Hydroxychloroquine: An Overview

Part II-2: Evidence as Treatment Against SARS-COV2 (Continued)

Triple Threat- HCQ, Azithromycin and Zinc Combination Therapy

So far many clinical studies conducted used a dual therapy of HCQ with either Zinc or Azithromycin. However, what would happen when all three are used together? The concern here would be whether there would be dangerous synergistic effects, but considering that Zinc is a vital mineral for our bodies, we could argue that supplementation with Zinc should not lead to increased adverse reactions.

In a retrospective analysis conducted by Derwand et. al. 2020 outpatient treatment with all 3 therapeutics showed a reduction in both hospitalization and death. More importantly, and one unique to this study, treatment groups were stratified by age and possible comorbidities, and indicated both therapeutic benefits as well as a relatively safe safety profile (emphasis mine):

A further strength of this approach was the simple risk stratification of symptomatic outpatients to determine the need for therapy, a strategy not yet applied in COVID-19 primary care [35] but routinely implemented in primary care for other diseases [36]. Underlying assumptions of the risk stratification used in this setting are different to other recommendations [37]. Here, age-stratified high risk was defined as >60 years (typically defined as >65 years) to encompass the common increase of co-morbidity incidences in this age group [38]. Patients ≤60 years with SOB, even without reduced pulse oximetry values, were treated because it was assumed the virus will likely spread from the upper to lower respiratory tract [39]. Also treated were patients ≤60 years with clinical symptoms and prognostically relevant co-morbidities [37]. By applying this risk stratification approach, respective care was tailored to patients with a higher likelihood for hospitalisation or fatality, which ensured that the medical principles of ‘patient first’ and ‘doing no harm’ were maintained [40]. As a result, 61.8% of COVID-19 patients were treated with standard of care only and recovered at home, and only 37.9% needed treatment with the triple therapy.

Taken from Derwand et. al. 2020. A triple therapy regimen lead to significant decrease in hospitalization. Although All-cause death rates declined, these were not seen as statistically significant.

This may suggest that a triple therapy regimen may prove more beneficial, and that toxicity of all 3 therapeutics taken together is relatively low and well tolerated. More importantly, all 3 therapeutics are able to be administered in an outpatient setting, increasing their availability to the general public. It’s interesting that many studies were not conducted examining all 3 therapeutics together, and more studies should be conducted to elucidate the effectiveness of a triple therapy treatment.

Something important to point out is that the researchers seemed to have used this stratified method in order to weigh the risks/benefits of these 3 drugs. Although in this circumstance it was done to prevent possible harm from adverse therapeutic reactions, we can see that the rewards of possible therapeutic benefits was also taken into account. Taking into account the various factors associated with patient therapeutics should be the way that patients are provided medications for diseases. This is a type of nuance that seems to be missing when we look at the way COVID treatment are given.

Contextualizing the Noisy Data

Overall, the data surrounding HCQ seems murky, but that may be due to lack of context more than lack of efficacy. Many of the French studies indicated that early combination treatment of HCQ with Azithromycin was effective, while other studies with later hospitalization did not indicate any effectiveness. Once again, this indicates the importance of examining the data in parallel; studies that look at outpatient treatment should be compared to other outpatient treatments. It should also be taken into consideration that moderate to late use of HCQ may not be beneficial because later progression of COVID is a disease of immune dysregulation more than it is of viral replication. In such a setting use of any antiviral may not prove beneficial.

But then why does HCQ, which is used as an immunomodulator, not prove effective in late stage COVID where cytokine storms are abundant? I’ll explain this position more in my Paid Subscriber Only post, but at that stage in the disease damage to vital organs such as the heart may sway the use of HCQ to becoming more risky than effective. At this point, the use as an immunomodulator may be more risky than the possible adverse cardiotoxicity that may occur due to heart damage that may manifest from prolonged COVID infection.

So it seems that the best time to use HCQ in combination with other therapeutics may be early on in the disease, something that many people have advocated for since the beginning of the Pandemic, and unfortunately it’s a point that seems to fall on deaf ears. But what may be more important is that comparisons of studies need to take into account the timing of when therapeutics were administered; a drug administered as a prophylaxis or for early treatment is not comparable to the same drug being administered in a hospital setting.

This becomes a big issue when it comes to meta-analysis, which may end up pooling together studies that should not be compared to one another. This indicates that the data may be tainted with biases that may skew the data in a certain way. This was also something I indicated in a previous posts, that it’s important to evaluate individual studies and see where the differences in protocols or patient demographic may affect the data.

And this seems to have occurred with meta-analysis of HCQ. In the meta-analysis of Fiolet et. al. 2021 there was a study that indicated a large increase in mortality in patients administered HCQ/Azithromycin.

One of these studies, a Rivera et. al. 2020 study showed the greatest increase in mortality, but if we examine the participants we can see a possible confounding variable:

Taken from Fiolet et. al. 2021. The Rivera study indicates the greatest risk ratio. Although the weight (11.6%) is lower than some of the other studies, biases from such a study may heavily skew the meta-data.

This study looked at a reduction in mortality when administered different therapeutics (HCQ, Remdesivir), however the participants were unique; they were all cancer patients. The study was conducted to uniquely examine the effects of different therapeutics in cancer patients, and in such a setting the risk of adverse events are much higher than would be the general public. In that sense, this study should have been looked at with a discerning eye that took into account this bias. Although the weight of this study is not very high, it’s one of the studies with the largest risk ratios and thus could have an effect by skewing the data.

This doesn’t mean that the combination therapy is absolutely safe, but it indicates that context is important when evaluating data. Many factors are at play with a cancer patient, and unless a study is powered to rule out previous and recurring cancer as a confounding variable it would be hard to argue that being a cancer patient and being administered chemotherapeutics would not increase the risk of adverse reactions.

In order to examine the effectiveness of HCQ in clinical studies, the studies must be comparable to one another. Not only is the timing and the dosage of the drug important, it’s also about possible synergistic compounds. It’s also important to look at the comorbidities, and understand that certain drugs should not be administered to certain groups of people if there’s a risk of increased adverse events. A doctor would absolutely not prescribe a blood thinner to someone who’s anemic, and the same rule applies here. Administration of HCQ seems to not be effective in later disease progression due to possible cardiotoxicity that someone might sustain from prolonged COVID infection.

The Hippocratic Oath, and the rules of “do no harm” do not apply to instances where no treatment is provided, but also that the provided treatments should always be assessed on a risk/reward basis. One drug that seems to have fallen under this scrutiny the most is HCQ, and the demonization of this drug has lead to its widespread banning over the cry of “cardiac arrhythmias”, but as we can see here there’s more to the story than just a complete ban of a drug over possible fears. Instead, it’s about the nuanced, varied circumstances that should indicate whether HCQ should be used.

In my Paid Only Post, I will examine the evidence and argue that the fear mongering around HCQ and cardiac arrhythmias are not only unfounded, but call into question the narrative of off-label use of therapeutics and the fear mongering as presented by the media.

As we are all aware of by now, the media plays a large role in influencing how certain drugs are portrayed and influences how these drugs are discussed in COVID discourse, and it is important to examine if these concerns are rooted in science or rooted in paranoia.

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Citations

1. Fantini et. al. 2020. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7128678/

2. Skalny et. al. 2020. Zinc and respiratory tract infections: Perspectives for COVID-19 (Review). Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255455/

3. Xue et. al. 2014. Chloroquine Is a Zinc Ionophore. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/

4. Carlucci et. al. 2020. Zinc sulfate in combination with a zinc ionophore may improve outcomes in hospitalized COVID-19 patients. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660893/

5. Abd-Elsalam et. al. 2020. Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine?: a Randomized, Multicenter Trial. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695238/

6. Derendorf. H. 2020. Excessive lysosomal ion-trapping of hydroxychloroquine and azithromycin. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204663/

7. Schermann, J. M. Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291928/

8. Gautret et. al. 2020. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102549/

9. Lagier et. al. 2020. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315163/

10. Million et. al. 2020. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199729/

11. Fiolet et. al. 2021. Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449662/

12. Cavalcanti et. al. 2020. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19i. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397242/

13. Derwand et. al. 2020. COVID-19 outpatients: early risk-stratified treatment with zinc plus low-dose hydroxychloroquine and azithromycin: a retrospective case series study. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587171/

14. Rivera et. al. 2020. Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study. Taken from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541683/