O. volvulus microfilariae in the anterior chambers of the eye and ocular adverse events after a single dose of 8 mg moxidectin or 150 µg/kg ivermectin: Results of a randomized double-blind Phase 3 trial in the Democratic Republic of the Congo, Ghana and Liberia

Abstract

Background After ivermectin became available, diethylcarbamazine (DEC) use was discontinued because of severe adverse reactions, including ocular reactions, in individuals with high O. volvulus microfilaridermia. Assuming long-term ivermectin use led to < 5 microfilariae/mg skin (SmfD) with little or no eye involvement, DEC + ivermectin + albendazole treatment a few months after ivermectin was proposed. In 2018, the US FDA approved moxidectin for treatment of O. volvulus infection. The Phase 3 study evaluated ivermectin-naïve individuals with ≥ 10 SmfD for skin and ocular microfilariae and adverse events (AEs) for 12–18 months after a single treatment (8mg moxidectin, n = 978 or 150µg/kg ivermectin n = 494).Methods We descriptively analyzed the data from 1463 participants with both eyes evaluated using six (0, 1–5, 6–10, 11–20, 21–40, > 40) categories for microfilariae in the anterior chamber (mfAC) and three pre-treatment (< 20, 20-<50, ≥ 50) and post-treatment (0, > 0–5, > 5) SmfD categories. A linear mixed model evaluated factors and covariates impacting mfAC levels. Ocular AEs were summarized by type and start post-treatment. Logistic models evaluated factors and covariates impacting the risk for ocular AEs.Results Moxidectin and ivermectin had the same effect on mfAC levels. These increased from pre-treatment to Day 4 and Month 1 in 20% and 16% of participants, respectively. Six and 12 months post-treatment, mfAC were detected in ≈ 5% and ≈ 3% of participants, respectively. Ocular Mazzotti reactions occurred in 12.4% of moxidectin- and 10.2% of ivermectin-treated participants without difference in type or severity. The risk for ≥ 1 ocular Mazzotti reaction increased for women (OR 1.537, 95% CI 1.096–2.157) and with mfAC levels pre- and 4 days post-treatment (OR 0:>10 mfAC 2.704, 95% CI 1.27–5.749 and 1.619, 95% CI 0.80–3.280, respectively).Conclusions The impact of SmfD and of mfAC levels before and early after treatment on ocular AEs needs to be better understood before decisions on the risk-benefit of strategies including DEC. Such decisions should consider interindividual variability in SmfD, mfAC levels and treatment response and risks to even a small percentage of individuals.Trial registration The study was registered on 14 November 2008 in Clinicaltrials.gov (ID: NCT00790998).

Identifying the Toxidrome of Ivermectin Toxicity

“…In vitro studies suggest that ivermectin acts by inhibiting the host importin alpha/beta-1 nuclear transport proteins, which are part of an intracellular transport process that viruses hijack to enhance infection by suppressing the host's antiviral response, underlying its use against viruses such as dengue virus, yellow fever virus, and Zika virus. Studies have also suggested anti-inflammatory properties, which have been hypothesized to be beneficial in SARS-CoV2 infections [ 3 , 4 , 5 , 6 ]. Despite these studies, no clinical trials have reported a clinical benefit of ivermectin against all these viral infections.…”

“…At therapeutic doses, ivermectin does not readily penetrate the blood-brain barrier, where GABA functions as a neurotransmitter. The therapeutic dosage recommended is 0.2-0.3mg/kg/day, with a maximum daily dosage of 0.4mg/kg/day [ 3 , 4 ]. Ivermectin has a high margin of safety in humans and does not readily cause serious adverse drug reactions since it is transported out of the central nervous system by ATP-binding cassette subfamily B member 1 (ABCB1) transporter [ 3 ].…”

“…Symptoms of neurotoxicity include lethargy, drooling, tremors/seizures, gait imbalance, decrease in sensorium, and disorientation [ 4 ]. In patients with mutations of the ABCB1 transporter, intake of therapeutic doses of ivermectin will result in serious neurological symptoms such as coma, ataxia, pyramidal signs, and binocular diplopia [ 3 , 7 ]. Non-neurological adverse events included pruritus, myalgia, cough, difficulty of breathing, nausea and vomiting, diarrhea, postural hypotension and serious skin reactions, and edematous swelling [ 8 , 9 ].…”

“…At present, there is insufficient evidence to recommend or discourage the use of ivermectin for the prevention and treatment of COVID-19 infection. Although the drug is generally well tolerated, non-neurological adverse effects may include nausea, vomiting, diarrhea, pruritus, and dizziness, while neurological adverse effects may include headache, encephalopathy, confusion, stupor, coma, dizziness, vertigo, and tremors [ 3 , 4 ]. There are no available data on the therapeutic window of ivermectin.…”

“…A case report shows that those with human ATP-binding cassette subfamily B member 1 (ABCB1) transporter nonsense mutations are those at risk for developing toxicity even with the intake of therapeutic doses of ivermectin [ 4 ]. Although studies on the neurological adverse effects of ivermectin are not locally available in the Philippines, a pharmacovigilance case series study showed serious adverse reactions such as toxidermias, encephalopathies, and confusional disorders after Ivermectin exposure [ 3 ]. In this study, we report the first locally-documented case of ivermectin overdose after intake of more than 10x the recommended maximum therapeutic dose of ivermectin and attempt to elucidate the possible adverse drug reactions from ivermectin toxicity.…”