research shows no benefit for hydroxychloroquine for COVID-19

Antimalarial drugs like hydroxychloroquine have a surprising history in times of pandemic: they keep showing up. But the case of hydroxychloroquine for COVID-19 gets curiouser and curiouser.

 

This blog is updated below.

Hydroxychloroquine is an antimalarial drug that has been suggested as a possible treatment for COVID-19. Several hospitals are offering it, often in combination with azithromycin to COVID-19 patients. Regulatory bodies in France and the US have authorized its use, but the European Union and the World Health Organization deny that the available science supports the decision (Lancet 2020;doi:doi.org/10.1016/S0140-6736(20)30817-5). In the US, an emergency use authorization permits using hydroxychloroquine and chloroquine only in adults and adolescents who weigh at least 50 kg.

Results in the hospitals has led some doctors to cautious and qualified tepid optimism. Tepid because the results have been neither dramatic nor a game changer. Qualified because hydroxychloroquine, though probably safer than chloroquine, still has a number of potential side effects and can’t be used in some of the people who need it most, like those with underlying diabetes or heart conditions.

According to the Mayo Clinic, Hydroxychloroquine can cause vision problems, heart problems, muscle and nerve problems, skin reactions and lowered white blood cell count. Several hospitals in Sweden have struggled with these side effects in COVOD-19 patients and have reportedly discontinued use of chloroquine especially because of vision problems, including loss of peripheral vision.

The Mayo Clinic says the risk of heart irregularities is increased in 1% of users. More dramatically, hydroxychloroquine can cause potentially fatal side effects like sudden cardiac death, according to Dr. Michael Ackerman, a genetic cardiologist and director of the Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. One study of 84 people with COVID-19 found that treatment with the combination of hydroxycholoroquine and azithromycin put a full 11% of patients at high risk of arrhythmia. Though adding azithromycin to hydroxychloroquine may enhance its efficacy, the addition may also enhance the danger.

Hydroxychloroquine is not the first antimalarial to be prescribed during times of pandemic. During the misleadingly labeled Spanish Flu, quinine, an earlier antimalarial, was recommended to patients. In 1921, The Domestic Health Society’s book, A Thorough and Concise Knowledge of the Prevention, Causes, and Treatments of Disease, Simplified for Home Use, published in New York, recommended “two to four doses of quinine of 5 grains each, one hour apart.” It also suggested hot mustard foot baths, plenty of hot lemonade or milk and keeping the bowels functioning.

And quinine and chloroquine are not the only antimalarials to come up. One of the many herbs that may be active against coronaviruses in vitro is Artemisia annua, a species of wormwood. The potential of Artemisia annua seen, not in people, but in test tubes, is leading to further study of this herb in Germany and Denmark. The researchers chose Artemisia annua because early studies in China identified an alcohol extract of the herb to be the second most powerful herb against SARS.

Though not yet proven, the appearance of Artemsia anua is intriguing because, like quinine and chloroquine, it is an antimalarial. Also known as Sweet Annnie, this herb has a very long history for malaria that is supported by research in China and at the Walter Reed Army Research Institute in the US. A controlled unblinded study found that Artemisia annua tea was as effective at symptom relief as quinine and effective, but not as effective, at completely curing the malaria (Trans R Soc Trop Med Hyg 2004;98:318-321). Better results would likely have been obtained if the researchers had used an alcohol extract instead of a tea. The researchers also say that they possibly should have used a higher dose.

Interestingly (but probably meaninglessly), lime juice has been shown to significantly shorten the time needed to improve malaria when it is added to drugs in children with malaria (Phytother Res 2011;25(10):1547-50). Remember the hot lemonade used during the Spanish flu?

Chloroquine was first developed by Bayer in 1934. That drug, and its relative hydroxychloroquine, are the pharmacy’s modern synthetic offering for malaria. They are used as a replacement for quinine which is an alkaloid extracted from the bark of several species of Cinchona trees found in South America. The synthetic drug chloroquine is structurally similar to quinine.

Though used in several hospitals for COVID-19 patients, the research is yet to be clarified. The first problem is the safety seen in Swedish hospitals and raised in the studies referenced by the Mayo Clinic. The high dose arm of a double-blind Brazilian study now in progress had to be discontinued prematurely after COVID-19 patients developed dangerous heart rhythm problems when given hydroxychloroquine and azithromycin: the same problem the study referenced by the Mayo Clinic found. The low dose arm of the study goes hopefully on.

This and other studies have been designed because of the promise of one French study (Int J Antimicrob Agents 2020;105949). The small, uncontrolled study suggested a benefit to treatment with hydroxychloroquine. The benefit was significantly greater when azithromycin was added. Unfortunately, as the Mayo Clinic has pointed out, adding azithromycin may be necessary, but it also increases the danger.

This French study has been criticized for its design. On April 3, 2020, an official statement of the International Society of Antimicrobial Chemotherapy, says that the board “believes the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.”

Surprised by the results of the French study, which they called “unexpected,” researchers put the results to the test. They used the same dose regimen of hydroxychloroquine and azithromycin as the French study, they followed eleven consecutive COVID-19 patients. However, they found no benefit to the treatment. 80% of patients were still positive after treatment and one died. The researchers say that their study “cast[s] doubts about the strong antiviral efficacy of this combination.” They also point out the little reported result of the earlier study that one person in that study died and three had to transfer to ICU. There were only 26 people in the study, so they say this too underlines “the poor clinical outcome” of the treatment.

A recent Chinese pilot study of COVID-19 patients supports these researchers’ conclusion. It found no benefit to treatment with hydroxychloroquine in terms of either clearance of the virus or clinical outcomes like duration of hospitalisation, temperature normalisation, radiological progression. The patients in the hydroxychloroquine group actually did slightly worse (J Zhejiang Univ Sci, 03 (2020), p. 03-).

So, although antimalarial drugs have a long and intriguing history during times of pandemic, the research on hydroxychloroquine still seems to be awaiting clarification.

Update:
Though not yet peer reviewed or published in a medical journal, a new U.S. study funded by he National Institutes of Health and the University of Virginia further hurts the case for hydroxychloroquine for people with COVID-19.

The study included 368 people hospitalized with COVID-19: it compared people treated with hydroxychloroquine to people treated with hydroxychloquine plus azithromycin and to people not treated with the drugs.

When people were given hydroxychloroquine, 27.8% of them died. When they were given hydroxychloquine plus azithromycin, 22.1% of them died. The shocking comparison is that when people were not given hydroxychloroquine, only 11.4% of them died. The risk of death from any cause was significantly higher in the hydroxychloroquine group than in the group of people who did not take the drug. Though almost twice as many people died in the hydroxychloquine plus azithromycin than in the group not treated by hydroxychloquine, the difference did not quite reach statistical significance.

The study also looked at how many of the patients had to be put on ventilators. The rates for all three treatments were similar, according to the study authors, though here the hydroxychloquine plus azithromycin group did do slightly better. 14.1% of those not treated with hydroxychloquine were put on ventilators compared to 6.9% of the hydroxychloquine plus azithromycin group and 14.1% of the group not treated with hydroxychloquine. Despite the slight improvement for ventilation, the study’s authors say that there was “no evidence that use of hydroxychloroquine, either with or without azithromycin, reduced the risk of mechanical ventilation in patients hospitalized with Covid-19.”

This study found no lifesaving benefit to the combination of hydroxychloquine plus azithromycin and an increased risk of death in those treated with hydroxychloquine alone (medRxiv 2020;doi:doi.org/10.1101/2020.04.16.20065920).

Latest Update: The Continued Frustration of Hydroxychloroquine
Researchers keep giving hydroxychloroquine the chance to struggle out from under the weight of failed studies. But the much-hyped drug continues to be stymied in its attempts at resurrection.

An open label, controlled study of 150 people admitted to hospital with confirmed COVID-19 compared standard care to the same standard care plus hydroxychloroquine. Most of the people in the study had mild to moderate disease; two were severe. The goal of the study was to see if rates of elimination of the virus were improved with the addition of hydroxychloroquine.

And the answer was no. The probability of being negative after 28 days was 85.4% in the standard care plus hydroxychloroquine group compared to a statistically similar 81.3% in the standard care alone group. Hydroxychloroquine also did not speed up recovery: the hydroxychloroquine eliminated the virus in an average of 8 days; the standard care group in a slightly faster 7 days. Symptom improvement was also no better in the hydroxychloroquine group. While only 59.9% of the hydroxychloroquine group had symptoms alleviated by day 28, 66.6% of the no hydroxychloroquine group did.

Making the picture worse was the greater risk when taking hydroxychloroquine: only 9% of people on standard care suffered adverse events, while a full 30% in the hydroxychloroquine did. Two of the adverse events in the hydroxychloroquine group were serious.

The researchers concluded that hydroxychloroquine did not significantly improve the chance of eliminating the virus but did increase the risk of adverse event (BMJ 2020;369:m1849).

The second study looked at 181 people admitted to hospital with COVID-19 pneumonia who required oxygen but not intensive care. The goal of the study was to see if hydroxychloroquine improved the rate of survival without the need to be transferred to intensive care at 21 days.

Again, hydroxychloroquine provided no benefit. 76% of people on standard care plus hydroxychloroquine survived without transfer to intensive care versus 75% in the standard care alone group. Overall, more people survived without hydroxychloroquine than with: 91% versus 89%. Survival without acute respiratory distress syndrome at day 21 was 69% in the hydroxychloroquine group compared with a superior 74% in the control group. 82% of people on hydroxychloroquine were weaned off oxygen by day 21 compared to 76% in the standard care alone group. Eight people in the hydroxychloroquine group had changes to their ECGs that forced them to stop treatment.

The researchers concluded that “the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen (BMJ 2020;369:m1844).



This blog was written by Ted Snider.


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