RESUMO

Periodic mass treatment with ivermectin in endemic communities prevents eye and dermal disease due to onchocerciasis. As part of an international global partnership to control onchocerciasis, The Carter Center's Global 2000 River Blindness Program (GRBP) assists the ministries of health in ten countries to distribute ivermectin (Mectizan, donated by Merck & Co.). The GRBP priorities are to maximize ivermectin treatment coverage and related health education and training efforts, and to monitor progress through regular reporting of ivermectin treatments measured against annual treatment objectives and ultimate treatment goals (e.g., full coverage, which is defined as reaching all persons residing in at risk villages who are eligible for treatment). Since the GRBP began in 1996, more than 21.2 million ivermectin treatment encounters have been reported by assisted programs. In 1999, more than 6.6 million eligible persons at risk for onchocerciasis received treatment, which represented 96% of the 1999 annual treatment objective of 6.9 million, and 78% of the ultimate treatment goal in assisted areas.

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The decision in 1987 by the pharmaceutical firm Merck & Co. to provide Mectizan (ivermectin) free of charge to river blindness control programs has challenged the international public health community to find effective ways to distribute the drug to rural populations most affected by onchocerciasis. In the Americas, PAHO responded to that challenge by calling for the elimination of all morbidity from onchocerciasis from the Region by the year 2007 through mass distribution of ivermectin. Since 1991, a multinational, multiagency partnership (consisting of PAHO, the endemic countries, nongovernmental development organizations, the Centers for Disease Control and Prevention in Atlanta, Georgia, as well as academic institutions and funding agencies) has developed the political, financial, and technical support needed to move toward the realization of that goal. This partnership is embodied in the Onchocerciasis Elimination Program for the Americas (OEPA), which is supported by the River Blindness Foundation (RBF) and now by the Carter Center. OEPA was conceived as a means of maintaining a regional initiative to eliminate what is otherwise a low priority disease. Since its inception in 1993, the OEPA has provided more than US$2 million in financial, managerial, and technical assistance to stimulate and/or support programs in Brazil, Colombia, Ecuador, Guatemala, Mexico and Venezuela, so as to take full advantage of the Merck donation. Now halfway into a five-year, US$ 4 million grant provided through the Inter-American Development Bank, the OEPA's capacity to support the regional initiative is assured through 1999

La decisión tomada en 1987 por la Merck & Co., fabricante de productos farmacéuticos, de proveer Mectizan® (ivermectina) gratuitamente a los programas de control de la oncocercosis ha obligado a la comunidad sanitaria internacional a buscar formas de distribuir el medicamento a las poblaciones rurales que se ven más afectadas por la enfermedad. En las Américas, la OPS respondió al reto con un llamado a eliminar de la Región toda morbilidad por oncocercosis para el año 2007 mediante la distribución de ivermectina al público. Desde 1991, una alianza multinacional de diversas entidades (la OPS, países con oncocercosis endémica, agencias de desarrollo no gubernamentales, los Centros para el Control y la Prevención de Enfermedades en Atlanta, Georgia, instituciones académicas y agencias de financiamiento) ha generado el apoyo político, económico y técnico necesario para tratar de alcanzar esa meta. Esta alianza está representada por el Programa de Eliminación de la Oncocercosis en las Américas (OEPA), subvencionado por la Fundación Ceguera de los Ríos y actualmente por el Centro Carter. El OEPA se creó como iniciativa de alcance regional destinada a eliminar una enfermedad que no merece atención prioritaria. Desde su aparición en 1993, el OEPA ha aportado más de US$ 2 millones en ayuda económica, administrativa y técnica para fomentar y subvencionar programas en Brasil, Colombia, Ecuador, Guatemala, México y Venezuela, logrando así aprovechar al máximo la donación de la Merck & Co. Ahora que hemos llegado a la mitad de una subvención de 5 años y US$ 4 millones aportada por el Banco Interamericano de Desarrollo, se sabe que el OEPA tiene la capacidad para apoyar la iniciativa regional hasta fines de 1999

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RESUMO

The decision in 1987 by the pharmaceutical firm Merck & Co. to provide Mectizan (ivermectin) free of charge to river blindness control programs has challenged the international public health community to find effective ways to distribute the drug to rural populations most affected by onchocerciasis. In the Americas, PAHO responded to that challenge by calling for the elimination all morbidity from onchocerciasis from the region by the year 2007 through mass distribution of ivermectin. Since 1991, a multinational, multiagency partnership (consisting of PAHO, the endemic countries, nongovernmental development organizations, the Centers for Disease Control and Prevention in Atlanta, Georgia, as well as academic institutions and funding agencies) has developed the political, financial, and technical support needed to move toward the realization of that goal. This partnership is embodied in the Onchocerciasis Elimination Program for the Americas (OEPA), which is supported by the River Blindness Foundation (RBF) and now by the Carter Center, OEPA was conceived as a means of maintaining a regional initiative to eliminate what is otherwise a low priority disease. Since its inception in 1993, the OEPA has provided more than US$ 2 million in financial, managerial, and technical assistance to stimulate and/or support programs in Brazil, Colombia, Ecuador, Guatemala, Mexico, and Venezuela, so as to take full advantage of the Merck donation, Now halfways into a five-year, US$ 4 million grant provided through the Inter-American Development Bank, the OEPA's capacity to support the regional initiative is assured through 1999 (AU)

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Community acceptance and participation are essential for the success of mass ivermectin chemotherapy programmes for onchocerciasis (river blindness). To explore the local understanding of the purpose of ivermectin and willingness to continue taking the drug, we performed questionnaire surveys in four communities with hyperendemic onchocerciasis after each of three ivermectin treatment rounds. More than 100 respondents participated in each KAP survey, representing the heads of 30% of the households in each community. The respondents rarely stated that the goal of the ivermectin treatment programme was to prevent visual loss. Instead, they said they were taking the drug for their general well-being, to cure the onchocercal nodule (filaria), or to cure the microfilaria, a term newly introduced by agents of the treatment programme. The principal reason identified for refusal to take ivermectin was anxiety about drug-related adverse reactions, and there were marked differences between communities in acceptance of treatment. In one community over 50% of residents initially refused to take ivermectin, although participation rates improved somewhat after programmatic adjustments. We recommend that ivermectin distribution programmes establish surveillance activities to detect where acceptance is poor, so that timely and community-specific adjustments may be devised to improve participation.

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As part of an effort to involve community members in malaria control activities, we studied knowledge, beliefs, and practices of residents of both the Pacific coastal plain and northeastern Guatemala related to malaria transmission and Anopheles albimanus control. Most residents recognized the role of mosquitoes in malaria transmission, but few knew how mosquitoes acquired their infections or understood the risk of having an untreated person in their midst. If this were more widely known, residents might put greater pressure on infected patients to seek timely and appropriate antimalarial treatment. Seventy-three percent of families owned one or more bed nets; however, even though most informants believed that bed nets help protect against malaria, the major reason for using them was to prevent nuisance mosquito bites. It is concluded that efforts should be made to promote bed net use by seeking ways to make them more affordable and by emphasizing their effectiveness as a barrier to nuisance mosquitoes. Although residents have a very positive opinion of the National Malaria Service spray teams, it is proposed that cooperation might be improved if malaria workers would emphasize the fact that house spraying reduces the numbers of nuisance mosquitoes and other pest insects, rather than focusing solely on malaria prevention, which most informants believed was less important. This study emphasizes the importance of understanding community beliefs and practices when planning or evaluating vector control activities.

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A novel phospholipid, 1-fatty acyl-2-(12-aminododecyl) phosphatidylcholine (APC), was synthesized and reacted with two different activated agarose matrices, differing in the spacer arm length: N-hydroxysuccinimidylester agarose (1-atom spacer arm) and N-hydroxysuccinimidylester-6-aminohexanoic acid agarose (8-atom spacer arm). Both immobilized phosphatidylcholines were readily degraded by Bacillus cereus phospholipase C at similar rates. By contrast, Crotalus adamanteus phospholipase A2 hydrolyzed long-spacer arm phosphatidylcholine, but had less than one tenth of the activity towards the short-spacer arm one. These results are interpreted in terms of a chain length-related steric hindrance caused by the matrix, affecting phospholipase A2 but not phospholipase C activity, supporting the view that the first involves a deeper burrowing of the substrate into the enzyme molecule.

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The authors evaluated the effects on malaria vectors of bed nets impregnated with permethrin over the course of a 16-month controlled study in four communities of Northern Guatemala. Anopheles albimanus and An. vestitipennis were the known malaria vectors in the area. Households were allocated to one of three experimental groups: those receiving bed nets impregnated with 500 mg/m2 of permethrin, those receiving untreated bed nets, and those where no intervention measures were taken. The impact of the treated and untreated bed nets on mosquito abundance, behavior, and mortality was determined by indoor/outdoor night-bite mosquito collections, morning pyrethrum spray collections, inspection of bed net surfaces for dead mosquitoes, and capture-release-recapture studies. The duration of the treated nets' residual insecticide effect was assessed by modified WHO cone field bioassays, and their pyrethrin content was estimated by gas-liquid chromatography analysis. The most important observation was that fewer mosquitoes were found to be resting in the households with treated bed nets. The treated nets probably functioned by both repelling and killing vector mosquitoes. Capture-release-recapture studies showed exit rates from houses with treated nets were higher (94%) than those from control houses (72%), a finding that suggests repellency. However, no significant differences were noted between the indoor night-bite mosquito collections at houses with and without treated nets. The horizontal surfaces of treated bed nets were nearly 20 times more likely to contain dead anopheline mosquitoes than were the comparable surfaces of untreated nets. the bioassays indicated that unwashed permethrin-impregnated bed nets retained their insecticidal activity for 6 months after treatment.

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Permethrin-impregnated bed nets were evaluated as a control measure for malaria in northern Guatemala. Twelve hundred forty participants were allocated to one of three experimental groups (impregnated bed nets [IBN], untreated bed nets [UBN], and controls) and followed up for a period of 13 months. The incidence density of malaria was significantly lower in both IBN (86 cases/1,000 person-years) and UBN groups (106/1,000) compared with that in controls (200/1,000). No difference in malaria incidence was noted between the IBN and UBN groups. Complaints of fever and chills were less frequent in the IBN group compared with controls. The participants were enthusiastic about the nets, which they saw as a means for avoiding nuisance insects more than for preventing malaria. Most (85%) wanted to wash their nets every 4-12 weeks, a practice known to shorten the duration of residual insecticide action. Larger studies are needed to determine whether or not impregnated bed nets offer an advantage over untreated nets in this setting.

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Male and female residents on a Guatemalan coffee plantation where Onchocerca volvulus infections were hyperendemic were offered oral ivermectin (100-200 micrograms/kg) as part of a community-wide treatment programme for onchocerciasis. Forty-five persons were treated and then questioned daily for 28 d about changes in their health. Those with complaints were monitored until all signs and symptoms had resolved. Sixty-seven percent complained of some adverse event after treatment; 60% developed observable adverse reactions attributed clinically to ivermectin. No reaction was life-threatening; the most common were oedema (53%) and fever (47%). Expulsion of intestinal helminths was reported by 38%. Almost all reactions began 24-48 h after treatment; their mean duration was 5 d, despite treatment with acetaminophen and antihistamines. Three patients had oedematous changes lasting over 2 weeks. Incidence, but not severity, of reactions was related to the pretreatment density of microfilariae in skin.

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Residents of five hyperendemic communities located in the central focus of onchocerciasis in Guatemala were treated with ivermectin (Mectizan) or placebo every six months for 30 months. The effects of treatment on prevalence and the intensity of skin infection (microfilarial skin density [MFD]) were evaluated. Significant and persistent reductions in both of these indices were achieved by coverage of 80.7% of the eligible populations. The highest proportionate reductions in both indicators of infection occurred after the first treatment, followed by more gradual decreases through the fourth treatment. In one community in which the mean coverage was 92.7%, prevalence decreased from 74.0% at pretreatment to 34.9% after four treatments, while the MFD decreased from 7.8 to 2.0; reductions of 52.8% and 74.3% from pretreatment values, respectively. In every ivermectin-treated community except one, in which drug acceptance was low, the mean community MFD values were reduced to the level associated with low infectiousness for the vector, Simulium ochraceum. Moreover, the category of MFD associated with high vector infectiousness was reduced at least ten-fold over the pretreatment level. One community had low participation during the first two treatments (32.8% and 22.7% of those eligible). This increased to 55.2% at the third treatment because of implementation of an educational program describing both the disease and the beneficial effects of ivermectin and because skin biopsies and nodulectomies were not performed. Secondary reaction rates for all communities were 29.5%, 9.9%, 10.3%, 8.2%, and 7.1% for the first through fifth treatments, respectively. Pruritus was the most common (34.0%) secondary reaction, followed by facial edema (31.8%). All reactions were classified as mild to moderate. Recommendations for mass distribution of ivermectin in Guatemala are given.

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The population from five Guatemalan plantations in areas endemic for onchocerciasis was surveyed, and 1032 individuals were recruited to participate in our study. From physical examination, past clinical history (5 to 8 yr), laboratory evidence and sample availability, a group of 778 long term residents with confirmed disease status were selected for detailed examination. We were able to identify 268 long term residents of endemic areas who had never been infected, 44 of these are from hyper- and mesoendemic areas. The 44 uninfected individuals from the hyper- and mesoendemic areas, because of their considerable exposure to this disease, were classified as "putatively immune." Intact nodules containing adult worms of Onchocerca volvulus were homogenized in the presence of protease inhibitors and fractionated into particulate and aqueous isotonic soluble antigens. Systematic analysis of these Ag fractions showed considerable amounts of Ig, presumably associated with Ag in the form of immune complexes. Individual specific antibody reactions from all 778 patients to nodule Ag were examined. Reactions to O. volvulus antigens by antibodies from patients with confirmed parasitic infections were almost exclusively restricted to IgG1 and IgG4 isotypes. Antigenic activity appeared to be primarily associated with low molecular mass (14 to 29 kDa) components. Some competitive blocking of antibody activities of other isotypes by IgG1 was observed, most notable was that of IgG3 and IgA. IgG4 and IgM activities were not significantly blocked.

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If ivermectin distribution programs are to have maximum impact on the morbidity and transmission of human onchocerciasis there must be broad and sustained acceptance within the endemic communities. Educational activities, developed with careful consideration of community attitudes, should promote positive treatment seeking behavior while simultaneously addressing local reservations about the control effort. To better understand the ambient knowledge, attitudes, and practices concerning onchocerciasis in the context of ivermectin use in Guatemala, we conducted a survey among 145 heads of households in five endemic communities. Given the country's long-standing nodulectomy program, it was not surprising that 100% of persons interviewed had heard of the disease 'la filaria', which they defined as a skin nodule that could cause blindness. Ninety-five percent of respondents identified surgery as the only cure for the condition. Relatively few (39%) knew that la filaria was caused by a worm, although slightly more (50%) knew that the condition was acquired by the bite of an insect. The term microfilaria was not broadly recognized. We also determined that onchocerciasis was not perceived as a serious health problem: few persons (12%) mentioned la filaria when requested to provide a complete list of illnesses that occurred in the community, and the gravity of infection (based on rank ordering of common illnesses) was similar to that of a bad cold. Recommendations were made which might assist long-term acceptance of a national chemotherapy initiative against onchocerciasis in Guatemala.

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This three-phase study was designed to compare high dose ivermectin with a standard diethylcarbamazine (DEC) regimen for patient tolerability, potential to kill adult filaria, and duration of microfilarial suppression in 30 Haitian subjects with Wuchereria bancrofti microfilaremia. All were first given a 1-mg oral dose of ivermectin (phase 1) to reduce microfilaria densities. Participants were randomized into three groups: Group 1 received DEC (6mg/kg per day for 12 days), Group 2 received 200 mcg/kg of ivermectin, and Group 3 received 400 mcg/kg of ivermectin (200 mcg/kg per day for 2 days). All drug regimens were well tolerated with few adverse reactions. Most reactions occurred during phase I and consisted primarily of headache, fever, and myalgia. At the end of phase 1, 27 of 30 (90%) patients were microfilaria negative. During phase 2, four of the six men receiving DEC developed scrotal reactions suggesting killing adult worms; no such reactions were noted in 10 men receiving ivermectin (p less than 0.05). At one-year follow up (phase 3), all treatment groups had less than 10% return to pretreatment microfilaria levels. The mean percent of baseline microfilaria counts were for Group 1, 0.9% (range 0-5%); Group 2, 8.2% (range 0-31%); and Group 3, 3.8% (range 0-25%). Seven individuals in Group 1 were microfilaria-negative, while only one and three individuals were microfilaria-negative in Groups 2 and 3, respectively. These results suggest that DEC causes more damage to the adult worms and greater reduction in microfilaria densities than ivermectin, but that high doses of ivermectin may suppress microfilaremia in lymphatic filariasis for periods much longer than previously reported.

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Changes in microfilaria (mf) densities in skin, blood and urine were followed over 72 hours in 8 Guatemalan patients who received invermectin (150 mcg/kg po in a single dose). After an initial increase at 6 hours, the significance of which is not clear, mf densities in skin snips decreased rapidly to reach 13% of their pre-treatment level by 48 hours and then fell much more slowly over the next 24-hour period. The fall in mf concentrations is thought to be mainly a result of movement away from the subepidermal layer. In contrast to what happens after DEC, it was not accompanied by any marked wave of microfilaraemia or microfilaruria, nor by the appearance of a papular rash, although brawny oedema of the skin sometimes developed. Reactions that occurred after ivermectin could not be correlated with the initial density of microfiladermia. It is hypothesized that the movement of mfs may be 1) into the deeper layers of the dermal collagen, 2) the subcutaneous fat, or 3) the lymphatic system.

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