Hydroxychloroquine: Hype and Reality
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A tweet from President Donald Trump over the weekend changed the pharmaceutical industry's view of hydroxychloroquine, an anti-malarial drug that has been in use since the 1950s and is now used to treat various autoimmune diseases.

"Hydroxychloroquine and azithromycin go together and have the chance to become one of the greatest drugs in the history of medicine," Trump tweeted. Thank you FDA for the special approval of the clinical use of this drug restrictive provisions! Hopefully they will all be ready for use immediately. People are dying. Action is needed. God help the people!"
The authors analyzed the literature studies cited by Trump to understand the efficacy of these drugs and whether we could be one step closer to treating this novel coronavirus that has affected the world for more than 2 months. Our results suggest that it is too early to call this pairing a "turning point" in history.
The following is the author's detailed analysis:



Sanofi did not conduct the study in France

In a tweet, President Trump cited the results of a French study published last week in the International Journal of Antimicrobial Agents titled "Hydroxochloroquine and azithromycin in combination with COVID-19: Results of an open, non-randomized clinical trial."

The study was carried out at the Timone Hospital of Ihu Mediterranee Infection in Marseille. Professor Didier Raoult posted a video explaining the tests on Monday, 16 March. All patients at the Mediterranean Infection Research Center in Marseille were given 200 mg of hydroxyl chloroquine sulfate orally 3 times daily for 10 days.

Social media posts misinterpreted the French study as a trial conducted by Sanofi, the country's largest drugmaker, and went on to recommend Sanofi's hydroxychloroquine as an "anti-crown drug."

The study's publication made no mention of Sanofi or Senon, attributing its financial support to the French government.


Inhibitory effect of hydroxychloroquine combined with azithromycin on COVID-19

Analysis of the study results showed that at day 6 of treatment, 36 patients had:

l  Hydroxychloroquine combined with azithromycin has a 100% effective rate (6/6 patients tested negative)


The little-known details: One patient died and three were transferred to intensive care

Actually, initially 42 patients were included in the study instead of 36 patients.One article unmasked the details of the withdrawal from the trial of these 6 patients treated with hydroxychloroquine who failed to complete the trial and could not be tested for the presence of covid-19 at day 6 for the following reasons:

The article also highlighted that one patient, who tested positive on day 6 while receiving hydroxychloroquine only, received azithromycin in addition to hydroxychloroquine and cured the infection on day 9.

However, another of these patients, who was taking a combination of hydroxychloroquine and azithromycin, tested negative on day 6 but tested positive on day 8.


Diagnostic criteria for negative results are low

In this French trial, a real-time PCR (RT-PCR) test method was used to determine whether patients had covid-19 and to record the reading of the cycle number (CT) when the amplification curve reached the threshold value.
Quantitative real-time PCR (RT-PCR) is based on Nobel laureates' PCR technique or polymerase chain reaction (PCR), a DNA amplification technique that laboratories typically use to amplify minute amounts of DNA to amounts sufficient for experimental needs to allow analysis.In order for scientists to detect a virus like covid-19, they also needed to convert the virus's genome made of single stranded RNA into DNA.To do this requires the use of an enzyme called reverse transcriptase.
Combining the two techniques gave rise to RT-PCR, which emits light only when the DNA is bound to fluorophores, allowing scientists to calculate how much DNA is there through PCR amplification of the DNA.
The cycle threshold (CT) is the number of cycles required for the fluorescent signal to cross an established threshold.CT levels also correlate inversely with the amount of target nucleic acids in the specimen (i.e., the lower the CT level the greater the viral load).
According to the assay published on the US Food and Drug Administration (FDA) website, "" a sample is considered negative if all covid-19 markers (N1, N2) do not cross the threshold line within 40 cycles (< 40.00 CT) when all control.
Whereas the French study reported a negative result with a CT value of 35, that is, no threshold line was exceeded within 35 cycles (< 35.00 CT), compared with the FDA published requirement of 40 cycles for detection, suggesting that the study's negative results did not meet the FDA requirement for detection.
In addition, as lower CT values indicated higher nucleic acid loads, they did not test negative when treated with hydroxychloroquine alone in all cases where the patient's CT value was less than 22 at the beginning of the study.
Whereas hydroxychloroquine in combination with azithromycin was only effective in patients with CT values greater than 23.


The demand for hydroxychloroquine is expected to surge
After the launch of trenp's tweet, Novartis commitment and others to donate a maximum of 130 million hydroxychloroquine tablets after approval of the new treatment covid-19, mylan also announced an increased manufacturing capacity to produce 50 million hydroxychloroquine tablets, and Teva also stated that 16 million hydroxychloroquine tablets would be donated to hospitals across the United States.
The international API market is flooded with the need for hydroxychloroquine sulfate, chloroquine phosphate (although the clinical safety profile of hydroxychloroquine over chloroquine in long-term use is favorable and higher daily doses are allowed), and azithromycin and drug substance vendors have also informed the authors that their capacity is sold out.
Because pharmacies have run out of their medicines, the FDA surprisingly disallowed the Indian formulation of IPCA labs (one of the main producers of chloroquine and hydroxychloroquine), which was banned 4 years ago.The company issued a listed company announcement that the company's FDA export warnings for hydroxychloroquine sulfate and chloroquine phosphate drug substances and hydroxychloroquine sulfate tablets have been partially relieved due to the potential clinical medical supply affected by shortages in certain pharmaceutical materials and formulations.In August 2019, at this most recent inspection, the FDA identified a "" string of violations "" in the quality division of IPCA.


The authors' perspectives

The author supports the authors of this study, who themselves also acknowledge that "" our study has some limitations, including a small sample size, limited long-term follow-up results, and 6 patients withdrew from the study, but in the present context, we believe that our findings should be shared with the scientific community. ""
An objective view of the two sides of the results is necessary when there is a desperate search for solutions worldwide.It must be reiterated that we are still far from finding a quick solution for one of the largest emergency medical incidents in recent years.


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