Thursday, April 2, 2020

Hydroxychloroquine and azithromycin as a treatment of COVID-19 2

Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D, Goldwirt L, de Castro N. No Evidence of Rapid Antiviral Clearance or Clinical Benefit with the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID-19 Infection. Medecine et Maladies Infectieuses (2020),doi:

The COVID-19 epidemic is the worst worldwide pandemic in a century with more than 500,000
cases and 25,000 deaths so far. In France, more than 30,000 cases have been reported up to
March 27, and nearly 2,000 have died.

Pending the availability of a vaccine, there is a critical need to identify effective treatments
and a number of clinical trials have been implemented worldwide.

Chloroquine analogs have been shown to inhibit the acidification of endosomes and to exhibit
in vitro a non specific antiviral activity at high micromolar concentration against a broad range
of emerging virus (HIV, dengue, hepatitis C, chikungunya, influenza, Ebola, SARS and MERS
viruses) and more recently COVID-19 (1-2).

In France, following the results of a clinical study in Marseille, there is considerable interest
for the use of hydroxychloroquine to treat COVID-19 disease, and the French Ministry of
Health recently allowed the use of hydroxychloroquine to treat COVID-19 disease pending the
results of ongoing clinical trials (3).

In their study, Gautret et al. reported a 100% viral clearance in nasopharyngeal swabs in 6
patients after 5 and 6 days of the combination of hydroxychloroquine and azithromycin (3).
This rate of viral clearance was lower with hydroxychloroquine alone (57.1%) and was only
12.5% in patients who did not receive hydroxychloroquine (p< 0.001).

Such a rapid and full viral clearance was quite unexpected and we wished to assess in a
prospective study virologic and clinical outcomes of 11 consecutive patients hospitalized in
our department who received hydroxychloroquine (600 mg/d for 10 days) and azithromycin
(500 mg Day 1 and 250 mg days 2 to 5) using the same dosing regimen reported by Gautret et
al. (3).

There were 7 men and 4 women with a mean age of 58.7 years (range: 20-77), 8 had significant
comorbidities associated with poor outcomes (obesity: 2; solid cancer: 3; hematological
cancer: 2; HIV-infection: 1).

At the time of treatment initiation, 10/11 had fever and received nasal oxygen therapy. Within
5 days, one patient died, two were transferred to the ICU. In one patient, hydroxychloroquine
and azithromycin were discontinued after 4 days because of a prolongation of the QT interval
from 405 ms before treatment to 460 and 470 ms under the combination. Mean through
blood concentration of hydroxychloroquine was 678 ng/mL (range: 381-891) at days 3-7 after
treatment initiation.

Repeated nasopharyngeal swabs in 10 patients (not done in the patient who died) using a
qualitative PCR assay (nucleic acid extraction using Nuclisens Easy Mag®, Biomerieux and
amplification with RealStar SARS CoV-2®, Altona), were still positive for SARS-CoV2 RNA in
8/10 patients (80%, 95% confidence interval: 49-94) at days 5 to 6 after treatment initiation.
These virologic results stand in contrast with those reported by Gautret et al. and cast doubts
about the strong antiviral efficacy of this combination. Furthermore, in their report Gautret et
al also reported one death and three transfers to the ICU among the 26 patients who received
hydroxychloroquine, also underlining the poor clinical outcome with this combination.

In addition, a recent study from China in individuals with COVID-19 found no difference in the
rate of virologic clearance at 7 days with or without 5 days of hydroxychloroquine, and no
difference in clinical outcomes (duration of hospitalization, temperature normalization,
radiological progression) (4). These results are consistent with the lack of virologic or clinical
benefit of chloroquine in a number of viral infections where it was assessed for treatment or
prophylaxis with sometimes a deleterious effect on viral replication (5-8).

In summary, despite a reported antiviral activity of chloroquine against COVID-19 in vitro, we
found no evidence of a strong antiviral activity or clinical benefit of the combination of
hydroxychloroquine and azithromycin for the treatment of our hospitalized patients with
severe COVID-19. Ongoing randomized clinical trials with hydroxychloroquine should provide
a definitive answer regarding the alleged efficacy of this combination and will assess its safety.

1. Wang  M,  Cao  R,  Zhang  L,  et  al. Remdesivir  and  chloroquine  effectively  inhibit  the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research 2020; 30:269-71.  2. Al-Bari  AA.  Targeting  endosomal  acidification  by  chloroquine  analogs  as  a  promising strategy  for  the  treatment  of  emerging  viral  diseases.  Pharmacology  research  and perspectives. 2017;5:e00293 3. Gautret  P,  Lagier  JC,  Parola  P,  et  al. Hydroxychloroquine  and  azithromycin  as  a treatment   of   COVID-19:   results   of   an   open-label   non-randomized   clinical   trial. International Journal of Antimicrobial Agents 2020 (ahead of print).   4. Chen J, Liu D, Lui L, et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 COVID-19). Journal of Zhejiang University 2020; 03-03  5. Roques P, Thiberville SD, Dupuis-Maguiraga L et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection. Viruses, 2018:10:268 6. Tricou V, Minh NN, Van TP et al. A randomized controlled trial of chloroquine for the treatment  of  dengue  in  Vietnamese  adults.  PLos  Neglected  tropical  diseases  2010; 4:e785.  7. Paton  NI,  Lee  L,  Xu  Y,  et  al. Chloroquine  for  influenza  prevention:  a  randomised, double-blind, placebo-controlled trial. Lancet Infectious Diseases, 2011; 11:677-83  8. Paton  NI,  Goodall  RL,  Dunn  DT,  et  al. Effects  of  hydroxychloroquine  on  immune activation   and   disease   progression   among HIV-infected   patients   not   receiving antiretroviral therapy: a randomized controlled trial. JAMA. 2012;308 (4):353-61.  


  1. Last month, residents of Kiryas Joel, a New York village of 35,000 Hasidic Jews roughly an hour’s drive from Manhattan, began hearing about a promising treatment for the coronavirus that had been rippling through their community.

    The source was Dr. Vladimir Zelenko, 46, a mild-mannered family doctor with offices near the village. Since early March, his clinics had treated people with coronavirus-like symptoms, and he had developed an experimental treatment consisting of an antimalarial medication called hydroxychloroquine, the antibiotic azithromycin and zinc sulfate.

    After testing this three-drug cocktail on hundreds of patients, some of whom had only mild or moderate symptoms when they arrived, Dr. Zelenko claimed that 100 percent of them had survived the virus with no hospitalizations and no need for a ventilator.

    “I’m seeing tremendous positive results,” he said in a March 21 video, which was addressed to President Trump and eventually posted to YouTube and Facebook.

    What happened next is a modern pandemic parable that illustrates how the coronavirus is colliding with our fragile information ecosystem: a jumble of facts, falsehoods and viral rumors patched together from Twitter threads and shards of online news, amplified by armchair experts and professional partisans and pumped through the warp-speed accelerator of social media…

    In a phone interview from his home, where he has been in self-isolation, Dr. Zelenko, who goes by Zev, described a dizzying week filled with calls from media and health officials from countries including Israel, Ukraine and Russia, all seeking information about his treatment. Some world leaders, including Brazil’s president, Jair Bolsonaro, are also talking up some of the same drugs as a cure.

    “It’s a very surreal moment,” said Dr. Zelenko, who has been practicing medicine for 16 years. “I’m a simple country doctor, you know. I don’t have connections.”…

    Critics have accused Dr. Zelenko of getting ahead of scientific research. Several small studies, including a controversial French one of 20 coronavirus patients, have found that hydroxychloroquine may be effective against the coronavirus. This week, doctors in China said it had helped to speed the recovery of a small number of patients who were mildly ill from the coronavirus. But other studies have contradicted those findings, or have been inconclusive.

    “Anyone who tells you these drugs work, or don’t work, is not basing that view on science,” said David Juurlink, the head of the division of clinical pharmacology at the University of Toronto. “There’s reason to be optimistic, and there’s also reason to be pessimistic.”
    Dr. Jeff Paley, an internist in Englewood, N.J., who shares some patients with Dr. Zelenko, said it was “irresponsible” for him to promote a treatment without warning people that the combination of hydroxychloroquine and azithromycin can cause severe side effects if not properly administered, especially in patients with pre-existing heart problems.

    “I’ve gotten numerous calls from patients demanding the regimen, saying they believe Dr. Zelenko is magically curing his patients,” Dr. Paley said.

    Dr. Zelenko, who learned two years ago that he had a rare form of cancer, was not the first doctor to recommend treating the coronavirus with hydroxychloroquine and azithromycin, though he was among the first to recommend that they be given to patients with only mild symptoms. He said that while he was optimistic, it was too early to tell whether the drugs would ultimately work.(continued)

  2. (continued)But hopes for a miracle cure have ballooned as the coronavirus spreads, and Mr. Trump and his allies are not waiting for the clinical trials to finish. An analysis by Media Matters last week found that Fox News had promoted hydroxychloroquine and chloroquine as a coronavirus cure more than 100 times over three days.

    Tech companies have begun cracking down on hyperbolic claims about the drugs. Last week, Twitter removed a tweet by Mr. Giuliani that said hydroxychloroquine was “100% effective” in treating Covid-19, the disease caused by the coronavirus. Facebook, YouTube and Twitter this week took down a video by Mr. Bolsonaro claiming that the drug “is working in all places.” YouTube later took down Dr. Zelenko’s video, saying it violated the site’s community guidelines…

    For more than a decade, Dr. Zelenko has been a fixture in Kiryas Joel, where a sign at the village entrance encourages visitors to “dress and behave in a modest way.” Unlike most of the residents, who belong to the Satmar sect of Orthodox Judaism, Dr. Zelenko is part of the Chabad-Lubavitch movement and does not live in Kiryas Joel itself, which has made him something of an outsider.

    Ari Felberman, a patient of Dr. Zelenko’s for years, called him a “phenomenal doctor” and said that if he had exaggerated the coronavirus threat in Kiryas Joel, it was only out of concern for his patients’ health.

    “When he spoke about how many people were affected, it was just to shake up the community and say, ‘Don’t take this lightly,’” Mr. Felberman said.

    Villagers began experiencing coronavirus symptoms in early March. Days later, after Dr. Zelenko began treating patients with his three-drug combination and saw many of them improving, he created a YouTube account and uploaded his video that addressed Mr. Trump.

    “At the time, it was a brand-new finding, and I viewed it like a commander in the battlefield,” he said of the video. “I realized I needed to speak to the five-star general.”…

    While dealing with his newfound fame, Dr. Zelenko, who has been practicing telemedicine from his home office, is working to keep his coronavirus patients alive. He said his team had seen about 900 patients with possible coronavirus symptoms, treating about 350 with his regimen. None had died as of Thursday, he said, though six were hospitalized and two were on ventilators.

    He is worried about his own health. One of his lungs was removed as part of his cancer treatment, and chemotherapy has weakened his immune system, putting him in a high-risk category for the coronavirus.

    “I have eight children, and I want to live,” he said. “I’m personally motivated to find a solution.”…

    Dr. Zelenko said he understood the need for clinical trials but added that ignoring a hopeful possibility was also risky.

    “I’m a strong supporter of clinical trials,” he said. “But they take time, and that’s one thing we don’t have. The virus is here, it’s World War III, and not everyone has fully comprehended that yet.”

  3. The malaria drug hydroxychloroquine helped to speed the recovery of a small number of patients who were mildly ill from the coronavirus, doctors in China reported this week.

    Cough, fever and pneumonia went away faster, and the disease seemed less likely to turn severe in people who received hydroxychloroquine than in a comparison group not given the drug. The authors of the report said that the medication was promising, but that more research was needed to clarify how it might work in treating coronavirus disease and to determine the best way to use it.

    “It’s going to send a ripple of excitement out through the treating community,” said Dr. William Schaffner, an infectious disease expert at Vanderbilt University.

    The study was small and limited to patients who were mildly or moderately ill, not severe cases. Like many reports about the coronavirus, it was posted at medRxiv, an online server for medical articles, before undergoing peer review by other researchers.

    Zhaowei Chen, Jijia Hu, Zongwei Zhang, Shan Jiang, Shoumeng Han, Dandan Yan, Ruhong Zhuang, Ben Hu, Zhan Zhang. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020.03.22.20040758; doi:

    This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

    Aims: Studies have indicated that chloroquine (CQ) shows antagonism against COVID-19 in vitro. However, evidence regarding its effects in patients is limited. This study aims to evaluate the efficacy of hydroxychloroquine (HCQ) in the treatment of patients with COVID-19. Main methods: From February 4 to February 28, 2020, 62 patients suffering from COVID-19 were diagnosed and admitted to Renmin Hospital of Wuhan University. All participants were randomized in a parallel-group trial, 31 patients were assigned to receive an additional 5-day HCQ (400 mg/d) treatment, Time to clinical recovery (TTCR), clinical characteristics, and radiological results were assessed at baseline and 5 days after treatment to evaluate the effect of HCQ. Key findings: For the 62 COVID-19 patients, 46.8% (29 of 62) were male and 53.2% (33 of 62) were female, the mean age was 44.7 (15.3) years. No difference in the age and sex distribution between the control group and the HCQ group. But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 32) compared with the control group (54.8%, 17 of 32). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia.

  4. An international poll of more than 6,000 doctors released Thursday found that the antimalarial drug hydroxychloroquine was the most highly rated treatment for the novel coronavirus.

    The survey conducted by Sermo, a global health care polling company, of 6,227 physicians in 30 countries found that 37% of those treating COVID-19 patients rated hydroxychloroquine as the “most effective therapy” from a list of 15 options.

    The U.S. Food and Drug Administration gave chloroquine and its next-generation derivative, hydroxychloroquine, emergency-use authorization Monday for treating the novel coronavirus, although the drug was already being used off-label by some doctors and hospitals for COVID-19 patients.

    Hydroxychloroquine, which is sold under the brand name Plaquenil, was prescribed mainly in the United States for the most severe cases, but not so in other countries.

    “Outside the U.S., hydroxychloroquine was equally used for diagnosed patients with mild to severe symptoms whereas in the U.S. it was most commonly used for high risk diagnosed patients,” the survey found.

  5. In addition to the small size of this trial[comment April 2.2020 10:56 pm], the unspecified components of the hospital standard treatment and its variance between patients confounds assessment of the effect of hydroxychloroquine, particularly on whether it lessened severity given the small number of patients who experienced a worsening course. Also, excluding severe illness from study entry leaves the effect of hydroxychloroquine on severe symptoms an open question.

    The trial results were posted on medRxiv, a non-peer reviewed site which expedites access to new research, often preceding peer reviewed publication. This report with 62 patients appears to be an initial phase, with the trial registration (unique identifier ChiCTR2000029559 on the Chinese Clinical Trial Registry) describing a target of 300 patients and the testing of a twice daily dose of 100mg as well as the 200mg.

    The trial is 1 of 23 that are, or will be testing hydroxychloroquine or chloroquine against COVID-19 on the Chinese Clinical Trial Registry. Of these, 18 are randomized controlled trials of the agent for acute treatment, not in combination with an antibiotic.

    There are currently 3 controlled trials outside of China listed at, which will be assessing hydroxychloroquine or chloroquine for acute treatment of COVID-19, excluding trials for prophylaxis and in combination with azithromycin. The largest is a phase 3 placebo-controlled trial with anticipated enrollment of 1300 participants conducted by researchers at the University Hospital, Angers, France.

  6. "Today we now have new and encouraging updates from Dr. Zelenko. In a one hour video. Dr. Zelenko provides a detailed medical explanation about why his cocktail of hydroxychloroquine sulfate, zinc and azithromycin (not Z-pac) works and why the three-drug combination are [sic] really needed in killing coronavirus."

  7. A doctor in Los Angeles is reporting remarkable success in treating COVID-19 patients with a combination of zinc and the Trump-touted anti-malarial drug hydroxychloroquine.

    Dr. Anthony Cardillo, an ER specialist and the CEO of Mend Urgent Care, has been prescribing the combination of drugs to patients experiencing severe symptoms of the disease after contracting the novel coronavirus.

    "Every patient I've prescribed it to has been very, very ill and within 8 to 12 hours, they were basically symptom-free," Cardillo said in an interview Sunday with KABC-TV. "So, clinically I am seeing a resolution."

    He added that combining the drug with zinc has been the key to the success. The hydroxychloroquine, he said, "opens the zinc channel" allowing the zinc to enter the cell, which then "blocks the replication of cellular machinery."

    Cardillo was careful to note that the drug should only be prescribed for patients who are extremely sick and in urgent need so as to not blow through the limited supply of the drug, which is used to treat other illnesses, as well.

    A doctor in Los Angeles is reporting remarkable success in treating COVID-19 patients with a combination of zinc and the Trump-touted anti-malarial drug hydroxychloroquine.

    Dr. Anthony Cardillo, an ER specialist and the CEO of Mend Urgent Care, has been prescribing the combination of drugs to patients experiencing severe symptoms of the disease after contracting the novel coronavirus.

    "Every patient I've prescribed it to has been very, very ill and within 8 to 12 hours, they were basically symptom-free," Cardillo said in an interview Sunday with KABC-TV. "So, clinically I am seeing a resolution."

    He added that combining the drug with zinc has been the key to the success. The hydroxychloroquine, he said, "opens the zinc channel" allowing the zinc to enter the cell, which then "blocks the replication of cellular machinery."

    Cardillo was careful to note that the drug should only be prescribed for patients who are extremely sick and in urgent need so as to not blow through the limited supply of the drug, which is used to treat other illnesses, as well.

    "We have to be cautious and mindful that we don't prescribe it for patients who have COVID who are well," he said. "It should be reserved for people who are really sick, in the hospital or at home very sick, who need that medication. Otherwise we're going to blow through our supply for patients that take it regularly for other disease processes."

  8. Medications that neither cure nor prevent a disease can still treat its symptoms. With hydroxychloroquine, the most likely benefit comes from the drug’s ability to tamp down inflammation.

    This is how it’s used to treat lupus, rheumatoid arthritis, and other auto-immune disease symptoms. In these disorders, an over-active immune system gets so ramped up that it can’t stop creating killer cells to fight foreign invaders. That barrage of killer cells, meant to destroy disease-causing organisms, instead turns against the body itself, damaging such systems as skin, cartilage, and vital organs.

    A misfiring, hyper-active immune system appears to be behind some of the worst coronavirus respiratory symptoms, too. The lungs become disastrously inflamed as the body attempts to expel the virus. If the inflammation becomes pronounced enough, it’s the immune response itself, rather than the virus, that can land someone on a ventilator in the ICU, and sometimes result in death.

    This means that, for those with or at risk of severe COVID-19 lung complications, hydroxychloroquine might be a good, potentially lifesaving treatment. It might reduce inflammation enough so that fewer people need ventilators, and those who do need them might have a better chance of survival. But, the emphasis is on the word “might.” As with everything being tried against COVID-19, doctors are practicing what amounts to battlefield medicine. People are dying daily and others are at imminent risk of death. There’s no time to await results from the large, blinded clinical trials that inform medicine in ordinary times.

    How has it worked, to date? With only a few small studies to guide treatment, or even identify those who might most benefit, hospitals have reported mixed results. Even when COVID-19 patients recover, it’s difficult to know whether they would have done so without the medication.

    One of the most dramatic press reports of apparent success came from a skilled nursing facility for veterans in Lebanon, Oregon. A doctor treated eight elderly veterans with a combination of hydroxychloroquine and azithromycin (an antibiotic that’s been used in tandem with the anti-malarial, and in a French study, showed better results than hydroxychloroquine alone). One died, but the others recovered, including a 103-year old who was “seriously declining” prior to getting the medication, and survived to celebrate his 104th birthday on April 1, 2020.

    Although there has been much hand-wringing about politicians and certain media touting an “unproven drug” like hydroxychloroquine, it cannot be stressed enough: There are no proven treatments for COVID-19.

  9. We have new data on hydroxychloroquine therapy to discuss. The numbers will not clear anything up.

    First off is an abstract from the Marseilles IHU group of Dr. Didier Raoult. It presents 1061 patients treated for at least 3 days with their hydroxychloroquine/azithromycin combination, with followup of at least 9 days. It includes the statement “98% of patients cured so far” and says also “No cardiac toxicity was observed”, and also says that mortality figures were improved in these patients as compared with others receiving standard-of-care without such treatment. The other release is a data table on these patients (there is no full manuscript as of yet). It does not include any sort of control group, nor (as far as I can see) does it even have a comparison in it to those other patients mentioned in the abstract. Let’s hold on to these thoughts as we discuss the next data.

    Here is a preprint from a large multinational collaboration presenting data obtained from health care systems (claims data or electronic medical records) in Germany, Japan, Netherlands, Spain, UK, and the USA. It (1) compares the safety of hydroxychloroquine in rheumatoid arthritis patients (956, versus thost patients (310,350 of them) taking another common RA drug, sulfasalazine, (2) compares the safety of the combination of hydroxychloroquine and azithromycin taken together (in 323,122 patients) versus the combination of hydroxychloroquine and another common antibiotic, amoxicillin (in 351,956 patients). Nothing like digging through the big health databases, is there?

    The good news is that the HCQ/sulfasalazine comparison does not show any real differences in adverse events over one-month courses of treatment. I should note that sulfasalazine is not the most side-effect-free medication in the whole pharmacopeia, but it has not been associated with (for example) QT prolongation, which is one of the things you worry about with hydroxychloroquine. The paper concludes that short-term HCQ monotherapy does appear to be safe, but notes that long-term HCQ dosing is indeed tied to increased cardiovascular mortality.

    The trouble comes in with the azithromycin combination. Like many antibiotics (although not amoxicillin), AZM is in fact tied to QT prolongation in some patients, so what happens when it’s given along with HCQ, which has the same problem?

    Worryingly, significant risks are identified for combination users of HCQ+AZM even in the short-term as proposed for COVID19 management, with a 15-20% increased risk of angina/chest pain and heart failure, and a two-fold risk of cardiovascular mortality in the first month of treatment.

    That isn’t good. I am very glad to hear that the Raoult group has observed no cardiac events in their studies so far, but I wonder how they have managed to be so fortunate, given these numbers. The authors again:

    As the world awaits the results of clinical trials for the anti-viral efficacy of HCQ in the treatment of SARS-Cov2 infection, this large scale, international real-world data network study enables us to consider the safety of the most popular drugs under consideration. HCQ appears to be largely safe in both direct and comparative analysis for short term use, but when used in combination with AZM this therapy carries double the risk of cardiovascular death in patients with RA. Whereas we used the collective experience of a million patients to build our confidence in the evidence around the safety profile, the current evidence around efficacy of HCQ+AZI in the treatment of covid-19 is quite limited and controversial.(continued)

  10. (continued)Indeed it is. And this morning, there is a picture of what appears to be the summary page of a manuscript under review at the NEJM. This is quite irregular, of course; this stuff is not supposed to be floating around on Twitter. It is apparently a study from Detroit of 63 consecutive patients admitted with coronavirus infection, with 32 assigned to receive hydroxychloroquine therapy and the others to standard-of-care. So this is again not a large study, and is rather similar in size to the Wuhan study discussed here that showed some benefit.

    That’s not the case in this work. If we are seeing is an accurate summary of the work, then HCQ treatment was actually associated with worse outcomes. I won’t go into more detail until this becomes more official and we can verify that we’re looking at a real manuscript – a quick check shows that the authors’ affiliation appear to be correct, but that many of them are ophthalmologists, and I’m not sure what to make of that. I am of two minds about whether to mention it at all, but these are unusual circumstances. More to come as the situation gets clearer.

    Update: here is another new preprint from a multinational team lead out of Brazil. It enrolled 81 patients in a trial of high-dose hydroxychloroquine (600 mg b.i.d. over ten days, total dose 12g) or low-dose (450mg b.i.d. on the first day, qd thereafter for the next four, total dose 2.7g). All patients also received azithromycin and ceftriaxone (a cephalosporin antibiotic). The high-dose patients showed more severe QT prolongation and there a trend toward higher lethality compared to the low dose. The overall fatality rate across both arms of the study was 13.5% (so far), which they say overlaps with the historical fatality rate of patients not receiving hydroxychloroquine. The authors actually had to stop recruiting patients for the high-dose arm of the study due to the cardiovascular events, but they’re continuing to enroll people in the low-dose group to look at overall mortality. The paper mentions that HCQ has been mandated as the standard therapy in Brazil, so there is no way to run a non-HCQ control group, though.

  11. French microbiologist Didier Raoult on Friday released some early results from his treatment of 1061 coronavirus patients with a combination of hydroxychloroquine and the antibiotic azithromycin.

    Raoult says the treatment had a good outcome in 91.7 percent of patients, a poor virological outcome in 4.4 percent (viral shedding persistence at day 10) and a poor clinical outcome in 4.3 percent (either death or transfer to intensive care unit or hospitalization for 10 days or more).

    He says 98 percent were eventually cured.

    There were 5 deaths.

    The abstract and the summary table of our paper on the treatment of 1061 patients are online ! … …

  12. Chloroquine diphosphate in two different dosages as adjunctive therapy of hospitalized patients with severe respiratory syndrome in the context of coronavirus (SARS-CoV-2) infection: Preliminary safety results of a randomized, double-blinded, phase IIb clinical trial (CloroCovid-19 Study)

    Mayla Borba, Fernando de Almeida Val, Vanderson Sousa Sampaio, Marcia Araujo Alexandre, Gisely Cardoso Melo, Marcelo Brito, Maria Mourao, Jose Diego Brito Sousa, djane Baia-da-Silva, Marcus Vinitius Farias Guerra, Ludhmila Hajjar, Rosemary Costa Pinto, Antonio Balieiro, Felipe Gomes Naveca, Mariana Xavier, Alexandre Salomao, Andre Siqueira, Alexandre Schwarzbolt, Julio Henrique Rosa Croda, Mauricio Lacerda Nogueira, Gustavo Romero, Quique Bassat, Cor Jesus Fontes, Bernardino Albuquerque, Claudio Daniel-Ribeiro, Wuelton Monteiro, Marcus Lacerda, CloroCovid-19 Team

    This article is a preprint and has not been certified by peer review. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

    Summary Background There is no specific antiviral therapy recommended for the disease caused by SARS-CoV-2 (COVID-19). Recent publications have drawn attention to the possible benefit of chloroquine (CQ). Our study aimed to comprehensively evaluate the safety and efficacy of two different CQ dosages in patients with established severe COVID-19. Methods We performed a parallel, double-blinded, randomized, phase IIb clinical trial, aiming to assess safety and efficacy of two different CQ dosages as adjunctive therapy of hospitalized patients with SARS in Manaus, Brazilian Amazon. Eligible participants were allocated to receive orally or via nasogastric tube high dose CQ (600mg CQ twice daily for 10 days or total dose 12g); or low dose CQ (450mg for 5 days, twice daily only on the first day, or total dose 2.7g). In addition, all patients received ceftriaxone and azithromycin. This study was registered with, number NCT04323527. (continued)

  13. (continued)Findings Out of a pre-defined 440 patients sample size, 81 patients were enrolled. The high dose CQ arm presented more QTc>500ms (25%), and a trend toward higher lethality (17%) than the lower dosage. Fatality rate was 13.5% (95%CI=6.9-23.0%), overlapping with the CI of historical data from similar patients not using CQ (95%CI=14.5-19.2%). In 14 patients with paired samples, respiratory secretion at day 4 was negative in only one patient. Interpretation Preliminary findings suggest that the higher CQ dosage (10-day regimen) should not be recommended for COVID-19 treatment because of its potential safety hazards. Such results forced us to prematurely halt patient recruitment to this arm. Given the enormous global push for the use of CQ for COVID-19, results such as the ones found in this trial can provide robust evidence for updated COVID-19 patient management recommendations.

  14. Coronavirus patients taking hydroxychloroquine, a treatment touted by President Trump, were no less likely to need mechanical ventilation and had higher deaths rates compared to those who did not take the drug, according to a study of hundreds of patients at US Veterans Health Administration medical centers.

    The study, which reviewed veterans' medical charts, was posted Tuesday on, a pre-print server, meaning it was not peer reviewed or published in a medical journal. The research was funded by the National Institutes of Health and the University of Virginia.
    In the study of 368 patients, 97 patients who took hydroxychloroquine had a 27.8% death rate. The 158 patients who did not take the drug had an 11.4% death rate.

    "An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs," wrote the authors, who work at the Columbia VA Health Care System in South Carolina, the University of South Carolina and the University of Virginia.

    Researchers also looked at whether taking hydroxychloroquine or a combination of hydroxychloroquine and the antibiotic azithromycin, had an effect on whether a patient needed to go on a ventilator.

    "In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19," the authors wrote.

    There are currently no products approved by the US Food and Drug Administration to prevent or treat Covid-19, although research is underway on many drugs. (see below)

  15. Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy Cummings, James W Hardin, S Scott Sutton, Jayakrishna Ambati. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. doi:

    This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

    BACKGROUND: Despite limited and conflicting data on the use of hydroxychloroquine in patients with Covid-19, the U.S. Food and Drug Administration has authorized the emergency use of this drug when clinical trials are unavailable or infeasible. Hydroxychloroquine, alone or in combination with azithromycin, is being widely used in Covid-19 therapy based on anecdotal and limited observational evidence. METHODS: We performed a retrospective analysis of data from patients hospitalized with confirmed SARS-CoV-2 infection in all United States Veterans Health Administration medical centers until April 11, 2020. Patients were categorized based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) as treatments in addition to standard supportive management for Covid-19. The two primary outcomes were death and the need for mechanical ventilation. We determined the association between treatment and the primary outcomes using competing risk hazard regression adjusting for clinical characteristics via propensity scores. Discharge and death were taken into account as competing risks and subdistribution hazard ratios are presented. RESULTS: A total of 368 patients were evaluated (HC, n=97; HC+AZ, n=113; no HC, n=158). Rates of death in the HC, HC+AZ, and no HC groups were 27.8%, 22.1%, 11.4%, respectively. Rates of ventilation in the HC, HC+AZ, and no HC groups were 13.3%, 6.9%, 14.1%, respectively. Compared to the no HC group, the risk of death from any cause was higher in the HC group (adjusted hazard ratio, 2.61; 95% CI, 1.10 to 6.17; P=0.03) but not in the HC+AZ group (adjusted hazard ratio, 1.14; 95% CI, 0.56 to 2.32; P=0.72). The risk of ventilation was similar in the HC group (adjusted hazard ratio, 1.43; 95% CI, 0.53 to 3.79; P=0.48) and in the HC+AZ group (adjusted hazard ratio, 0.43; 95% CI, 0.16 to 1.12; P=0.09), compared to the no HC group. CONCLUSIONS: In this study, we found no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19. An association of increased overall mortality was identified in patients treated with hydroxychloroquine alone. These findings highlight the importance of awaiting the results of ongoing prospective, randomized, controlled studies before widespread adoption of these drugs.

  16. Upon hearing the surprising results of the VA study, Dr. Raoult reviewed their findings and discovered several glaring instances of “scientific misconduct.” Fox News’ Laura Ingraham reported on Raoult’s response on her program Wednesday night.

    Ingraham read about the first problem from Raoult’s response, “In the current period, it seems that passion dominates rigorous and balanced scientific analysis and may lead to scientific misconduct and this article [VA findings] is an absolutely spectacular example of this. The analysis of the data shows two major biases…Lymphopenia is twice as common in the HCQ groups as the non-HCQ group and there is an absolute correlation between lymphopenia and fatality rate, which is well known.”

    One of the major problems Raoult found was that the HQC and the HQC/Zpak were given after the patients had been intubated. “This is unreasonable at the time of the cytokine storm [after patient is critically ill], as it is unlikely that HCQ alone would be able to control patients at this stage of the disease.”

    Ingraham translates: “The later you take HCQ, the worse the outcome will be.”

    The second problem: “Incomprehensibly, the ‘untreated group’ actually received azithromycin in 30% of cases, without this group being analyzed in any distinct way. Azithromycin is also a proposed treatment for COVID-19 (Gautret 2020) with in-vitro efficacy.”

    Well, then you can’t call these patients untreated. I suppose we won’t be seeing any media coverage of the serious problem Raoult discovered in the VA study.

    It looks as if the VA researchers had been trying to achieve a particular result.

  17. Infectious disease expert Dr. Stephen Smith told "The Ingraham Angle" Monday night that a study published last week indicating the antimalarial drug hydroxychloroquine showed no benefit for coronavirus patients in U.S. veterans hospitals was a "sham."

    "I've no idea why [University of Virginia School of Medicine opthamology professor Dr. Jayakrishna Ambati] delved into this study, which isn't a study. It's a sham," Smith said. "I can't believe anyone took this seriously. There's not one dosage listed, cumulative or daily, of hydroxychloriquine or anthromicin. And people call this a study."

    The research, which was published in the medRxiv online depository and has not been peer-reviewed, analyzed the medical records of 368 male veterans hospitalized with confirmed coronavirus infection at Veterans Health Administration medical centers who died or were discharged by April 11.

    About 28 percent of patients who were given hydroxychloroquine plus usual care died versus 11 percent of those getting routine care alone. About 22 percent of those getting the drug plus azithromycin died too, but the difference between that group and usual care was not considered large enough to rule out other factors that could have affected survival.

    "Not one person in that paper saw one COVID patient. Only three are MDs [and] all [those] are ophthalmology trained," Smith said of the research. "It's a sham. It's a shame on UVA. I sent an email to the dean of the medical school at UVA. I have not heard back from them. It is an embarrassment that UVA allows this thing to be called a study."

  18. Preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of COVID-19
    Mingxing Huang, Man Li, Fei Xiao, Jiabi Liang, Pengfei Pang, Tiantian Tang, Shaoxuan Liu, Binghui Chen, Jingxian Shu, Yingying You, Yang Li, Meiwen Tang, Jianhui Zhou, Guanmin Jiang, Jingfen Xiang, Wenxin Hong, Songmei He, Zhaoqin Wang, Jianhua Feng, Changqing Lin, Yinong Ye, Zhilong Wu, Yaocai Li, Bei Zhong, Ruilin Sun, Zhongsi Hong, Jing Liu, Huili Chen, Xiaohua Wang, Zhonghe Li, Duanqing Pei, Lin Tian, Jinyu Xia, Shanping Jiang, Nanshan Zhong, Hong Shan

    Background Effective therapies are urgently needed for the SARS-CoV-2 pandemic. Chloroquine has been proved to have antiviral effect against coronavirus in vitro. In this study, we aimed to assess the efficacy and safety of chloroquine with different doses in COVID-19. Method In this multicenter prospective observational study, we enrolled patients older than 18 years old with confirmed SARS-CoV-2 infection excluding critical cases from 12 hospitals in Guangdong and Hubei Provinces. Eligible patients received chloroquine phosphate 500mg, orally, once (half dose) or twice (full dose) daily. Patients treated with non-chloroquine therapy were included as historical controls. The primary endpoint is the time to undetectable viral RNA. Secondary outcomes include the proportion of patients with undetectable viral RNA by day 10 and 14, hospitalization time, duration of fever, and adverse events. Results A total of 197 patients completed chloroquine treatment, and 176 patients were included as historical controls. The median time to achieve an undetectable viral RNA was shorter in chloroquine than in non-chloroquine (absolute difference in medians -6.0 days; 95% CI -6.0 to -4.0). The duration of fever is shorter in chloroquine (geometric mean ratio 0.6; 95% CI 0.5 to 0.8). No serious adverse events were observed in the chloroquine group. Patients treated with half dose experienced lower rate of adverse events than with full dose. Conclusions Although randomised trials are needed for further evaluation, this study provides evidence for safety and efficacy of chloroquine in COVID-19 and suggests that chloroquine can be a cost-effective therapy for combating the COVID-19 pandemic.

  19. Membrillo de Novales, F.J.; Ramírez-Olivencia, G.; Estébanez, M.; de Dios, B.; Herrero, M.D.; Mata, T.; Borobia, A.M.; Gutiérrez, C.; Simón, M.; Ochoa, A.; Martínez, Y.; Aguirre, A.; Alcántara, F.D.A.; Fernández-González, P.; López, E.; Campos, S.; Navarro, M.; Ballester, L.E. Early Hydroxychloroquine Is Associated with an Increase of Survival in COVID-19 Patients: An Observational Study. Preprints 2020, 2020050057 (doi: 10.20944/preprints202005.0057.v1).

    Background: There is no treatment proven effective against COVID-19. Several drugs with in vitro potential against SARS-CoV-2 virus have been proposed. Hydroxychloroquine has in vitro anti-viral and immunomodulatory activity, but there is no current clinical evidence of its effectiveness changing the outcome of the disease. Methods: We enrolled all 18-85 years old inpatients from Central Defense Hospital “Gómez Ulla”, Madrid, Spain, who were hospitalised for COVID-19 and had a definitive outcome (dead or discharged). We used a statistical survival analysis to detect treatment differences associated with in-hospital death. Results: We analysed first 220 medical records. 166 patients met the inclusion criteria. 48,8 % of patients not treated with HCQ died, 22% of those treated with hydroxychloroquine (p=0,002). According to clinical picture at admission, hydroxychloroquine increased the mean cumulative survival in all groups from 1,4 to 1,8 times. This difference was statistically significant in the mild group. Conclusions: in a cohort of 166 patients from 18 to 85 years hospitalised with COVID-19, hydroxychloroquine treatment with 800mg added loading dose increased survival when patients were admitted in early stages of the disease. There was a non-statistically significant trend towards survival in all groups, which will have to be clarified in subsequent studies.

  20. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France
    MatthieuMillion,Jean-ChristopheLagier, PhilippeGautretac, PhilippeColson, Pierre-EdouardFournier, SophieAmrane, MarieHocquart MorganeMailheaVeraEsteves-Vieiraa BarbaraDoudiera CamilleAubrya FlorianCorrear AudreyGiraud-Gatineau YanisRoussel CyrilBerenger NadimCassir PisethSeng ChristineZandottia…DidierRaoult

    In France, the combination hydroxychloroquine (HCQ) and azithromycin (AZ) is used in the treatment of COVID-19.

    We retrospectively report on 1061 SARS-CoV-2 positive tested patients treated with HCQ (200 mg three times daily for ten days) + AZ (500 mg on day 1 followed by 250 mg daily for the next four days) for at least three days. Outcomes were death, clinical worsening (transfer to ICU, and >10 day hospitalization) and viral shedding persistence (>10 days).

    A total of 1061 patients were included in this analysis (46.4% male, mean age 43.6 years – range 14–95 years). Good clinical outcome and virological cure were obtained in 973 patients within 10 days (91.7%). Prolonged viral carriage was observed in 47 patients (4.4%) and was associated to a higher viral load at diagnosis (p < .001) but viral culture was negative at day 10. All but one, were PCR-cleared at day 15. A poor clinical outcome (PClinO) was observed for 46 patients (4.3%) and 8 died (0.75%) (74–95 years old). All deaths resulted from respiratory failure and not from cardiac toxicity. Five patients are still hospitalized (98.7% of patients cured so far). PClinO was associated with older age (OR 1.11), severity at admission (OR 10.05) and low HCQ serum concentration. PClinO was independently associated with the use of selective beta-blocking agents and angiotensin II receptor blockers (p < .05). A total of 2.3% of patients reported mild adverse events (gastrointestinal or skin symptoms, headache, insomnia and transient blurred vision).

    Administration of the HCQ+AZ combination before COVID-19 complications occur is safe and associated with very low fatality rate in patients.

  21. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. Published online May 11, 2020. doi:10.1001/jama.2020.8630

    Key Points
    Question Among patients with coronavirus disease 2019 (COVID-19), is there an association between use of hydroxychloroquine, with or without azithromycin, and in-hospital mortality?

    Findings In a retrospective cohort study of 1438 patients hospitalized in metropolitan New York, compared with treatment with neither drug, the adjusted hazard ratio for in-hospital mortality for treatment with hydroxychloroquine alone was 1.08, for azithromycin alone was 0.56, and for combined hydroxychloroquine and azithromycin was 1.35. None of these hazard ratios were statistically significant.

    Meaning Among patients hospitalized with COVID-19, treatment with hydroxychloroquine, azithromycin, or both was not associated with significantly lower in-hospital mortality.

    Importance Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and associated adverse events.

    Objective To describe the association between use of hydroxychloroquine, with or without azithromycin, and clinical outcomes among hospital inpatients diagnosed with COVID-19.

    Design, Setting, and Participants Retrospective multicenter cohort study of patients from a random sample of all admitted patients with laboratory-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 hours between March 15 and 28, 2020. Medications, preexisting conditions, clinical measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was April 24, 2020.

    Exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither.(continued)(

  22. (continued)Main Outcomes and Measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal electrocardiogram findings (arrhythmia or QT prolongation).

    Results Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 saturation lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]), . In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal electrocardiogram findings.

    Conclusions and Relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly associated with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.

  23. Researchers at NYU's Grossman School of Medicine found patients given the antimalarial drug hydroxychloroquine along with zinc sulphate and the antibiotic azithromycin were 44 percent less likely to die from the coronavirus.

    "Certainly we have very limited options as far as what we have seen work for this infection so anything that may work is very exciting," said Dr. Joseph Rahimian, Infectious Disease Specialist at NYU Langone Health.

    The study looked at the records of 932 COVID-19 patients treated at local hospitals with hydroxychloroquine and azithromycin.

    More than 400 of them were also given 100 milligrams of zinc daily.

    Researchers said the patients given zinc were one and a half times more likely to recover, decreasing their need for intensive care.
    One theory is that hydroxychloroquine may aid a cell’s ability to absorb the zinc which has antiviral properties and responds to the infection.

    "It sort of boosts the zinc activity which is one of the reasons we thought to look at zinc here and in this observational study we did see a difference suggesting that maybe that boosting activity of the hydroxychloroquine with the zinc helps the zinc to work better and lead to a benefit," Rahimian said.

    Dr. Rahimian says patients in the more critical stages of infection did not fare as well.

    And he cautioned that more research is needed - in particular a randomized controlled trial - to prove how and how well the drug combination works.

  24. Nolte: The One Fact that Shuts Down Media’s Fake Outrage About Trump & Hydroxychloroquine

    President Trump conferred with his physician, which means he handled his decision to take hydroxychloroquine in the exact right way.

    That’s it.

  25. Mandeep R Mehra, Sapan S Desai, Frank Ruschitzka, Amit N Patel. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. Published:May 22, 2020DOI:



    Hydroxychloroquine or chloroquine, often in combination with a second-generation macrolide, are being widely used for treatment of COVID-19, despite no conclusive evidence of their benefit. Although generally safe when used for approved indications such as autoimmune disease or malaria, the safety and benefit of these treatment regimens are poorly evaluated in COVID-19.


    We did a multinational registry analysis of the use of hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19. The registry comprised data from 671 hospitals in six continents. We included patients hospitalised between Dec 20, 2019, and April 14, 2020, with a positive laboratory finding for SARS-CoV-2. Patients who received one of the treatments of interest within 48 h of diagnosis were included in one of four treatment groups (chloroquine alone, chloroquine with a macrolide, hydroxychloroquine alone, or hydroxychloroquine with a macrolide), and patients who received none of these treatments formed the control group. Patients for whom one of the treatments of interest was initiated more than 48 h after diagnosis or while they were on mechanical ventilation, as well as patients who received remdesivir, were excluded. The main outcomes of interest were in-hospital mortality and the occurrence of de-novo ventricular arrhythmias (non-sustained or sustained ventricular tachycardia or ventricular fibrillation).


    96 032 patients (mean age 53·8 years, 46·3% women) with COVID-19 were hospitalised during the study period and met the inclusion criteria. Of these, 14 888 patients were in the treatment groups (1868 received chloroquine, 3783 received chloroquine with a macrolide, 3016 received hydroxychloroquine, and 6221 received hydroxychloroquine with a macrolide) and 81 144 patients were in the control group. 10 698 (11·1%) patients died in hospital. After controlling for multiple confounding factors (age, sex, race or ethnicity, body-mass index, underlying cardiovascular disease and its risk factors, diabetes, underlying lung disease, smoking, immunosuppressed condition, and baseline disease severity), when compared with mortality in the control group (9·3%), hydroxychloroquine (18·0%; hazard ratio 1·335, 95% CI 1·223–1·457), hydroxychloroquine with a macrolide (23·8%; 1·447, 1·368–1·531), chloroquine (16·4%; 1·365, 1·218–1·531), and chloroquine with a macrolide (22·2%; 1·368, 1·273–1·469) were each independently associated with an increased risk of in-hospital mortality. Compared with the control group (0·3%), hydroxychloroquine (6·1%; 2·369, 1·935–2·900), hydroxychloroquine with a macrolide (8·1%; 5·106, 4·106–5·983), chloroquine (4·3%; 3·561, 2·760–4·596), and chloroquine with a macrolide (6·5%; 4·011, 3·344–4·812) were independently associated with an increased risk of de-novo ventricular arrhythmia during hospitalisation.


    We were unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or with a macrolide, on in-hospital outcomes for COVID-19. Each of these drug regimens was associated with decreased in-hospital survival and an increased frequency of ventricular arrhythmias when used for treatment of COVID-19.

  26. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19 [published online ahead of print, 2020 Jun 3]. N Engl J Med. 2020;10.1056/NEJMoa2016638. doi:10.1056/NEJMoa2016638


    Background: Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.

    Methods: We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.

    Results: We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.

    Conclusions: After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; number, NCT04308668.).