Bruce M. Greene

Comparison of Ivermectin and Diethylcarbamazine in the Treatment of Onchocerciasis

We compared ivermectin with diethylcarbamazine for the treatment of onchocerciasis in a double-blind, placebo-controlled trial. Thirty men with moderate to heavy infection and ocular involvement were randomly assigned to receive ivermectin in a single oral dose (200 micrograms per kilogram of body weight), diethylcarbamazine daily for eight days, or placebo. Diethylcarbamazine caused a significantly more severe systemic reaction than ivermectin (P less than 0.001), whereas the reaction to ivermectin did not differ from the reaction to placebo. Diethylcarbamazine markedly increased the number of punctate opacities in the eye (P less than 0.001), as well as the number of dead and living microfilariae in the cornea over the first week of therapy. Ivermectin had no such effect. Both ivermectin and diethylcarbamazine promptly reduced skin microfilaria counts, but only in the ivermectin group did counts remain significantly lower (P less than 0.005) than in the placebo group at the end of six months of observation. Analysis of adult worms isolated from nodules obtained two months after the start of therapy showed no effect of either drug on viability. Ivermectin appears to be a better tolerated, safer, and more effective microfilaricidal agent than diethylcarbamazine for the treatment of onchocerciasis.

Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution.

Ivermectin is the drug of choice for community-based treatment of onchocerciasis. Since pregnancy testing during mass distribution campaigns is not feasible, the safety of ivermectin in pregnancy must be established. During a 3-year study, ivermectin was distributed to the population of a rubber plantation (14,000 people) in Liberia. Only 31% of women were aware of their pregnancy status during the first month; it was calculated that about half of women in the first trimester of pregnancy are likely to be treated inadvertently. 203 children born to women inadvertently treated during pregnancy were identified. In this limited sample, there was no significant difference in birth defects between treated and untreated mothers in the same population or compared with a reference population. Children of treated and untreated mothers showed no difference in developmental status or disease patterns. Further surveillance is necessary; however, since no major effects of ivermectin on pregnancy outcome were detected, there seems no need to change existing strategies of ivermectin distribution.

Isolation and characterization of expression cDNA clones encoding antigens of Onchocerca volvulus infective larvae.

The isolation of recombinant cDNA clones expressing antigens found in Onchocerca volvulus infective larvae is described. To isolate such clones, an expression cDNA library constructed from adult O. volvulus RNA was screened with antiserum raised against infective larvae. One clone, designated lambda RAL-1 was characterized further. The recombinant antigen produced by lambda RAL-1 stimulates proliferation of peripheral blood mononuclear cells from O. volvulus infected humans. Lambda RAL-1 is derived from a 1450 bases message that encodes a protein with an apparent molecular weight of 42,000 in adult O. volvulus. The inserted DNA of lambda RAL-1 contains an open reading frame of 1008 bp. The amino acid sequence predicted by this open reading frame contains three repeats of the sequence KKPEDWD. The identification of clones such as lambda RAL-1 will provide quantities of purified antigens sufficient to begin to study the immune response to and explore the development of immunity against the infectious form of the parasite.

Safety of and compliance with community-based ivermectin therapy.

In a study of the safety, acceptability, and efficacy of ivermectin for community-based mass treatment of onchocerciasis, the drug was issued twice, one year apart, to the population of a rubber plantation (14,000 people) in Liberia, where over 80% of the adults have Onchocerca volvulus infection. The plantation microfilarial load in a sample of adults was reduced by 86% 6 months after initial treatment and by 78% after 1 year. Compliance was 97% with each round of treatment. After the initial treatment of 7699 people, 101 (1.3%) had moderate adverse reactions. After re-treatment only 37 (0.5%) people had moderate adverse reactions. No ivermectin-related death or severe adverse reactions occurred. The data show that community-based treatment with ivermectin is well accepted and effective in reducing microfilarial loads. Ivermectin is likely to provide the first realistic means of chemotherapy-based control of onchocerciasis on a mass scale.

Use of Ivermectin in Humans

Ivermectin (Campbell et al. 1983) has been extensively tested in human onchocerciasis, and is now considered the drug of choice. In a single yearly dose, it suppresses microfilariae in the skin and eyes, and in most infected persons prevents disease progression. It also shows considerable promise for treatment of lymphatic filariasis and strongyloidiasis.

OCULAR MANIFESTATIONS OF ONCHOCERCIASIS IN A RAIN FOREST AREA OF WEST AFRICA

The epidemiology and natural history of onchocerciasis and its ocular complications in rain forest areas are poorly understood. The present study was conducted on a rubber plantation in a hyperendemic area in the rain forest of Liberia, West Africa, where 800 persons were examined. The prevalence of infection was 84% overall 29% had intraocular microfilariae, and 2.4% were blind in one or both eyes. Onchocerciasis was the cause of all binocular blindness and one-third of all visual impairment. Over half of the visual impairment caused by onchocerciasis was due to posterior segment diseases. Chorioretinal changes were present in 75% of people, and included intraretinal pigment clumping in 52% and retinal pigment epithelium atrophy in 32%. Atrophy of the retinal pigment epithelium was associated with increasing age and severity of infection. Intraretinal pigment was strongly associated with anterior uveitis. There was a strong correlation between uveitis and the inflammatory chorioretinal sequelae: retinitis, intraretinal pigment, subretinal fibrosis, and optic neuropathy. These findings indicate that considerable visual impairment associated with rain forest onchocerciasis is common and is due largely to chorioretinal disease.

Longitudinal study of lesions of the posterior segment in onchocerciasis.

Onchocerciasis is a major cause of blindness, and much of the blindness due to onchocerciasis is caused by chorioretinitis. Little is known about the progression of lesions in the posterior segment in either untreated or treated disease. The authors studied the progression of onchocercal chorioretinitis in 57 patients from 1 to 3 years. Changes were documented from detailed ocular examinations, fundus photographs, and fluorescein angiograms, and included live intraretinal microfilariae, intraretinal hemorrhages, cotton-wool opacities, intraretinal pigment, white and shiny intraretinal deposits, retinal pigment epithelial window defects, and atrophy. Depigmentation at the edge of chorioretinal scarring progressed at a rate of up to 200 microns per year. Ivermectin or mebendazole treatment did not appear to alter the progress of depigmentation at the edge of chorioretinal scars. These observations suggest that onchocercal chorioretinitis is associated with early changes in the retina and retinal pigment epithelium, and that disease in the posterior segment may progress rapidly.

Effect of single-dose ivermectin therapy on human Onchocerca volvulus infection with onchocercal ocular involvement.

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.

Prevalence of Hypertension in Rural West Africa

The prevalence of hypertension in rural African communities has been reported previously to be relatively low, with prevalence rates ranging between 2.5% and 10.9%. The authors obtained blood pressure recordings in 3,588 adult residents (age > 20 years) of the Liberian Agricultural Company rubber plantation, located in rural Liberia, West Africa. Blood pressures were obtained using automated digital blood pressure machines in a house-to-house survey. Individuals with a systolic blood pressure greater than 139 mm Hg or a diastolic blood pressure greater than 89 mm Hg were referred to a central site, where three subsequent blood pressure determinations were made, the mean of which was used to determine whether people were hypertensive. The overall prevalence of hypertension (blood pressure > 139/89 mm Hg) was 12.5%. Hypertension was most common in the older women (prevalence 5.7% in women age 20–24 years old, 50% in women older than 55). Using more stringent criteria for hypertension, systolic blood pressure greater than 159 mm Hg or diastolic blood pressure greater than 94 mm Hg, 20% of women between 50–54 had hypertension and 26% of the women older than 55 had hypertension. In some ethnic groups, the prevalence of hypertension was as high as 25%. Based on these results, the prevalence of hypertension in some rural African communities may be higher than reported previously, particularly in older women and among certain ethnic groups, possibly suggesting a strong hereditary component.

The Onchocerca volvulus homologue of the multifunctional polypeptide protein disulfide isomerase

Protein disulfide isomerase (PDI) functions to catalyze the formation of correct disulfide bonds in nascent proteins, and also acts as one of the subunits of prolyl-4 hydroxylase, the enzyme responsible for the oxidative maturation of procollagen. Since the cuticle of parasitic nematodes consists primarily of a network of collagen molecules which are connected through intermolecular disulfide bonds, PDI might be expected to be involved in the process of cuticle biosynthesis. The isolation and characterization of a cDNA encoding the PDI homologue of Onchocerca volvulus is described. This cDNA contains a single, long open reading frame that encodes sequence motifs identical to the two known active sites of PDI for isomerase activity. The O. volvulus PDI appears to be encoded by a single copy gene. Both in situ hybridization and immunolocalization data suggest that PDI is both spatially and temporally regulated in O. volvulus. The pattern of spatial and temporal regulation is consistent with the involvement of PDI in the biosynthesis of the parasite cuticle. The parasite protein appears to be an antigen recognized by a minority of individuals exposed to O. volvulus.