Concerns as Ivermectin ‘craze’ grips Nigeria

*Survey shows more people have taken to drug to prevent, treat condition leading to rise in price
Following the endorsement of Ivermectin by the Vice President, Prof. Yemi Osinbajo and a team of medical professors led by the Chief Medical Director, Lagos University Teaching Hospital (LUTH) Idi Araba, Prof. Chris Bode, more Nigerians are scrambling for the drug, which has led to rise in its price.

Osinbajo had, in January, welcomed efforts by a team of Nigerian professors and scientists investigating the effectiveness of, and roles that Ivermectin drug can play in the treatment of COVID-19.

The team, which is composed of Nigerian scholars at home and abroad, has also submitted their report on the usefulness of the drug to the World Health Organisation (WHO), which has already appointed a Peer Review expert from the United Kingdom.

The report is titled “A randomised controlled trial for the repurposing of Ivermectin in the management of COVID-19.” The research, carried out in LUTH, was undertaken following the report of a 5,000-fold reduction in viral load by Australian workers with in-vitro use of Ivermectin on COVID-19 in culture.

The Principal Investigator (PI) has worked extensively with Ivermectin on the Onchocerciasis-River Blindness control programme, through which many Nigerians have used Ivermectin.

The study indicated that clinical trials of Ivermectin were carried out in at least 21 countries worldwide, including Nigeria. It referenced the “Meta-analysis of clinical trials of Ivermectin to treat COVID-19 infection” by Dr. Andrew Hill, Department of Pharmacology, University of Liverpool, UK.

Highlighting the practical applications, the study proposed “Ivermectin should be considered for adoption into the uniform treatment guidelines of COVID- 19 in Nigeria,” noting the “potential use of Ivermectin as prophylaxis pending the rollout of vaccination programmes or alongside it.”

However, the study emphasized that Ivermectin “is not meant to replace other COVID-19 measures such as social distancing, face masking and hygiene, or vaccinations,” adding that, “It is possibly an additional tool which can be deployed to fight the pandemic.”

The Guardian investigation revealed that the nationwide endorsement enjoyed by Ivermectin has led to rise in its prescription by doctors and dispensing by pharmacists with concomitant increase in the price of the drug.

But the Director General and Chief Executive Officer (CEO), Nigeria Centre for Disease Control (NCDC), Dr. Chikwe Ihekweazu, told The Guardian: “Ivermectin has not been approved for the prevention or treatment of COVID-19. There have been early researches in laboratory settings and among small groups of people. However, additional testing in clinical trial settings is needed to determine whether Ivermectin might be appropriate to prevent or treat coronavirus or COVID-19. The safety and efficacy of Ivermectin against COVID-19 is still under extensive research.”

Ihekweazu, who is also an epidemiologist, said it is very important that people do not take any medicine to treat or prevent COVID-19 unless it has been reviewed and approved for use by the Federal Ministry of Health (FMoH) through the relevant health agencies. “We are constantly monitoring the evolving scientific evidence and will update the national case management guidelines based on this,” he said.

A consultant pharmacist and President, Pharmaceutical Society of Nigeria (PSN), Mazi Sam Ohuabunwa, said Ivermectin is a drug used for public health intervention against onchocerciasis (river blindness) and some other worm infestations in endemic population. He said while Nigerians await further studies from clinical trials on mechanism of action, pharmacokinetics and dynamics of Ivermectin in COVID-19, all health care professionals and Nigerians in general must exercise caution on use of Ivermectin for non-approved indications such as COVID-19. The pharmacist said this is because every drug is a poison and can cause hitherto unreported or under reported side effect or adverse events, especially when used for new indications with different dosing regimen.

Ohuabunwa said pharmacovigillance must be on top gear to eliminate possible medication therapy issues and interactions, especially in the vulnerable groups with co morbidities and multiple medications.

Joint Pioneer of In Vitro Fertilisation (IVF) in Nigeria and Medical Director, Medical Art Centre (MART) Maryland, Lagos, Prof. Oladapo Ashiru, told The Guardian: “Right now, until we can get the vaccines and vaccinate the population, it is our only option. The Academy of Medicine Specialties has endorsed the use of Ivermectin and supplements like Zinc and Vitamin D and C as a proactive approach to cope with the pandemic. The government should accept this and ensure that there should be no price increase.”

Ashiru added: “The situation is sad. What has helped us in Nigeria is our immunity from our environment and our ready access to supplements, local herb mixtures, and Ivermectin. The Ministry of Health or the government is yet to give a clear plan of action.”

The fertility expert said the Academy of Medicine Specialties had released a unified statement supporting public health measures to combat COVID-19. “In addition to the above for Nigeria in particular pending the arrival of vaccines we encourage the use of treatment protocols to have been found to reduce the mortality and morbidity of the disease.

They include the use of anti-inflammatory drugs, such as steroids example dexamethasone, non-steroidal anti-inflammatory drugs example Colchicine, and the experimental drugs like Ivermectin. These treatments are inexpensive and they are well suited for our environment where cost is a major issue,” it noted.

A virologist and Chairman, Expert Review Committee on COVID-19, Prof. Oyewale Tomori, told The Guardian: “Also on this no comment except to say the verdict on Ivermectin is still in the courts of science and research. Those with incomplete data and who are prone to sensation currently have the field.”

A clinical research fellow at the Nigerian Institute for Medical Research (NIMR) Yaba, Lagos, said: “I am happy you mentioned Ivermectin. If it has come into wide use for COVID-19 management, the doomsday scenario described in our hospitals might soon change for the better, if most people adopt the right COVID-19 preventive behaviour and response to infection as well.”

Meanwhile, a team of researchers based in Peru and the United States (U.S.) recently examined the role of the anti-parasitic drug Ivermectin in treating COVID-19. The team has released their findings on the medRxiv* preprint server.

Ivermectin is a semisynthetic drug, used to treat helmintic infestations. Its mode of operation is via binding to glutamate-gated chloride ion channels, found in invertebrate nerve and muscle cells.

As part of the avermectins, ivermectin is extensively used to treat and control parasitic infestations in large animals, including tick infestations and scabies. It has also been used to prevent human filariasis and to treat scabies in humans. With a good safety profile at recommended dosages, and with U.S. Food and Drug Administration (FDA) approval, it became a mainstream drug in the treatment of COVID-19.

Earlier reports suggested that it had antiviral activity in both Ribo Nucleic Acid (RNA) and Deoxy ribonucleic Acid (DNA) viruses. This was followed by another study examining its pharmacokinetics, which concluded that even at tenfold the approved human dosage, the compound could not inhibit Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) in lung tissue.

The current study aimed to review the range of studies that reported the clinical efficacy of ivermectin in the treatment of the illness.The researchers included 12 qualitative and five quantitative studies, mostly preprints. These studies originated from all over the world, two being from the U.S., two from Spain, two from South America, one each from Iraq and Iran, and four from Bangladesh.

Altogether, there were around 7,400 participants, with a mean age of 47.5 years. About 60 per cent were male. The treatment protocols for all included studies comprised ivermectin either alone or in combination with another anti-inflammatory, antibiotic or blood-thinning drug like azithromycin, hydroxychloroquine, dexamethasone, enoxaparin, aspirin or dicloxacillin.

The majority of patients had been diagnosed by reverse transcriptase-polymerase chain reaction (RT PCR), and were hospitalized, though one study included asymptomatic families.

Five randomized controlled trials (RCTs) had missing data on study outcomes, leading to a serious risk of bias. Four cohort studies also showed a high risk of bias.

In one analysis of four preprints, based on retrospective studies, there was no evidence of reduced mortality following ivermectin use. Patient recovery was also not affected.

The GRADE system was used to assess the quality of evidence, using mortality and recovery outcomes. The mortality outcome was evaluated in over 3,600 participants, while recovery was assessed in about 400 participants. The first was based on five retrospective studies, and the latter from three preprint retrospective studies.

Ivermectin was not significantly associated with a lower mortality or higher recovery of patients in this meta-analysis. However, the majority of studies were preprints, allowing for later changes in the data on which these conclusions are based.

The basis of ivermectin use was because of a study published in Australia that reported this drug’s in vitro efficacy in Vero cells in culture. The clinical applicability of this finding is far from certain, but physicians rapidly began to use ivermectin in the treatment of hospitalized COVID-19 patients.

This was more likely in hard-hit countries such as Peru, where ivermectin became a first-line treatment and preventive against SARS-CoV-2 infection.

However, the safety and efficacy of this drug in preventing and treating this illness is not yet proven, especially because the studies were poorly designed. This has cast doubt on the accuracy of the effect measures. Even when the odds ratio showed a significant benefit for ivermectin use in terms of an 85 per cent reduction in mortality, the certainty of evidence was conceded to be very low.

Thirdly, the dose effective in human SARS-CoV-2 infections is still unknown, with the study doses ranging from 120 uM/kg to 200 uM/kg per dose, and the route of administration varying from intramuscular to oral. Such high doses have not been approved for human use.

Finally, efficacy testing of ivermectin in humans must be based on a dose-response trial with a placebo control group. In the absence of such studies, the optimal high dosage of ivermectin remains unclear.

The heterogeneous study populations and methods may also grossly reduce the accuracy of the review’s findings. After adjusting for such differences, the researchers found that their assessment of biases and effect measure size was close to the actual results. The lack of certainty of evidence for the estimated effect, as shown by GRADE criteria, indicates a serious difference between the true and estimated effect.

Also, Ivermectin has been hailed as breakthrough treatment for lymphatic filariasis (LF).The World Health Organisation (WHO) had in 2017 recommended an alternative three-drug treatment to accelerate the global elimination of LF – a disabling and disfiguring neglected tropical disease.

The treatment, known as IDA, involves a combination of Ivermectin, Diethylcarbamazine citrate and Albendazole. It is being recommended annually in settings where its use is expected to have the greatest impact.

Evidence from recent research studies has demonstrated that adding Ivermectin to the currently recommended combination of Diethylcarbamazine citrate plus Albendazole clears microfilaria more efficiently from the blood than the two-drug regimen and is equally safe.

Large randomized community studies conducted in four countries found that IDA is as safe as the two-drug regimens when used during Mass Drug Administration (MDA).