Disclaimer: This blog post is written for informational purposes only. It does not provide medical advice. If you are concerned about COVID-19, including the use of drugs against COVID-19, please seek advice from an accredited medical professional.
In the last blog post, I introduced chloroquine and hydroxychloroquine and how they are used to treat malaria, rheumatoid arthritis and SLE. I also explained how these drugs can produce many side effects which explains why medical professionals need to conduct regular health checks when prescribing these drugs to their patients. In this blog post, we will explore the in vitro (cellular) and in vivo (human) studies of chloroquine and hydroxychloroquine in COVID-19 and explain how more detailed studies are required to show whether these drugs can be used to treat COVID-19.
In vitro studies on drugs in COVID-19
In vitro studies involve exposing cells outside the body to virus and/or the drug for a period of time. We then measure whether and to what extent the virus has infected cells by measuring viral RNA and protein levels inside and/or outside cells. Chloroquine was initially used in an in vitro study during the 2002-2003 SARS epidemic. Chloroquine given before or after cells were infected inhibited replication of the SARS-CoV-1 virus, the pathogen that causes SARS. This highlighted the potential of chloroquine to treat SARS, though no clinical trials were run as the SARS epidemic quickly subsided.
Chloroquine re-emerged in the early stages of the COVID-19 pandemic from a drug screen of existing approved antivirals. Chloroquine was found to inhibit the replication of the SARS-CoV-2 virus at doses that are achievable by standard treatment. This has generated much buzz that chloroquine could be used to treat COVID-19. However, these in vitro studies have two important limitations:
- Chloroquine was tested on Vero cells, epithelial cells from the kidneys of African green monkey. As the SARS-CoV-2 virus mostly infects the respiratory tract and lungs, these studies do not answer whether chloroquine and hydroxychloroquine will work effectively in the lung to treat COVID-19-induced respiratory infection, particularly in humans.
- In vitro studies only look at the direct effects of a drug on a cell isolated from an animal. It does not simulate the many interactions a drug makes with other cells inside the human body which may reduce its effectiveness and produce side effects.
In vivo studies on drugs in COVID-19
In vivo studies involve humans taking a drug to assess a drug’s efficacy and toxicity against a particular disease. These studies account for the modifications and interactions a drug may encounter while inside a human body as it travels to specific cells to treat disease. So far, there is no universal consensus on whether chloroquine and hydroxychloroquine are effective against COVID-19.
Initial studies found that chloroquine and hydroxychloroquine are effective against COVID-19 in humans. These results are hyped up by some people, including Donald Trump and Jair Bolsonaro. However, the scientific community is very sceptical of these results as these studies either do not show any results to back up their conclusions or have fundamental flaws in their study. Furthermore, other studies have not seen an effect of chloroquine or hydroxychloroquine in eliminating the virus or curing COVID-19 quicker. These drugs also produced more mild and serious side effects, with one study having to prematurely abort a high dose chloroquine treatment group as this group experienced increased mortality than the low dose group.
Hence, medical standards to date do not endorse the wide use of chloroquine and hydroxychloroquine to prevent and treat COVID-19. The use of these drugs in COVID-19 are restricted to clinical trials and compassionate use for very sick patients. More robust, well-controlled studies showing that these drugs can control COVID-19 are needed before they can be widely prescribed to the general population. These studies would be encompassed by randomised controlled trials (RCTs).
Randomised controlled trials: the way forward
Imagine that you want to test whether a certain liquid fertiliser enhances the growth of your turnips. You take a bag of turnip seeds, split it in half and plant them in separate areas side-by-side. Your neighbour pours some liquid fertiliser or water into two separate bottles A and B. When he passes the bottles to you, you do not know what each bottle contains. Despite this, each day you add the contents of the bottles into separate watering cans before watering the turnips. During the experiment, you track the growth of the turnips in each area over time. Once you finish the experiment, you talk to your neighbour who reveals what he has poured in bottles A and B.
This analogy represents how RCTs are run. RCTs are the gold standard in testing novel drugs to different diseases against standard treatment (being treated without the drug) or a placebo (an inert tablet that does not contain the drug). The aim of an RCT is to show that the novel drug is more effective in treating the disease compared to standard treatment or the placebo. In particular, a placebo is included in RCTs to account for the well-known placebo effect which describes how an inert placebo can still benefit the participant similar to taking a novel treatment or drug. RCTs involve four things:
- Generating a single group of participants (study sample) that satisfies the selection criteria, where only those that are eligible for the study are included (i.e., fulfils all the inclusion and none of the exclusion criteria). Participants also have to provide informed consent before they can participate.
- Randomising the participants into two separate groups with approximately equal numbers and similar characteristics (e.g., similar distribution of ages and comorbidities such as heart disease). This minimises the differences between the groups so that any changes in the treatment group are due to the treatment itself and not another variable (called a confounding variable). Randomisation is usually done by a third-party that is not involved in the study such as a study centre or an independent statistician.
- Blinding the participant and investigator. Neither the investigator nor the participant knows what treatment they are giving or receiving respectively. This avoids the bias of favouring participants who are taking the treatment over those that do not.
- Monitoring and reporting side effects to assess the risks of administering the treatment and to stop a RCT if too many people are suffering serious side effects or deaths from the treatment.
How is an initial study flawed?
The people that are endorsing the use of chloroquine and hydroxychloroquine to treat COVID-19 are most likely referencing a study conducted in France. In this study, investigators found that patients taking hydroxychloroquine cleared the virus more quickly than those that did not. However, this study has been widely criticised by scientists and medical professionals because how they conducted the study is flawed. This study did not follow the principles of how an RCT is run:
- The two groups are taken from different parts of France. While those that received hydroxychloroquine (the treatment group) come from one centre in Marseille, those that did not receive the drug (the control group) came from different centres around Southern France (not just Marseille but also Nice, Avignon and Briançon). Hence, any differences between the two groups could be due to location.
- The two groups were also different in age with patients in the treatment group being older than those in the control group. Hence, age could have also contributed to the differences in results between the two groups.
- The control group included people that were not eligible in the study or who refused treatment. This not only inflates the differences between the two groups but it is also unethical as excluded people cannot participate in the study at all (not even as a control).
- The two groups were treated differently. While the treatment group was monitored every day, some of the control group were only monitored every second day. Accurate results cannot be collected from the control group which heavily skews the results to favour the treatment group.
- Within the treatment group, some patients were excluded from the final analysis because they were either transferred to ICU or other reasons (death, left hospital early, side effect). This action skews the result in favour of the treatment group and excludes any potential side effects that should be reported upfront before the treatment is given widely to other people.
Hence, because of the flaws in the study, we cannot be confident that their results are legitimate and can be replicated in other studies and in other places. This is shown by other studies which have shown that hydroxychloroquine is ineffective in treating COVID-19. More studies are being run in different countries to rigorously test chloroquine’s and hydroxychloroquine’s effectiveness in COVID-19 in humans. In addition, hydroxychloroquine have been tested against COVID-19 in the WHO-run Solidarity clinical trial. This was stopped early on 17 June 2020 as data from this and other clinical trials found that hydroxychloroquine did not reduce the mortality of hospitalised COVID-19 patients compared to standard of care.
Conclusion
The world is in need of treatments that are effective against COVID-19. To show this; however, requires robust studies and RCTs that indicate that a treatment is effective against COVID-19. As explained in this blog post, current studies are insufficient and inconclusive for showing that chloroquine and hydroxychloroquine are effective against COVID-19. Endorsing these drugs from a lack of evidence is not only a waste of money and resources but may also harm people by producing serious side effects without benefiting the patient. The world must wait for more results to arrive showing that these drugs work before prescribing them widely to their patients to treat COVID-19. This will take time, but in the long run it will allow people to be treated based on strong evidence without exposing them to unnecessary harm.
Update (26/5/2020): the WHO Director-General announced on 25/5/2020 that chloroquine and hydroxychloroquine use in the Solidarity clinical trial has been suspended pending further review by the Executive Group. The blog post has been updated to include this detail.
Update (5/6/2020): the WHO Director-General announced on 3/6/2020 that the Executive Group did not find increased mortality in patients taking hydroxychloroquine. Hence, the hydroxychloroquine arm of the Solidarity clinical trial has been resumed. In addition, the paper that caused WHO to halt the hydroxychloroquine arm of the Solidarity clinical trials has been retracted. The blog post has been modified in light of these events.
Update (3/7/20): WHO announced on 17/6/2020 that the hydroxychloroquine arm of COVID-19 has been stopped. Data from the Solidarity trial and other trials, including those from France and the UK, and a Cochrane review has found that hydroxychloroquine failed to reduced the mortality of hospitalised COVID-19 patients when compared to control patients. The blog post has been updated to reflect these results.