Hydroxychloroquine and Ivermectin Combined: A synergistic combination for COVID-19?
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:
- Prevention or Prophylaxis e.g. vaccine
- Early out-patient treatment
- Hospital treatment
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| McCullough et al. Reviews in Cardiovascular Medicine, 2020 |
All these treatments come with various technologies and 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.
The medical community themselves are battling over ivermectin and hydroxychloroquine on whether they should be used to treat and prevent COVID-19. On one side are experts telling you that more research is needed before the treatment can be fully authorised and confirmed. On the other, are experts telling you that the potential benefits outweigh the risk and a 'wait and do nothing' position is not acceptable. Confused?
How do you deal with different expert groups dishing out conflicting guides? A common issue is that certain groups have pre-defined narrative that they would like to support. Therefore, only studies that support that pre-defined narrative are picked and cited as references. This is what we call as 'cherry-picking'. Cherry picking will naturally lead to a 'biased' and 'manipulated' decision. In order to get the truth out, scientific information needs to be analysed in a comprehensive, updated and non-biased manner.
In this article, we would like to cover 2 popular treatments i.e. Ivermectin and Hydroxychloroquine and the possible synergistic action if given together.
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.
www.onedaymd.com
A Cochrane-standard (=highest) 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.
June 7, 2021: Epidemiologic Analyses on Ivermectin and COVID-19.
Results of Ivermectin's success in treating COVID-19 outbreaks in India, Mexico, Peru, Paraquay, Argentina, Brazil and Slovakia.
June 1, 2021: The Drug that Obliterates 97% of New Delhi Cases by Justus R. Hope, MD
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).
- 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 Ōmura, 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.
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.
Ivermectin is also lipophilic and therefore, bioavailability is maximised on a full stomach; or best to be taken with meal.
Ivermectin for COVID-19: Real-time meta analysis
Check out the evidence tracking on Ivermectin versus COVID-19 from Ivmmeta.com (constantly updated).
Related: List of Doctors that will prescribe Ivermectin
Hydroxychloroquine and COVID-19
Historically, hydroxychloroquine was discovered during efforts to synthesise alternatives to quinine as anti-malarials. Is quinine similar to hydroxychloroquine? Hydroxychloroquine and quinine are both anti-malarial drugs. However, hydroxychloroquine is not the same as quinine as hydroxychloroquine is a synthetic drug while quinine is a naturally occurring compound found in cinchona bark.
Quinine, was first recognized as a potent antimalarial agent hundreds of years ago. Since then, the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in addition to malaria.
Hydroxychloroquine, developed in the 1950s from chloroquine, an old anti-malarial drug, is registered in around 60 countries under trade names such as Plaquenil, Quensyl and Plaquinol.
Hydroxychloroquine, a less toxic derivative of Chloroquine is a widely used medication by people with lupus or arthritis.
As of August, 2021 there have been 30 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.
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 patients, not 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 details. There 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.
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.
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)
Source: Page 16 of FLCCC Alliance – COVID-19 Management Protocol (version May 25, 2021)
That said, a group of Australian researchers reported on the suitability of nebulized hydroxychloroquine for treatment of COVID-19 (Pharmaceutics, Aug 2021). Dr Zelenko has also developed a white paper on nebulised hydroxychloroquine as a promising alternative to achieve adequate lung concentrations.
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".
Ivermectin and Hydroxychloroquine
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.
Theoretically, hydroxychloroquine (HCQ) would behave as a first-level barrier by inhibiting the entry of the virus into the host cell, while ivermectin could reduce viral replication if the virus did get in, strengthening HCQ antiviral effects.
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.
The dosages as per Zelenko protocol:
- Hydroxychloroquine (HCQ) 200mg 2 times a day for 5-7 days
- Ivermectin 0.4 mg/kg/day for 5-7 days
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.
Summary
The most 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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