All available published literature from 1980 was gathered through a computer-assisted search of the bibliographic databases: Medline, ISI Web of Knowledge, and PubMed. Publications on “ivermectin” in combination with any of the keywords “onchocerciasis”, “river blindness”, “Onchocerca volvulus”, or “single dose” were selected. The references of retrieved studies were searched for articles that were not identified in database searches. Attempts were made to include non-English language
ReviewEffect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis
Introduction
Human onchocerciasis (river blindness) is caused by Onchocerca volvulus, a filarial parasite that is transmitted by blackflies (Simulium spp). Of the 34 endemic countries, 27 are in Africa, one is in the Arabian peninsula, and six are in Latin America. Recent surveys done by the African Programme for Onchocerciasis Control (APOC) indicate that approximately 37 million people may be infected,1 twice that of the 18 million figure usually quoted.2 In 1995, approximately 2 million disability-adjusted life-years were estimated to be lost annually to onchocerciasis,3 although this fell to about 1·5 million in 2003,1 probably because of large-scale treatment with ivermectin. Loss of vision is the most serious effect of onchocerciasis and skin disease contributes to 60% of the disease burden.1, 3 In addition to substantial ocular and cutaneous morbidity, excess mortality of blind people, and of sighted individuals with heavy onchocercal infection accounts for 5% of deaths in the Onchocerciasis Control Programme (OCP) area in west Africa.4, 5, 6 Because the disease reduces income-generating capacity, incurs substantial health expenditures, and exerts a devastating socioeconomic effect, onchocerciasis control (antivectorial or antiparasitic) is cost effective.7, 8, 9, 10
In 1987, mass treatment of endemic populations became feasible with the donation of ivermectin by Merck.11 Ivermectin causes a rapid, pronounced, and long-lasting decrease in the numbers of microfilariae that inhabit the skin lymphatics, are transmitted to vectors, and are responsible for most of the pathogenic repercussions of the infection. 14 days after treatment, microfilarial loads have been reduced by approximately 99% of pretreatment levels, these not being regained even 1 year later.12, 13 Regular mass treatment with ivermectin has been shown to decrease incidence, and to reduce morbidity and disability.14, 15
In 1988, ivermectin was added to the antivectorial OCP strategy.16, 17 The Onchocerciasis Elimination Program for the Americas (OEPA), and APOC were launched in 1993 and 1995, respectively, as antiparasitic strategies based on ivermectin distribution18 (biannually in OEPA19, 20 and annually in APOC21). Although both programmes are reducing morbidity,22, 23 uncertainty remains about the best frequency and duration of mass drug administration to limit the risk of infection and disease recrudescence. This requires an improved understanding of the effects of ivermectin on O volvulus population biology. Mathematical models have shed light on some of these questions,24 but their predictions are very sensitive to assumptions made on the basis of current understanding of adult worms' reproductive biology and lifespan, and on ivermectin efficacy.24, 25
Mathematical modelling of community-wide annual treatments in west Africa has concluded that to explain observed skin repopulation rates by microfilariae, ivermectin would not only have to kill 95–99% of parasites soon after treatment (microfilaricidal effect), but also to halt all microfilarial production by adult female worms (embryostatic effect).26, 27 Two possible scenarios were consistent with these data: (1) all worms slowly resumed microfilarial production but reached a value irreversibly reduced by about 35% at 10 months after treatment; and (2) about 30% of worms never resumed microfilarial production (an irreversible sterilising or macrofilaricidal effect), with the remaining 70% of females returning to full production by 10 months after treatment.26 However, the effects of ivermectin on adult O volvulus may not be irreversible,28, 29 drug efficacy may not remain constant with increasing number or frequency of treatments, and there is difficulty in defining and quantifying the embryostatic effect.
We therefore did a systematic review, meta-analysis, and mathematical model of all available data from ivermectin-naive individual and population-based single, standard dose trials, to (1) provide a comprehensive estimate of drug effects on both O volvulus microfilariae and macrofilariae that help improve our ability to predict the long-term effect of treatment; (2) investigate the temporal dynamics of the microfilaricidal, macrofilaricidal, and embryostatic effects of single-dose ivermectin; and (3) characterise parasitological profiles that correspond to a normal drug response, because this would provide a baseline against which to compare responses deemed suboptimum,30, 31 or may alert clinicians to a potential loss of drug efficacy under ivermectin pressure.
Section snippets
Methods
All available randomised and non-randomised controlled trials, non-controlled trials, comparative dose and frequency trials, and field trials on the effect of ivermectin on O volvulus-positive individuals (or endemic communities) were inspected for inclusion. Literature was gathered and inclusion criteria were set a priori to incorporate studies in which: (1) participants were given a single, standard dose of ivermectin (150 μg/kg bodyweight); (2) in the case of microfilariae, their geometric
Results
From the initial 438 articles retrieved, 26 on the effect of ivermectin on O volvulus microfilariae were eligible, and described 35 trials with appropriate information on geometric mean microfilarial density, which we included in the microfilarial meta-analysis (figure 1, table). Overall, 3540 patients were recruited at the time of treatment for the ivermectin group, 775 for the placebo group, and 613 as untreated controls. Their respective distributions across the different study types were as
Discussion
Despite many years of onchocerciasis chemotherapy research and widespread use of ivermectin, knowledge remains scarce about the mechanisms by which ivermectin exerts its antiparasitic effects and the best treatment regimens to control disease and eliminate infection. Mathematical models may help to answer some of these questions, but only if the effects of ivermectin on the population and reproductive biology of O volvulus are well quantified. We characterised the temporal dynamics of skin
Search strategy and selection criteria
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