Hydroxychloroquine, Azithromycin, Zinc and Zelenko Protocol Review (December 2021)

In 2020, Hydroxychloroquine (HCQ) was touted as the most controversial drug in the world. Around the same time, the Zelenko protocol was in the news as well. It has been more than a year since the controversy started. Is HCQ still relevant? Is there any new evidence to suggest who has been right and wrong all along? In this article, we review some of the latest evidence related to this controversial drug, the associated Zelenko protocol and other related medications.

The Zelenko Covid-19 Protocols was developed by Dr Vladimir Zelenko. The protocol has as its centerpiece, but not exclusive piece, the combined use of Hydroxychloroquine (HCQ) and Zinc as a means by which a person can both help to prevent or mitigate the contraction of COVID-19, or can actually treat the disease once it has been diagnosed. Dr. Zelenko’s main hypothesis was based on the data showing that early intervention and treatment of high-risk patients with COVID-19 results in significantly few hospitalizations and deaths. 

Is there evidence that the protocol is effective, peer-reviewed and published? Yes. This treatment regimen involving zinc, low-dose hydroxychloroquine, and azithromycin; apparently known as, “The Zelenko Protocol.” has been published in the International Journal of Antimicrobial Agents.

Who makes hydroxychloroquine? Hydroxychloroquine (generic or scientific name) comes in various brand names. Plaquenil is a brand name of hydroxychloroquine from Sanofi. 

Hydroxychloroquine, Zinc and Azithromycin are among the handful of COVID-19 treatments that are being studied as potential candidates that might influence the outcome in the prevention and management of COVID-19. 

In terms of early drug treatment for patients who are quarantining at home, Dr Peter McCullough and Dr Harvey Risch recommend (The American Journal of Medicine) using a combination of HCQ and zinc lozenges, along with several other drugs (depending on your symptoms).

HCQ is a zinc ionophore, meaning it shuttles zinc into the cell, and there’s compelling evidence to suggest the primary benefit of the HCQ protocol actually comes from the zinc, which effectively inhibits viral replication.

Hydroxychloroquine (HCQ) is an antimalarial/anti-inflammatory drug that impairs endosomal transfer of virions within human cells. HCQ is also a zinc ionophore that conveys zinc intracellularly to block the SARS-CoV-2 RNA-dependent RNA polymerase, which is the core enzyme of the virus replication.

The currently completed retrospective studies and randomized trials have generally shown these findings:

1.when started late in the hospital course and for short durations of time, antimalarials appear to be ineffective

2.when started earlier in the hospital course, for progressively longer durations and in outpatients, antimalarials may reduce the progression of disease, prevent hospitalization, and are associated with reduced mortality …

A typical HCQ regimen is 200 mg bid for 5 days and extended to 30 days for continued symptoms. A minimal sufficient dose of HCQ should be used, because in excessive doses the drug can interfere with early immune response to the virus ...

Zinc is a known inhibitor of coronavirus replication … This readily available nontoxic therapy could be deployed at the first signs of COVID-19. Zinc lozenges can be administered 5 times a day for up to 5 days and extended if needed if symptoms persist.

The amount of elemental zinc lozenges is <25% of that in a single 220-mg zinc sulfate daily tablet. This dose of zinc sulfate has been effectively used in combination with antimalarials in early treatment of high-risk outpatients with COVID-19.”

It’s worth noting that in areas where hydroxychloroquine is hard to get a hold of, the nutritional supplement quercetin may be a useful substitute, as its primary mechanism of action is identical to that of the drug. It also has antiviral activity of its own.

Zinc Is a Crucial Key

While much attention is placed on HCQ, it in and of itself is not the answer. Zinc is. Both HCQ and quercetin are zinc ionophores, meaning they shuttle zinc into the cell, (Medical Hypotheses) and there’s compelling evidence to suggest the primary benefit of the HCQ protocol actually comes from the zinc, which effectively inhibits viral replication.

If given early, zinc along with a zinc ionophore should, at least theoretically, help lower the viral load and prevent the immune system from becoming overloaded. The problem is that zinc does not readily enter cells, which is why a zinc ionophore is needed.

Evidence of this was presented in a September 2020 study in the Journal of Medical Microbiology. In it, they compared outcomes in hospitalized COVID-19 patients treated with one of three regimens: HCQ alone, Azithromycin alone, or a triplet regimen of hydroxychloroquine, azithromycin and zinc.

While the addition of zinc had no impact on the length of hospitalization, ICU duration or duration of ventilation, univariate analyses showed it did:
  • Increase hospital discharge frequency
  • Decrease the need for ventilation
  • Decrease ICU admission rates
  • Decrease the rate of transfer to hospice for patients who were never admitted to the ICU
  • Decrease mortality
Emerging and updated evidence of Hydroxychloroquine and COVID-19

Is HCQ still relevant?

Emerging evidence has shown 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 December 2021, there have been more than 30 studies of Hydroxychloroquine for early treatment – with an overall average improvement of 64%. 

Here’s also a chart from c19early.com that shows that hydroxychloroquine is better than ivermectin: 

The overall improvement for hydroxychloroquine is better than ivermectin (for early treatment); 75% vs 52% in terms of death rate. A crucial point to note here is that hydroxychloroquine needs to be given 'early'.

The difference in terms of effectiveness for hydroxychloroquine is distinctly different when given early vs late treatment (75% vs 19%), as shown in the summary chart below:

The evidence tracking on Hydroxychloroquine versus COVID-19 is available at c19hcq.com (constantly updated).

Azithromycin for COVID-19

Azithromycin is a widely prescribed generic antibiotic. While it's mainly used to fight bacteria, not viruses, there is some research suggesting the drug has antiviral properties.

Who makes azitromycin? Azithromycin (scientific name) comes in various brand names as well. Zithromax (from Pfizer), Zithromax Tri-Pak (3 days), Zithromax Z-Pak (5 days), Zmax are the brand names available for azithromycin in the US. Generic azithromycin can cost approximately $37 without insurance, while a branded azithromycin such as Zithromax can cost upwards of $200. 

As of December 2021, there are more than 120 studies that have been launched to investigate the benefits of Azithromycin against COVID-19. You can review the status of these trials on clinicaltrials.gov. Several trials are testing azithromycin in combination with hydroxychloroquine.

In a retrospective cohort study published in the Lancet, it is found that 50% of COVID-19 patients who died had bacterial co-infections in pneumonia. Bacterial coinfections have also been shown to increase the risk of mortality for COVID-19 patients [Chen et al].

One potential concern is serious heart side effects. Both drugs can cause abnormal changes in the rhythm of the heart. These can be fatal, particularly for susceptible patients who already have heart problems. Many studies are using EKG tests to closely monitors patients receiving this treatment combination.

While QT-prolonging medication use has been associated with increased risk of death, this risk may be smaller than the potential benefit from treatment of COVID-19 for some patients (American College of Cardiology).

Zelenko Protocol - Treatment Plan for Patients with Covid-19 symptoms

Fundamental Principles (Dr Zelenko Protocol When to Start)

Treat patients based on clinical suspicion as soon as possible, preferably within the first 5 days of symptoms. Perform PCR testing, but do not withhold treatment pending results.

Patient Categories

Low risk patient - Younger than 45, no co-morbidities, and clinically stable
High risk patient - Older than 45, younger than 45 with co-morbidities, or clinically unstable

Treatment Options

Low risk patients - over the counter options:

Supportive care with fluids, fever control, and rest

1. Zinc (Elemental) 50mg 1 time a day for 7 days (PubMed) (Amazon)

2. Quercetin 500mg 2 times a day for 7 days (PubMed) (Amazon

3. Vitamin C 1000mg 1 time a day for 7 days (Amazon)

4. Vitamin D3 5000 IU 1 time a day for 7 days (Amazon)

Alternative for Quercetin: Epigallocatechin-gallate (EGCG) 400mg 1 time a day for 7 days (J. Agric. Food Chem) (Amazon)

Moderate / High risk patients
  1. Zinc (Elemental) 50-100mg once a day for 7 days
  2. Vitamin C 1000mg 1 time a day for 7 days
  3. Vitamin D3 10,000 iu once a day for 7 days or 50,000 iu once a day for 1-2 days
  4. Azithromycin (Z Pack) 500mg 1 time a day for 5 days (Clin Drug Investig) OR Doxycycline 100mg 2 times a day for 7 days
  5. Hydroxychloroquine (HCQ) 200mg 2 times a day for 5-7 days (ScienceDirect)

Ivermectin 0.4-0.5mg/kg/day for 5-7 days (ivmmeta.com). (Find a Doctor)

Hydroxychloroquine and ivermectin combined? Either or both HCQ and IVM can be used, and if one only, the second agent may be added after about 2 days of treatment if obvious recovery has not yet been observed etc.

If HCQ is not available, Quercetin 500mg 3 times a day for 7 days OR
EGCG 400mg 2 times a day for 7 days

Both protocols can be viewed from his website.

Other treatment options 
  • Dexamethasone 6-12mg 1 time a day for 7 days OR Prednisone 20mg twice a day for 7 days, taper as needed (not suitable during viral phase)
  • Budesonide 1mg/2cc solution via nebulizer twice a day for 7 days (not suitable during viral phase)
  • Blood thinners (i.e. Lovenox, Eliquis, Xarelto, Pradaxa, Aspirin) (Amazon)
  • Colchicine 0.6mg 2-3 times a day for 5-7 days (MedRxiv 2021)
  • Monoclonal antibodies
  • Home IV fluids and oxygen
  • Curcumin: 500 mg twice a day (Ref)  (Amazon)
  • 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).
  • If you can’t get fluvoxamine (Luvox), using 30mg once a day of fluoxetine (Prozac) is equally effective (equivalent to 50mg twice a day of fluvoxamine).
  • Pulse Oximeter: Monitoring your oxygen saturation with a pulse oximeter and to go to the hospital if you get below 94%. (Amazon)
  • Mouthwash: 3 x daily – gargle (do not swallow) antiseptic mouthwash with cetylpyridinium chloride (e.g. Crest, Scope mouthwash™), ListerineTM with essential oils, or povidone/iodine 1 % solution as alternative (Betadine® Antiseptic Sore Throat Gargle™). (Ref)
  • Nasal Spray: Xlear Nasal Spray with Xylitol (Ref) (Amazon)
  • Aspirin: 325 mg/day unless contraindicated. (Amazon) (not suitable during viral phase)
  • Bromhexine 8 mg three times a day (Ref) (Lazada Malaysia*)
* Not available on Amazon

  • Precautionary Note: 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. 
  • Due to the possible drug interaction between quercetin and ivermectin (may increase ivermectin levels), these drugs should not be taken simultaneously (i.e. should be staggered morning and night). 
  • Ivermectin is also lipophilic and therefore, bioavailability is maximised on a full stomach; or best to be taken with meal.
  • Vitamin D3 RDA (Recommended Daily Allowance) is 800–1000 IU/day. The safe upper-dose daily limit is likely < 4000 IU/day. Be aware that most of the 'treatment' dosages for nutrients are above the recommended dietary allowance (RDA) and therefore such dosages should not be maintained on a long term basis. 
  • Vitamin D deficiency has been associated with an increased risk of acquiring COVID-19 and from dying from the disease. Vitamin D supplementation may therefore prove to be an effective and cheap intervention to lessen the impact of this disease, particularly in vulnerable populations, i.e. the elderly and obese. 
  • When Is the Best Time to Take Vitamin D? Morning or Night? It is possible that increasing vitamin D levels during the day may act, in part, as a signal that suppresses melatonin generation (source). Therefore, it's better to take vitamin D (with meal) during the day and melatonin to be taken just before bedtime.
  • It is likely that vitamin C and quercetin have synergistic prophylactic benefit. Quercetin should be used with caution in patients with hypothyroidism and TSH levels should be monitored.
  • Please consult with a qualified doctor and only use human ivermectin. Ivermectin for animals contain excipients (binding and storage compounds such as polyethylene glycol (PEG)) that are known to cause liver failure in high doses.  
  • Although ivermectin and hydroxychloroquine (HCQ) are relatively safe drugs, they are still synthetic chemicals that can have side effects. Vitamin D, C, Zinc and Quercetin 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.
  • Some 200 peer-reviewed studies (C19Study.com) by government and independent researchers deem HCQ safe and effective against Coronavirus, especially when taken prophylactically or when taken in the initial stages of illness along with zinc and azithromycin. Unfortunately, some of the RCTs that have been conducted to date used toxic doses of HCQ and/or were given very late in the disease.
  • Inorganic zinc such as zinc sulfate, is not as effective or useable by your body as chelated zinc sources. 
  • Z-Stack Supplement: In an effort to make it easier for patients, Dr Zelenko has developed an oral supplement that contains all four: vitamin C, quercetin, vitamin D3 and zinc. It’s called Z-Stack Vitamins

Early Treatment Prevents 'Long Haul' Side Effects

It's worth noting that when you treat early, your risk of developing long-term side effects, commonly referred to as "long-haulers," is virtually nil. Not a single one of Zelenko's patients who received treatment within the first five days of symptom onset went on to develop long-haul symptoms afterward.

According to Dr Zelenko:
"I had patients that were long-haulers, but they came to me after that window, and they were already advanced in the inflammatory process. At that point, the cytokine storm had already taken hold. They had developed blood clots, some of them had pulmonary infarct, or strokes actually.

Others developed ARDS or catastrophic lung damage and pneumonias, and others just are not themselves. I don't know how to describe it, but it ate away part of their souls. They're not the same people. There's depression, there's lack of energy. There's a psychological impact as well.

So, it's not that I don't deal with long-haulers, I do. But the way to prevent the long-hauler syndrome is to intervene within the first five days, with appropriate antiviral medication in high-risk patients. That is 100% successful."

Ivermectin vs Hydroxychloroquine

Clinical evidence to date has reported promising results 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.

Can hydroxychloroquine and ivermectin be used together? The 2 drugs do not seem to have a between-drug interaction. However, no in vitro or in vivo studies have been conducted on the combined effect of HCQ and ivermectin on COVID-19 infection.

That said, the Zelenko protocol recommends that both hydroxychoroquine and ivermectin can be used together, especially for high risk patients. If you have started with only one, the second agent may be added after about 2 days of treatment if obvious recovery has not yet been observed.

Quercetin is a viable stand-in, if you simply cannot get hydroxychloroquine or ivermectin. Quercetin works best when taken with vitamin C and Bromelain, as vitamin C helps activate it and bromelain helps with the absorption. Do not forget to combine it with zinc.

About the Wellness Alliance: The Wellness Alliance was formed as a working group to share information, experience and guides related to the current COVID-19 pandemic. They are a network of multi-disciplined medical professionals and senior experienced executives from corporate backgrounds within different industries who have come together, to leverage on their experience and relationships in different parts of the world and industries. Follow them on Twitter for updates.


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