Reduction in incidence of optic nerve disease with annual ivermectin to control onchocerciasis. Ophthalmological results from a placebo controlled comparative 3-dose ivermectin study in the treatment of onchocerciasis. Effect of single-dose ivermectin therapy on human Onchocerca volvulus infection with onchocercal ocular involvement.
The safety and efficacy of ivermectin in the prevention of blindness from onchocerciasis have been established in many studies that have addressed the drug's effects on the front of the eye. We undertook a study with sufficient statistical power to detect an effect on optic nerve disease (OND), probably the main cause of blindness in the disorder. The trial was based in 34 mesoendemic communities in Kaduna State, Nigeria. Villagers aged 5 years and older were randomly assigned annual dosing with ivermectin or placebo for 3 years. Participants underwent medical and ophthalmological examinations before the first, third, and fourth treatments. 3522 villagers aged 15 and older were re-examined at least once. Skin-snip samples were taken at baseline for calculation of microfilarial load. The outcome measure was development of disc pallor accompanied by objective evidence of deterioration in visual function; 116 subjects (45 ivermectin-treated, 71 placebo-treated) showed such changes during the trial. The incidence rate ratio (ivermectin vs placebo) was 0.90 (95% CI 0.54-1.51) for subjects with loads of 0-10 mf (microfilariae) per mg skin and 0.52 (0.29-0.93) for subjects with more than 10 mf/mg. The incidence rate ratio varied little when account was taken of age, sex, presence of pre-existing disc pallor in one eye, previous use of diethylcarbamazine citrate, or doses of ivermectin or placebo received. There was evidence that ivermectin reduced the incidence of OND in subjects with microfilarial loads above 10 mf/mg but had little effect in those with lower loads. Sustained annual delivery of ivermectin could prevent a substantial proportion of onchocercal blindness in mesoendemic communities. One hundred and ninety eight patients with moderate to heavy infection with Onchocerca volvulus and with eye involvement in most, were allocated randomly to treatment with 100, 150 or 200 mcg/kg body weight of ivermectin or placebo given as a single oral dose in a double-blind dose finding study. The patients were drawn from an area under over ten years of vector control in Northern Ghana by the Onchocerciasis Control Programme, OCP. They underwent detailed clinical, laboratory and ophthalmological examination before treatment and in the review period of one year in hospital. Ivermectin given in a dose of 100, 150 or 200 mcg/kg eliminated microfilariae similarly slowly over 3-6 months and was associated with inflammatory reaction in the anterior segment which resolved without treatment. No changes in the fundus of the eye was detected by fluorescein angiography and no no-table other adverse eye reaction was observed. The ceiling of therapeutic activity of ivermectin in the eye is therefore put at 100 mcg/kg which is lower than the level fo 150 mcg/kg found in the skin. The apparent discrepancy may be due to different dose requirements on account of different mechanisms of action of ivermectin at the two sites. In the skin there is active killing while in the eye it is presumed there is a passive elimination of microfilariae. Ivermectin has shown promise as a potentially safe and effective microfilaricidal drug for the treatment of onchocerciasis. Several limited studies have shown it to have fewer side effects, especially ocular complications, than the currently available drug, diethylcarbamazine. The detailed ocular findings in 200 moderately to heavily infected Liberians who were enrolled in a safety and dose-finding study are presented. They received either 0, 100, 150, or 200 micrograms/kg of ivermectin and were followed up for 12 months. In clinical studies so far carried out ivermectin in a dose of 100, 150, or 200 micrograms/kg has not been associated with any major adverse reactions nor were there any sight-threatening effects even in the presence of severe ocular disease. Each of these doses significantly reduced the ocular microfilaria load for at least 12 months when compared with either the placebo (p less than 0.05) or pretreatment values (p less than 0.001). However, the 100 and 150 micrograms/kg doses caused fewer minor side effects than the higher dose. These results confirm that ivermectin in a single oral dose may be a safe and effective microfilaricidal drug for the treatment of onchocerciasis and that it appears to be free of major ocular side effects.
The lack of evidence for prevention of visual impairment and blindness should not be interpreted to mean that ivermectin is not effective, however, clearly this is a key question that remains unanswered. The main evidence for a protective effect of mass treatment with ivermectin on visual field loss and optic nerve disease comes from communities mesoendemic for the savannah strain of O.volvulus. Whether these findings can be applied to communities with different endemicity and affected by the forest strain is unclear. Serious adverse effects were rarely reported. None of the studies, however, were conducted in areas where people are infected with Loa loa (loiasis).