘Hey, isn’t that the stuff they’re talking about on TV?’ ” the wife, who was not named, told the network. “We were afraid of getting sick.”

    The couple reportedly poured some of the fish tank cleaning chemical, chloroquine phosphate, into soda and drank it. They hoped it would stave off a coronavirus infection.

    “Within thirty minutes of ingestion, the couple experienced immediate effects” that sent them to the emergency room, a Banner Health spokeswoman said in a statement Monday. They felt dizzy and started vomiting. The husband died at the hospital, and the wife is under critical care, according to the statement.

    “Given the uncertainty around COVID-19, we understand that people are trying to find new ways to prevent or treat this virus, but self-medicating is not the way to do so,” Daniel Brooks, Banner Poison and Drug Information Center medical director, said in the hospital’s statement. “The last thing that we want right now is to inundate our emergency departments with patients who believe they found a vague and risky solution that could potentially jeopardize their health.”

  20. While health officials are not condoning that people with mild symptoms start self-medicating with hydroxychloroquine, doctors are starting to use it on their sickest patients in the hospital.

    At Johns Hopkins, for example, six of the hospital’s two dozen or so COVID-19 patients are receiving the drug. Doctors at both the UCLA Medical Center and Boston’s Brigham and Women’s Hospital are now starting to treat patients with severe COVID-19 symptoms with hydroxychloroquine when other treatments don’t work. “We consider the use of hydroxychloroquine on a case-by-case basis for hospitalized patients who are at risk of disease progression,” says Dr. Daniel Kuritzkes, chief of the division of infectious diseases at Brigham and Women’s Hospital and professor at Harvard Medical School.
    It’s not ideal, but as physicians get desperate watching patients decline with respiratory failure, such off label use of hydroxychloroquine in particular may become more common. Off label use means drugs, like hydroxychloroquine, that are already approved for one use can be prescribed for another use, as long as the doctor is comfortable with the unknown risks and side effects. “If someone is sick in the ICU you try everything possible you can for that person,” says Dr. David Boulware, a University of Minnesota professor of medicine. Especially as hospitals start getting concerned about dwindling supplies of equipment such as ventilators, anything that can prevent patients declining from mild to severe disease is worth a try.

    “We are reserving it for those who might get the most benefit from the treatment because they may be at the highest risk of severe COVID-19 disease when they enter the hospital,” says Sullivan. If the drug can prevent severe disease, then that may spare the hospital and the health care system from the most expensive and invasive types of care such as days spent in the ICU with expensive mechanical breathing support. That, in turn, could help stymie the COVID-10 pandemic.

    While there isn’t a deep well of scientific data on how to use hydroxychloroquine to treat viral infections, doctors aren’t flying completely blind. There have been lab studies of hydroxychloroquine suggesting that in people, cells in the respiratory tract, for example, engulf coronaviruses within a tiny pouch. The virus needs to puncture this pouch in order to release its genetic material into the cell and turn it into a viral copying machine to pump out more virus. To do all that, SARS-CoV-2 requires an acidic environment. Hydroxychloroquine is an alkaline compound, so it raises the pH levels of the host environment, preventing the virus from releasing its genes for copying. The end result: the coronavirus is bumped out of cells and can’t infect them. (How azithromycin contributes to this process isn’t clear yet, but doctors suspect that it may quell the worst respiratory symptoms of COVID-19 by reducing inflammation caused by the viral infection in the lungs.)(continued)

  21. (continued) “The problem is that what happens in the lab often doesn’t predict what happens in a patient,” says Dr. Otto Yang, from the department of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at the University of California, Los Angeles. In fact, hydroxychloroquine turned out not to be as successful in stopping infection in animals and people.

    More rigorous studies will hopefully shed additional light on if, and when, hydroxychloroquine could treat COVID-19, as well as provide important information about what side effects it may cause. Boulware, for example, is leading a study to test first, whether hydroxychloroquine can be used to prevent healthy people from getting infected if they are exposed, and second, whether it can treat people who are already infected, but early in their disease, from getting worse and needing to be hospitalized. The study is currently enrolling 1,500 people in each part, and each person who qualifies will be randomly assigned to receive hydroxychloroquine or placebo, and they won’t know which. The team is moving fast: after a volunteer is approved, they are sent a five-day supply of the drug or placebo overnight, and Boulware expects to see results in as early as four weeks.

    Those results will be critical for lessening the impact of the pandemic. Protecting people who are at a high risk of infection—such as health care workers or people who live in a household with infected family members—would be critical to stopping community spread of the virus, and could be a type of substitute for a vaccine, since that would take at least a year to develop and test. If the drug could provide some barrier to spreading the virus, then that could flatten the peak of cases and speed the waning of the pandemic. In addition, it could be used to keep people who are infected from progressing on to serious disease. That in turn, would lift the burden on the health care system, since those with mild to moderate symptoms can be treated at home, without the need for intensive ventilator care or hospitalization.

    Boulware’s study will also track any potential side effects of the treatment. What concerns doctors most is hydroxychloroquine’s tendency to disrupt electrical signaling in the heart, which can lead to arrhythmias that could be fatal in people with pre-existing heart conditions. And those are the very people who are at highest risk of COVID-19 infection, and who may need something like hydroxychloroquine to slow their disease. That’s why many hospitals are not using the combination of hydroxychloroquine and azithromycin, because each raises the risk of arrhythmia, and together, the risk could be too high.

    However, until studies provide more definitive data, doctors are urging people not to find ways to self-medicate for COVID-19, especially since people with rheumatic diseases and lupus desperately need hydroxychloroquine to treat their symptoms. “Don’t add to the frenzy that may deny them the treatment they need,” says Yang. “We need to stop and act rationally based on facts rather than unsubstantiated hunches, even hunches that have some scientific rationale.”

  22. Vice President Mike Pence said Tuesday that “the FDA [Food and Drug Administration] is approving off-label use for the [anti-malarial drug] hydroxychloroquine right now" to help coronavirus patients.

    Pence made the comment during Fox News’ virtual coronavirus town hall in response to a question from Dr. Mehmet Oz about the drug, which has shown encouraging signs in small, early tests. A similar drug, Chloroquine has also showed positive signs.

    Dr. Oz noted that “the FDA appropriately desires randomized critical trials for proof to guide the medical community,” but asked the vice president how the clinical trials can be accelerated “while also satisfying the demand from physicians, front-line doctors, who want to use these pills for their patients and themselves?”

    In response, Pence said, “The good news is, the chloroquine medication, we actually deployed in the state of New York resources to be able to be administered to the people.”

    New York has reported more than 25,600 confirmed coronavirus cases and 210 deaths, the most in the U.S., according to data compiled by Fox News.

    “Doctors can prescribe that medication, which as you know is a perfectly legal and approved malaria medication," Pence told Dr. Oz, "but doctors can now prescribe chloroquine for that off-label purpose of dealing with the symptoms of coronavirus. We are making that clear across the country."…

    During a news conference on Sunday, New York Gov. Andrew Cuomo announced that the state has acquired 70,000 doses of hydroxychloroquine, 10,000 doses of the antibiotic zithromax and 750,000 doses of chloroquine, with trials set to start Tuesday.

    “The president’s very optimistic, he’s very hopeful that some of these anecdotal results that we’ve seen around the country will prove out to be true,” Pence said on Tuesday. “I want to assure you, there is no barrier to access the chloroquine in this country. We’re working to add to that supply even as we speak.”

    He went on to say that the Trump administration is working with companies that produce vast amounts of chloroquine, adding that at the same time “we are engaging in a clinical trial while we make this broadly available for off-label use. Because we do want to take the opportunity, we are doing that in New York state, to study the results of this so that we can better understand the impact going forward.”

  23. Nevada’s governor on Tuesday banned the use of anti-malaria drugs chloroquine and hydroxychloroquine to treat coronavirus patients.

    Democratic Gov. Steve Sisolak’s executive order came after President Trump touted the medication as holding promise for combating the illness.

    Sisolak said there was no consensus among experts or Nevada doctors that the drugs can treat people with COVID-19.

    His order also limits a prescription of the medicines — which are also used to treat illnesses like lupus and arthritis — to a 30-day supply to ensure it’s available for “legitimate medical purposes” and so people don’t stockpile the drug.

  24. “HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine.” President Trump tweeted this in response to a poorly conducted clinical trial.

    Despite warnings from his scientific advisers, he told the world that anti-malarial medications like hydroxychloroquine and chloroquine could revolutionize the treatment of Covid-19. But whether the president knows it or not, these medications can have very serious psychiatric side effects. Furthermore, the public may not know this. And there has now been an alarming surge in people looking for these medications. Pharmacists have told us they are out of stock, in part because some doctors — including dentists — are reportedly stockpiling the medications for themselves and friends and families. Non-physicians are calling in fraudulent prescriptions for themselves.

    As psychiatrists, we are worried about the shocking increase in people self-medicating with these drugs. To emphasize this point: These are not harmless medications. They could have serious consequences — like death.

    That’s not theoretical. An Arizona man died (and his wife is in critical condition) after ingesting chloroquine phosphate, which in one formulation is sold to clean fish tanks. Similar overdoses have been reported internationally.

  25. Hydroxychloroquine, a medicine for malaria that President Donald Trump has touted as a treatment for coronavirus, was no more effective than conventional care, a small study found.

    The report published by the Journal of Zhejiang University in China showed that patients who got the medicine didn’t fight off the new coronavirus more often than those who did not get the medicine.

    The study involved just 30 patients. Of the 15 patients given the malaria drug, 13 tested negative for the coronavirus after a week of treatment. Of the 15 patients who didn’t get hydroxychloroquine, 14 tested negative for the virus.

    The results of the study weren’t statistically significant.

  26. On Tuesday morning, the controversial and experimental coronavirus treatment program being run by a Hasidic doctor who claimed he had kept more than 500 symptomatic patients out of the hospital was shut down. By afternoon, after intervention from the White House, it was up and running again.

    The doctor, Vladimir Zelenko, has been in isolation because he is immunocompromised. But he is directing perhaps the world’s most extensive, unsanctioned medical experiment related to coronavirus — the use of the anti-malaria drug hydroxychloroquine to treat Covid-19, a something President Donald Trump has been touting for days as a “game changer” in the fight against the virus.

    The experiment is controversial: Trump’s top medical adviser, Dr. Anthony Fauci, has cautioned against use of the drug to treat the virus, calling evidence of its effectiveness “anecdotal.” On Monday evening, New York banned off-label use of the drug, which is also used to treat lupus and rheumatoid arthritis, outside state-approved clinical trials.

    But on Tuesday afternoon Vice President Mike Pence announced on Fox News that the Food and Drug Administration was approving off-label use of the drug “right now.”

    “Doctors can now prescribe chloroquine for that off-label purpose of dealing with the symptoms of coronavirus,” Pence said.

    See the March 22, 2020 at 12:27 PM comment above.

  27. Antiviral medications, unlike antibiotics, typically aim to disrupt the ability of a virus to reproduce and proliferate, not to kill the virus directly. Chloroquine’s antiviral properties stem from its apparent ability to block some of the cellular processes associated with the ability for some viruses, including coronaviruses as a broad group, to replicate. Used for this purpose, some evidence suggests, the drug could potentially slow the spread of the novel coronavirus and thus reduce severe complications.

    One of the most severe complications from COVID-19 may be related not to the virus itself but to the immune system’s overreaction to the presence of that virus. Increasing evidence suggests that a subgroup of COVID-19 patients experience an immune system reaction known as a cytokine storm. In these cases, the immune system overloads the lungs with inflammation-producing chemicals, causing severe and sometimes fatal damage. Some evidence exists that hydroxychloroquine inhibits the ability of cells to secrete cytokines, blocking this immune-system overreaction.

    Why might azithromycin, an antibiotic, play a role in treating a viral infection like COVID-19? In general, viral infections often produce co-infections that are bacterial in nature, so antibiotics’ use in treatment with viral infections is not novel or unusual. However, the idea Trump presented — that the combination of hydroxychloroquine and azithromycin would be a “game changer” — comes from a single, limited, and widely criticized French study. This study reported that “preliminary results also suggest a synergistic effect of the combination of hydroxychloroquine and azithromycin.” As discussed below, experts have strong reservations about the study that produced that result.

    Despite the established theoretical basis for hydroxychloroquine as a potential antiviral for coronavirus, and its clinical use in countries like China and South Korea, the U.S. Centers for Disease Control and Prevention (CDC) cautions that “there are no currently available data from Randomized Clinical Trials (RCTs) to inform clinical guidance on the use, dosing, or duration of hydroxychloroquine for prophylaxis or treatment of SARS-CoV-2 infection.”

    Evidence of hydroxychloroquine’s specific efficacy against COVID-19 comes primarily from three sources: a small, limited study performed on laboratory cell cultures; an “expert consensus” from Chinese health officials that asserts “chloroquine might improve the success rate of treatment, shorten hospital stay and improve patient outcome”; and the aforementioned French study that suggested the combination of hydroxychloroquine and azithromycin.

    Even if a chemical like hydroxychloroquine does prevent proliferation of the novel coronavirus in the lab, as the study from China showed, that does not mean it will have the same effect on living beings. A recent commentary piece published in the academic journal Antiviral Research provides the important context that while chloroquine/hydroxychloroquine has shown promise in the lab for many viral infections, the drug shows no benefit when tested on an animal. “Chloroquine has been proposed several times for the treatment of acute viral diseases in humans without success,” the authors argue.

    Much of the information presented in other Chinese studies or consensus statements provides no data. For example, a paper titled “Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies,” cites as its primary source an audio recording of a news briefing from the State Council of China in which the government asserted without publicly releasing its data, “that chloroquine phosphate, an old drug for treatment of malaria, had demonstrated marked efficacy and acceptable safety in treating COVID-19 associated pneumonia in multicenter clinical trials conducted in China.”(continued)

  28. (continued)The French study is part of a clinical trial in which the authors published preliminary results they contend show “that hydroxychloroquine is efficient in clearing viral nasopharyngeal carriage of [the novel coronavirus] in COVID-19 patients in only three to six days, in most patients.” This is the study Trump referenced in his tweets, and this paper, in particular, has been criticized widely. As Dan Vergano reported at BuzzFeed News:

    Outside experts have heavily criticized the French study, however. Infectious disease geneticist Gaetan Burgio of the Australian National University noted that statistically, weighing national responses to a pandemic on a study of 20 people was unwise, that the French study was not conducted with doctors and patients blind to the treatment, and that only a quarter of the placebo patients had their viral load measured. “This is insane!” he said on Twitter.

    Even worse, six patients dropped out of the trial from the group receiving the drug, and three of them ended up in intensive care and one died. These could be viewed as failures of the drug to work against the virus, Alfred Kim of the Washington University Lupus Clinic told Undark magazine.

    In short, a dearth of reliable data remains on the efficacy of hydroxychloroquine against COVID-19, and some of the evidence cited so far, including the French study that Trump promoted, appears to be of limited value. Additionally, the combination of hydroxychloroquine and azithromycin can be potentially dangerous for people with some heart conditions.

    More Data Needed

    None of this is to say that hydroxychloroquine, with or without azithromycin, may not become a valuable tool in the fight against COVID-19. But information is lacking to make that conclusion or to provide accurate clinical guidance on how and when it should be used. On March 20, 2020, the World Health Organization announced it would start four “mega trials” of the most promising treatments in an effort to gather this crucial information as quickly as possible. Chloroquine and hydroxychloroquine are among the four treatments being tested in this program.

  29. I like to read a new study in the context of what I call "the pre-study probability of success." In other words, how likely was this drug to work before we got the data from the trial? Let me show you how this works with two recent examples.

    I'm going to start with the big one.

    It seems like everyone is talking about hydroxychloroquine, thanks to one little study appearing in the International Journal of Antimicrobial Agents that is generating a lot of press—thanks to a shout-out from Donald Trump, no less.

    What is our pre-study probability that hydroxychloroquine would be effective for COVID-19?

    There's a lot of literature here. Hydroxychloroquine has a long history as an antibiotic and antiviral drug and, encouragingly, seems to inhibit coronavirus replication in vitro. It also changes the structure of the receptor that coronavirus binds to.

    I'd put the pre-study probability here at around 50/50, but feel free to disagree.

    Now let's look at the study. Thirty-six patients in France with COVID-19 were examined. Twenty of them got hydroxychloroquine and 16 were controls. But this was not randomized; treated patients were different from those not receiving treatment. The researchers looked at viral carriage over time in the two groups and found what you see here:[figure at link]

    This appears to be a dramatic reduction in coronavirus carriage in those treated with hydroxychloroquine. Awesome, right? Sure, it's not randomized, but when we need to make decisions fast, "perfect" may be the enemy of "good." Does this study increase my 50/50 prediction that hydroxychloroquine could help?

    Well, with data coming at us so fast, we have to be careful. There is a huge fly in the ointment in this study that seems to have been broadly overlooked, or at least underplayed. There was differential loss to follow-up in the two arms of the study; viral positivity was not available for six patients in the treatment group, none in the control group. Why unavailable? I made this table to show you:[table at link]

    Three patients were transferred to the ICU, one died, and the other two stopped their treatment. By the way, none of the patients in the control group died or went to the ICU. Had these six patients not been dropped, the story we might have is that hydroxychloroquine increases the rate of death and ICU transfer in COVID-19.

    Before reading this study, I was 50/50 on hydroxychloroquine. After?

    Yeah, I'm right where I started. Because of the problems with the study design—not just its observational nature but that differential loss to follow-up—the data from the French study don't move the needle for me at all.

    That doesn't mean hydroxychloroquine failed.

    What we have to decide now is whether 50/50 is good enough to try. Given the relatively good safety profile of hydroxychloroquine and the dire situation we find ourselves in, it may be very reasonable to use this drug, even despite that study.

    Tweets like this, though, aren't helpful: [picture at link]

    They misrepresent the data, which are equivocal at best. Further, they may encourage people to think, we've solved this, and stop their social distancing. There are already reports of these medicines being hoarded. The key to evidence-based medicine during this epidemic is being transparent about what we know and what we don't. If we want to use hydroxychloroquine, that is a reasonable choice, but we need to tell the public the truth: We're not too sure it will work, and it may even be harmful…

    The bottom line is that we don't need to abandon evidence-based medicine in the face of the pandemic. We need to embrace it more than ever. But in that embrace, we need to realize what we've known all along: Evidence-based medicine is not just about randomized trials; it's about appreciating the strengths and weaknesses of all data, and allowing the data to inch us closer and closer toward truth.

  30. The much-touted anti-malarial drug seen as a possible treatment for coronavirus has been used successfully in Bahrain, a top health official said Tuesday.

    Bahrain, according to the state-run Bahrain News Agency, is one of the first countries to use the decades-old malaria drug known as hydroxychloroquine to treat coronavirus patients. The agency quotes Lt. Gen. Dr. Shaikh Mohammed bin Abdullah Al Khalifa, the head of the Bahrain’s coronavirus task force, who said hydroxychloroquine had been effective in “alleviating the symptoms of the virus and reducing its complications.”

    Doctors in Bahrain first used hydroxychloroquine, which is also a treatment for lupus and acute or chronic rheumatoid arthritis, on Feb. 26, Khalifa said.

    The jury is still out on whether the experimental drug is an effective treatment for coronavirus. In France, the anti-malarial was used in combination with azithromycin, an antibiotic typically prescribed for bacterial pneumonia, to treat some two dozen patients in Marseille.

  31. An old malaria medicine, hydroxychloroquine, has gone viral on the internet. But is it really an antiviral drug?

    The medicine has been seen as a potential treatment for Covid-19, the disease caused by the novel coronavirus SARS-CoV-2, almost since outbreaks started. This week it made headlines, due in part to tweets from President Trump and in part because of a small French study of 42 patients that seemed to show that hydroxychloroquine, particularly when combined with the antibiotic azithromycin, helped decrease patients’ levels of coronavirus. Unfortunately, the rumors about the drug’s efficacy have also encouraged some to buy and even consume a similarly named fish tank cleaner; one person has died.

    But a second study emerged last week from Shanghai University in China of 30 patients hospitalized for Covid-19. Whether patients received hydroxychloroquine or not, their body temperature returned to normal a day after hospitalization, and the time it took for levels of the virus to become undetectable was comparable. Unlike the study from France, the patients in this study were randomly assigned to either hydroxychloroquine or the control group, which makes the results more reliable.

    The first mention of the Shanghai study came from a paper in The Lancet Global Health, where the results were described as positive. One of the authors of the Lancet paper, Oriol Mitjà, wrote via email that changes on CT scans showed “that the drug has some efficacy” against Covid-19. In the Shanghai study, worsening of the disease that could be picked up on a CT scan happened in 33% of those on hydroxychloroquine (that’s 5 patients) versus 47% of those in the control group (7 patients).

    Mitjà was even more optimistic about the French study, saying it has “new and stronger data.”

    But objections have been raised to the French study paper, even as it’s bounced around the Internet. Fox host Sean Hannity even shared another doctor’s letter on his experience using the hydroxychloroquine/azithromycin combination on his television show on March 23.

    Three statisticians published a review of the French study that argued that the way it was designed made the treatments look better than they actually are. They pointed to the lack of randomization, as well as an inappropriate control group composed partly of people who refused to take the drug. They also noted that the study dropped some patients from the analysis — the small study of 42 patients actually only included data from 36. The Shanghai study, which showed less impact from the treatments, adds to the questions about the French study, wrote Tim Morris, a statistician at the MRC clinical trials unit at University College, London.

    “The [French] study gave very little useful information about whether hydroxychloroquine might help,” Morris wrote. “The Shanghai study is better (because they had a meaningful control group) but gives us very little information that hydroxychloroquine doesn’t help.” The data, he wrote, are “compatible with a wide range of possible effects,” which is statistician-speak for, “Nobody knows whether the drug helps or not.”

    The Shanghai study, Morris wrote, is a step in the right direction toward some bigger, better trials that are kicking off. The first of these might give some answers in April — a short time when it comes to clinical trials, but potentially after the United States, and particularly New York City, will have seen a tsunami of Covid-19 cases.(continued)

  32. (continued)Some doctors on the front lines will use these drug combinations, particularly with patients who are so sick they are on ventilators. As one doctor told me, the risks associated with these drugs, like heart rhythm disturbance or worsening psoriasis, don’t warrant not using them in patients who are in serious trouble. But there is also a need to conduct studies of them to find out if they are truly effective. New York Governor Andrew Cuomo signed an executive order saying that pharmacists should not dispense the drugs to treat Covid-19 unless they are part of a clinical trial. Studies for another drug, remdesivir from Gilead Sciences, are expected to read out in the coming weeks.

    Zach Weinberg, one of the co-founders of Flatiron Health, a division of Roche, remembers the difficult transition of going from working in online advertising, where his first company was focused, to Flatiron, which is focused on cancer. In software, more data is better. In cancer, the wrong type of data can lead to conclusions that are not only incorrect but dangerous.

    “Sometimes people confuse saying, ‘the study doesn’t tell you anything’ with saying the drug doesn’t work,” Weinberg said. “That’s a really important distinction. They’re not the same thing. I’m not saying the drug doesn’t work or does work. What I’m actually saying is nobody knows if the drug works or doesn’t work.”

    His lesson: when dealing with a pandemic, listen to experts who are used to grappling with these problems.

    “Society tends to put people who’ve been successful in one area on a pedestal, and draw the conclusion that means they’re expert at many things even though the expertise that they had in one area has nothing to do with the other,” Weinberg said.

  33. How Chloroquine and Hydroxychloroquine can possibly Treat COVID-19

    To start off with, we must go back to some basic understanding of the viral infection process. The main thing about viruses is that they love an acidic environment. It is the only way that they can survive in our body. Inside every cell in our body the cytoplasm is acidic, along with the endoplasmic reticulum, and the golgi apparatus. When a virus first attaches to a cell, it tries to merge with the wall of the cell. Then once it fuses, it proceeds into the cytoplasm, then into the Endoplasmic Reticulum (where it starts to replicate), then into the golgi apparatus, where it finalizes the invasion, in which it has now taken over our cell. That’s the simple version, but now you have an idea of the process, and it will allow you to understand the potential for chloroquine and hydroxychloroquine in treating COVID-19.

    Chloroquine and Hydroxychloroquine are intentionally basic by design. When these drugs are administered, they make the blood stream, and all the cells they come in contact with, basic. Specifically, the cytoplasm, the endoplasmic reticulum, and the Golgi Apparatus. When these are no longer acidic, it does not allow the virus to attach to, or invade the cell. It also stops the replication of the virus.

    This is the main mechanism by which these drugs are believed to have so much potential.

    The second mechanism happens when these drugs are present in the blood stream and in the cells, they allow for Zinc to be put into the cytoplasm of the cell. Without a facilitator, Zinc cannot enter into the cytoplasm of the cell. So, when zinc is allowed to enter into the cytoplasm of the cell, most of the time it will attach to RNA- dependant RNA polymerases or, RDRP for short, in the cell. If zinc is in the cell taking up all of the RDRP then there is none left for the virus to utilize, and since the RDRP is necessary for the virus to be able to take over the cell, the process is squashed right then and there and the cell is protected.

    Now, there is plenty of research to support this, but the problem is that these are not particularly safe drugs. So, the risk and the reward have to be weighed, and it has to be done by a medical professional. The dose is weight specific and very sensitive, and thus can be easily overdosed. In an overdose, there are a multitude of things that can go wrong, including death. If you have other underlying conditions, these drugs pose an even greater risk. So, that is the fear right now with naming these as a cure and an active treatment. These drugs, though they have great potential, pose a great risk as well.

  34. And a new study - this is really big. This just broke tonight -from the French research team that was led by the renowned epidemiologist, Didier Raoult, just posted online, this study offers more hope that the combination of hydroxychloroquine and azithromycin is helping COVID-19 patients.

    Now, this was a study of 80 patients, more than double the size Professor Oz's (ph) earlier study had, but it's still not controlled. Nevertheless, 54 of the patients had CT scans for COVID pneumonia. Only three of them required an ICU, and the median age was 52, that's fairly young. About two- thirds or so had underlying medical conditions, and the results were stunning.

    This is what it said, in part. "By administrating hydroxychloroquine combined with azithromycin, we were able to observe an improvement in all cases, except in one patient who arrived with an advanced form, who was over the age of 86 and in whom the evolution was irreversible. For all other patients in this cohort of 80 people, the combination of hydroxychloroquine and azithromycin resulted in a clinical improvement that appeared significant when compared to the natural evolution in patients with a definite outcome, as described in the literature."

  35. While doctors in hospitals nationwide have been using the drug for critical cases, Zelenko is one of a handful contending it should be in widespread distribution to people at higher risk of having a serious case of Covid-19 with mid-level symptoms, most often without even confirming their illness is in fact connected to coronavirus.

    He wrote in the emails sent on Friday that his clinic had so far given 669 outpatients the drug cocktail, and that none had died. He attached a spreadsheet in which he listed 54 high-risk cases, including three who required hospitalization.

    In an interview Friday, Zelenko encouraged doctors to resist calls from infectious disease experts to prescribe the drug only as part of clinical trials and to critical patients.

    “This is a World War III situation — it’s the virus versus humanity,” he said. “If we were to adopt their approach, there would be an extra million dead people.”…

    Zelenko has been buoyed by support for the drug from conservative voices, like Home Depot billionaire Bernard Marcus and Fox News commentator Sean Hannity. And prescriptions for the drug are growing, with a large tele-health company now prescribing the drug to people across the country.

    Other doctors are following Zelenko’s approach, including an internist in New Jersey and DocTalkGo, a San Diego telehealth company, which said it has prescribed the drug to 20 patients nationwide.

    “I speak to physicians and patients and emergency responders — it’s being prescribed all over the place,” said Dr. Richard Roberts, a retired pharmaceutical executive.

    Yet Zelenko said that his ability to prescribe the medication has been hampered since New York Gov. Andrew Cuomo signed an executive order early this week aimed at curtailing use of the drug to treat Covid outside of clinical trials. Zelenko said he had thought that FDA approval of the drug for off-label use — announced by Vice President Mike Pence the day after Cuomo signed his order — would circumvent the New York state rule.

    But because the order specifically limited the ability of pharmacists — who are licensed by the state — to fill prescriptions of the drug, Zelenko said his patients are going to New Jersey, Connecticut and Pennsylvania to fill their prescriptions.

    Zelenko praised Trump’s role in pushing for the drug, which he has done while his top medical advisor, Dr. Anthony Fauci, has dismissed evidence of the drug’s effectiveness as anecdotal.

    “I want to thank the president for making this drug an issue that we are talking about,” Zelenko said. “I need his help to make it more readily available to my patients.”

  36. Novartis Chief Executive Vas Narasimhan said his Sandoz generics unit's malaria, lupus and arthritis drug hydroxychloroquine is the company's biggest hope against the coronavirus, Swiss newspaper SonntagsZeitung reported on Sunday.

    Novartis has pledged to donate 130 million doses and is supporting clinical trials needed before the medicine, which U.S. President Donald Trump also has been promoting, can be approved for use against the coronavirus.

    Other companies including Bayer and Teva have also agreed to donate hydroxychloroquine or similar drugs, while Gilead Sciences is testing its experimental drug remdesivir against coronavirus.

    "Pre-clinical studies in animals as well as the first data from clinical studies show that hydroxychloroquine kills the coronavirus," Narasimhan told the newspaper. "We're working with Swiss hospitals on possible treatment protocols for the clinical use of the drug, but it's too early to say anything definitively."

    He said the company is currently looking for additional active drug ingredients to make more hydroxychloroquine, should clinical trials be successful.

    Narasimhan said three other Novartis drugs - Jakavi for cancer, multiple sclerosis drug Gilenya and fever drug Ilaris - are being studied for their effect on complications related to COVID-19, the newspaper reported. This follows separate efforts to re-purpose drugs made by companies including Roche and Sanofi to treat complications related to the disease.

  37. The same French researchers who created buzz over a potential treatment for COVID-19 released new data that they say bolsters the idea that HCQ with azithromycin is effective in battling the virus. The uncontrolled study of 80 patients found a significant decrease in viral load, but it failed to convince skeptics who want to see studies that include a comparator group.

    The new data are "complementary," said Benjamin Davido, MD, a French infectious diseases expert, but they do not provide new information or new statistical evidence. He told Medscape France that he personally believes in HCQ, but it would be "a shame to think that we have found the fountain of youth and to realize, in four weeks, that we have the same number of deaths."

    Perry Wilson, MD, provided further context by describing data from the earlier French study as "equivocal at best," arguing for complete transparency about what is known and what is not. "If we want to use hydroxychloroquine, that is a reasonable choice, but we need to tell the public the truth: We're not too sure it will work, and it may even be harmful," he said.

  38. “We are using hydroxychloroquine as an off-label use,” Varga said on Monday. “We use it for our intubated patients for the most part. We’re also using it for some of our nursing home patients because that's a group that you don't want to get sick, don't want to it to spread because they're so vulnerable.”

    “And the other trial that we are looking at right now that we hope to get launched later this week, we’ve actually had it fast-tracked up until now, is actually using hydroxychloroquine for what we call chemoprophylaxis or prevention for front-line caregivers,” he added…
    Varga went on to say that there are currently 1,400 coronavirus patients in Hackensack Meridian Health facilities, with more than 300 in the ICU and more than 300 on ventilators.

    “We’re probably using the hydroxychloroquine recipe in some way shape or form in about three-quarters of our patients right now,” Varga said.

  39. A more detailed explainer of the potential role of anti-malarial drugs like hydroxychloroquine against the COVID-19 coronavirus disease, with or without antibiotics, can be found here. Zelenko’s claims, however, rest solely on taking him at his word: He has published no data, described no study design, and reported no analysis.

    In an open letter to Trump dated March 23, 2020, and published online in various locations, Zelenko provided his first batch of assertions without providing evidence to support his treatment regime:

    I developed the following treatment protocol in the pre-hospital setting and have seen only positive results. […]

    The rationale for my treatment plan is as follows. […] We know that hydroxychloroquine helps Zinc enter the cell. We know that Zinc slows viral replication within the cell. Regarding the use of azithromycin, I postulate it prevents secondary bacterial infections. These three drugs are well known and usually well tolerated, hence the risk to the patient is low.

    Since last Thursday, my team has treated approximately 350 patients in Kiryas Joel and another 150 patients in other areas of New York with the above regimen. Of this group and the information provided to me by affiliated medical teams, we have had ZERO deaths, ZERO hospitalizations, and ZERO intubations. In addition, I have not heard of any negative side effects other than approximately 10% of patients with temporary nausea and diarrhea.

    In sum, my urgent recommendation is to initiate treatment in the outpatient setting as soon as possible in accordance with the above. Based on my direct experience, it prevents acute respiratory distress syndrome (ARDS), prevents the need for hospitalization and saves lives.

    As has been noted elsewhere, combining hydroxychloroquine and azithromycin can cause serious problems for people with certain heart conditions. Though zinc appears to be an important factor in several immune functions, a potential mechanism for how it might work against viral infections is not well-understood.

    In an interview with Forward, Zelenko “acknowledged that his regimen was new and untested, and that it was too soon to assess its long-term effectiveness.” He instead argued that “the risks of waiting to verify its efficacy” were greater. This is an assertion with which public health officials largely disagree.

    Regardless, making an assertion in a blog post or in a YouTube interview that neither describes the study design nor provides the actual data used to reach a conclusion about efficacy cannot, in any way, be critically evaluated. As such, this claim is rated “Unproven.”