The World Health Organisation (WHO) has removed the drug hydroxychloroquine from its Solidarity trial, in which possible treatments for Covid-19 are being tested.
The latest development is yet another twist in the extraordinary tale of an inexpensive drug that has been used for decades to treat rheumatoid arthritis and is also given to patients with malaria and lupus.
In the case of Covid-19, the use of hydroxychloroquine as a treatment or a prophylactic has been the subject of huge controversy and the drug has now been rejected by the behemoths of the global health establishment, the WHO and the Food and Drug Administration (FDA) in the United States.
The US president, Donald Trump, even entered the fray over hydroxychloroquine, saying that he had been taking it as a prophylactic.
In what has become known as Lancetgate, a major article about hydroxychloroquine that influenced global policy has been retracted.
The Recovery trial
The results of a study that was conducted during the Recovery trial in the UK, and influenced the WHO in its most recent decision, have also been challenged. Critics of the study say the researchers used a dangerously high dose of hydroxychloroquine.
It has also been pointed out by medical professionals who have used hydroxychloroquine as a treatment for Covid-19 that it has shown benefits when used during the early stages of the disease, not when patients are critically ill.
On June 5, the Recovery trial’s lead investigators announced that they were halting the use of hydroxychloroquine after reviewing early data.
They said: “The trial has proceeded at unprecedented speed, enrolling over 11,000 patients from 175 NHS hospitals in the UK. Throughout this time, the independent Data Monitoring Committee has reviewed the emerging data about every two weeks to determine if there is evidence that would be strong enough to affect national and global treatment of Covid-19.”
The investigators said they had concluded that there was “no beneficial effect of hydroxychloroquine in patients hospitalised with Covid-19”.
They said they had decided to stop enrolling participants to the hydroxychloroquine arm of the Recovery trial with immediate effect.
They stated: “A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10). There was also no evidence of beneficial effects on hospital stay duration or other outcomes.
“These data convincingly rule out any meaningful mortality benefit of hydroxychloroquine in patients hospitalised with Covid-19. Full results will be made available as soon as possible.”
In reporting their results ahead of a full release of the data, the Recovery trial scientists give a high p-value of 0.1, a hazard ratio of 1.11, and a 95 percent confidence interval.
Hazard ratios are measures of association widely used in prospective studies. A hazard ratio of 1 means lack of association, a hazard ratio greater than 1 suggests an increased risk, and a hazard ratio below 1 suggests a smaller risk.
The confidence interval, which is calculated to measure the effect of a treatment, shows the range within which the true treatment effect is likely to lie (subject to a number of assumptions).
P-values are calculated to assess whether trial results are likely to have occurred simply through chance. They provide a cut-off point beyond which it can be asserted that the findings are statistically significant. By convention, this is p<0.05.
It has been pointed out that, if the Recovery trial researchers had used a p-value of 0.05, they would not have been able to reject the possibility that there was neither a risk nor a benefit from the use of hydroxychloroquine.
One netizen in India, who noticed a discrepancy in the published statistics tweeted: “ … at p=0.05, you could not reject hazard ratio of 1, therefore used p=0.1. Statistically, you did not determine with 95% confidence that hcq increases the risk of fatality.”
The netizen, who is a data scientist, explained to Changing Times: “The researchers could only reject the null hypothesis of benefit from hydroxychloroquine by using a high p-value of 0.1 rather than the usual 0.05 or lower.
“They had to increase the p-value to 0.1 as the standard value of 0.05 did not preclude hydroxychloroquine being beneficial.”
In a particularly surprising development, the Recovery trial researchers have been accused of confusing hydroxychloroquine with another drug, hydroxyquinoline. One of the leading scientists involved in the trial, Peter Horby, (pictured left) denies that there was such confusion and tweeted “ … it is not true. Dose was based on detailed pharmacokinetic modelling of chloroquine and hydroxychloroquine”.
Another of the leading scientists involved in the trial, Martin Landray, (pictured left) told the French newspaper France Soir: “The doses were chosen on the basis of pharmacokinetic modelling and these are in line with the sort of doses that you used for other diseases such as amoebic dysentery.”
James Todaro, MD, who investigated the Lancetgate study and the source of the data for that research, tweeted, however: “HCQ isn’t used for amoebic dysentery though Iodoquinol (a hydroxyquinoline) is used for amoebic dysentery at ~2,000 mg daily. (Oral absorption is low, so high doses are tolerable.)
“HCQ, however, is readily absorbed orally and a dose this high approaches lethal dose of 4,000 mg.”
Todaro (pictured left) added: “In my 8 years of medical school/residency training, I’ve never heard of a patient given 2,400 mg per day of HCQ. Furthermore, the lethal dose of HCQ is far lower than the ‘6 or 10 times’ 2,400 mg as stated by RECOVERY chief investigator Martin Landray (lethal dose ~4,000 mg).”
Professor Christian Perronne from the Raymond Poincaré University Hospital in Garches, France, told France Soir that, in 1975, during his medical internship at the Claude Bernard hospital, he saw a lot of amoebiasis and chloroquine was no longer used to treat it.
“It is the first time that I learn that we use hydroxychloroquine in amoebic dysentery, in super-toxic doses for humans,” Peronne said.
“The classic treatment for colonic amoebiasis is the hydroxyquinoline combination of tiliquinol and tilbroquinol.”
There is now a demand for the Recovery trial researchers to release details of their “pharmacokinetic modelling”.
Hydroxychloroquine use around the world
While hydroxychloroquine is now no longer being tested by the WHO, it is still being used in several countries, including Brazil, Malaysia, and India. In India it is being used as a prophylactic for healthcare workers and police.
Malaysia’s health director-general, Noor Hisham Abdullah, said patients who were in categories one and two, in terms of the severity of their Covid-19 illness, did not deteriorate into categories four and five when treated with hydroxychloroquine.
Only five percent of Covid-19 patients in Malaysia needed to be admitted to an intensive care unit as compared with ten percent of patients in other countries, he said.
As a result of using hydroxychloroquine, 88 percent of Covid-19 cases in Malaysia were stage one and two, just seven percent were stage three, and five percent were stage four or five, Noor Hisham said.
Stage one is when a patient tests positive for Covid-19, but has no symptoms. At stage two, a patient has only mild symptoms. At stage three, patients have lung infections, but don’t need assistance to breathe and, at stage four, patients, do require help to breath. At stage five, patients need to be put on a ventilator.
Emergency use authorisation revoked
The FDA has revoked the emergency use authorisation (EUA) for hydroxychloroquine and chloroquine, from which hydroxychloroquine is derived, for treating Covid-19.
The agency said that, based on the latest scientific evidence, the two drugs were unlikely to be effective in treating Covid-19.
After reviewing new information from large clinical trials the agency now believed that the suggested dosing regimens were “unlikely to produce an antiviral effect”, the FDA’s chief scientist Denise Hinton said in a letter announcing the decision.
“As of the date of this letter, the oral formulations of HCQ and CQ are no longer authorised by FDA to treat Covid-19,” Hinton (pictured left) stated.
Hinton added: “FDA has concluded that, based on this new information and other information discussed in the attached memorandum, it is no longer reasonable to believe that oral formulations of HCQ and CQ may be effective in treating COVID-19, nor is it reasonable to believe that the known and potential benefits of these products outweigh their known and potential risks.”
The FDA has been accused of cherry picking the data it used to make its decision to revoke the EUA and of relying on weak studies. Critics of the decision point to the high doses of hydroxychloroquine used in one small study by Tang et al. (the initial dose was 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for two or three weeks, and only 150 patients were studied).
The request to revoke the EUA was made by the Biomedical Advanced Research and Development Authority (BARDA). BARDA said its request was based on new information, including clinical trial data results, that had led the authority to conclude that hydroxychloroquine may not be effective to treat patients with Covid-19 “and that the drug’s potential benefits for such use do not outweigh its known and potential risks”.
The US now has a huge stockpile of hydroxychloroquine.
The FDA’s decision has been criticised by the health authorities in Brazil. According to media reports, the Brazilian health ministry said on June 15 that it would be recommending that hydroxychloroquine be used in early treatment for children and pregnant women diagnosed with Covid-19.
A health ministry official was quoted as saying that the studies referenced by the FDA could not be used as examples for Brazil or for the rest of the world.
The US Health and Human Services secretary, Alex Azar, (pictured left) has said that the FDA’s decision to revoke its EUA for hydroxychloroquine and chloroquine as treatments for Covid-19 “removes a potential barrier” and makes it easier to access the drugs.
Azar said the FDA had not found enough data to support the use of hydroxychloroquine for hospitalised patients so took away the EUA.
He added: “At this point, hydroxychloroquine and chloroquine are just like any other approved drug in the United States. They may be used in hospital, they may be used in out-patient, they may be used at home – all subject to a doctor’s prescription.”
Azar said the FDA’s removal of the EUA took away what had been a significant misunderstanding by many that had made people think that somehow it could only be used in a hospital setting.
“It’s a drug. It’s approved in the United States. Has been for decades,” he said. “If a doctor wishes to prescribe it, working with a patient, they may prescribe it for any purpose that they wish to do so. And this actually removes a potential barrier to that.”
In an article for FactCheck.org, Jessica McDonald and Eugene Kiely write that Azar’s comments were misleading.
It was true that the FDA’s decision only pertained to hospitalised patients, they said, but Hinton had herself said in the revocation letter that it was “no longer reasonable to believe that oral formulations of HCQ and CQ may be effective in treating COVID-19”.
McDonald and Kiely say experts balked at Azar’s suggestion that removing the EUA was lifting a “potential barrier” to hydroxychloroquine’s use when the move in fact reduced access to the drug by eliminating the option of getting it from the national stockpile.
The writers quoted Neil Schluger, a pulmonologist and critical care specialist at Columbia University who has studied hydroxychloroquine for the treatment of Covid-19.
Azar was somehow implying that the EUA made people think you could only use hydroxychloroquine as a treatment for Covid-19 for hospitalised patients, and, now that it had been removed, the drug could be used to treat Covid patients anywhere, Schluger was quoted as saying, but it was “exactly the opposite of that”.
McDonald and Kiely said Azar was correct in saying that, because the FDA has approved chloroquine and hydroxychloroquine for the treatment of other conditions including malaria (and, in the case of hydroxychloroquine, rheumatoid diseases), they can be prescribed to Covid-19 patients off-label.
“But that has always been true. The EUA never changed that, and the revocation also does not change that,” they wrote.
The writers quoted Rachel Sachs, a law professor at Washington University in St Louis, as saying: “The EUA had no impact on whether physicians could prescribe the drug off-label, whether patients could receive it off-label.
“It just made it easier for hospital-based providers to obtain the drug from the stockpile and to administer it to their patients.”
Sachs is further quoted as saying: “Sec. Azar’s framing sounds like what the FDA is doing is opening up hydroxychloroquine for broader use. But that’s actually not what’s going on – they’re actually restricting one avenue for its use by withdrawing the EUA.”
On June 2, the Association of American Physicians and Surgeons (AAPS) filed a lawsuit against the Department of Health and Human Services and the FDA, in which it calls on the FDA “to end its arbitrary interference with the use of hydroxychloroquine”.
The AAPS added: “Two million doses of HCQ are being sent by the Trump administration to Brazil to help medical workers there safeguard themselves against the spread of the virus.
“But at the same time the FDA continues to block Americans’ access to this medication.”
The Lancetgate scandal
The WHO has made numerous about-turns on hydroxychloroquine. It had already suspended its testing of the drug after the publication in The Lancet, on May 22, of the results of the controversial study by Mehra et al. that covered six continents and contained an analysis of data from more than 96,000 patients.
Enrolment for the hydroxychloroquine trial was temporarily suspended on May 24.
The executive group had decided to implement a “temporary pause” of the hydroxychloroquine arm of the Solidarity trial while the safety data was reviewed by the data safety and monitoring board, the WHO said.
Announcing the suspension on May 25, the WHO said it wanted to “err on the side of caution”.
The WHO then announced that, after the Solidarity trial’s data safety and monitoring committee had reviewed the available mortality data, it was resuming the hydroxychloroquine trial.
This was on June 4, the same day that three of the four authors of the paper published in The Lancet – Mandeep R. Mehra, Frank Ruschitzka, and Amit N. Patel – retracted their article.
In its comment about the retraction, The Lancet said the authors were unable to complete an independent audit of the data underpinning their analysis and, as a result, had concluded that they could no longer vouch for the veracity of the primary data sources.
“The Lancet takes issues of scientific integrity extremely seriously, and there are many outstanding questions about Surgisphere and the data that were allegedly included in this study,” The Lancet said.
Surgisphere is a small Chicago-based company operated by Sapan Desai, the fourth author of the retracted paper. It is members of the staff of Surgisphere who collected the data analaysed by Mehra et al. The data was collected from patients with Covid-19 who received hydroxychloroquine alone or in combination with antibiotics.
Mehra et al. had said that the chloroquine and hydroxychloroquine drug regimens were associated with an increased risk of death. They said their study suggested that treatment treatment with chloroquine or hydroxychloroquine (taken with or without the antibiotics azithromycin or clarithromycin) offered no benefit for patients with Covid-19.
The researchers said their study showed that treatment of Covid-19 patients with chloroquine or hydroxychloroquine, either alone or in combination with macrolide antibiotics, was linked to an increased risk of serious heart rhythm complications.
The study was criticised by 120 scientists from around the world who wrote an open letter to the authors, and the editor of The Lancet, in which they questioned the researchers’ methodology. The scientists listed ten main concerns about the statistical models and the data used by Mehra et al. They demanded more transparency about the provenance of the data and independent validation of Mehra et al.’s analysis.
The clinicians, medical researchers, statisticians, and ethicists who wrote the letter said the results of the study by Mehra et al. had had a considerable impact on public health practice and research.
“The WHO has paused recruitment to the hydroxychloroquine arm in their Solidarity trial. The UK regulatory body, MHRA, requested the temporary pausing of recruitment into all hydroxychloroquine trials in the UK (treatment and prevention), and France has changed its national recommendation for the use of hydroxychloroquine in Covid-19 treatment and also halted trials,” the signatories to the letter wrote.
“The subsequent media headlines have caused considerable concern to participants and patients enrolled in randomised controlled trials seeking to characterise the potential benefits and risks of these drugs in the treatment and prevention of Covid-19 infections.”
The criticisms of Mehra et al.’s study listed in the open letter included the following:
- there was inadequate adjustment for known and measured confounders (disease severity,
temporal effects, site effects, and dose used),
- there is no data/code sharing and availability statement in the paper,
- there was no ethics review,
- there was no mention of the countries or hospitals that contributed to the data source, and
- data from Australia were not compatible with government reports (too many cases for just
five hospitals, and more in-hospital deaths than had occurred in the entire country during the study period).
The letter’s signatories also questioned the data from Africa and say there were “unusually small reported variances in baseline variables, interventions, and outcomes between continents”.
They further questioned the mean daily doses of hydroxychloroquine cited in the study and say there are “implausible ratios of chloroquine to hydroxychloroquine use in some continents”.
French orthopaedic surgeon, oncologist, and statistician Gérard Delépine wrote an article for Agora Vox in which he also challenged the study’s findings, saying they were based on data that was neither verified nor verifiable.
Delépine said there had been an “organised lynching” of chloroquine and hydroxychloroquine by the media.
The media lauded the study as “the largest international study” about chloroquine and hydroxychloroquine, he said, but it was not even a macroanalysis.
“In reality, we are dealing only with a large collection of unsupported data, based on non-verifiable elements, recovered by a private for-profit site,” Delépine said.
None of the authors of the study was an infectious disease specialist, Delépine says, and none had treated a patient with Covid-19; and there was conflict of interest.
It is no coincidence, Delépine says, that, while hydroxychloroquine is being lynched, the drug remdesivir, which, he says, “will in reality only do good to the shareholders of Gilead” is being vaunted.
Delépine points out that the study by Mehra et al. referred only to hospitalised patients. “The aim of treatment with hydroxychloroquine is to avoid hospitalisation by treating patients early in the course of the disease.
It’s unscientific and biased, Delépine says, to select only the failures of a treatment to supposedly assess its global interest. The conclusion that chloroquine and hydroxychloroquine were ineffective was invalidated by Mehra et al.’s own figures, he said.
The researchers’ conclusions about excess mortality after treatment with chloroquine or hydroxychloroquine were biased by their sampling and/or their a priori, Delépine says.
“Only a prospective study could assess the risk of mortality and the cardiac risk,” he said.
“The risk of heart rhythm disturbances after treatment with hydroxychloroquine alone has been known for seventy years and is well below one percent. The possibility that the risk could be increased if azithromycin is also given cannot be excluded in the elderly with heavy comorbidity, but has not been observed in pregnant women in malaria-endemic countries where these drugs are frequently used together.”
Mehra, Ruschitzka, and Patel said in their statement about the retraction of their article: “After publication of our Lancet article, several concerns were raised with respect to the veracity of the data and analyses conducted by Surgisphere Corporation and its founder and our co-author, Sapan Desai, in our publication.
“We launched an independent third-party peer review of Surgisphere with the consent of Sapan Desai to evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper.”
The authors said that their independent peer reviewers informed them that Surgisphere would not transfer the full data set, client contracts, and the full ISO audit report to their servers for analysis as such transfer would violate client agreements and confidentiality requirements.
“As such, our reviewers were not able to conduct an independent and private peer review and therefore notified us of their withdrawal from the peer-review process,” they added.
“We always aspire to perform our research in accordance with the highest ethical and professional guidelines. We can never forget the responsibility we have as researchers to scrupulously ensure that we rely on data sources that adhere to our high standards.
“Based on this development, we can no longer vouch for the veracity of the primary data sources. Due to this unfortunate development, the authors request that the paper be retracted.”
The three authors said that they all entered the collaboration “to contribute in good faith and at a time of great need during the Covid-19 pandemic”.
They added: “We deeply apologise to you, the editors, and the journal readership for any embarrassment or inconvenience that this may have caused.”
The WHO’s reasoning
In its statement issued on June 17, the WHO said that the Solidarity trial’s executive group and principal investigators made their decision to end the testing of hydroxychloroquine on the basis of evidence from the Solidarity trial, the Recovery trial, and a Cochrane review of other evidence about hydroxychloroquine.
The WHO stated that data from Solidarity (including the French Discovery trial data) and the recently announced results from the UK’s Recovery trial “both showed that hydroxychloroquine does not result in the reduction of mortality of hospitalised Covid-19 patients, when compared with standard of care”.
The organisation added that investigators would not randomise further patients to hydroxychloroquine in the Solidarity trial. Patients who had already started hydroxychloroquine but who had not yet finished their course in the trial could complete their course or stop at the discretion of the supervising physician.
The WHO added that its decision applied only to the conduct of the Solidarity trial and did not apply to the use or evaluation of hydroxychloroquine in pre- or post-exposure prophylaxis in patients exposed to Covid-19.
The Solidarity trial is still testing remdesivir, the HIV medication lopinavir-ritonavir, and lopinavir-ritonavir with interferon beta-1a as potential treatments for Covid-19.
Raoult casts aside danger claims
One of hydroxychloroquine’s leading advocates is the director of the Institut Hospitalo-Universitaire (IHU) Méditerranée Infection in Marseille, Didier Raoult, who casts aside claims that the drug is too dangerous to be used as a treatment for Covid-19.
Raoult said in March that there had been positive results from clinical trials in which hydroxychloroquine, in the form of the drug Plaquenil, was given to patients.
He said that, of the 24 patients with Covid-19 who were treated with Plaquenil, three-quarters of them were no longer carriers of the virus after six days. Ninety percent of the patients in the study who didn’t receive Plaquenil were still carriers after six days.
Raoult advocates using hydroxychloroquine in combination with azithromycin, an antibiotic used in the treatment of bacterial pneumonia, which has been used against the Zika virus.
The positive results in the treatment of Covid-19 are “even more spectacular” when hydroxychloroquine and azithromycin are used together, Raoult says.
There are patients, Raoult says, who have been taking hydroxychloroquine as a treatment for rheumatoid arthritis for thirty years.
Ocular side effects never occur over a period of about ten days, which is the length of time such treatment would be needed in the case of Covid-19, Raoult says. They occur, he says, in the case of one percent of patients after five years’ treatment.
Raoult argues that using hydroxychloroquine, which is already well known, is safer than using new drugs whose toxicity has not yet been established.
He says hydroxychloroquine can be contraindicated if a patient is taking the heart medication Cordarone, but this, he says, is derisory given the positive effects the drug can have.
Raoult says there are no major risks in the use of azithromycin, but, as a precaution, certain patients would need to undergo an electrocardiogram before they are given it.
Raoult has been prescribing chloroquine for 25 years and has been writing about it for thirty years and says it is crazy that, in France, the experience of Chinese doctors in the use of chloroquine was not properly taken on board earlier.
On March 23, France’s Health Minister, Olivier Véran, said chloroquine could be administered in France to patients suffering from the severest forms of Covid-19.
He told reporters that France’s High Council for Public Health had recommended that the treatment should only be used in grave cases, when the patient was hospitalised, and only on the basis of a decision taken by doctors, and under strict medical surveillance.
On May 27, just two days after the WHO announced that there would be a “temporary pause” of the hydroxychloroquine arm of the Solidarity trial, the French government revoked its decree that had allowed hospital doctors to prescribe hydroxychloroquine in some Covid-19 cases and stated that the drug should not under any circumstances be prescribed for patients with Covid-19.
France’s High Council for Public Health told the country’s health ministry that there was no proof that hydroxychloroquine helped Covid-19 patients and said data indicated that the drug could cause heart problems, particularly when used in combination with azithromycin.
Vladimir Zelenko from the Buffalo School of Medicine and Biomedical Science in the US says Covid-19 patients need to be given hydroxychloroquine within five days of the onset of their symptoms. He says he has seen a 99.7 percent survival rate in the patients he has treated with the drug, and an 84 percent reduction in hospitalisations.
Like Raoult, he says that hydroxychloroquine needs to be prescribed with azithromycin, and he also prescribes 220 mg of zinc sulfate.
The Zelenko protocol
Elise Klement-Frutos, who is an infectious diseases specialist at the Pitié Salpêtrière hospital in Paris, told the publication Marianne that care needed to be taken in the use of hydroxychloroquine and that people should not be taking it without proper medical advice.
Alerts have been been raised in several other countries, including Nigeria, where people self-medicated with chloroquine and suffered poisoning.
Two cases of chloroquine poisoning were reported after Donald Trump touted hydroxychloroquine as a promising treatment for Covid-19. The two people were hospitalised in Lagos for chloroquine overdoses.
Health officials warned Nigerians not to self-medicate after demand for the drug surged in Lagos.
Oreoluwa Finnih, who is the senior health assistant to the governor of Lagos, said chloroquine was still in a testing phase in combination with other medication and had not yet been verified as a preventive treatment or a curative option.
In the United States, the governor of Nevada, Steve Sisolak, banned the use of chloroquine and hydroxychloroquine to treat patients with Covid-19.
Sisolak said there was no consensus among experts or Nevada doctors that hydroxychloroquine or chloroquine were successful treatments for patients with Covid-19.
He said prescriptions for hydroxychloroquine or chloroquine should be limited to a thirty-day supply to ensure that it’s available for “legitimate medical purposes” and so that people didn’t stockpile the drugs.
Michael J. Ackerman, who is a genetic cardiologist at the Mayo Clinic in Minnesota in the US, says that hydroxychloroquine is known to cause drug-induced prolongation of the QTc of some people.
The QTc is an indicator of the health of the heart’s electrical recharging system. “Patients with a dangerously prolonged QTc are at increased risk for potentially life-threatening ventricular rhythm abnormalities that can culminate in sudden cardiac death, Ackerman said.
“Correctly identifying which patients are most susceptible to this unwanted, tragic side effect and knowing how to safely use these medications is important in neutralising this threat.”
Ackerman also says that hydroxychloroquine blocks one of the critical potassium channels that control the heart’s electrical recharging system.
“This interference increases the possibility that the heart’s rhythm could degenerate into dangerous erratic heart beats, resulting ultimately in sudden cardiac death,” he said.
The Indian Council of Medical Research (ICMR) has also warned against inordinate use of hydroxychloroquine and issued an advisory about using it as a preventive drug against Covid-19.
The ICMR’s head of epidemiology, Dr Raman Gangakhedkar, said the use of hydroxychloroquine as a preventive treatment for Covid-19 was “experimental” and should be restricted to asymptomatic healthcare workers involved in the care of suspected or confirmed cases of Covid-19 and asymptomatic household contacts of laboratory-confirmed cases.
Hydroxychloroquine should only be given when prescribed by a registered medical practitioner, Gangakhedkar said.
‘More trials needed’
In a report published in the New England Journal of Medicine on May 7, Joshua Geleris et al. said that the administration of hydroxychloroquine was not associated with either a greatly lowered or an increased risk of intubation or death.
The report gave the results of a study of hospitalised patients diagnosed with Covid-19. The researchers said randomised, controlled trials of hydroxychloroquine in patients diagnosed with Covid-19 were needed.
Poll of doctors
Valerie Richardson, reporting for The Washington Times, said that an international poll of more than 6,000 doctors released on April 2 found that the hydroxychloroquine was the most highly rated treatment for Covid-19.
Richardson said the survey, conducted by Sermo, of 6,227 physicians in thirty countries found that 37 percent of those treating Covid-19 patients rated hydroxychloroquine as the “most effective therapy” in a list of 15 options.
Sermo found that hydroxychloroquine usage for Covid-19 treatment was most widespread in Spain, where 72 percent of physicians surveyed said they had prescribed it, followed by Italy (49 percent). The drug was least popular among those surveyed in Japan, where just seven percent said they had used it to treat Covid-19.
One critic of the Sermo study said it was a non-random survey of physicians, a survey of doctors’ gut instincts. Randomised, double-blind experiments were the only way to truly measure effectiveness, the netizen said.
The anti-viral drug remdesivir, which is much more expensive than hydroxychloroquine and was invented by the pharmaceutical company Gilead Sciences, originally to treat Ebola, has been much vaunted by the director of the National Institute of Allergy and Infectious Diseases (NIAID), Anthony Fauci. In the case of Ebola, remdesivir was found to be adequately tolerated, but less effective than several monoclonal antibody therapeutics.
Fauci said data shows that remdesivir “has a clear-cut and significant positive effect in diminishing the time to recovery” in cases of Covid-19.
Elizabeth Lee Vliet, writing for The Association of American Physicians and Surgeons website, talks of the rapid and unusual FDA authorisation for remdesivir.
“Initially for treating Ebola, it failed to show benefit and was shelved,” Lee Vliet wrote. “If remdesivir is used to treat Covid-19, Gilead shareholders, not the taxpayers, will profit.”
In the article entitled ‘A Tale of Two Drugs: Money vs. Medical Wisdom’, Lee Vliet also wrote about how, at a presidential briefing on April 30, Fauci announced early results, prior to peer review, of one clinical trial of remdesivir.
“At the ‘warp speed’ currently in vogue for the Fauci-led push to a new vaccine, the very next day the FDA issued an Emergency Use Authorisation (EAU) for remdesivir to be used in seriously ill hospitalised patients,” she wrote.
“To announce the emergency approval, President Trump met with the CEO of the drug’s manufacturer, Gilead Sciences, in the Oval Office.”
In the case of hydroxychloroquine, Lee Vliet wrote, it took two months from the publication of reports of successful use in China and South Korea to get the March 28 FDA EUA for use in hospitalised COVID-19 patients.
“HCQ was approved in 1955 for malaria, and later for lupus and rheumatoid arthritis. Over the last 65 years, hundreds of millions of prescriptions have been written for HCQ worldwide,” Lee Vliet wrote.
“The EUA for HCQ did not, however, expand its availability but imposed restrictions to prevent non-hospitalised patients from accessing the government’s stockpile of the drug.”
The New Straits Times (NST) in Malaysia has reported that hydroxychloroquine will no longer be used in the country as a treatment for Covid-19 patients.
The NST quoted the country’s health director-general, Noor Hisham Abdullah, as saying the decision was made after data collected from 500 cases showed that hydroxychloroquine “had no effect on those infected with the virus”.
Noor Hisham was quoted as saying: “It has been used on Covid-19 patients as an off-label medication at the early stage because it has anti-inflammatory properties.
“”Based on data collected from 500 cases, we found that the drug has no effect. We stopped using it when we learned about the outcome.”
Noor Hisham was also quoted as saying the ministry was still studying the effectiveness of other drugs, including the combination medication lopinavir-ritonavir.
In a retrospective analysis published yesterday (Thursday) in Travel Medicine and Infectious Disease Jean-Christophe Lagier et al. reported on the outcomes for 3,737 Covid-19 patients treated with hydroxychloroquine and azithromycin and with other drug regimens in Marseille, France.
The researchers concluded that patients receiving the hydroxychloroquine/azithromycin treatment for at least three days had a better clinical outcome, were less likely to be transferred to an intensive care unit, stayed in hospital for a shorter duration, and had a shorter duration of viral shedding than patients who did not receive this drug combination.
A total 3,119 of the patients were treated with hydroxychloroquine and azithromycin for three days or more. They were given 200 mg of oral hydroxychloroquine three times daily for ten days and 500 mg of oral azithromycin on day 1 followed by 250 mg daily for the next four days.
The researchers stated: “Although this is a retrospective analysis, results suggest that early diagnosis, early isolation and early treatment of Covid-19 patients with at least three days of HCQ-AZ lead to a significantly better clinical outcome and a faster viral load reduction than other treatments.”
Of the patients studied, 3,284 were younger than 65 years of age and 453 were older, with a mean age of 45.3 years.
The mortality rate was 0.5 percent among patients treated with hydroxychloroquine and azithromycin for three days or more. None of the patients aged under 60 died.
The researchers say that treatment with hydroxychloroquine and azithromycin for three days or more was “an independent protective factor against death and/or transfer to ICU”.
The significant association between treatment with hydroxychloroquine and azithromycin for three days or more and the reduction of risk of death was confirmed to be independent of age, comorbidities, and severity of the disease, they said.
The researchers reported an overall 1.1 percent case fatality rate for the 3,737 patients included in the study.
A prolongation of QTc (the indicator of the health of the heart’s electrical recharging system) was observed in 25 patients, leading to the cessation of treatment in 12 cases.
NEWS2 is the National Early Warning Score that determines the degree of illness of a patient and prompts critical care intervention.
The results of a retrospective study about hydroxychloroquine are presented in an article by Vladimir Zelenko, Martin Scholz, and Roland Derwand that was published online as a preprint today (July 3). The paper has not been peer reviewed.
Scholz is an adjunct professor for experimental medicine at Heinrich Heine University Düsseldorf in Germany and Derwand is a medical doctor and life science industry expert, based in Munich.
Reporting on the early treatment of Covid-19 patients with low-dose hydroxychloroquine administered with zinc and azithromycin, Zelenko, Scholz, and Derwand say the treatment was associated with “significantly less hospitalisations and five times fewer all-cause deaths”.
A total of 141 Covid-19 patients with laboratory confirmed SARS-CoV-2 infections were studied and independent public reference data from 377 confirmed Covid-19 patients from the same community were used as an untreated control.
Of the 141 treated patients, only four of them were hospitalised as compared with 58 of the 377 untreated patients.
“The odds of hospitalisation of treated patients were 84 percent less than in the untreated group,” Zelenko et al. said.
There was one death in the treatment group as compared with 13 in the untreated group.
The researchers observed no cardiac side effects in the treated group.
They concluded: “Risk stratification-based treatment of Covid-19 outpatients as early as possible after symptom onset with the used triple therapy, including the combination of zinc with low dose hydroxychloroquine, was associated with significantly less hospitalisations and five times fewer all-cause deaths.”
Zelenko said: “Hydroxychloroquine’s main function is to allow zinc to enter the cell, while zinc is a virus killer. Azithromycin prevents secondary bacterial infection in the lungs, and reduces the risk of pulmonary complications.”
The three scientists said their findings need to be validated in prospective controlled clinical trials. They added that only outcome data for the untreated control group based on public reference was available and they did not have access to information about other patient characteristics, clinical symptoms, etc.
They point out that they are drawing no conclusions about the efficacy and safety of the triple therapy if it were to be used for severely ill hospitalised patients.
In a paper published on Wednesday (July 1) in the International Journal of Infectious Diseases, Samia Arshad et al. reported on the rate of mortality of Covid-19 patients hospitalised in Michigan in the US.
The researchers studied 2,541 patients, with a median total hospitalisation time of six days. The median age was 64 years.
“In this multi-hospital assessment, when controlling for Covid-19 risk factors, treatment with hydroxychloroquine alone and in combination with azithromycin was associated with reduction in Covid-19 associated mortality,” the researchers said, adding that prospective trials were needed to examine this impact.
The researchers reported that the mortality rate of patients given hydroxychloroquine and azithromycin, was 20.1 percent; when hydroxychloroquine was used on its own the rate was 13.5 percent; when azithromycin was used on its own the rate was 22.4 percent, and when neither drug was given the rate was 26.4 percent.
The primary cause of death (in 88 percent of cases) was respiratory failure.
When hydroxychloroquine was given alone, two doses of 400 mg were given on day 1, followed by 200 mg twice daily on days two to five.
Azithromycin was dosed at 500 mg give once on day 1, followed by 250 mg once daily for the next four days.
The combination of hydroxychloroquine and azithromycin was reserved for selected patients with severe Covid-19 and with minimal cardiac risk factors.
Arshad et al. said their findings indicated a potential role for hydroxychloroquine in the treatment of hospitalised COVID-19 patients without co-administration of azithromycin.
“However, our results should be interpreted with some caution and should not be applied to patients treated outside of hospital settings,” they added.
“Our results also require further confirmation in prospective, randomised controlled trials that rigorously evaluate the safety, and efficacy of hydroxychloroquine therapy for Covid-19 in hospitalised patients.
“Considered in the context of current studies on the use of hydroxychloroquine for Covid-19, our results suggest that hydroxychloroquine may have an important role to play in reducing Covid-19 mortality.”
The WHO announced today that it had accepted the recommendation from the Solidarity trial’s international steering committee to discontinue trials of hydroxychloroquine and lopinavir-ritonavir.
The organisation said the steering committee formulated its recommendation “in light of the evidence for hydroxychloroquine vs standard-of-care and for lopinavir/ritonavir vs standard-of-care from the Solidarity trial interim results, and from a review of the evidence from all trials presented at the 1-2 July WHO Summit on Covid-19 research and innovation”.
The WHO said: “These interim trial results show that hydroxychloroquine and lopinavir-ritonavir produce little or no reduction in the mortality of hospitalised Covid-19 patients when compared to standard of care.
“Solidarity trial investigators will interrupt the trials with immediate effect.”
The WHO added: “For each of the drugs, the interim results do not provide solid evidence of increased mortality. There were, however, some associated safety signals in the clinical laboratory findings of the add-on Discovery trial, a participant in the Solidarity trial.”
The organisation said its decision applied only to the conduct of the Solidarity trial in hospitalised patients and did not affect the possible evaluation in other studies of hydroxychloroquine or lopinavir-ritonavir in non-hospitalised patients or as a pre- or post-exposure prophylaxis for Covid-19.
“The interim Solidarity results are now being readied for peer-reviewed publication,” the WHO added.
Recovery trial report and critique
In a preprint published on medRxiv, which has not been peer reviewed, members of the Recovery trial collaborative group presented a detailed preliminary report on the use of hydroxychloroquine in hospitalised patients with Covid-19.
Echoing and expanding on what they said in an earlier press release, the scientists state that, in patients hospitalised with Covid-19, “hydroxychloroquine was not associated with reductions in 28-day mortality but was associated with an increased length of hospital stay and increased risk of progressing to invasive mechanical ventilation or death”.
They said there was “no excess of new major cardiac arrhythmia”.
They reported that patients given hydroxychloroquine were less likely to be discharged from hospital alive within 28 days (60.3% as compared with 62.8% of the patients allocated care without hydroxychloroquine) “and those not on invasive mechanical ventilation at baseline were more likely to reach the composite endpoint of invasive mechanical ventilation or death” (29.8% versus 26.5%).
The Recovery trial group said that 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients given “usual care” died within 28 days.
In the press release issued on June 5, the scientists said: ‘We have concluded that there is no beneficial effect of hydroxychloroquine in patients hospitalised with Covid-19. We have therefore decided to stop enrolling participants to the hydroxychloroquine arm of the Recovery trial with immediate effect.”
Indian data scientist Vijay Gupta has published a line-by-line critique of the Recovery trial report. He notes that there are significant differences between the information presented in the new report and the early data presented in the June 5 press release.
On June 5, it was stated: “A total of 1542 patients were randomised to hydroxychloroquine and compared with 3132 patients randomised to usual care alone. There was no significant difference in the primary endpoint of 28-day mortality (25.7% hydroxychloroquine vs. 23.5% usual care; hazard ratio 1.11 [95% confidence interval 0.98-1.26]; p=0.10).
However, in the report published on medRxiv on July 15, it is stated: “1561 patients randomly allocated to receive hydroxychloroquine were compared with 3155 patients concurrently allocated to usual care. Overall, 418 (26.8%) patients allocated hydroxychloroquine and 788 (25.0%) patients allocated usual care died within 28 days (rate ratio 1.09; 95% confidence interval [CI] 0.96 to 1.23; P=0.18).”
The group given hydroxychloroquine increased by 1.23% and the control sample increased by 0.73%, and the p-value changed from 0.1 to 0.18. Also, the hazard ratio changed from 1.11 to 1.09.
Gupta said: “Comparing the sample size given in the press release and the one given in the preprint, one sees that it has increased. The impact on the p-value is startling for such a small increase in sample size.
“The press release said p=0.1. It now seems that it is 0.18 taking the confidence out of bounds of standards. To say with confidence that the hazard ratio is 1.09 and not =< 1 is not within any statistical standard bounds.
“At hazard ratio below 1, hydroxychloroquine works.”
Gupta asks: “Was more data added or was something changed in the regression? Was it the 1% whose PCR test was awaited, but they were already included? Or was a confounder added?
Regression is a technique used to model and analyse the relationships between variables and how they contribute and are related to producing a particular outcome together.
Gupta adds: “This starts looking like a hit job on hydroxychloroquine. A hazard ratio of 1.09 with a confidence interval that dips into territory that shows hydroxychloroquine as beneficial, yet no sub-group shows a benefit?”
He also points to the fact that the sub-groups in the trial are not defined by pre-existing illnesses and neither obesity nor blood type are specified. “Why is this? Maybe hydroxychloroquine works for late-stage patients if they are diabetic or obese.
“A weak statistical method has been used for the sub-group analysis. A model with interaction effects would have been a much better approach instead of the chi-square method for sub-group analysis.”
A chi-square (χ2) statistic is a test that measures how expectations compare to actual observed data (or model results).
The Recovery trial scientists state in their report that, on June 4, in response to a request from the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, the independent Data Monitoring Committee conducted a review of the data and recommended that the chief investigators review the unblinded data on the hydroxychloroquine arm of the trial.
“The chief investigators and trial steering committee concluded that the data showed no beneficial effect of hydroxychloroquine in patients hospitalised with Covid-19,” they said.
“Therefore enrolment of participants to the hydroxychloroquine arm was closed on 5 June and the preliminary result for the primary outcome was made public. Investigators were advised that any patients currently taking hydroxychloroquine as part of the study should discontinue the treatment.”
Gupta said: “Given the confidence interval, the steering committee should logically have looked properly into sub-groups.
“If the confidence interval goes into the range where hydroxychloroquine is beneficial then it is possible that the hazard ratio is less than 1 for a sub-group such as diabetics or obese diabetics.”
Gupta says this analysis could have been done for sub-groups after the study, but was only done beforehand.
“It was ridiculous to not include pre-existing conditions such as obesity and risk factors such as blood type as sub-groups.
“This is a major error in the design of the trial. This analysis could have been done post-hoc. It is strange that the confidence intervals never go completely above or below 1 for any sub-group.”
Gupta noted: “Hydroxychloroquine is an interesting medicine because it is good for diabetes and for several other illnesses. They should have done the analysis. It can still be done.”
Gupta also points out that the trial included patients who did not have a positive SARS-CoV-2 test.
Ten percent of the patients given hydroxychloroquine (153 patients) tested negative for SARS-CoV-2 infection, as did 9% (291) of those who did not receive the drug.
Gupta asks: “Are the results robust and stable enough to be resistant to small changes in sample size? If 9% more people were added could the hazard ratio become 0.9 or the p-value become 0.75?
“What would happen if those who did not have a positive SARS-CoV-2 test were dropped from the sample? Or if obesity was included as a confounder?”
Gupta also raises the issue of the late-stage treatment with hydroxychloroquine. Maybe, he says, the optimal time to use hydroxychloroquine is before the patient has vascular problems.
“The focus in this trial, and in Western countries generally, has been on hydroxychloroquine as an anti-viral treatment. It has a blood protecting mechanism that should be taken into consideration.”
Patients in the Recovery trial who were given hydroxychloroquine sulfate were given 200 mg tablets (containing 155 mg base equivalent).
They received a “loading dose” of four tablets (800 mg) at zero and six hours, followed by two tablets (400 mg) starting at 12 hours after the initial dose and then every 12 hours for the next nine days or until discharged (whichever occurred earlier).
The dose is four times higher than that recommended by the Indian Council of Medical Research. It is much higher than the doses used by Didier Raoult in France and Vladimir Zelenko in the US.
Raoult uses hydroxychloroquine in conjunction with azithromycin and the Zelenko protocol adds zinc.
There are more than 120 countries in which hydroxychloroquine is being used as a treatment for Covid-19 and it’s very rarely used as a monotherapy.
The Recovery trial scientists said that the concentrations of hydroxychloroquine and chloroquine required to inhibit SARS-CoV-2 replication in vitro were relatively high in comparison with the free plasma concentrations observed in the prevention and treatment of malaria.
“These drugs are generally well tolerated, inexpensive and widely available,” they said. “Following oral administration they are rapidly absorbed, even in severely ill patients.”
Gupta commented: “The authors are stating this for malaria. How do they know this will happen in the case of Covid-19? Are they trying to justify the very high loading and total dose?”
The Recovery trial researchers say they didn’t collect information on physiological, electrocardiographic, laboratory, or virologic parameters.
Gupta says this is very difficult to believe. “Is there a legal reason? How else would you identify obesity, hypertension, viral load, etc.?”
A total 11,197 patients were recruited for the Recovery trial. In about one third of the cases hydroxychloroquine was “unavailable” or “considered unsuitable”. A total 1,010 were allocated to receive lopinavir-ritonavir, 1,170 to receive dexamethasone, and 617 to receive azithromycin.
Gupta says the report should have included a separate annex in which the exclusion criteria are explained.
He added: “The Oxford group incorrectly state that the dose they gave was ‘substantially’ lower than the chloroquine dose given in the Brazil study, which was stopped. But it is the same equivalent hydroxychloroquine dose as that used in the Brazil study.”
Researchers from Brazil and the US published a paper about hydroxychloroquine in the New England Journal of Medicine (NEJM) on July 23.
Alexandre B. Cavalcanti et al. concluded that “among patients hospitalised with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care”.
They said the addition of azithromycin did not improve outcomes.
They added: “Patients who received hydroxychloroquine, either with azithromycin or alone, had more frequent events of QTc interval prolongation and elevation of liver-enzyme levels than patients who did not receive either agent.”
In Brazil, hydroxychloroquine has been formally recommended for the treatment of Covid-19 by the Ministry of Health since March 25 for severe cases and since May 20 for mild cases.
Vijay Gupta has also analysed this report and says the study misdefines mild and moderate.
“All the patients studied were hospitalised and 42% of them were receiving supplemental oxygen,” he said.
The general understanding of mild Covid-19 is that a person has symptoms such as a sore throat, cough, and fever and moderate is usually understood to mean that or she has similar symptoms, but the illness is more advanced. Neither term would usually be used to refer to a hospitalised patient needing oxygen.
Gupta points out that, in a large number of the cases studied, infection by SARS-CoV-2 was not laboratory confirmed.
“Some account is taken of these cases, but should they not have been removed or the study title and aim changed?” he said.
Of 667 patients recruited for the study, only 504 were confirmed to be SARS-CoV-2 positive. The 15-day follow-up was completed for 665 patients. (One patient withdrew consent and one had been enroled twice.) The patients’ average age was fifty years.
Gupta also says that, as in the Recovery trial, hydroxychloroquine was given too late.
The trial began “within 14 or fewer days” after the onset of symptoms. The median was seven days after symptom onset.
“In 25% of cases, the treatment was given more than nine days after the onset of symptoms,” Gupta said.
Gupta points out that there are hardly any confounders in the statistical models used by the researchers. Only age was used as a confounder, he says. “As the main study has tables including co-morbidities and other data, one assumed that these were used in the regression models, but they weren’t.”
There is no inclusion of such confounders as obesity, the use of anti-virals or steroids, gender, or blood type, Gupta points out. This, he says, is a critical flaw in the study.
The report’s authors stated that all statistical models were adjusted for age and the use of supplemental oxygen at admission. “These are insufficient to explain the outcome and will cause crippling omitted-variable bias,” Gupta said.
The report’s authors state that the use of “glucocorticoids, other immunomodulators, antibiotic agents, and antiviral agents” was allowed during the trial. Gupta asks: “What are ‘other immunomodulators’? Does this include Ivermectin? It definitely does include anti-flu medication.
“Most experts would assume that interventions, or at least the major ones, are included in the regressions. But they are not.”
In the supplementary appendix, there is a table showing that a quarter of the patients in the trial were given oseltamivir and one-fifth were given steroids. “Why are these not included in the regression,” Gupta asks.
The patients studied received either standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for seven days.
Gupta wonders why the sample size was so small, given the number of hospitals involved. The trial was conducted at 55 hospitals in Brazil.
He again notes that the researchers have displayed what he considers to be a poor understanding of hydroxychloroquine’s mechanisms in the treatment of Covid-19, only looking at the drug’s antiviral impact and not immune modulation or haemoprotection.
And why not add zinc to the treatment, he asks, when the hydroxychloroquine/azithromycin/zinc cocktail has shown benefits in “real-world use”.
There are many relevant studies not referenced in the NEJM article, Gupta says .
“A good literature review in a pandemic should review international research, comment on national guidelines and treatments being used by physicians, and mention studies that are not anti-hydroxychloroquine,” he said.
“Why are Brazilians not referencing studies from India, Africa, South Korea, and Egypt, etc.? Was this study targeted not at empirical research, but at influencing an Anglo-American and generally Western audience?”
Three randomised controlled trials (RCTs) are referenced by the study authors: one each from US and the UK, and the Tang China study.
“The Tang study also reads like a study for an American/Western audience,” Gupta said. “One RCT is the poorly designed Boulware University of Minnesota study with the major problem of outcome measurement, the Oxford Recovery study with a self-admitted high dose and probably misspecified regression (no obesity) on data from late-stage cases, and the Tang study with ‘mild’ and ‘moderate’ used inappropriately for hospitalised patients as in this Brazilian study.”
On the statistics, Gupta says there is a very high variance of estimates. “An odds ratio that ranges from 0.69 to 2.11 is massive,” he said. “And where are the regression equations?”
An odds ratio tells whether the chance of a particular outcome happening is increased because of a factor or treatment.
The researchers should also give their rationale for selecting the specific algorithm they used and for the way it was applied, Gupta says.
The scientists noted the following study limitations:
- Although the point estimate of effect suggests no major difference between the groups with respect to the primary outcome, the trial cannot definitively rule out either a substantial benefit of the trial drugs or a substantial harm. “For the comparison between hydroxychloroquine and control, for example, our data are compatible with odds ratios as low as 0.69 and as high as 2.11.”
- The trial was not blinded.
- Despite intense efforts to maintain adherence to the assigned treatments, a lack of medications that were perceived as beneficial by clinicians and patients led to some protocol deviations.
- The use of hydroxychloroquine plus azithromycin was widespread among patients hospitalised with Covid-19 in participating hospitals. “The enrolment of patients with no previous use of these medications was challenging, so we decided to enrol patients provided that their previous use since the onset of symptoms was limited to 24 hours,” the researchers said.
- They added: “Although the median time from symptom onset to randomisation was seven days, we included patients up to 14 days after the beginning of symptoms; it is conceivable that interventions that may limit viral replication (e.g., hydroxychloroquine) may be more effective earlier in the course of the disease.”
In their report, the researchers state: “No P-values are reported for secondary outcomes; the widths of the confidence intervals for the secondary outcomes have not been adjusted for multiple comparisons, so the intervals should not be used to infer definitive treatment effects.”
They admit that higher doses of chloroquine (600 mg twice daily for 10 days) have possibly been associated with higher mortality. A total 12,000 mg of chloroquine is the equivalent of 9,600 mg of hydroxychloroquine.
In the Recovery trial 2,400 mg of hydroxychloroquine were given over 24 hours, with another 400 mg given every 12 hours over nine days.
In a letter to the editor published in the International Journal of Infectious Diseases on July 29, Antonella d’Arminio Monforte et al. said that a study of 539 hospitalised Covid-19 patients in Milan showed that, after adjustment for a number of key confounders, the use of hydroxycholoroquine and azithromycin was associated with a reduction in risk of death as compared to controls.
D’Arminio Monforte from the Institute of Infectious and Tropical Diseases at the University of Milan, three of her colleagues from the University of Milan, and one from University College London said that their analysis also suggested a larger effectiveness of hydroxychloroquine in patients with less severe Covid-19 disease.
The researchers said their results of their study, which was carried out from February 24 to May 17, were remarkably similar to those reported by Arshad et al.
They reported that 174 of the patients in their study died. The percentage of deaths was 27% in the group receiving hydroxycholoroquine alone, 23% in the group treated with hydroxycholoroquine and azithromycin, and 51% in the group receiving neither drug.
Mechanical ventilation was used in 4.3% of the patients treated with hydoxychloroquine, 14.2% of those receiving hydroxycholoroquine and azithromycin, and 26.1% in the group receiving neither drug.
The researchers said: “Some important weaknesses of the analysis by Arshad have been pointed out (Lee et al., 2020) but not all of these apply to our study. Our propensity scores include some of the potential confounders that were missing in the analysis by Arshad (e.g. calendar day of admission, disease severity, cardio-vascular disease (CVD), baseline plasma (CRP).”
They added that they had excluded people receiving other drugs that could have biased the effect of hydroxychloroquine when used in combination.
In the control group, ten patients began treatment with HIV antivirals, one was given the antibiotic teicoplanin, 12 were treated with immunomodulatory drugs or corticosteroids, 23 were given the anticoagulant heparin, and 46 remained untreated.
The researchers said that residual confounding was possible; there were, for example, more people with CVD in the control group.
A team of scientists from the University of Oxford and the Mahidol Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand, are planning to test whether hydroxychloroquine and chloroquine can prevent Covid-19 developing.
The COPCOV researchers aim to enrol 40,000 healthcare workers in hospitals in what will be a double-blind, randomised, placebo-controlled study. Hydroxychloroquine or chloroquine will be chosen depending on availability in the participating countries.
The trial will last three months and participants will be given a loading dose of 10 mg base/kg (four 155 mg tablets for a person who weighs 60 kg), followed by 155 mg daily (250 mg of chloroquine phosphate salt or 200 mg of hydroxychloroquine sulfate). They will be followed up thirty, sixty, and ninety days after the trial ends.
The researchers said that hydroxychloroquine could prevent Covid-19 and save tens of thousands of lives around the world, but they are concerned that their trial, COPCOV, may be hampered by the politicisation of the drug.
The scientists say that “fraudulent data, unjustified extrapolation and exaggerated safety concerns together with intense politicisation and negative publicity” may stop them from finding out whether hydroxychloroquine is an effective preventive treatment in the case of Covid-19.
The Oxford university and MORU scientists say that safety concerns about hydroxychloroquine have been exaggerated.
One of the lead investigators in the trial, Sir Nicholas White, said: “Chloroquine and hydroxychloroquine have a very good safety record in the treatment of malaria and rheumatological conditions over the past sixty years.”
Billions of chloroquine and hydroxychloroquine treatments have been given, White says, and concerns that they might cause heart arrhythmias are not supported by the evidence from the randomised trials involving patients with Covid-19. “And, in rheumatological conditions, hydroxychloroquine has actually been shown to reduce the risk of heart arrhythmias,” he added.
“There is very strong evidence that the doses being evaluated for prevention in the COPCOV study are safe.”
Chloroquine and hydroxychloroquine have been used to treat people with atrial fibrillation, the scientists add. “In the chronic treatment of lupus, which may affect the heart, patients receiving hydroxychloroquine have less arrhythmias than those receiving other drugs.”
The researchers added: “In recent years there has been increasing concern about drugs which prolong the electrocardiograph QT interval. This is because some drugs which have this property predispose to a potentially lethal ventricular tachycardia called ‘torsade de pointes’.
“This is rare, but it has led to several drugs being withdrawn from the market. Chloroquine and hydroxychloroquine (and several other similar drugs) do prolong the QT interval but there is no convincing evidence that this has caused ‘torsade de pointes’ in people with normal hearts.”
Combining chloroquine or hydroxychloroquine with other drugs that may also prolong the QT interval may be unwise, the researchers said, but they added that “for healthy people who are not taking regular medications which prolong the QT interval, there should be no concerns about cardiotoxicity”.
COPCOV is the only large, global clinical trial to test the use of hydroxychloroquine as a prophylactic against Covid-19. Other major trials have tested it as a treatment after patients have been diagnosed as SARS-CoV-2 positive. Previous studies about prevention were too small to show conclusively whether hydroxychloroquine works as a prophylactic.
The other lead investigator in the trial, Will Schilling, said: “We really don’t know if hydroxychloroquine works or not in prevention or very early treatment. That question remains unanswered. The benefits found in small post-exposure treatment trials, although modest, could be very valuable if they were confirmed.”
MORU director Nicholas Day says early use of hydroxychloroquine could be critical. “By the time patients are admitted to hospital virus multiplication is well past its peak and inflammation in the lungs and other complications may prove lethal.
“At this stage the steroid dexamethasone, which reduces inflammation, saves lives, but the antivirals hydroxychloroquine and chloroquine do not.”
Day says hydroxychloroquine and chloroquine could be effective much earlier in the illness.
He added: “Prevention is much easier than cure. The COPCOV study will find out if these drugs can prevent Covid-19 or not.”
The trial scientists say that side effects from the use of hydroxychloroquine and chloroquine are usually mild and include stomach upset and nausea, headache, and temporary blurring of vision.
Chloroquine, more than hydroxychloroquine, can sometimes cause itching, they say. “If too high a dose is taken, these drugs can be dangerous or even cause death. They may cause toxicity to the eyes and muscles if taken regularly for years, but this does not occur with short-term use (such as three months for prevention against Covid-19).”
It remains to be seen whether health officials in countries where hydroxychloroquine is already being used as a prophylactic and an early-stage treatment for Covid-19 patients will want to be involved in such a trial, not least as it would mean giving a control-group placebo to frontline healthcare professionals whose risk of being infected by SARS-CoV-2 is particularly high.
Eleven Belgian scientists published a paper in the International Journal of Antimicrobial Agents on August 24 in which they conclude that hydroxychloroquine monotherapy, administered at a low dosage of 2,400 milligrams over five days, “was independently associated with a significant decrease in mortality compared to patients not treated with hydroxychloroquine”.
The researchers said that this impact was observed in both early and late treatment groups, i.e. there was lower mortality irrespective of the duration of symptoms.
The scientists conducted a retrospective analysis of records of in-hospital mortality contained in Belgium’s national Covid-19 hospital surveillance data. The records of 8,075 patients were studied.
The researchers said that their findings suggested that the benefit observed might be mediated by immunomodulatory properties, “a hypothesis worth addressing as evidence of an antiviral activity of hydroxychloroquine on SARS-CoV-2 appears increasingly inconsistent”.
One of the paper’s authors, Nicolas Dauby, notes that the study was peer reviewed in two major journals and was reviewed by ten people. It is, he adds, an observational study “with its limitations”.
Hydroxychloroquine has no antiviral activity in vivo, Nicolas Dauby points out. The possible benefits observed in the Belgian study, and in other observational studies, could be related to the drug’s anti-inflammatory action, he says.
Dauby adds that the patients who died had a shorter duration of symptoms before admission.
He notes that, in Belgium 2,400 milligrams of hydroxychloroquine were given over five days whereas in the Recovery trial in the UK, this dosage was administered in just 24 hours.
Patients who received another Covid-19-related treatment (macrolides, tocilizumab, lopinavir/ritonavir, remdesivir, atazanavir, or anakinra) were excluded from the Belgian study. Incidental use of steroids was very low in both groups, although slightly higher in the group treated with hydroxychloroquine.
The Belgian researchers say that, considering the availability and cheapness of hydroxychloroquine, it seems worth further investigating the clinical effect of optimised dosage of the drug “and designing add-on studies in ongoing trials to monitor, beyond the viral shedding and infectiousness, a relevant set of inflammatory markers during the course of SARS-CoV-2 infection”.
Of the 8,075 patients studied, 4,542 received hydroxychloroquine as a monotherapy and 3,533 received “supportive care”. There were 804 deaths among those treated with hydroxychloroquine (17.7%) and 957 (27.1%) in the group receiving only supportive care.
About 60% of the hospitalised Covid-19 patients studied were aged above 65 years. In general, participants were severely ill with more than 80% having radiological pneumonia. Many of them had pronounced hypoxemia (a low level of oxygen in the blood) and 5% required immediate admission to an intensive care unit.
The patients treated with hydroxychloroquine were younger than those receiving only supportive care, were more frequently male, and had a lower proportion of cardiovascular disease, hypertension, chronic kidney disease, neurocognitive disorders and cancer, but there was more obesity.
Inflammatory markers were higher in the patients treated with hydroxychloroquine as was the incidence of pneumonia and acute respiratory distress syndrome, and the rate of admission to an intensive care unit within 24 hours of the person entering the hospital. There was also more invasive ventilation support.
After all adjustments, hydroxychloroquine remained significantly associated with decreased mortality, the researchers say.
Non-survivors were older than those who survived, and were more likely to be men and to suffer from pre-existing conditions.
Indian data scientist Vijay Gupta points out the Belgian researchers take into account more confounders than are included in any other Western study of the use of hydroxychloroquine as a treatment for Covid-19.