Do Repurposed Treatments Provide a Viable Path to Ending the COVID-19 Pandemic?
20 September 2021
by Wilton Alston, David Bell, Shibrah Jamil, Sandi Brown, Herman Edeling

The second basic thesis is that intellectual freedom is essential to human society — freedom to obtain and distribute information, freedom for open-minded and unfearing debate and freedom from pressure by officialdom and prejudices. Such a trinity of freedom of thought is the only guarantee against an infection of people by mass myths, which, in the hands of treacherous hypocrites and demagogues, can be transformed into bloody dictatorship. Freedom of thought is the only guarantee of the feasibility of a scientific democratic approach to politics, economics and culture.

~ Andrei D. Sakharov, from “Reflections on Progress, Peaceful Coexistence and Intellectual Freedom”

Since March 2020, much of the world has been preoccupied with the response to an infectious disease pandemic referred to as COVID-19, or “Novel Coronavirus,” preceded by exposure to the SARS-CoV-2 virus. Its severity and mortality is highly so skewed towards the very old and those with identifiable risk factors that it should have been an ideal candidate for a focused protection approach, prophylaxis and early treatment to the high risk-group. Instead, the response to this pandemic has been unique, as targeted treatments have been shunned and draconian population-wide measures, including lockdowns, have been used in their place[1].

Firstly, proven safe and therapeutic candidate treatments were largely ignored, often suppressed and/or negatively portrayed in the popular press, rather than urgently investigated. It has been publicly stated that the response, “poured billions of dollars into ventilator production and new drug and vaccine development, but spent virtually nothing on research and trials using existing drugs and nutraceuticals.”[2] Secondly, and just as alarmingly, international institutions such as the World Health Organization (WHO), which had previously prioritized repurposed, off-patent drugs for low-income populations, reversed course on this strategy.

Thirdly, all hope from the early stages onward was concentrated upon the development and distribution of vaccines. While they became available sooner than almost anyone expected, this should not have come at the cost of ignoring treatment candidates.  Failure to implement early treatment has likely contributed to considerable additional preventable loss of life, compounding the loss of livelihood and collateral deaths due to lockdowns.

The willful misrepresentation of historically-safe, and widely-used drugs culminated in some of those drugs being banned from use for COVID-19 in some countries, an unprecedented approach in Western medicine. Negative, and in some cases apparently fraudulent[3] papers showing lack of benefit were passed through peer review and published in major medical journals, while trials and meta-analyses that are cited in this article and which show apparent benefit have been roundly ignored. The result has been a failure to institute early effective treatments for the disease. However, the situation can still be remedied. Quick action, as described in this paper, could not only lead to improved outcomes, but also has the potential to remove the fear of variants. This document does not constitute medical advice – it merely serves as a brief, explanatory overview with references and a convenient introduction.

Introduction and History

The four main pillars[4] of a pandemic response include:

  1. Contagion control;
  2. Prophylaxis and early home treatment;
  3. Late-stage hospital treatment; and,
  4.  Vaccination.

These steps are complementary, but the first three are normally prioritized during the early stages of an outbreak, reducing contact with the pathogen by avoiding poorly ventilated indoor places and mitigating the effects of infection. The last pillar requires specific development and becomes available later – the COVID-19 vaccines now dominate the response to the pandemic, but should be considered complementary to the first three pillars. Furthermore, it could be argued that if treatment options are sufficient, the incremental benefits of vaccination are relatively small, as immunity can safely be acquired through infection, which is almost always associated with mild illness in the young and middle-aged without specific comorbidities.

Before the COVID-19 pandemic response, there was a broad emphasis on repurposed therapies, particularly to overcome cost-barriers for low-income populations. Nothing about this approach is new. One of the advantages of using repurposed therapies is leveraging well-established safety data, in addition to the low cost of off-patent products. Understanding the pathophysiology of COVID-19 has enabled the development of safe COVID-19 treatment protocols. There is an abundance of scientific evidence for home-based treatment of COVID-19 in the distinctly different phases of the disease, using repurposed therapies. Dedicated medical scientists have already published a wide array of COVID-19 prevention and treatment recommendations. Some of the most widely-used protocols and regimens are discussed here. It is worth noting that the fact that a drug with a long history of safety has not gone through an exhaustive trial specific to COVID-19 should not preclude its use, nor should it be unethical to prescribe said drug in an emergency situation. In fact, it is exactly because these treatments are low-cost and have an established safety profile that using them—even for a small actual benefit—is worthy of consideration.

Categories of existing drugs for fighting COVID-19 include:

  • Therapies with Antiviral Properties, such as Zinc Lozenges and Zinc Sulfate,
  • Antimalarials, such as hydroxychloriquine (HCQ) and Primaquine,
  • Antimicrobials, such as Azithromycin and Clindamycin;
  • Immunomodulators, such as Dexamethasone, Prednisone or nebulized Budesonide (Corticosteroids), Anti-inflammatory agents, such as Colchicine;
  • Antihistamines, such as Promethazine and Cimetidine
  • Antiplatelet Agents and Antithrombotics, such as Aspirin, Enoxaparin or Riveroxaban; and finally,
  • Delivery of Therapeutic Oxygen[5].

Some candidate therapeutics fall into a number of these categories. Ivermectin (IVM), which has been approved for the treatment of parasites since 1997[6], is an example, having potential antiviral and immune-modulatory properties. It has been the subject of multiple meta-analyses, with systematic reviews showing positive results[7]. Each of these approaches fits the historic and traditional WHO emphasis of deploying  currently available, low-cost, effective therapies, particularly to low-income populations. Furthermore, given their history and availability, they have the advantage of being readily available in an emergency when a new pathogen outbreak demands a rapid response. Finally, given the relationship between immune response and overall patient health, there exist a variety of nutraceuticals, such as Vitamin D, that enhance immune response without generating any side effects.

Drug and Treatment Examples

Below are examples of drugs with existing use histories and the rationale for their application against SARS-CoV-2, listed in the categories identified above. Early, broad, and well-monitored use of these safe drugs could have provided valuable definitive data on their impact without endangering patients.

COMBINATION ANTIVIRAL THERAPIES[8]

Zinc Lozenges and Zinc Sulfate Zinc

Zinc is a known inhibitor of coronavirus replication. Clinical trials of zinc lozenges in the common cold have demonstrated modest reductions in the duration and/or severity of symptoms.

Antimalarials and Antibiotics

  1. Hydroxychloroquine, (HCQ) is an antimalarial/anti-inflammatory drug that impairs endosomal transfer of virions within human cells. HCQ is also a zinc ionophore. HCQ has a long history, having been recommended by the WHO as a first-line therapy for vivax malaria. It has been deployed in tens of millions of doses, is considered highly safe, and has historically been routinely dispensed by low-trained health workers. As a mitigation measure for COVID-19, studies indicated that it is safe in short-term prophylaxis. As an aside, examples of the places where HCQ is not generally used, either widely or as a prophylaxis, include the United States and Great Britain.[9]
  2. Azithromycin is a commonly used macrolide antibiotic that has antiviral properties mainly attributed to reduced endosomal transfer of virions, as well as established anti-inflammatory effects. Initially It was commonly used in COVID-19 studies in combination with HCQ based on French reports[10] demonstrating a marked reduction in the duration of viral shedding, fewer hospitalizations and reduced mortality.
  3. Chloroquine, an antiviral, was shown in 2005 to act as “a potent inhibitor of SARS infection and spread.”[11] In cell culture models, it is effective in preventing the spread of SARS-CoV. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS-CoV infection. In addition, the indirect immunofluorescence assay described in the cited paper represents a simple and rapid method for screening SARS-CoV antiviral compounds.

IMMUNOMODULATORS[12]

Dexamethasone

In COVID-19, some of the early respiratory symptoms include cough and difficulty breathing, attributable to inflammation and cytokine activation. The administration of corticosteroids during the appropriate phase of the disease is a rational intervention for COVID-19 patients with these symptoms, as they would be for other inflammatory lung disorders. The RECOVERY trial[13] randomized 6425 hospitalized patients with COVID-19 in a 2:1 ratio to dexamethasone 6 mg po/IV daily for up to 10 days and found dexamethasone reduced mortality.

Colchicine

Colchicine is a non-steroidal anti-mitotic drug that blocks metaphase by binding to the ends of microtubules to prevent the elongation of the microtubule polymer. This agent has proven useful in gout and idiopathic recurrent pericarditis. The GRECCO-19 randomized open-label trial in 105 hospitalized patients with COVID-19 found that colchicine was associated with a reduction in D-dimer levels and improved clinical outcomes.

Budesonide[14]

Budesonide is an inhaled glucocorticoid drug that is a simple, safe, well-studied, inexpensive, and widely-available treatment. This agent, administered for a short duration via a nebulizer or inhaled directly, might be an effective treatment for early COVID-19 in adults. This is based on the encouraging results of a trial known as STOIC, a randomized, open-label, parallel-group, phase 2 clinical trial done in the community in Oxfordshire, UK.

IVERMECTIN[15]

Ivermectin (IVM), as alluded to above, has been a standard recommendation by the WHO as a mass treatment for river blindness, severe scabies, and has been considered for malaria (it kills biting mosquitoes). In addition to studies conducted in humans[16], several of which are cited herein, IVM also has extensive safety data in animals, given its widespread veterinary uses. It is a known anti-viral and anti-inflammatory. Meta-analyses[17] based on 18 randomized controlled treatment trials of IVM in COVID-19 have found large, statistically significant reductions in mortality, time-to-clinical-recovery, and time-to-viral-clearance. Furthermore, results from numerous controlled prophylaxis trials [IVM taken preventatively prior to possible infection] report significantly reduced risks of contracting COVID-19 with regular use. Finally, examples of IVM distribution campaigns[18] associated with rapid population-wide decreases in morbidity and mortality indicate that an oral treatment,  effective in all phases of COVID-19, has been identified.

ANTICOAGULANTS OR ANTITHROMBOTICS

Ambulatory patients can also be treated with subcutaneous low-molecular weight heparin, or with oral novel anticoagulant drugs (apixaban, rivaroxaban, edoxaban, dabigatran) in dosing schemes similar to those used in outpatient thromboprophylaxis. In a retrospective study[19] of 2773 COVID-19 inpatients, 28% received anticoagulant therapy within 2 days of admission, and despite being used in more severe cases, anticoagulant administration was associated with a reduction in mortality, HR = 0.86 per day of therapy, 95% CI: 0.82-0.89; P < 0.001. Contemporary use of in-hospital anticoagulants has remained in ~30% of cases.

NUTRACEUTICALS, SUCH AS VITAMIN D[20]

Vitamin D deficiency has been associated with increased COVID-19 mortality and is commonly confounded by increasing age, obesity, diabetes, darker skin tones and lack of fitness. With good rationale, one small, randomized trial of vitamin D3 supplementation found reduced mortality in patients with COVID-19. According to the cited paper, the suggested dose is 5000 IU of vitamin D3 per day.

Analysis of WHO Recommendations

The handling of any pandemic calls for applying multiple approaches, particularly those with a track record, versus reliance on a single intervention, such as a vaccine. Sick people are normally treated early to avoid deterioration – the COVID-19 management approach has been extraordinary in many countries for not doing this – vulnerable people with a positive test were sent home with no specific management and told to return only if unable to breathe normally.

It seems clear that in the media there has been an over-emphasis of the possible side-effects of extremely safe, well-established drugs contrasted with a corresponding under-emphasis of safety issues apparent with the new vaccines. For completeness, and balance, below are the current WHO guidance statements on two of the re-purposed treatments noted above: Ivermectin and hydroxychloroquine. Thereafter, a brief discussion of counter points for each WHO position is provided.

IVERMECTIN
(published 31 March 2021)

The recommendation addressing Ivermectin was informed by results from a systematic review and network meta-analysis that pooled data from 16 RCTs with 2407 participants. Of the included trials, 75% examined patients with non-severe disease and 25% included both severe and non-severe patients. None of the included RCTs enrolled children under 15 years old or pregnant women. Given this, the applicability of this recommendation to children is uncertain, though there is no rationale to suggest they would respond differently.

We recommend not to use Ivermectin in patients with covid-19 except in the context of a clinical trial, regardless of disease severity or duration of symptoms.

Balance of benefit and harm—For most important outcomes, the guideline panel considered the evidence to be of very low certainty. A combination of serious risk of bias and very serious imprecision contributed to very low certainty of evidence for mortality, despite a point estimate and confidence interval that seem to suggest benefit with Ivermectin. The picture was similar for other important outcomes, including mechanical ventilation, hospital admission, duration of hospitalization, and viral clearance. The very low certainty of evidence was a critical factor in the recommendation.

Ivermectin is a very cheap drug. As noted above, its track record is long. The apparent priority for fighting COVID-19 would seem to exceed that for fighting river blindness, yet Ivermectin is not recommended for COVID-19, while continuing to be a key component in other mass-use applications.  Furthermore, the WHO’s suggestion that a clinical trial is needed before Ivermectin can be used does not seem to balance with the otherwise urgent need for treatments to combat COVID-19. Either the WHO is disinterested in applying readily available approaches, or a conflict of interest underpins this recommendation against Ivermectin.

HYDROXYCHLOROQUINE
(published 17 December 2020)

The recommendation addressing hydroxychloroquine was informed by results from the same systematic review and network meta-analysis that pooled data from 30 RCTs with 10 921 participants. Of note, none of the included RCTs enrolled children or adolescents under the age of 19 years. Given this, the applicability of this recommendation to children is currently uncertain.

We recommend against using Hydroxychloroquine or chloroquine in addition to usual care for the treatment of patients with covid-19, regardless of disease severity or duration of symptoms (strong recommendation).

Balance of benefit and harm—Hydroxychloroquine and chloroquine probably do not reduce mortality or mechanical ventilation and may not reduce duration of illness. The evidence does not exclude the potential for a small increased risk of death and mechanical ventilation with Hydroxychloroquine. The effect on other less important outcomes—including time to symptom resolution, admission to hospital, and duration of mechanical ventilation—remains uncertain.

In stark contrast to this handling of HCQ, Remdesivir received its EUA approval based on what the WHO terms above a “less important outcome,” that of a shortened (or no) hospital stay, versus mortality reduction. Remdesivir is priced far outside the reach of most people in low-income countries. The WHO appears disinterested in affordable treatments such as HCQ, despite a similar outcome profile and despite its long track record as an antiviral agent. Again, as with Ivermectin, the WHO applies  a “high bar” for the use of a long-standing treatment. It is telling that this high bar is not similarly applied to newly-deployed, emergency use authorized vaccines. In fact, several significant concerns have been raised about the trial design for several of the EUA vaccines.[21]

Conclusion

Application of any medical intervention relies on risk-benefit analyses. These should include not only the treatment efficacy of a candidate drug, but also its safety history and availability. Repurposed drugs have well-established long-term safety data. More importantly, a blanket statement, such as, “Hydroxychloroquine does not work,” is fallacious simply because there are multiple variables that influence efficacy. For example, many locales that use repurposed treatments such as IVM and HCQ do so in a “cocktail,” versus administering them individually[22]. Timing of treatment and dosage obviously affect efficacy as well.  Treatment of COVID-19 is a good potential target for repurposed drugs, as the disease progression presents several points where severity can be mitigated through drug treatment. Well-established precedents for the use of repurposed treatments exist, e.g., Hydroxychloroquine, an anti-malarial drug, is widely used in autoimmune inflammatory diseases[23] while its analogue anti-malarial, chloroquine, has been demonstrated to inhibit the SARS-CoV virus in-vitro[24]. When there are high case numbers, conducting large-scale randomized control trials is straightforward, particularly with historically safe drugs. In an emerging pandemic, these studies should be prioritised. Why would the WHO or CDC wholesale deny the usage of these repurposed drugs, versus allowing doctors to determine how best their patients might benefit from them? Even before trial data is available, a doctor’s right to prescribe a safe, repurposed drug is normally uncontroversial when there is a reasonable, postulated mechanism of action to suggest benefit.

Apparent disinterest by the WHO, combined with the stifling of safe treatment options, led to the prolongation of the pandemic and resulted in many preventable deaths with COVID-19. In some cases, even after doctors prescribed specific repurposed treatments such as HCQ, pharmacists have refused to fill the prescriptions[25]. This is both shocking and unprecedented. Furthermore, the same approach that promoted the widespread use of a relatively-new and minimally-tested vaccine was not applied to repurposed treatments with a long history of safe multi-purpose use. It is not the purpose of this article to attempt to find a reason for this disinterest. Nor do we want to belabor the point that a multitude of people were tested, only to subsequently develop COVID-19 and be left with no alternatives but to simply wait for the disease to progress to a severity that required oxygen therapy or other drastic and/or heroic hospital measures. Instead, we simply state that this is an extraordinary and unfortunate way to manage an infectious disease. Over-reliance on a single mode of managing a life-threatening crisis is a grave error in judgement.

Not prioritizing investigation of affordable options that could potentially have saved lives is an abrogation of responsibility and a betrayal by the WHO. At the very least, a new emphasis on large-scale serious trials of repurposed treatments, while allowing sensible use of what are highly safe medicines, is warranted. A panel, populated by experts from both sides of the current “debate” should sift through the evidence in a serious, balanced manner, whilst bans of safe potential therapies should be removed immediately as this discussion proceeds. The right to select a treatment from the wide variety of existing treatments should be restored to the patient and their doctor.

 

References

[1] Smart B, Combrink H, Stricter P, Direct and Indirect Health Effects of Lockdown in South Africa

[2] Opening Statement of Chairman Ron Johnson “Early Outpatient Treatment: An Essential Part of a COVID-19 Solution, Part 2”, as per Dr. Peter McCullough. December 08, 2020. A56C7595-1F07-4F5C-B48F-B7133A5565D1 (senate.gov)

[3] Covid-19: Lancet retracts paper that halted hydroxychloroquine trials | Coronavirus | The Guardian

[4] Ibid.

[5] McCullough PA, Kelly RJ, Ruocco G, Lerma E, Tumlin J, Wheelan K, Katz N, Lepor NE, Vijay K, Carter H, Singh B, McCullough SP, Bhambi BK, Palazzuoli A, De Ferrari GM, Milligan G, Safder T, Tecson KM, Wang DD, McKinnon JE, O’Neill WW, Zervos M, and Risch HA. Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection. Am J Med 2020.

[6] Ivermectin | COVID-19 Treatment Guidelines (nih.gov)

[7] Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19, Kory, et.al., 2020

[8] Ibid. McCullough, et.al.

[9] HCQ Use Worldwide, real-time analysis. HCQ for COVID-19: real-time analysis of all 321 studies (c19hcq.com)

[10]  Lagier JC, Million M, Gautret P, et al. Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: a retrospective analysis. Travel Med Infect Dis 2020;36:101791. https://doi.org/10.1016/j.tmaid.2020.101791

[11] Chloroquine is a potent inhibitor of SARS coronavirus infection and spread | Virology Journal | Full Text (biomedcentral.com), Vincent, Burgeron, et.al.

[12] Ibid. McCullough, et.al.

[13] Randomised Evaluation of COVID-19 Therapy (RECOVERY). Dexamethasone results. Available at: https://www.recoverytrial.net/results/ dexamethasone-results.

[14] Inhaled budesonide in the treatment of early COVID-19 (STOIC):  a phase 2, open-label, randomized controlled trial, Ramakrishman, Nicolau, Jr., et.al. April, 2021

[15] Early Ambulatory Multidrug Therapy Reduces Hospitalization and Death in High-Risk Patients with SARS-CoV-2 (COVID-19), Proctor, et.al. International Journal of Innovative Research in Medical Science.

[16] A RANDOMIZED TRIAL – INTENSIVE TREATMENT BASED IN IVERMECTIN AND IOTA-CARRAGEENAN AS PRE-EXPOSURE PROPHYLAXIS FOR COVID- 19 IN HEALTHCARE AGENTS | medRxiv

[17] Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19 – PubMed (nih.gov)

[18] Forbes.com, Siladitya Ray, Indian State Will Offer Ivermectin to Entire Adult Population

[19] McCullough, PA, et.al., “Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19)”

[20] McCullough, PA, et.al. Ibid.

[21] Peter Doshi: Pfizer and Moderna’s “95% effective” vaccines—we need more details and the raw data – The BMJ

[22] Ibid. Early Ambulatory Multidrug Therapy.

[23] R.I. Rynes, “Hydroxychloroquine treatment of rheumatoid arthritis,” https://pubmed.ncbi.nlm.nih.gov/3052053/

[24] Vincent, Burgeron, et.al., “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread,” https://virologyj.biomedcentral.com/articles/10.1186/1743-422X-2-69

[25] Florida Doctor Says CVS Pharmacy Refused COVID Patient’s Prescribed Hydroxychloroquine (newsweek.com)

 

Photo by Derek Finch on Unsplash

Publisher’s note: The opinions and findings expressed in articles, reports and interviews on this website are not necessarily the opinions of PANDA, its directors or associates.

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