Covid-19 HCQ update: Studies in France, Brazil, China raise more questions on its efficacy, safety

By PharmaCompass

2020-04-16

Impressions: 3680

Last month, we had carried an article ‘Hydroxychloroquine: Hype versus reality’ that highlighted some of the limitations of the study undertaken in France at the infection hospital l'Institut Hospitalo-Universitaire (IHU) Méditerranée Infection in Marseille. On March 16, Professor Didier Raoult had published a video explaining the trials following which the US President Donald Trump had tweeted last month that hydroxychloroquine (HCQ) taken together with azithromycin had a real chance to be one of the biggest game changers in the history of medicine.

The excitement over HCQ being a potentially effective treatment for Covid-19 led to a tremendous demand surge globally for the drug and countries like India, Hungary and Finland, which are major manufacturers of the active pharmaceutical ingredient (API) restricted exports. Following direct discussions between President Trump and India’s Prime Minister Narendra Modi last week, India relaxed its restrictions and cleared the export of 3.58 million tablets of HCQ to the US along with nine metric tons of API required in the manufacturing of the drug.

While the consignment of HCQ from India arrived in the US last week, Raoult has since been criticized by the scientific community for his methods, especially the lack of a control group to establish a benchmark for the success of his experimental treatments.

The pushback started last month, when clinical studies published in Chinese patients showed limited clinical improvement over standard care. In a controlled clinical study on 30 patients, a report published by the Journal of Zhejiang University in China revealed that patients who got treated by HCQ didn’t fare any better than those who did not get the medicine.

This week, we examine some of the findings of fresh studies undertaken in France, Brazil and China on HCQ to examine its efficacy in the treatment of Covid-19.

French study results do not support HCQ use in hospitalized patients

A study undertaken in France, spearheaded by doctors in Paris, collected data from routine care of adults in four French hospitals with documented SARS-CoV-2 pneumonia and who required oxygen to emulate a target trial aimed at assessing the effectiveness of HCQ at 600 mg/day.

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This study included 181 patients with SARS-CoV-2 pneumonia; and out of this 84 received HCQ within 48 hours of admission (HCQ group) and 97 did not (no-HCQ group).

An analysis of this study reveals that 20.2 percent patients in the HCQ group were transferred to the ICU or died within seven days as opposed to 22.1 percent in the no-HCQ group. In the HCQ group, 2.8 percent of the patients died within seven days as against 4.6 percent in the no-HCQ group. And 27.4 percent and 24.1 percent, respectively, in both the groups developed acute respiratory distress syndrome within seven days. Eight patients receiving HCQ (9.5 percent) experienced electrocardiogram (ECG) modifications requiring HCQ discontinuation.

The authors concluded that the results do not support the use of HCQ in patients hospitalized for documented SARS CoV-2-positive hypoxic pneumonia.

Chinese study shows benefits in alleviation of symptoms but not in clearing virus

In another randomized controlled trial in China, which tracked 150 patients hospitalized with Covid-19, 75 patients were assigned to HCQ plus standard of care (SOC) and 75 were assigned to SOC alone. The results concluded that administration of HCQ did not result in a higher negative conversion rate but more alleviation of clinical symptoms than SOC alone in patients hospitalized with Covid-19. Adverse events were significantly increased in HCQ recipients.

While the primary endpoint for this trial was the negative conversion of SARS-CoV-2 within 28-days, the study does mention that more rapid alleviation of clinical symptoms with SOC plus HCQ than with SOC alone was observed during the second week.

Minimum requirements for the SOC included the provision of intravenous fluids, supplemental oxygen, regular laboratory testing, and SARS-CoV-2 test, hemodynamic monitoring and intensive care and the ability to deliver concomitant medications.

HCQ was administrated with a loading dose of 1,200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: two weeks for mild/moderate patients, three weeks for severe patients).

Brazilian study reports hazards on its analog chloroquine

A small study undertaken in Brazil on the effects of the anti-malaria drug chloroquine (CQ), which is structurally similar to HCQ, was abruptly halted because some patients taking high doses developed irregular heart rates generating “safety hazards.” The findings were revealed in a study funded by the Brazilian state of Amazonas.

The Brazilian study included 81 hospitalized patients, with about half being given a 450 milligram dose of chloroquine twice on the first day of the study followed by one daily 450 milligram dose for four more days. The other participants were prescribed a dose of 600 milligrams twice daily for 10 days.

Patients taking higher doses experienced heart arrhythmias within three days. Eleven patients died by the sixth day of treatment and the research on the high-dosages, therefore, had to be ended.

“Preliminary findings suggest that the higher CQ dosage (10-day regimen) should not be recommended for Covid-19 treatment because of its potential safety hazards,” the study's abstract said. “Such results forced us to prematurely halt patient recruitment to this arm.”

The lower-dosage portion of the study did not include enough patients to gauge whether it is effective in treating severely ill patients. The researchers said that more studies assessing the efficacy of chloroquine are “urgently needed.”

Heart incidents linked to HCQ in France

France has reported 43 cases of heart incidents linked to treating Covid-19 patients with HCQ. According to a statement issued by the French drug safety agency ANSM, the country has recorded about 100 health incidents and four deaths linked to experimental drugs for Covid-19 patients since March 27. Three other patients had to be revived.

Some 82 incidents were deemed “serious.” Most of those were split between HCQ and HIV antivirals lopinavir-ritonavir.

Last month, Nigeria reported cases of chloroquine poisoning. “These drugs should only be used in hospitals, under close medical supervision,” ANSM said.

Our view

A large multinational collaboration presenting data obtained from health care systems (claims data or electronic medical records) in Germany, Japan, Netherlands, Spain, UK and the USA concludes that short-term HCQ monotherapy does appear to be safe. However, it notes that long-term HCQ dosing is indeed tied to increased cardiovascular mortality.

Moreover, significant risks are identified for combination users of HCQ and azithromycin, even in the short-term. There is a 15-20 percent increased risk of angina/chest pain and heart failure, and a two-fold risk of cardiovascular mortality in the first month of treatment.

At the same time, French Professor Didier Raoult published expanded study results highlighting that 1,061 patients treated for at least three days with the HCQ and azithromycin combination had a cure rate of 98 percent and “no cardiac toxicity was observed”.

As of today, controlled studies undertaken on HCQ indicate that the drug does little to eliminate the presence of the virus but it does help in the short-term to make patients feel better, especially those who have a milder Covid-19 infection.

For now, there is likelihood that HCQ may turnout of be another TamiFlu. The drug was widely prescribed during the swine flu outbreak in 2009. A recent study concluded that the drug reduced the persistence of flu symptoms from seven days to 6.3 days in adults and to 5.8 days in children. But the report’s authors said drugs such as paracetamol could have had a similar impact. If that indeed is the case with HCQ, millions of dollars may get wasted on the drug, just as they were wasted in 2009 during the swine flu outbreak.

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Image Credit : thinker by Fredrik Rubensson is licensed under CC BY 2.0 // Modification: text was added to the original image.

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