Ivermectin vs Hydroxychloroquine vs Zinc for COVID-19: What are the Differences?

Ivermectin, hydroxychloroquine and zinc have received various media and social media attention for the past few months. 'No high quality evidence', "can only be used in a clinical trial setting', 'double blinded randomised controlled clinical trial needed', "insufficient data to recommend either for or against the use" are some of the medical and scientific technicalities that you might read in various social media channels. Confused? 

The number of options for the treatment of COVID-19 has increased drastically in recent months, thus making it complicated when it comes to choosing the right combination. In general, there are 3 broad categories of medical interventions:

  1. Prevention or Prophylaxis e.g. vaccine
  2. Early out-patient treatment
  3. Hospital treatment



McCullough et al. Reviews in Cardiovascular Medicine, 2020

All these treatments come with various technical jargons, thus could be overwhelming and confusing for you as a consumer.

Generally, multiple treatments and strategies are used in combination to achieve the best possible outcome.

In this article, we would like to cover 3 popular treatments i.e. Ivermectin, Hydroxychloroquine and Zinc.

Ivermectin and COVID-19

As of August 2021, there are more than 80 on-going trials globally on Ivermectin for treatment and prevention of COVID-19 on covid-nma.com.

Ivermectin is an anti-parasitic medication widely used in low- and middle-income countries to treat parasitic worm infections in adults and children. It’s been used for decades for this purpose by over 3.7 billion people, and is considered safe and effective. It has an increasing list of indications due to its antiviral and anti-inflammatory properties, and is included on the WHO’s Model List of Essential Medicines.

Check out the "P values". These results are not by chance.

Ivermectin and COVID-19 Updates:

July 29, 2021: Ivermectin's recent Cochrane review applies tight selection filters, e.g. eliminating 7 of the 10 RCTs with mortality end-point, and splits the rest in 2 subgroups (in/outpatients) to reach an unavoidable conclusion of inconclusiveness. The live French Ivermectin RCT meta-analysis allows to contextualize the loss of information from Cochrane's selection of 3 papers only.

A Cochrane-standard review and meta-analysis of Ivermectin against Covid-19 by Bryant-Lawrie, now peer-reviewed and published, concludes that the evidence justify the global adoption.

Results of Ivermectin's success in treating COVID-19 outbreaks in India, Mexico, Peru, Paraquay, Argentina, Brazil and Slovakia.

May 16, 2021: Do the NIH and WHO COVID treatment recommendations need to be fixed? By Steve Kirsch. Published on TrialSiteNews.
Great article on where we stand on the COVID-19 treatment front debate - COVID19Crusher

According to a review on peakprosperity.com:
Heads up — go over to TrialSiteNews and read this totally brilliant new (very long) article on Ivermectin, hydroxychloroquine and fluvoxamine. It blows the NIH and WHO’s opposition to these drugs out of the water. A total annihilation job. Surgical and hatchet.

May 4, 2021: Meta-analysis of Mortality, Need for ICU admission, Use of Mechanical Ventilation and Adverse Effects with Ivermectin Use in COVID-19 Patients (N=15,002). Published on medrxiv.org.

May 03, 2021 - Joint Statement on Widespread Use of Ivermectin in India for Prevention and Early Treatment by U.K. Evidence-Based Medicine Consultancy Ltd (E-BMC Ltd) and U.S. FLCCC (Front Line Critical Care Alliance).

Apr 26, 2021: The new FLCCC outpatient protocol (I-MASK+) with the addition of fluvoxamine and nasal/oral "sanitation". Fluvoxamine 50 mg twice daily for 10–14 days. Add to ivermectin if: 1) minimal response after 2 days of ivermectin; 2) in regions with more aggressive variants; 3) treatment started on or after day 5 of symptoms or in pulmonary phase; or 4) numerous co-morbidities/risk factors. Avoid if patient is already on an SSRI (Selective Serotonin Reuptake Inhibitor).

Apr 26, 2021: The new FLCCC hospital treatment protocol (MATH+) with the notable additions of Fluvoxamine and anti-androgen therapy (Dutasteride/Finasteride).

Apr 14, 2021: Open Letter by U.S. Doctors: JAMA Ivermectin Study (Lopez-Medina et al) Is Fatally Flawed, TrialSiteNews reported. The abstract failed to mention that much larger benefits are seen for serious outcomes, including the original primary outcome, and that the reason for not reaching statistical signficance is the low number of events in a low risk population where most recover quickly without treatment (ivmmeta.com).

Apr 9, 2021: FLCCC (Front Line Critical Care Alliance) statement on Washington Post article.

Apr 1, 2021: WHO reaches ivermectin recommendation without a vote, TrialSiteNews reported.

Mar 31, 2021: FLCCC (Front Line Critical Care Alliance) statement on WHO's Ivermectin guide.

Mar 30, 2021: Argentina Ministry of Health Clinical Trial: Ivermectin Shows Benefit Treating Outpatients with Mild COVID-19; TrialSiteNews reported.

Mar 10, 2021: Dr. Satoshi ┼îmura, co-author of the newly published paper, “Global trends in clinical studies of ivermectin in COVID-19” was one of the four researchers from Kitasato University in Tokyo, Japan who received the Nobel Prize in Physiology or Medicine in 2015 for their discovery of ivermectin. 

“When the effectiveness of ivermectin for the COVID-19 pandemic is confirmed with the cooperation of researchers around the world and its clinical use is achieved on a global scale, it could prove to be of great benefit to humanity. It may even turn out to be comparable to the benefits achieved from the discovery of penicillin—said to be one of the greatest discoveries of the twentieth century.”—From Global trends in clinical studies of ivermectin in COVID-19, published in the Japanese Journal of Antibiotics, March, 2021.

Mar 5, 2021: [Europe] Ivermectin is now approved for COVID-19 use in 2 European countries: Czech Republic and Slovakia.

Feb 25, 2021: Drug used to treat lice and scabies drug could cut Covid deaths by up to 75%, research suggests, DailyMail reported (more than 16,000 shares).

Feb 25, 2021: Scabies and head lice drug could be 'global solution to the pandemic' says study; Mirror UK reported.

Jan 19, 2021: A pilot study published in the Lancet on January 19, 2021 showed some promising results but the authors concluded that the study warrants further exploration under larger trials with clinical outcomes in patients with risk factors or more severe disease.

Jan 18, 2021: Updated version of Frequently Asked Questions on Ivermectin in COVID-19 by the FLCCC.

Jan 16, 2021: Apparently, a judge just ordered the Millard Fillmore Suburban Hospital to allow an 80-year old woman to be treated with Ivermectin. According to the family and attorney, the treatment saved the life of Judith Smentkiewicz. Apparently, a doctor ordered the drug off-label in the intensive care unit (ICU), and as she improved, more than likely due to the drug, she was moved to another unit, and the doctor there stepped in and disallowed the use of the drug. Family members immediately involved lawyers and legal action to resume treatment. The New York Supreme Court Judge Henry J. Nowak aligned with the family; TrialSiteNews reported.

Jan 14, 2021: The National Institutes (NIH) has issued a new statement on the use of the anti-parasitic drug ivermectin for the treatment of COVID-19. Previously, it recommended against this treatment, but now states that its Panel “has determined that there are insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19.”

Jan 13, 2021: The BIRD meeting was convened by Dr. Tess Lawrie in order to present the findings from her rapid systematic review and meta-analysis of studies on the use of ivermectin to prevent and treat COVID-19. Dr. Lawrie presented evidence in the form of a DECIDE evidence-to-decision framework, a format used by the World Health Organization for the development of guidelines and recommendations in medical practice. Twenty experts from around the world and the UK attended the meeting, including 13 clinicians, and seven representatives from the public.

Related Ivermectin and COVID-19 Publications:

  • Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 by Kory et al., published on American Journal of Therapeutics.
  • Dr. Satoshi ┼îmura, co-author of the newly published paper, “Global trends in clinical studies of ivermectin in COVID-19” was one of the four researchers from Kitasato University in Tokyo, Japan who received the Nobel Prize in Physiology or Medicine in 2015 for their discovery of ivermectin. Global trends in clinical studies of ivermectin in COVID-19, published in the Japanese Journal of Antibiotics, March, 2021.
  • A multi-centre randomised controlled study in Egypt (Elgazzar, Research Square) reported that the death rate was significantly lower in Ivermectin treated patients group (severe patients) vs non-Ivermectin group (2% vs 20%). 1,300 patients were included in this randomized controlled trial. 
  • This randomized controlled trial out of Iran (Hashim, pre-print) used Ivermectin and Doxycycline in mild, moderate, and severe hospitalized COVID-19 patients. No patients in the mild and moderate COVID-19 category died and 18% of the severe patients perished taking this medication combo. In the control group, no mild-moderate patients died, but 27% of the severe COVID patients died. The patients who also got Ivermectin had a shorter recovery.
  • A randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical trial at five hospitals (Iran) and 180 patients with mild to severe disease (Niaee, ResearchSquare, Nov 2020). Ivermectin as an adjunct reduced the rate of mortality, the duration of low oxygen saturation, and the duration of hospitalization.
  • The ICON study in US, published in Chest, Oct 2020 reported that Ivermectin treatment was associated with lower death rate vs Control (13.3% vs 24.5%) during treatment of COVID-19, especially in patients with severe pulmonary involvement.
  • A double-blinded randomised controlled study in Bangladesh (Mahmud et al) reported that the death rate was 0% (0/183) in the Ivermectin arm vs 1.67% (3/180) in the control arm in mild to moderate COVID-19 patients.
  • The IDEA (Ivermectin, Dexamethasone, Enoxaparin and Aspirin) study from Argentina reported 1 death out of 167 patients studied. The patient that died was a severe COVID-19 patient that required ventilator support.
  • The pre-AndroCoV trial from Brazil reported that early detection of COVID-19 followed by a pharmaceutical approach with different drug combinations (Azithromycin, Hydroxychloroquine, Nitazonide, Ivermectin) yielded irrefutable differences compared to non-treated controls in terms of clinical outcomes, ethically disallowing placebo-control randomized clinical trials in the early stage of COVID-19 due to the marked improvements.
  • A retrospective study out of Bangladesh (Khan, Archivos de Bronconeumologia 2020). This retrospective study enrolled a total of 325 from April to June 2020. 248 adult COVID-19 patients were looked at in two groups, 115 received ivermectin plus standard care (SC), while 133 received only standard care (SC). This study showed that Ivermectin was efficient at rapidly clearing SARS-CoV-2 from nasal swabs (median 4 days). This was much shorter than in the COVID-19 patients receiving only SC (15 days) or receiving a combination of three antiviral drugs (7–12 days). In addition, fewer Ivermectin patients developed respiratory distress leading to ICU admission. In fact, with Ivermectin, there was a quick hospital discharge (median 9 days) in 114 out of 115 patients; the one remaining patient had been admitted with advanced disease.

Ivermectin for COVID-19: Real-time meta analysis

For an up-to-date overview of all published studies on ivermectin in the treatment and prevention of COVID-19 we recommend visiting c19ivermectin.com; in addition, a meta-analysis of all studies can be found at ivmeta.com (constantly updated). For adoption and regulatory status of ivermectin globally, check out ivmstatus.com.

Notes: 
  • Ivermectin has a number of potentially serious drug-drug interactions. Please check for potential drug interaction at Ivermectin Drug Interactions - Drugs.com. The most important drug interactions occur with cyclosporin, tacrolimus, anti-retroviral drugs, and certain anti-fungal drugs. 
  • Quercetin and ivermectin interactions? According to Drugs.com: "No interactions were found between ivermectin and Quercetin. This does not necessarily mean no interactions exist. Always consult your healthcare provider."
  • Ivermectin is also lipophilic and therefore, bioavailability is maximised on a full stomach; or best to be taken with meal.

Hydroxychloroquine and COVID-19

Hydroxychloroquine, a less toxic derivative of Chloroquine is a widely used medication by people with lupus or arthritis. It was first approved in the 1950s. 

Hydroxychloroquine (HCQ) is not effective when used very late with high dosages over a long period (RECOVERY/SOLIDARITY), effectiveness improves with earlier usage and improved dosing. Early treatment consistently shows positive effects. Negative evaluations typically ignore treatment time, often focusing on a subset of late stage studies.

As of June, 2021 there have been 29 studies of Hydroxychloroquine for early treatment – all with zero negative results for the most serious outcome reported. The average risk reduction for the most serious outcome reported in these trials was 65%. Here’s a chart from c19hcq.com that shows this: 



According to Steve Kirsch (published on TrialSiteNews):

Skeptics might argue the reason all the studies are positive is that journals are more likely to publish positive results than negative results. But in fact, there is a good argument that the bias is the reverse for HCQ, where negative studies are more likely to be published than positive studies. But in this case, those arguments don’t matter as the skeptics can’t point to a negative early treatment trial that has not been published so the debate is moot.

Now, let’s talk safety. HCQ is on the WHO list of essential medicines, i.e., one of the safest and most effective drugs in a health system

Lupus patients are put on HCQ and remain on the drug for life. The drug was FDA-approved more than 65 years ago. In 2016, it was the 135th most-prescribed medication in the United States, with more than 4 million prescriptions. Dose escalation studies in lupus patients and in rheumatoid arthritis patients established that 800 mg per day for life and 1,200 mg per day for 6 weeks are extremely well-tolerated.

The WHO says HCQ is safe to take for autoimmune diseases or malaria. However, they admit that there is weak evidence supporting their contention that HCQ is unsafe to take for COVID. But the problem with this is 1) they admit that the certainty of the evidence is “low” to “very low” and 2) they don’t break it out by the disease phase. We are interested in early treatment, not late treatment. You can’t just lump all the studies into one analysis.

In order to see what is actually happening in early treatment patients when they take HCQ, I reached out to Brian Tyson and George Fareed, whose practice has used HCQ in treating more than 6,000 people of all ages with COVID. The risk of diarrhea and nausea/vomiting claimed by the WHO is both “very rare and very minimal.” In general, diarrhea is more likely to be caused by COVID than the drug. 

Fareed said he has had “zero cardiac issues” with any patients. They have never had any reason to drop HCQ from their treatment protocol and I don’t know of any physician in the US who has a lower rate of hospitalization for COVID than Tyson and Fareed. If the WHO is right, then how do they explain this anomaly? Tyson and Fareed certainly didn’t get lucky on 6,000 patients and the average age of their patients is 60 years old. 

So the bottom line so far is 29 studies all positive, and real-world evidence on thousands of cases is also         consistent with the studies. Our hypothesis that the drug is effective is consistent with the data. But the WHO and NIH say we should not use this drug, yet have no plausible explanation for the consistently positive data. 

Some scientists will cite the HCQ analysis published in Nature which definitively shows that HCQ is harmful. But that was a meta analysis, which heavily weighted studies of high dose HCQ given to very late stage hospitalized patients. No early treatment outpatient trials were included. The paper says “Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.” I agree! 

I’m not arguing for high dose HCQ in late-stage hospitalized patients. That’s a losing proposition. As you can clearly see, all the early treatment results are all positive (top graph) whereas if you look at all stages, that’s when the negative results occur, so it is very important to pay attention to segregating the data when doing meta-analyses.


Here’s a simple analogy as to why drug timing makes a huge difference: a small bucket of water works great if the fire is small (early stage). After the house burns down, the same bucket of water will do nothing to repair the damage, even if we increase the amount of water, and will probably further damage any remains.
  
Other scientists might reference the fact that the FDA revoked the EUA on HCQ, but the revocation was based on studies on hospitalized patientsnot outpatients. So that argument doesn’t hold water.
 
  
Finally, some people may reference the Skipper study, an outpatient HCQ early treatment trial that concluded that “hydroxychloroquine did not substantially reduce symptom severity in outpatients with early, mild COVID-19.” I know a few things about that particular study because I was one of the “private donors” who funded it. The summary means that the study was underpowered, not that the drug didn’t work. Indeed, if you look at each metric they looked at, the cohort who got the HCQ always did better. See this analysis for detailsThere is much more to this study that will come out later that will show that HCQ works even better than the 51.7% drop in hospitalization rate reported in the paper. 

In short, HCQ is both effective and safe for early treatment at dosages of 600mg per day and more. If anyone tells you otherwise, please ask them for both clinical studies and real-world evidence to back up their claim. At that point, they will say that they don’t have time to talk to you and walk away. This happens to me all the time. It’s frustrating.

Do you need a prescription for hydroxychloroquine? 

Yes, hydroxychloroquine is a prescription drug and you do need it to be prescribed to you by a doctor. 
Editor's Note on Hydroxychloroquine (HCQ): The use of HCQ is highly controversial. The best scientific evidence from randomized controlled trials suggests that HCQ has limited/no proven benefit for post exposure prophylaxis, for the early symptomatic phase and in hospitalized patients. Considering, the unique pharmacokinetics of HCQ it is unlikely that HCQ would be of benefit in patients with COVID-19 infection (it takes 5–10 days to achieve adequate plasma and lung concentrations). Finally, it should be recognized that those studies which are widely promoted to support the use of HCQ are methodologically flawed.
Source: Page 16 of FLCCC Alliance – COVID-19 Management Protocol (version May 25, 2021)

Hydroxychloroquine and COVID-19 Updates

June 9, 2021: Study shows hydroxychloroquine treatments increased coronavirus survival rate by almost three times.

Apr, 2021: Prevention study from Singapore (N=3,037) showed "Positive impact of oral hydroxychloroquine and povidone-iodine throat spray for COVID-19 prophylaxis: an open-label randomized trial."

Jan 24, 2021: Dr Vladimir Zelenko published a white paper on "Nebulized Hydroxychloroquine for COVID-19 Treatment: 80x Improvement in Breathing".

Zinc and COVID-19

Foods that are high in zinc include oysters, crab, lobster, mussels, red meat, and poultry. Cereals are often fortified with zinc. Most multivitamin and nutritional supplements contain zinc.

As of August 2021, there are more than 50 studies that have been launched to investigate the benefits of Zinc against COVID-19. You can review the status of these trials on clinicaltrials.gov.

A retrospective observational study (Carlucci P, Sep 2020) compared zinc supplementation to no zinc supplementation in hospitalized patients with COVID-19 who received hydroxychloroquine and azithromycin from March 2 to April 5, 2020. A total of 932 patients were included in this analysis; 411 patients received zinc, and 521 did not. After adjusting for the time at which zinc sulphate was added to the protocol, an increased frequency of being discharged home and reduction in mortality or transfer to hospice among patients who did not require ICU level of care remained significant. This study provides the first in vivo evidence that zinc sulphate may play a role in therapeutic management for COVID-19.

study in Spain (Gonzalez, The Lancet preprint, Oct 2020) among people hospitalised with COVID-19 found that having very low blood levels of zinc was associated with more severe disease and higher mortality rates.

Taking zinc long term is typically safe for healthy adults, as long as the daily dose is under the set upper limit of 40 mg of elemental zinc (PubMed).

Be aware that typical daily doses of zinc provided by zinc lozenges generally exceed tolerable upper limits for zinc, and for this reason, they should not be used for longer than about a week. 

Excessive doses may interfere with copper absorption, which could negatively affect your immune system as it can cause copper deficiencies, blood disorders, impair the absorption of antibiotics and potentially permanent nerve damage or loss of smell.

The ideal dose for prevention while the COVID-19 risk is high is 40-100 mg/d, a portion of which comes from zinc lozenges to spread the zinc through the tissues of the nose, mouth and throat. It should be accompanied by at least 1 mg copper from food and supplements for every 15 mg zinc.

Do take note that you should keep the dosage back to within 40 mg/d once the exposure risk is back to normal.

Zinc Sulphate is also part of Dr. Vladimir Zelenko anti-coronavirus experimental protocol. Please take note that the protocol is experimental and has not been 100% proven. Do discuss with your doctor before taking the medication as per the protocol. You can check out his publication in the International Journal of Antimicrobial Agents

Based on the statement released on 2 October by the U.S. president’s physician, zinc is also part of the treatment given to the US President. According to the president's physician, "Trump has been taking zinc, vitamin D, famotidine, melatonin and a daily aspirin.”

Editor's note: Hydroxychloroquine is a zinc ionophore. If increased intracellular Zn ion concentration is required to disrupt viral replication, perhaps using multiple zinc ionophores would increase that concentration thus decreasing viral replication further. Other OTC (over the counter) zinc ionophores include quercetin (QCT) and epigallocatechin-gallate (EGCG – green tea extract).


Ivermectin vs Hydroxychloroquine vs Zinc

Clinical evidence to date has reported promising results (see above) for Ivermectin in prevention, early treatment as well as late treatment for COVID-19. While both Ivermectin and Hydroxychloroquine might be useful for early treatment, Ivermectin has a broader potential benefit i.e. prevention, early treatment as well as late treatment / hospital treatment.

Hydroxychloroquine and Quercetin are both zinc ionophores i.e. they transport zinc into the cells. A study (Frontera, Oct 2020) published in the NIH Preprint database, showed that zinc with hydroxychloroquine was associated with increased rates of discharge home and a 24% reduced risk of in-hospital death rate among COVID-19 patients, while neither zinc alone nor hydroxychloroquine alone reduced death rate.

Although ivermectin and hydroxychloroquine are relatively safe drugs, they are still synthetic chemicals that can have side effects. Quercetin and Vitamin D, C and zinc are nutrients that your body require for optimal health. Nutrients are safer alternatives especially if your risk is low e.g. age below 50 and no other chronic illness. Discuss with your doctor on the benefit vs risk for each treatment. If you are on multiple medications, be aware of supplement-drug interactions that might enhance the possibilities of adverse effects.

Ivermectin, Zinc and FLCCC I-MASK+ Protocol

For updated prevention and early outpatient protocol  for COVID-19 positive, please check out FLCCC I-MASK+ protocol.


Key Takeaways

Nutrients are safer alternatives especially if your risk is low e.g. age below 50 and no other chronic illness. Discuss with your doctor on the benefit vs risk for each treatment. If you are on multiple medications, be aware of supplement-drug interactions that might enhance the possibilities of adverse effects.

The important key takeaway is that you should never attempt to self medicate without the guidance of a licensed medical provider. If you are not a medical doctor, you are likely to find the above information overwhelming. The aim of this article is to empower you with a better understanding of the options available and to discuss the options with your medical doctor.

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Supplements you can purchase from Amazon for COVID-19 'prevention' based on the FLCCC prevention protocol >
    • Quercetin: 1 capsule daily (Amazon)
    • Zinc, Vitamin D3 and Vitamin C: 1 lozenge daily (Amazon)
    • Melatonin: 1 tablet before bedtime (causes drowsiness) (Amazon)
    Related item: Fingertip Pulse Oximeter (Amazon)

    Be aware that most supplements have two categories of dosages: i.e. 
    1. treatment (therapeutic) dosages are normally higher than the RDA dosages and 
    2. 'maintenance' or 'preventive' dosages that are normally based on the recommended daily value.
    You should ideally supplement your micro-nutrients from healthy and wholesome foods, fruits and vegetables.

    Disclaimer: Always see your doctor before taking these supplements. Be aware that most of the 'treatment' dosages are above the recommended dietary allowance (RDA) and therefore such dosages should not be maintained on a long term basis. 

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