Chloroquine and hydroxychloroquine: Are they effective against COVID-19?

 

Based on: published evidence of VERY LOW CERTAINTY and press reports of unpublished evidence. So INTERPRET WITH CAUTION.

 

The history of medicine is plagued with treatments that promise to be effective but at the end of the day they are not. It is not easy to prove that, in a given situation, the benefits of a drug will outweigh its risks. The road is long and has many stages, and it takes time to complete it, usually at a high cost. 

 

Hence, when the preliminary stages of a research project come up with promising results, it is not uncommon for the media to present those results as definitive. When the disease in question has no known cure, the phenomenon is exacerbated. And in the face of a crisis like today’s COVID-19 pandemic, the worst in 100 years, the problem is immense.

 

Although several medications have already been proposed as the COVID-19 cure that we all hope for, none has created as much enthusiasm as the antimalarials chloroquine and hydroxychloroquine. On February 15, 2020, a meeting in China brought together the authors of 15 ongoing clinical studies, along with government and regulatory agencies officials. Their conclusion, it was announced, was that chloroquine has a potent activity against COVID-19 and it was recommended to include it in the “Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19”, issued by the National Health Commission of the People’s Republic of China. However, to this date none of the 15 studies have reported their results. 

 

Another key scientific output was a non-randomized study conducted in France, released on March 19, 2020 and which  many of our researchers received via WhatsApp before its eventual publication in scientific databases. Less than 72 hours after it was shared, it has already been critically analyzed by several experts worldwide, and there is a clear consensus: the study presents severe methodological limitations. 

 

The skepticism of the scientific community and the cautionary notes from experts have not reduced the excessive enthusiasm of the press, investors, the pharmaceutical industry, the US government, the finance sector, and health systems, which are already facing a depletion of the stock of these drugs.

 

 

What does today’s evidence tell us about the effectiveness of chloroquine or hydroxychloroquine in COVID-19?

 

With the help of COVID-19 L. OVE Working Group, an international team created with the objective of responding to the evidence generated by the pandemic, we inform that:

 

1. After a systematic review of all the existing literature, we did not find any study, apart from the study previously described.
2. After a broad search of studies on the effectiveness of chloroquine and hydroxychloroquine for COVID-19 – which included various sources of information: guidelines and official documents; general search engines like Google; academic search engines like Google Scholar and Microsoft Academic; direct contact with local experts; and searches on twitter – there is no additional information to that published by the aforementioned study. 
3. We coincide with other experts in that the study provides very low certainty evidence (preliminary evidence). The certainty is so low that, according to rigorous parameters, such as those used by Cochrane, the study does not even meet the minimum criteria to be included in a systematic review.
4. Regarding the research announced in China on February 15, our team analyzed the 15 studies mentioned. Until today, March 22, 2020, none of them have reported their results or the data useful to other research teams. 

 

Of the 15 studies, only a few aim to answer whether chloroquine or hydroxychloroquine are effective, and 6 appear to be canceled, apparently due to the absence of positive results (according to information in the Chinese study registry). Only 1 of the 15 studies is in the “complete recruitment” phase, that is, only 1 of the 15 studies managed to incorporate the number of defined patients. This study, however, does not seek to establish whether chloroquine and hydroxychloroquine work against placebo or against usual care, but compares them with other treatments. Usually this is done only after it has been demonstrated that the drug is superior to placebo. 

 

The quality of the clinical studies carried out in China has been questioned for some time now, mostly due to structural deficiencies in the country’s research system. This makes it even harder to reach conclusions like the ones drawn by the February meeting, and provides one more reason to demand speedy and transparent access to information.

So far, the history of COVID-19 is disturbingly similar to what happened in 2009 with the H1N1 influenza pandemic. Hopefully the lessons learned back then will help us have more information available in a timely and transparent manner, and will translate into decisions made in the interest of the people.

 

Unfortunately, the current pressure on health professionals and health authorities is so high, that decisions will most likely be based on the non-scientific information available now in the public domain, and that despite most experts recommend caution.

 

What is the compromise decision-makers face?

 

Like most of the time, there is no black or white answer. Evidence-based medicine’s third principles states that the evidence alone is never enough to make decisions. You always have to take into account the balance between benefits and risks, the associated burden, and the costs that a decision entails, taking into account the uniqueness of the values ​​and preferences of each person and each context”. 

 

On the one hand, there is an uncertain benefit for a disease without a known treatment; on the hand, there is the risk of adverse effects. Chloroquine and hydroxychloroquine, at the doses suggested by the French study or the Chinese studies (which are even higher than those of the French study), have potentially manageable adverse effects with hospitalized and well-monitored patients, but unmanageable in the hands of a population in panic. In fact, the first cases of death from chloroquine poisoning have already been reported. Furthermore, the analysis must consider the enormous cost and feasibility of keeping appropriate stock levels in all centers, to treat not only patients with COVID-19, but also those with other conditions for which chloroquine and hydroxychloroquine are known, effective treatments. 

 

With the aim of informing those who are making decisions at the global level as quickly as possible, and before finishing the regular publication process of a scientific article, we will make available a preliminary report with the necessary data to analyze the benefits and risks of this therapy. Stay tuned!

 

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