One of the chief problems that exacerbated the intensity of the pandemic in its initial inception period was the lack of adequate treatment options for controlling the virus and the complications caused by it. To keep the mortality rate in check, medical experts and physicians repurposed several medications into possible treatment options for Covid-19 that later turned out to be overhyped.
Hydroxychloroquine was one such medication that, along with Chloroquine ( the older version of Hydroxychloroquine), was initially given a lot of attention as a possible treatment option and preventative measure for Covid-19. During the early stages of the pandemic, when monoclonal antibodies and antiviral pills had not been developed, Hydroxychloroquine and Chloroquine were regarded as possible off-label options for battling the symptoms of covid.
The evidence during this time regarding using it was a mixed review of positive and neutral outcomes when used in Covid-positive settings. With the increasing mortality rates as the result of the infection out of which 40% were that of healthcare workers or hospital staff, the drug was given a chance of a trial so it could be evaluated whether or not it could be used in inpatients and outpatients infected with Sars Covid.
Before proceeding further about the covid status of Hydroxychloroquine, it is important to have a brief idea about the medication and its therapeutic properties.
A word about Hydroxychloroquine
It belongs to the antimalarial class of medications ( drugs used for treating and preventing antimalarial infections). Additionally, it has DMARD properties and helps suppress inflammation caused by overactive or immune responses. In addition to being FDA approved for the treatment and prevention of malaria and rheumatoid arthritis, it is on the WHOs list of Essential Medications owing to its therapeutic properties.
In conditions of the Sars-Covid, Hydroxychloroquine when tested in laboratory conditions was observed to have a positive effect on inhibiting its viral multiplication successfully. It was further observed during its initial laboratory testing period that the medication could impair the terminal glycosylation of the ACE-2 receptors, that is, the point of binding of the virus spike for entry into the body.
Image credit – https://www.nature.com/articles/s41419-020-2721-8
In short, using the medication could reduce virus entry inside the host cells and prevent them from replicating and spreading inside the body after entry. Further in-vitro studies proved that it has an additive anti-HIV property with immune activation properties. This helps manage the cytokine storm induced by the sars-covid virus on the system and its subsequent multi-organ failure.
In a study conducted by the ICMR to evaluate the effectiveness of Hydroxychloroquine as a prophylactic measure for Covid, two-thirds of the participants agreed that it should be included as a prophylactic measure against the Covid virus. The reason is satisfactory results yielded by the drug with its tolerance.
But even then, the results were problematic and of a variable nature that did not support a favorable response of the medication to Covid virus infection.
Why was Hydroxychloroquine overhyped for Covid-19 treatment?
From the beginning, there were controversies about the effectiveness and reliability of the first clinical trials of the drug. Animal studies, considered a vital part of evaluating the effectiveness of a drug, did not support the effectiveness of it for covid conditions.
In infected Syrian hamsters evaluated in vitro, neither a prophylactic dose nor a treatment dose of 6.5mg/kg nor a high dose of 50mg/kg had any beneficial effect on the replication or shedding of the sars-covid virus. Even in infected bigger mammals like the Rhesus monkey, an HCQ prophylactic treatment of 6.5mg/kg did not improve the clinical outcome or reduce Sars-Covid replication/shedding in the upper and lower respiratory tract of the animal subjects. The study concluded that preclinical animal studies do not support Hydroxychloroquine use in prophylaxis/treatment of Covid-19.
Image credits- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301902/
Inspite of the initial reservations, Hydroxychloroquine was promoted as a covid treatment option. It became a part of multiple large-scale trials, including one of four initial treatment options in the WHO Solidarity clinical trials for Covid-19. In these trials, four drugs: Remdesivir, Hydroxychloroquine, Lopinavir, and Interferon Beta-la, were administered to Covid patients hospitalized because of the infection.
The trial was adaptive, i.e., designed in such a manner as to drop the unpromising drugs and add others if required. Daily doses were those that were used for other diseases. Still, for patient safety, the hydroxychloroquine dose was based on amoebic liver abscess rather than a lower malarial dose as the drug tends to cause arrhythmia and hypotension at higher doses. Treatments stopped after the discharge of the patient. It was administered thrice on the first day at a dose of four tablets, followed by two twice daily for ten days. Each tablet contained 200 mg of hydroxychloroquine sulfate (155 mg of hydroxychloroquine base per tablet or 155 mg of chloroquine base per tablet).
During the entire trial duration, the main outcomes of mortality, initiation of ventilation, and hospitalization duration were not reduced by any of the four trial drugs. Nor did any trial drug, including Hydroxychloroquine, reduce the initiation of mechanical ventilation. The findings of the WHO study, supported by analysis of the combined outcome of death or ventilation initiation, proved that Hydroxychloroquine did not affect major disease progression caused by the covid invasion. Rather its use was associated with multiple adverse effects like cutaneous adverse reactions, hepatic failure, and ventricular arrhythmia, added by overdose risks in patients using them.
Image credit – https://www.nejm.org/doi/full/10.1056/nejmoa2023184
These drugs were eventually dropped from the trial and replaced by monoclonal antibodies that successfully dealt with virus-induced disease progression.
Fda verdict on the use of Hydroxychloroquine for Covid
The FDA has recently updated its guidance by warning against using Hydroxychloroquine outside of hospital settings because of serious adverse effects associated with its use. In addition to the WHO Solidarity Trial, several other clinical trials have discontinued Covid related trials of Hydroxychloroquine because of a lack of evidence for therapeutic efficacy in their results added by the side effects of the medicine. Authors have even retracted a few studies because they are unable to confirm their claims’ authenticity. A Multinational UK-based Hydroxychloroquine trial has even been paused after starting because of safety concerns.
During the initial days of the Covid-19 pandemic, several early treatment trials were rushed to find a quick treatment option. It was one such medication the studies regarding which were improperly conducted or had irrelevant results that did not reach a conclusive endpoint. Several Hydroxychloroquine trials were too small, which impacted the results and the overall verdict regarding their efficacy as antiviral treatment options. But clinicians and physicians kept using them because of a lack of other treatment options, giving them an overhyped reputation. Hydroxychloroquine can be used as an antimalarial and antirheumatic drug. But its use as an antiviral for the Sars Covid virus is contraindicated for the patient’s safety.