Effects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone

doi:10.1016/0140-6736(91)91963-U

The Lancet

Volume 338, Issue 8775, 2 November 1991, Pages 1100-1103

https://doi.org/10.1016/0140-6736(91)91963-U Get rights and content

Abstract

Ivermectin seems to be a safe and effective treatment for onchocerciasis when given in a single dose, but less is known about the effects of repeated doses. Also, there seem to be differences in its effectiveness in anterior and posterior segment ocular disease. The ocular effects of ivermectin were studied in 586 villagers who were taking part in a double-blind, placebo-controlled, randomised trial in Sierra Leone. Only those who had received four doses, with 6-month intervals, of ivermectin or placebo were eligible. The 296 ivermectin-treated subjects and the 272 who received placebo were comparable with respect to age, sex, Onchocerca infection, blindness, and visual impairment before treatment. After treatment, the ivermectin group had less anterior segment disease than the placebo group, with significantly lower prevalences of microfilariae in the anterior chamber and cornea, and punctate keratitis (all p<0·001), and iritis (p<0·05). There was no significant difference in the prevalence of sclerosing keratitis, optic atrophy, or chorioretinitis between the groups. Visual acuities tended to be better in the ivermectin group, but the difference was not significant. There was a small but significant (p<0·01) excess of vascular sheathing in the ivermectin group. These differences persisted when subjects who were blind or visually impaired at baseline were excluded from analysis. The long-term effects of ivermectin, particularly on posterior segment disease, need further evaluation. In the mean time, the mass distribution of ivermectin should be promoted for all communities with hyperendemic onchocerciasis at risk of anterior segment disease.

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Citation Excerpt :
Ivermectin (Mectizan®, Merck & Co.) is a semisynthetic macrocyclic lactone derived from Streptomyces avermitilis, which was registered for the treatment of human onchocerciasis in October 1987 in France. Ivermectin was the first microfilaricide suitable for large-scale onchocerciasis treatment (Awadzi et al., 1985; De Sole et al., 1989; Remme et al., 1989; Prod’hon et al., 1991; Whitworth et al., 1991; Collins et al., 1992). Donated free by Merck & Co.
Onchocerciasis is a filarial infection which causes blindness and debilitating skin lesions. The disease occurs in 37 countries, of which 30 are found in Africa (the most affected in terms of the distribution and the severity of the clinical manifestations of the disease), six in the Americas and one in the Arabian Peninsula. The latest WHO Expert Committee on Onchocerciasis estimated that in 1995 around 17.7 million persons were infected, about 270 000 of whom were blind and another 500 000 severely visually impaired. The disease is responsible for 1 million DALYs. Eye disease from onchocerciasis accounts for 40% of DALYs annually although severe skin disease is also recognized as of public health significance. Great progress has been made in the last thirty years in the control of onchocerciasis, both in Africa and the Americas, and this progress has been due largely to international public–private partnerships, sustained funding regional programmes, and new tools and technology. Landmarks in the global control of river blindness include the significant success of the Onchocerciasis Control Programme of West Africa (1975–2002), and the donation of ivermectin (Mectizan^®) by Merck & Co. Inc., in 1988, a medicine that is distributed to millions free of charge each year. Future major technical challenges of onchocerciasis control include ivermectin mass administration in areas co-endemic for the parasite Loa loa in the light of possible severe adverse reactions, ivermectin treatment in hypoendemic areas hitherto excluded from African control programmes, sustainability of ivermectin distribution, post-control surveillance for recrudescence detection, surveillance for emergence of resistance, and decisions of when to stop mass ivermectin treatments. There is the need to develop the appropriate information systems and diagnostic tools to help in accomplishing many of these tasks. A search for a second-line treatment or as an additional drug to ivermectin as well as a search for a macrofilaricide are issues that need to be addressed in the future.
The impact of five years of annual ivermectin treatment on skin microfilarial loads in the onchocerciasis focus of Asubende, Ghana
1994, Transactions of the Royal Society of Tropical Medicine and Hygiene
Following the registration of ivermectin (Mectizan^®) for human use in the treatment of onchocerciasis, in 1987 the Onchocerciasis Control Programme in West Africa (OCP) begun a series of trials in order to determine the safety of the drug when used on a large scale and its potential for morbidity control. This paper reports the changes in skin microfilarial loads during the first 5 years of annual treatment in the holoendemic focus of Asubende in Ghana, which was the largest trial area and which also had the longest series of followup surveys. The general observed pattern was a marked reduction of microfilarial loads shortly after each treatment followed by a steady repopulation of the skin until a subsequent treatment round. The overall reduction of microfilarial loads observed between the base line survey and one year after the last treatment was 90% for the total population examined and over 93% for a cohort which received the drug at all 5 treatment rounds. In contrast, there was only a very gradual decrease in the prevalence of infection in the population after subsequent treatments. The study further emphasizes that even a single treatment with ivermectin has a significant medium-term impact on microfilarial loads. Microfilarial counts barely increased after 14–16 months of treatment and stabilized around 55% of pre-treatment counts 2–4 years after a single treatment.
ONCHOCERCIASIS. Ivermectin and onchocercal optic nerve lesions
1993, The Lancet
Reduction in incidence of optic nerve disease with annual ivermectin to control onchocerciasis
1993, The Lancet
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 (ON D), 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% Cl 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.
A community trial of ivermectin for onchocerciasis in sierra leone: Clinical and parasitological responses to four doses given at six-monthly intervals
1992, Transactions of the Royal Society of Tropical Medicine and Hygiene
Clinical and parasitological responses were studied in villagers receiving all 4 doses of treatment, at 6-monthly intervals, in a placebo-controlled community trial of ivermectin for onchocerciasis in Sierra Leone. Skin microfilarial loads were markedly lowered by ivermectin throughout and there were reductions in the severity, but not the prevalence, of skin lesions. Markers of general health and the prevalences of itching, Onchocerca nodules and visual loss were not significantly reduced during the study period. Despite our inability to demonstrate obvious clinical benefit, treatment with ivermectin was well accepted throughout the study. Simple clinical measures for evaluating the short to medium term impact of the mass distribution of ivermectin on populations with onchocerciasis need further development.

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ORIGINAL ARTICLESEffects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone

Abstract

Trans R Soc Trop Med Hyg

Ophthalmology

Lancet

Lancet

Am J Ophthalmol

Ophthalmology

Trans R Soc Trop Med Hyg

Lancet

Trans R Soc Trop Med Hyg

Trans R Soc Trop Med Hyg

third report

Onchocerciasis

Commun Eye Health

Onchocerciasis

Ocular Onchocerciasis

Trop Dis Bull

Ocular onchocerciasis

Trop Doct

ORIGINAL ARTICLES
Effects of repeated doses of ivermectin on ocular onchocerciasis: community-based trial in Sierra Leone