When Chloroquine became an anathema – Part 2
However, in the 1950s the first case of quinine resistant malaria was reported. By the 1990s the efficacy of quinine declined due to resistance from multiple mutations of the malaria parasite. In 2006, quinine was no longer recommended as a frontline drug for the treatment of malaria.
Chloroquine and hydroxychloroquine can both be used in the treatment of COVID-19. Hydroxychloroquine differs from chloroquine only by the possession of a side chain in its biochemical composition. During this pandemic, chloroquine and its hydroxychloroquine sibling have been used but their use or non-use has seeped in several controversies.
There are advantages to using hydroxychloroquine. It is tolerated at higher doses. Chloroquine is toxic at high doses. Therefore, the dosage for chloroquine in the treatment of malaria is usually at a high dose given over a few days or at a low dose given over a long period. At very low doses of less than 4.0mg/kg per day for a mean of 7 years, it can be used to treat rheumatoid arthritis. On the other hand, hydroxychloroquine can be used to treat rheumatoid arthritis at a higher dose of 6.5mg/kg per day for a mean of 7 years. At toxic levels, chloroquine affects the eyes. Chloroquine has a broad spectrum of action against bacteria, fungi, and viruses, not just the novel coronaviruses. It has been explored in laboratory studies using cell and tissue cultures for repurposing its use in the treatment of HIV and other viruses like rabies, poliovirus, hepatitis A and C, zika virus, Lassa fever virus, Dengue virus, Influenza A and B viruses, Ebola virus and some of the human coronaviruses including SARS-CoV.
The positive laboratory results gained from these viruses were not always replicable in humans. After investigating the positive outcome of the use of chloroquine on 100 patients, the Chinese Medical Advisory Board, recommended the inclusion of chloroquine in the treatment of COVID-19. There are several clinical trials ongoing on the use of chloroquine and hydroxychloroquine for the treatment of COVID-19. Chloroquine use can also affect the heart.
The United States Food and Drug Administration (FDA) warned of abnormal heart rhythms from the use of chloroquine when combined with azithromycin and recommended its use only in hospital settings where patients can be monitored or in clinical trials. Chloroquine and hydroxychloroquine have both been shown to cause arrythmias. This warning leads doctors to monitor their patients’ heart signs but the health watchdog did not detail the dosage of chloroquine and azithromycin that caused the arrythmias. The FDA did not show the data but informed consumers that the data were from a large database on adverse drug reporting, poison centers, and published articles. Some of the adverse reports also came from doctors whose patients had been on long term treatment for rheumatoid arthritis with chloroquine or hydroxychloroquine. Some had been on treatment for as long as three years. The use of either of these two drugs in the management of COVID-19 is not long term. While not totally neglecting the significance of the arrythmias much consideration should be given to the hundreds of thousands who are dying from COVID-19 without first giving them a chance of survival by treating with chloroquine or hydroxychloroquine.
For several months Italy was the epicentre of the disease with more than 900 people dying in a single day, every day. A multi-center study conducted across Italy involving 33 Italian hospitals has shown that patients that were treated with hydroxychloroquine had a 30 percent lower rate of dying. About 3,451 patients were observed in the study. The patients were given 200mg of hydroxychloroquine, twice a day.
Other studies that did not observe a reduction in death rate used doses that were higher than 200mg. It could be that some of the negative outcomes in the treatment of COVID-19 with chloroquine were because of the high dosage used. All the studies on chloroquine and COVID-19 have not used the same dose of chloroquine. They have not started the use of chloroquine at the same point. Some studies started the dose within 48 hours of the onset of symptoms, some started only after the patients had been hospitalized, some started with different combinations of azithromycin, zinc, vitamins C and D and some started only after confirmation of test results. Confirmation of test results may take days or weeks by which time the disease would have progressed to its severe form. Further, some patients were using regular multivitamins that had high doses of zinc and high doses of vitamins C and D which increases the chances of a positive outcome. It would be difficult to paint with a broad brush and say that chloroquine worsens the patient outcome. It can appear to worsen the patient outcome when the dosage is high, when the treatment is commenced late in the disease process and when the patient has some co-morbidities especially those that affect the respiratory system.
Studies on chloroquine have shown at least five ways in which it inhibits the replication of viruses. The mode of inhibition varies slightly depending on the type of virus. When a virus like the SARS-CoV-2 enters the host, it needs to attach itself to the lining of the host cell, sort of like the plunger to the kitchen sink. For this attachment to occur, the virus needs sialic acid to be produced. Chloroquine interferes with the production of this acid.
Angiotensin Converting Enzyme 2 (ACE 2) is a virus-cell surface receptor. Before the virus can attach to the host cells, a sugar molecule must be added to ACE 2. Without the addition of the sugar molecule, the virus cannot attach to the host cell. Chloroquine prevents the addition of this sugar molecule to ACE 2. Angiotensin-Converting Enzyme 2 is significantly prominent in the lungs of people with respiratory disease and perhaps this is why persons with respiratory diseases are more susceptible to COVID-19.
If despite the inhibition of sialic acid and prevention of glycosylation of the ACE 2, the virus was still able to attach to the host cells, chloroquine still has many more weapons in its arsenal to inhibit the replication of the virus. Chloroquine causes alkalization of the tiny cells within the cells of the host. These are the endosomes. The virus needs an acidic medium inside the endosomes to initiate the replication process where it would discharge its nucleic acid contents before commanding its own replication. Chloroquine changes the acidic medium into an alkaline one thus inhibiting viral replication. If the virus was still able to replicate, the alkalization will also affect the proper maturation process of the viruses. In addition, chloroquine is able to present the viruses closer to the antibodies that will destroy them. It also inhibits the enzymes that will signal to the viruses to begin replication, thus acting as an anti-inflammatory and immune-modulatory agent.
Without a drug like chloroquine or any antiviral drug to inhibit its replication, the virus is able to deposit its genomic material into the cell compartment in an acidic medium, gathering more enzymes in the process and continues its replication, subsequently wreaking havoc on the human host.
When chloroquine is used with other drugs like azithromycin, zinc, vitamins C and D, the combined effects are amplified to give an overall positive outcome for the patient, especially when used at the onset of the disease. After the virus has gained entry, begun its replication and the cytokine storm has set in, recovery from the virus becomes complicated and the drugs are less likely to work.
When the government of Switzerland banned the outpatient use of hydroxychloroquine, the number of deaths from COVID-19 increased by about four-fold. When hydroxychloroquine was reinstated, the mortality rate due to COVID-19 went down to former levels.
Before President Trump publicly advocated for the use of hydroxychloroquine, several countries had been using hydroxychloroquine and chloroquine as a first-line drug against COVID-19. In the face of an ongoing pandemic that has crippled world economies, crushed achievements in education increased the pre-existing gaps between the haves and have nots, threatened food security, crippled weakened health infrastructures, and increased nationalism especially around the accessibility of anti-coronavirus vaccine, it would seem logical to cautiously investigate further any known properties of chloroquine to combat the ongoing onslaught on the human race and not withhold the use of a drug that humans have successfully used for almost 100 years.
Unfortunately, the use or non-use of chloroquine has become so politicized that is has become an anathema depending on the side of the political spectrum you belong to. In the USA, those in support of their President are more likely to advocate for its use. Recently, a video showing a Nigerian-trained medical doctor, in the USA garnered 17 million online views and even got a nod from President Trump and his son. The video had been shared almost 600,000 times before it was finally taken down by Facebook. Unsurprisingly, the online video came less than 100 days before the presidential elections and the polls had shown that the American incumbent had been trailing behind his Democratic rival, Joe Biden. The video was a mixture of half-truths and misinformation.
Truth be told, chloroquine would work if taken at the onset of COVID-19 symptoms when the symptoms are mild. One should not wait for the test results to come out before commencing on chloroquine especially if one has been exposed to the virus through contact with an infected person. There have been several published articles on the positive and negative outcomes of chloroquine or hydroxychloroquine use in the treatment of COVID-19. However, in the video pulled down by Facebook, the Nigerian-trained doctor, a Cameroonian made some utterances that should not have been attributed to a medical doctor. Her excited speech leaned towards a Republican political ideology. She was promoting non-wearing of masks, reopening of schools, and opening up instead of lockdown; all the ideas that President Trump’s party was in support of. A medical doctor should not advocate for non-wearing of masks, opening up and reopening of schools in a country at the peak of an uncontrolled pandemic that is transmitted by aerosols and droplets. While she might have been on track for chloroquine and hydroxychloroquine use, she was off-track on her remaining recommendations. However, she must be commended for her boldness to speak about chloroquine. It has renewed interest in its use. Even then, she did not provide any reproducible data on her use of the drug.
Several countries are still using chloroquine or hydroxychloroquine but some are now using them stealthily because of fear of backlash. Senegal’s population of 16.7 million people has not shied away from the public eye. It routinely uses hydroxychloroquine and has one of the lowest COVID-19 case fatality rates in the world. In addition, it has achieved massive testing. As of the 26th of August, Senegal had 13,013 confirmed cases and 272 persons had died from the virus. The case fatality is 2 percent, below the global case fatality rate. In July, Senegal’s case fatality rate was 1.5 percent.
Chloroquine is effective when given in combination with azithromycin, zinc, vitamins C, and D. The gold standard of testing the efficacy of a drug is a double-blind study. However, in the case of COVID-19 where the disease is ravaging human lives and an inexpensive, time-tested, well-established drug is available, it will be tantamount to the treachery of the Hippocratic oath to withhold such treatment from patients and subsequently leave them to succumb to the clutches of the deadly virus while awaiting the results of double-blind studies.
Several observational studies have shown positive outcomes with chloroquine and hydroxychloroquine. There is still so much unknown about the effects of the virus on the human body. In a chloroquine-politicized world, a lot of biases have become actors in some of these studies. Unfortunately, as the editors of two leading medical journals revealed; The Lancet and New England Journal of Medicine, big pharmaceutical companies pressured them to push forward studies that denounced chloroquine and hydroxychloroquine and push back studies that proved their efficacy. This revelation came after several scientists pointed out the biases and errors in one of such articles. The article was a faulted observational study published in the Lancet. The WHO withdrew its clinical trial on hydroxychloroquine based on this highly faulted research.
The article was later retracted but not before several countries had stopped administering chloroquine and hydroxychloroquine to their COVID-19 patients. One can only imagine the loss of lives that would have followed and continue to follow from the discontinuation of these drugs. The interpretation of biased research studies can be made to go either way. While some clinical trials on chloroquine and hydroxychloroquine are ongoing around the world, some have had to be discontinued because of an inadequate number of volunteers as some people including doctors have become reluctant to use or recommend the use of the drugs. The hype around these drugs has also led to stockpiling such that people using them for other diseases like rheumatoid arthritis or an autoimmune disease like lupus erythematous are finding it difficult to access them.
Several studies have also been published on the efficacy and safety of chloroquine and hydroxychloroquine but do not get as much publicity. These drugs are being used and are saving lives but because of the skepticism, controversy, negative publicity, and brouhaha that has now been attached to it and in some countries the fear of being summoned by the medical board, many doctors are afraid of using it and many journals are not keen on publishing articles on positive outcomes with chloroquine and hydroxychloroquine. As I pointed out in my article in The Guardian of 26th May 2020. The title of the article was “Taking Ownership in the Management of COVID-19”, when chloroquine is used in the early onset of the disease, before the cytokine storm, it works. The cytokine storm is a result of overreaction of the host’s immune system. On the 21st of May in an interview on “Frequently Asked Questions About COVID-19” with Arise TV, I explained similar issues about chloroquine.
If a ship is sinking and a rescue boat comes along. You cannot refuse to board the boat and stop others from boarding saying that that rescue boat does not meet your gold standard. Even if the rescue boat does not meet your gold standard, at least use it to get off the sinking boat. Chloroquine and hydroxychloroquine are the rescue boats and we should not refuse the offer of hope in them.
In the future, post-COVID-19 pandemic, journalists, medical historians, sociologists, and psychologists would analyse what happened to the anathema around chloroquine and perhaps we would have learned our lessons on politicization of our health. And like the Titans and Olympians in Greek mythology, Zeus left hope in Pandora’s box. Hope has been given to us in chloroquine and hydroxychloroquine, we should not shut it out. We should not throw away the baby with the bathwater.
Obilade, a medical doctor and an Associate Professor of Public Health wrote from Abuja.