Hydroxychloroquine (HCQ) or chloroquine (CQ) is used to treat malaria and autoimmune diseases such as lupus and rheumatoid arthritis. HCQ is modified from CQ to increase its solubility in water, so it tends not to concentrate in tissues. HCQ is, thus, safer than CQ with lower toxicity to the kidneys and eyes.
HCQ has been highly politicized in the U.S as a treatment for Covid-19, earning its name as the most controversial drug to date. HCQ is also among the top studied drugs in Covid-19. But studies after studies continue to give conflicting findings. Fortunately, there are a few published meta-analyses in August that answer a few ambiguities about HCQ.
Meta-analysis 1: Covid-19 death rates
The paper, “Effect of hydroxychloroquine with or without azithromycin on the mortality of COVID-19 patients: a systematic review and meta-analysis,” was published in the journal, Clinical Microbiology and Infection. Researchers identified 29 studies on HCQ and Covid-19 mortality, of which three are randomized placebo-controlled trials (RCTs) and the rest non-randomized. And 12 non-RCTs have a critical risk of bias — with a flawed study design that their results are likely false — and thus were removed from further analyses. So, the pooled data from 17 studies equated to:
[Note: HCQ may be used with azithromycin (AZI; an antibiotic) for presumed synergistic effects on Covid-19.]
- HCQ alone (17 studies): A 17% reduced risk of death compared to standard care (absolute risk: -4.4%), but this result did not reach statistical significance. Results did not change when studies with a critical risk of bias were included, or when non-RCTs or RCTs were excluded.
- HCQ + AZI (7 studies): A statistically significant 27% increased risk of death compared to standard care (absolute risk: +7%). But the only one RCT examing HCQ + AZI found no significant differences.
[Relative vs Absolute risks: E.g., a treatment cuts death rates from 10% to 5%, the relative risk is 50% reduction whereas the absolute risk is 5% reduction.]
This meta-analysis showed that HCQ neither increases nor decreases Covid-19 mortality. But HCQ and AZI combined can be dangerous. These two outcomes are also consistent with a meta-analysis published in July that synthesized 13 Covid-19 studies.
“In conclusion, this meta-analysis clearly shows that HCQ alone is not effective for the treatment of Covid-19 patients and that the combination of HCQ and AZI increases the risk of mortality,” the authors wrote. “Our results suggest that there is no need for further studies evaluating these molecules, and the [ongoing] European DisCoveRy clinical trial or the WHO international Solidarity clinical trial have already discontinued treatment arms using HCQ.”
Meta-analysis 2: Covid-19 clinical progression
The study, “Hydroxychloroquine for treatment of non‐severe COVID‐19 patients; systematic review and meta‐analysis of controlled clinical trials,” was published on 18 August in the Journal of Medical Virology.
This meta-analysis found six placebo-controlled studies that looked at HCQ in non-severe Covid-19 patients, of which four were randomized (i.e., RCTs). And their pooled analyses are as follows:
- Virus clearance (3 studies): No significant differences.
- Disease progression based on CT chest scans (2 studies): A 20% reduction in absolute risk in the HCQ group compared to control.
- Clinical symptom progression (4 studies): No significant differences.
- Mortality rate (2 studies): No significant differences.
- Gastrointestinal side effects (3 studies): A 59% increase in absolute risk in the HCQ group compared to control.
- Neurological side effects (3 studies): A 23% increase in absolute risk in the HCQ group compared to control.
- Skin side effects (3 studies): No significant differences.
- Heart side effects (2 studies): No significant differences.
So it appears that HCQ is not helpful for non-severe cases of Covid-19 as well. Although HCQ slows down lung damage (as evidenced by CT chest scans), it still offers trivial clinical value as it does not improve important clinical metrics such as virus clearance, symptom progression, or mortality but comes with additional side effects instead.
“There are no tangible beneficial effects of adding HCQ to the treatment of patients suffering from non-severe PCR confirmed Covid-19 infection,” the researchers concluded. “Failure of HCQ to show viral clearance or clinical benefits with additional adverse effects outweigh its protective effect from radiological progression in non-severe Covid-19 patients.”
Meta-analysis 3: HCQ safety profile
The article, “Safety of hydroxychloroquine in COVID-19 and other diseases: a systematic review and meta-analysis of 53 randomized trials,” was published on 11 August in the European Journal of Clinical Pharmacology.
In this meta-analysis, scientists identified 53 pertinent studies, but only four involved Covid-19 patients, and the others were researching other diseases. And ten of the studies used HCQ dosage of over 400mg. Their pooled results are as follows:
- General side effects (44 studies, 4 on Covid-19): A 15% increase in absolute risk in Covid-19 and 3% in patients with other diseases. In subgroup analyses, a high HCQ dosage led to a +19% absolute risk in Covid-19 patients only.
- Gastrointestinal side effects (32 studies; 2 on Covid-19): A 11% increase in absolute risk in Covid-19 patients and 3% in patients with other diseases.
- Skin side effects (28 studies; 3 on Covid-19): No changes in Covid-19 patients, but +2% absolute risk in patients with other diseases.
- Eye side effects (30 studies; 2 on Covid-19): No changes in all patients.
- Heart side effects (9 studies; 1 on Covid-19): No changes in all patients.
- Serious side effects (36 studies; 4 on Covid-19): No changes in all patients.
- Termination of treatment due to serious side effects (29 studies; 2 on Covid-19): No changes in all patients.
This meta-analysis verifies that HCQ brings extra side effects, especially of the gastrointestinal system, to patients including Covid-19. “HCQ is associated with more total AEs [adverse effects], gastrointestinal AEs, and skin and subcutaneous tissue AEs compared with placebo or no intervention in the overall population,” the authors concluded.
Might HCQ still play a role in this pandemic?
Since HCQ is ineffective in reducing Covid-19 clinical progression or mortality but comes with extra side effects, it makes sense that the scientific community drops HCQ altogether. Indeed, the two major clinical trials have discontinued HCQ. And, in June, the FDA withdrew its authorization of HCQ for emergency use in Covid-19 patients.
Yet, there are still over 100 trials involving HCQ listed in ClinicalTrials.gov for Covid-19, as identified by an August systematic review. Why is HCQ still being studied so extensively?
Reason 1: Preventive medicine
One potential use of HCQ in this pandemic lies in disease prevention. “We know now that it doesn’t work in the treatment of hospitalized [Covid-19] patients,” Nick White, a professor of tropical medicine at the University of Oxford, said in August. “But it’s still is a medicine that may prove beneficial in preventing Covid-19.”
The reason is that the ACE2 receptor needs to undergo glycosylation before SARS-CoV-2 can invade the cell, and HCQ blocks this glycosylation step.
However, a 2020 August RCT published in The New England Journal of Medicine (NEJM) — with 821 symptomless participants exposed to Covid-19 — showed that HCQ administered within four days of exposure is not any better at preventing the development of Covid-19 than placebo. This led to early conclusions that HCQ does not even work as preventive medicine.
But an editorial in NEJM argued that HCQ might prevent Covid-19 if it’s taken much earlier, before SARS-CoV-2 exposure, “suggesting that the potential prevention benefits of HCQ remain to be determined.” Thus, some of the ongoing clinical trials examining HCQ as a preventive drug for Covid-19, which is nearly a third of them, may have the rationale to proceed.
Anyhow, such preventive application of HCQ must also be weighed against its potential side effects. “Both HCQ and CQ are immunomodulatory drugs and have the potential to suppress normal immune system activation,” stated a review published this month in Genes and Environment. “Current literature indicates that healthy individuals should refrain from the use of these drugs [as preventive medicine] until further investigation.”
Reason 2: A zinc transporter
At least eight ongoing clinical trials are hoping to see some efficacy with HCQ (or CQ) plus zinc combinational therapy for Covid-19. Why might zinc be a possible game-changer for HCQ?
HCQ could promote the cell uptake of zinc. And zinc is an essential nutrient that the cell needs to generate an antiviral response. Zinc by itself further stops the virus’s enzyme (i.e., RNA polymerase) needed for its replication.
Aside from antiviral and immunomodulatory activities, HCQ also acts as a zinc ionophore. Ionophore is a transporter that brings fat-insoluble molecules like zinc across the cell membrane, which is made up of fat. Hence, HCQ could promote the cell uptake of zinc. And zinc is an essential nutrient that the cell needs to generate an antiviral response. Zinc by itself further stops the virus’s enzyme (i.e., RNA polymerase) that is needed for its replication.
“Could the mode of action, or at least one of the possible modes of action of CQ/HCQ be as simple as being an ionophore, thus bringing more Zn(II) [zinc], a potent RNA-based polymerase inhibitor, into the cell?,” wrote a research review published in Pharmaceuticals. “Clinical studies that aim to answer it are still ongoing.”
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