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Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers shows no effect
Does a regimen of hydroxychloroquine, 600 mg, per day, reduce the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a pre-exposure prophylaxis strategy when taken by hospital-based health care workers?
In this double-blind, placebo-controlled randomized clinical trial that included 132 participants and was terminated early, there was not a significant difference in reverse-transcriptase polymerase chain reaction–confirmed SARS-CoV-2 incidence between hydroxychloroquine and placebo cohorts.
Among hospital-based health care workers, daily hydroxychloroquine did not prevent SARS-CoV-2 infection.
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" higher dosage of chloroquine diphosphate for 10 days was associated with more toxic effects and lethality"
The preliminary findings from the CloroCovid-19 trial suggest that higher dosage of chloroquine should not be recommended for the treatment of severe COVID-19, especially among patients also receiving azithromycin and oseltamivir, because of safety concerns regarding QTc interval prolongation and increased lethality.
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No difference occurred between HCL and Placebo groups in the primary outcome. The findings were the same at 5, 10, and 14 days.
A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.
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.
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Study: more people got better without hydroxychloroquine than with it, in treatment of patients with COVID-19.
JOURNAL OF ZHEJIANG UNIVERSITY March 2020
http://www.zjujournal.com/med DOI : 10.3785/j.issn.1008-9292.2020.03.03
Results: One patient in HCQ group developed to severe during the treatment. On day 7, COVID-19 nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P＞0.05).
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"Our patient developed COVID-19 while on hydroxychloroquine and although more work is needed, this calls into question the role of these medications as preventive therapy."
They appear to have an antiviral effect mediated through increasing the endosomal pH thereby impeding virus to cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV-2 [5,6].
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"They did this analysis several ways, and each time the result was the same: no benefit of HCQ"
Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19
n this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.)
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"Researchers cut chloroquine study short as 'primary outcome' was 'death'"
FDA issues warnings on chloroquine and hydroxychloroquine after deaths and poisonings reported
The agency also said it became aware of reports of "serious heart rhythm problems" in patients with the virus who were treated with the malaria drugs.
The Food and Drug Administration warned consumers Friday against taking malaria drugs chloroquine and hydroxychloroquine to treat Covid-19 outside a hospital or formal clinical trial setting after deaths and poisonings were reported.
The agency also said it became aware of reports of "serious heart rhythm problems" in patients with the virus who were treated with the malaria drugs, often in combination with antibiotic azithromycin, commonly known as a Z-Pak. It also warned physicians against prescribing the drugs to treat the coronavirus outside of a hospital.
"Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT interval prolongation and a dangerously rapid heart rate called ventricular tachycardia," the agency wrote in the notice. "We will continue to investigate risks associated with the use of hydroxychloroquine and chloroquine for COVID-19 and communicate publicly when we have more information."
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"This represents the strongest evidence to date of the lack of benefit and potential harm of HCQ as a treatment for COVID-19."
Hydroxychloroquine Not Effective in Large British Randomized Controlled Trial. This is another report from the UK RECOVERY trial, which previously concluded that low-dose dexamethasone significantly reduces mortality in more severely ill patients with COVID-19 (preprint server, not peer reviewed). In this arm of the study, 1,561 hospitalized patients with COVID-19 were randomized to hydroxychloroquine (HCQ) 800 mg at 0 and 6 hours, followed by 400 mg every 12 hours for up to nine days, whereas 3,155 were allocated to usual care. They excluded anyone known to have a prolonged QTc interval. This was an open label trial, and allocation was appropriately concealed. The mean age of participants was 65 years of age, 38% were female, 57% had at least one major comorbidity, and 76% were receiving supplemental oxygen or assisted ventilation. Very little crossover occurred, with 92% in the HCQ group getting at least one dose (mean duration six days) and only 0.4% in the usual care group receiving the drug. No difference occurred between groups with regard to 28-day mortality (26.8% HCQ vs. 25.0% usual care, rate ratio [RR] 1.09, 95% CI 0.96 to 1.23). Patients in the HCQ group had a longer time to hospital discharge (16 vs. 13 days) and were less likely to be discharged alive within 28 days (60.3% vs. 62.8%, RR 0.92, 95% CI 0.85 to 0.99, number needed to treat [NNT] = 40). Patients in the HCQ group were also more likely to experience the combined outcome of mechanical ventilation or death (29.8% vs. 26.5%, RR 1.12, 95% CI 1.01 to 1.25, NNT = 30). This represents the strongest evidence to date of the lack of benefit and potential harm of HCQ as a treatment for COVID-19.
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Hydroxychloroquine Not Effective for COVID-19 in U.S. Veterans
Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin.
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No evidence of clinical efficacy of hydroxychloroquine in patients
hospitalised for COVID-19 infection and requiring oxygen: results of a
study using routinely collected data to emulate a target trial
Results
This study included 181 patients with SARS-CoV-2 pneumonia; 84 received HCQ within
48 hours of admission (HCQ group) and 97 did not (no-HCQ group). Initial severity was well
balanced between the groups. In the weighted analysis, 20.2% patients in the HCQ group
were transferred to the ICU or died within 7 days vs 22.1% in the no-HCQ group (16 vs 21
events, relative risk [RR] 0.91, 95% CI 0.47–1.80). In the HCQ group, 2.8% of the patients
died within 7 days vs 4.6% in the no-HCQ group (3 vs 4 events, RR 0.61, 95% CI 0.13–2.89),
and 27.4% and 24.1%, respectively, developed acute respiratory distress syndrome within 7
days (24 vs 23 events, RR 1.14, 95% CI 0.65–2.00). Eight patients receiving HCQ (9.5%)
experienced electrocardiogram modifications requiring HCQ discontinuation.
Interpretation
These results do not support the use of HCQ in patients hospitalised for documented SARSCoV-2-positive
hypoxic pneumonia.
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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.
The absence of an effective treatment against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led clinicians to redirect drugs that are known to be effective for other medical conditions to the treatment of COVID-19. Key among these repurposed therapeutic agents are the antimalarial drug chloroquine and its analogue hydroxychloroquine, which is used for the treatment of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis.1, 2 These drugs have been shown in laboratory conditions to have antiviral properties as well as immunomodulatory effects.3, 4 However, the use of this class of drugs for COVID-19 is based on a small number of anecdotal experiences that have shown variable responses in uncontrolled observational analyses, and small, open-label, randomised trials that have largely been inconclusive.5, 6 The combination of hydroxychloroquine with a second-generation macrolide, such as azithromycin (or clarithromycin), has also been advocated, despite limited evidence for its effectiveness.7 Previous studies have shown that treatment with chloroquine, hydroxychloroquine, or either drug combined with a macrolide can have the cardiovascular adverse effect of prolongation of the QT interval, which could be a mechanism that predisposes to ventricular arrhythmias.8, 9
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Spanish RCT of Hydroxychloroquine for Patients with Early, Nonsevere COVID-19 Finds No Benefit
his Spanish study sought to determine whether early treatment with hydroxychloroquine is beneficial for patients with COVID-19. The researchers identified adults in Catalonia with a positive test for SARS-CoV-2, were symptomatic but did not require hospitalization, and were within five days of symptom onset. The mean age of the 293 included patients was 42 years, 69% were women, 87% were health care workers, and the median time from symptom onset to enrollment was three days. This was an open label study, but allocation to groups was concealed from patients and investigators; lab workers were masked to treatment assignment. Patients were followed for up to a month. Patients were randomized to hydroxychloroquine 800 mg on day 1 and 400 mg once daily on days 2 through 7 or usual care alone. The primary outcome was viral load at three and seven days, but they also tracked symptom improvement. Absolutely no difference occurred between groups at days 3 or 7 in viral load. No difference occurred in hospitalization rates (7.1% vs. 5.9% in the intervention group), and no deaths occurred during the study period. Also, no difference occurred in the mean days to resolution of symptoms (12 in the control arm vs. 10 in the treatment arm, p = 0.21). Adverse events (mostly gastrointestinal and nervous system related) were much more common in the treatment group (72% vs. 9%). No serious adverse events attributed to hydroxychloroquine occurred.
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No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection
In a prospective study, French investigators assessed virologic and clinical outcomes of 11 consecutive hospitalized patients (seven men and four women with mean age of 59 years) who received hydroxychloroquine ([HCQ] 660 mg/d for 10 days) and azithromycin (500 mg on day 1 and 250 mg on days 2 to 5); eight patients had significant comorbidities. At the time of treatment initiation, 10 out of 11 had fever and received nasal oxygen therapy. Within five days, one patient died and two were transferred to the ICU. In one patient, HCQ and azithromycin were discontinued after four days because of a prolongation of the QT interval. Repeated nasopharyngeal swabs in 10 patients (not completed in the patient who died) using a qualitative PCR assay were still positive for SARS-CoV2 RNA in eight of 10 patients 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 effectiveness of this combination.
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Neither Hydroxychloroquine nor Azithromycin Are Associated with Decreased In-Hospital Mortality in New York. They also found, however, that patients taking the combination of HCQ plus azithromycin were twice as likely to suffer a cardiac arrest whereas no increase in risk occurred for patients taking either drug alone.
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.
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"hydroxychloroquine increased the risk of adverse events"
BMJ “Live” Systematic Review of Drugs for Treating SARS-CoV-2. This team performed a high-quality systematic review of randomized trials of treatments for people with suspected, probable, or confirmed COVID-19. Their review process included searching for studies from more than 31 databases and preprint servers every day and assessing the risk of bias of the included studies. The team extracted several kinds of data, including study characteristics (e.g., publication status, study status, design features, etc.), patient demographics, smoking habits, comorbidities, setting and type of care, COVID severity, and outcomes. The outcomes included a spectrum of less patient-relevant events such as time to viral clearing to more clinically important ones such as mechanical ventilation and death. In addition to the systematic review, the authors pooled data and performed network meta-analyses for the various outcomes. Their process identified 13 published trials (2,568 persons), 10 preprints (7,167 persons), and nine more (6,156 persons) upcoming. All except two studies were at “probably high” or “high” risk of bias. In other words, the data that exist are of questionable reliability, and there are lots more data that have yet to be peer-reviewed. This is a true work in progress. The BMJ online version of the paper includes a really nice interactive feature that allows you to quickly see summary data and conclusions for each of the eight individual outcomes, a few of which are summarized. In 15 trials (8,654 persons), only glucocorticoids were likely to reduce mortality compared with standard care (37 fewer deaths per 1,000 persons). In eight trials (6,953 participants), only glucocorticoids were likely to reduce the need for mechanical ventilation (30 fewer per 1,000 persons). In the 11 trials (1,875 participants) that reported adverse events, the authors found that remdesivir decreased the duration of symptoms and did not cause any additional harm compared with standard care and that hydroxychloroquine increased the risk of adverse events. It appears that more data are out there, and fortunately, the authors plan to revisit the data frequently.
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"Adverse events were significantly increased in HCQ recipients"
Negative conversion rate at day 4, 7, 10, 14 or 21 was also similar between the two groups. No different 28-day symptoms alleviation rate was observed between the two groups.
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CDC quietly deletes hydroxychloroquine guidance as study hyped by Trump comes into question
The Centers for Disease Control and Prevention on Tuesday quietly removed bizarre guidelines for using the malaria drug hydroxychloroquine as a potential treatment for the new coronavirus. The unproven treatment has been repeatedly hyped by President Donald Trump in spite of the warnings of Dr. Anthony Fauci.
The CDC published "highly unusual" dosing guidance based on "unattributed anecdotes rather than peer-reviewed science" last month amid pressure on federal health officials from Trump, Reuters reported. The agency now appears to have quietly removed those guidelines from its website this week.
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A hospital in France has had to stop an experimental treatment using hydroxychloroquine on at least one coronavirus patient after it became a "major risk" to their cardiac health.
He said electrocardiogram recordings of patients involved with the trial were being constantly monitored. An ECG measures electrical activity in the heart, and represents this on a graph as a QT interval. Ferrari said these recordings are interpreted and, if anomalies are reported, treatment is stopped.
Asked if this had happened yet, he said: "Yes, from the start of the trial. Thanks to this ECG follow-up, we highlighted the major risks of a very serious accident in a patient, and the treatment was immediately stopped."
The potential cardiac side effects of hydroxychloroquine were highlighted by the Mayo Clinic at the end of March. An article on its website said the drug has the potential to lead to sudden cardiac death in some patients. In a small number of patients it has the potential to lead to a prolonged QTc , which can result in an abnormal heart rhythm.
Hydroxychloroquine, Mayo Clinic said, blocks one of the channels that controls the heart's electrical recharging systems. "This interference increases the possibility that the heart's rhythm could degenerate into dangerous erratic heart beats, resulting ultimately in sudden cardiac death."
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FDA just gave a thumbs down to Trump’s favorite COVID-19 drugs
The U.S. Food and Drug Administration (FDA) today revoked its emergency use authorization (EUA) for hydroxychloroquine sulfate (HCQ) and chloroquine phosphate (CQ) to treat COVID-19. The two antimalaria drugs, touted by President Donald Trump and others as potential game-changers in tackling the new coronavirus that causes COVID-19, have failed in recent randomized controlled clinical trials to prevent disease in newly infected people or treat those with symptoms. In April, former FDA leaders decried the agency’s decision to authorize emergency use of the drugs, asserting it was based on political pressure, not scientific evidence.
“I’m glad to see FDA remediate an action that was a significant departure from its science-based approach. I hope this is a step forward to FDA regaining its independence and for making decisions that are based on science and the public interest,” says Luciana Borio, a former FDA acting chief scientist who directed medical and biodefense preparedness for Trump’s National Security Council.
Citing its ongoing scientific review, the agency said in a statement: “FDA has determined that CQ and HCQ are unlikely to be effective in treating COVID-19 for the authorized uses in the EUA. Additionally, in light of ongoing serious cardiac adverse events and other serious side effects, the known and potential benefits of CQ and HCQ no longer outweigh the known and potential risks for the authorized use.”
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Wisconsin Woman Who Took Hydroxychloroquine for Nearly 2 Decades Contracts Coronavirus: 'How Can I Be Sick?'
A Wisconsin woman was reportedly surprised to learn of her COVID-19 diagnosis after taking hydroxychloroquine for nearly two decades, the same drug President Donald Trump recently said he is taking to ward off the virus.
Kim, who asked to be identified by her first name only, has been taking hydroxychloroquine as a lupus treatment for 19 years, according ABC affiliate WISN. The drug has long been approved by the Food and Drug Administration (FDA) to treat lupus, rheumatoid arthritis and malaria. It has not been approved to treat or prevent COVID-19.
"When they gave the diagnosis, I felt like it was a death sentence. I was like, 'I'm going to die,'" Kim told the outlet. "I'm like, 'How can I be sick? How? I'm on the hydroxychloroquine.' They were like, 'Well, nobody ever said that was the cure or that was going to keep you safe' and it definitely did not."
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"...not able to prevent infection of human lung cells with the novel coronavirus"
The Infection Biology Unit of the German Primate Center (DPZ)—Leibniz Institute for Primate Research in Göttingen, together with colleagues at the Charité in Berlin, was able to show that the malaria drug chloroquine, which has been demonstrated to inhibit the SARS-CoV-2 infection of African green monkey kidney cells, is not able to prevent infection of human lung cells with the novel coronavirus. Chloroquine is therefore unlikely to prevent the spread of the virus in the lung and should not be used for the treatment of COVID-19.
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Regulators split on antimalarials for COVID-19
US and French authorities have authorised the use of chloroquine and hydroxychloroquine,
but the EU regulator and WHO say the science doesn’t support the decision. Susan Jaffe reports
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Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease (ORCHID)
ORCHID is a multicenter, blinded, placebo-controlled, randomized clinical trial evaluating hydroxychloroquine for the treatment of adults hospitalized with COVID-19. Patients, treating clinicians, and study personnel will all be blinded to study group assignment.
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The Australian Department of Health has placed new restrictions on hydroxychloroquine
n addition, the TGA warns that medicines such as hydroxychloroquine and the similar compound chloroquine (which is not marketed in Australia) pose well-known serious risks to patients including cardiac toxicity (potentially leading to sudden heart attacks), irreversible eye damage and severe depletion of blood sugar (potentially leading to coma).
“Given the limited evidence for effect against COVID-19, as well as the risk of significant adverse effects, the TGA strongly discourages the use of hydroxychloroquine outside of its current indications at this time other than in a clinical trial setting or in a controlled environment in the treatment of severely ill patients in hospital,” it says.
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World Health Organization temporarily halts hydroxychloroquine trials citing concerns about serious side-effects
The World Health Organization says it is temporarily dropping hydroxychloroquine — the malaria drug U.S. President Donald Trump said he was taking — from its global study into experimental COVID-19 treatments.
In a press briefing on Monday, WHO Director General Tedros Adhanom Ghebreyesus said in light of a paper published last week in the Lancet that suggested people taking hydroxychloroquine were at higher risk of death and heart problems, there would be "a temporary pause" on the hydroxychloroquine arm of its global clinical trial.
"This concern relates to the use of hydroxychloroquine and chloroquine in COVID-19," said Tedros, who pointed out the drugs are approved treatments for malaria and some autoimmune diseases.
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The paper that triggered the Trump administration’s obsession with hydroxychloroquine received a statement of concern from the society that publishes the journal.
The April 3, 2020, notice, from the International Journal of Antimicrobial Agents, states that the March 20 article, “Hydroxychloroquine and azithromycin as a treatment of Covid-19: results of an open-label non-randomized clinical trial”
does not meet the [International Society of Antimicrobial Chemotherapy’s] expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.
The notice, which is from the ISAC and not the journal itself, is a bit ambiguous. The society says it “shares the concerns” about the paper, but it doesn’t appear to be taking additional action.
The study was led by Didier Raoult, of the University of Marseille, whose publication history has come under scrutiny.
Last month, Elisabeth Bik took a close look at the IJAA article and detailed a long list of serious problems with the study, including questions about its ethical underpinnings, messy confounding variables, missing patients, rushed and conflicted peer review, and confusing data.
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Hydroxychloroquine Is Ineffective In Treatment Of Patients Hospitalized With Covid-19, According To A Controlled Trial From Shanghai
Results from a controlled clinical trial from China on the use of hydroxychloroquine as a treatment for Covid-19 have shown no significant differences in health outcomes between the control group and patients who received the experimental drug.
As Tara Haelle skillfully summarized in an earlier piece for Forbes, thirty patients hospitalized for Covid-19 participated in the trial. Fifteen were treated with 400mg of chloroquine for five days and fifteen received the standard supportive care. On Day 7 of the trial both groups were evaluated
The results:
CT scans showed there was little difference in the progression of the disease for those given the hydroxychloroquine treatment and those who received conventional care.
Of the thirty patients, only one patient progressed to severe stages of the disease — that patient had received hydroxychloroquine as part of their treatment.
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"Not be used where significant heart or retinal disease exists"
April 10, 2020 — Enrollment began April 9 at Henry Ford Hospital for the first large-scale study in the United States of the effectiveness of the anti-malarial drug hydroxychloroquinein in preventing COVID-19 in healthcare workers and first responders who volunteer to participate.
In less than a day the study already had more than 1,000 volunteers enroll. Interim results are expected in 30 days and final results of this lighting-speed trial will be available by this summer.
The “Will Hydroxychloroquine Impede or Prevent COVID-19,” or WHIP COVID-19, study is a 3,000-subject look at whether hydroxychloroquine prevents front-line workers from contracting the COVID-19 virus. This is a randomized, double-blinded study designed to produce a scientific answer to the question: Does it work? Preliminary results are expected in about four months. Currently, there are no FDA-approved preventions, vaccines or treatments for the novel coronavirus (COVID-19, SARS-CoV-2) virus.
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More deaths, no benefit from malaria drug in VA virus study
There were more deaths among those given hydroxychloroquine versus standard care, researchers reported.
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Professor Didier Raoult, from the Mediterranean University Hospital Institute (IHU), a controversial advocate of hydroxychloroquine, charged with "charlatanism": the use of a "remedy or an illusory or insufficiently tested process"
The departmental council of the order of doctors of Bouches-du-Rhône had seized the departmental disciplinary chamber of first instance on October 12, for "breaches of medical ethics as defined by the public health code", explained Me. Philippe Carlini, who led the action. Among these sprains, the accusation of "charlatanism": the use of a "remedy or an illusory or insufficiently tested process". The CNOM has chosen to join this action.
Professor Raoult immediately reacted to this announcement by filing a complaint in turn against the president of the CNOM, Patrick Bouet, for “harassment”, announced his lawyer, Me Fabrice Di Vizio, during the day.
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