Evaluations of efficacy for COVID-19 therapeutics are challenging since most patients with this disease typically recover; the worldwide cumulative case fatality rate is 2% as of September 2021.1. Thus, randomized clinical trial (RCT) results are important, yet interpretations, for example, of the more than 20 mostly positive RCT results for COVID-19 treatment with the drug ivermectin (IVM), a macrocyclic lactone used widely worldwide since 1987, as summarized below, are controversial. Even for a drug such as remdesivir that was tested with several RCTs having large patient cohorts, opposite conclusions were drawn by the US FDA2 and the World Health Organization3 as to efficacy against COVID-19.
As a complement to positive RCT results for a COVID-19 therapeutic, a quantifiable determination of rapid, major improvement in pulmonary function, especially for severe COVID-19 patients, would further indicate efficacy and provide insights into that drug’s underlying biological mechanism. The simplest indicator of lung function is blood oxygen saturation level, SpO2, as detectable using a pulse oximeter. However, the immediate administration of supplemental oxygen to any severe COVID-19 patient would typically preclude meaningful pre-and post-treatment comparisons of SpO2 values. For this retrospective study conducted in Zimbabwe, ironically, challenges that constrained treatment capabilities also provided the opportunity to track changes in SpO2, all on room air, for 34 severe COVID-19 patients within 12 to 48 hours after beginning IVM treatment (see Figure 1). At the same time, these challenges tested whether severe COVID-19 patients with limited opportunities for hospitalization could be successfully treated at home or in clinics with rudimentary facilities.
Zimbabwe, a landlocked country in Southern Africa that shares a border with South Africa, had its first reported case of COVID-19 in March 2020.4 Eight cases and one death from COVID-19 followed in the same month.5 The first death occurred in the Wilkins hospital, Zimbabwe’s main COVID-19 treatment center in the capital city of Harare. Facilities were limited at this hospital at the time; no capacity for ventilation was available. Given the rapid increase in COVID-19 patients in Harare after March 2020,6 additional medical facilities began treating them.
COVID-19 wards were created at a general practice clinic by converting two staff rooms into a 4-bed ward and a storeroom into a 2-bed ward. Available equipment included several oxygen cylinders, an oxygen concentrator, six beds, and three monitors for SpO2 and blood flow parameters. The staff consisted of the lead author and another primary care physician who was off duty for several weeks after being injured in a vehicle accident on July 27, 2020, and either one or two nurses at different times, each on 12-hours shifts. During the initial months of the pandemic, in the absence of proven therapies and protocols, the standard of care evolved through early August 2020 to include corticosteroids, clopidogrel, aspirin, enoxaparin, rivaroxaban, a nebulized nano-silver preparation, zinc sulfate, hydroxychloroquine, azithromycin, doxycycline and in some cases an IV antibiotic.
However, the efficacy of these treatments was found to be limited, and by the end of July 2020, several COVID-19 deaths were recorded in the country. Based upon reports of initial success using IVM for COVID-19 treatment from colleagues in Johannesburg, South Africa, the College of Primary Care Physicians of Zimbabwe (CPCPZ) adopted and included IVM in their COVID-19 treatment protocol from August 8, 2020, starting initially with a 10-12 mg stat dose. Treatment of COVID-19 with IVM continued after the first patients showed improved outcomes, with more rapid recoveries achieved at doses higher than the standard of 200 ug/kg as initially used.
In August 2020, after it became apparent that IVM added to standard of care was significantly reducing the death rate, together with the hospital system being overwhelmed, CPCPZ physicians decided to treat COVID-19 patients where an IVM-based protocol could be administered, including at local general practice clinics which had nursing care and oxygen, and at some patients’ homes with nursing support and oxygen supplementation as available. As knowledge of this successful treatment regimen spread in Zimbabwe, other physicians began offering the same treatment, with improved outcomes, which led to the formation of the Zimbabwe COVID Front Line Clinicians Society.
IVM for COVID-19 treatment
The decision to include IVM in COVID-19 treatment protocols in Zimbabwe was made as the pandemic swept through that nation, overwhelming limited clinical care facilities, with no drug developed to treat COVID-19 being generally accepted as effective. A published case-controlled study of IVM treatment for COVID-19 conducted at four US hospitals7 that had been initially released in a preprint in June 2020 found a 40% reduction in mortality among 173 patients treated with low dose IVM vs 107 case-matched controls (15% vs 25.2% deaths). Interest in IVM was supported by its Nobel prize-honored pedigree and its extensive use to treat a variety of human diseases in over 3.7 billion doses worldwide since 1987.8–10 Another favorable characteristic of this drug is its extraordinary record of safety, well tolerated at high doses,11,12 including in studies for COVID-19 treatment.13,14 It is generally non-toxic even at doses far exceeding the therapeutic range.15,16 Since August 2020, inpatient and outpatient treatments of COVID-19 with IVM have been applied across 25 countries,10 with more than 20 RCTs conducted for IVM treatment regimens.10,17,18
Seven of nine meta-analyses of these RCTs for IVM treatment reporting in 2021, all conducted using Cochrane analysis methodology, found significant18–22 or possible23,24 indications of IVM efficacy, with a mean 0.33 relative risk (RR) of mortality vs controls. Most of these 20 RCTs for IVM treatment of COVID-19 showed statistically significant mortality reductions or other clinical benefits. Among the most recent and detailed of the nine meta-analyses noted above reported a pooled total 67% reduction in mortality for IVM vs controls, with a statistical significance for an overall effect of p=0.005.20 A comprehensive review of the entire body of clinical studies for IVM treatment of COVID-19 by the Nobel co-laureate for IVM, Dr Satoshi Omura and colleagues, concluded that IVM yielded major reductions in mortality.10 Two animal studies of IVM treatment at low human-equivalent doses, one for the SARS-CoV-2 virus in golden hamsters25 and another for a related betacoronavirus (MHV-A59) in mice,26 found statistically significant treatment benefits, consistent with those found in the RCTs noted above. The indicated biological mechanism of IVM, competitive binding with SARS-CoV-2 spike protein,27 is likely non-epitope specific, possibly yielding full efficacy against emerging viral mutant strains.
The demonstrated safety of IVM at much higher than standard doses11–14 allowed the latitude for dose escalation for IVM treatment of COVID-19 over time. On September 19, 2020, the CPCPZ held a seminar at which the use of a combination of IVM, doxycycline and zinc was presented, along with aggressive diabetes control, steroid use and anticoagulation, and this was suggested as the most effective and affordable care available at the time. Afterwards, combination therapy centered around IVM plus doxycycline and zinc became the standard COVID-19 treatment protocol used by the CPCPZ. The potential efficacy of these adjuncts was later supported by successful clinical trials results with treatments using IVM in combination with doxycycline28 or with doxycycline and zinc.29 This combination therapy for COVID-19 has been researched and advanced by Thomas Borody,30 who in 1990 published the first clinical trial of using a triple therapy of three inexpensive repurposed drugs for H. pylori,31 the underlying bacterial cause of peptic ulcers. This triple therapy of repurposed drugs became the worldwide standard of care for peptic ulcers a decade later, after the patents for the palliative drugs Tagamet and Zantac expired, and the discovery of H. pylori as the cause of peptic ulcers was honored with the Nobel Prize for Medicine in 2005.30