treatment of onchocerciasis

DISEASE MANAGEMENT Drugs 1996 Dec; 52 (6); 861-869 0012-6667/96/0012-0861/$09.00/0 ----------- ---© Adis International limited. All rights reserved.

Treatment of Onchocerciasis Yves Van Laethem and Cristina Lopes Department of Infectious Diseases, Saint-Pierre University Hospitat Brussels, Belgium

Contents Summary 1. Overview

1 .1 Epidemiology 1.2 The Parasite

2. The Disease 3. Diagnosis .... 4. Treatment . . . .

4.1 Older Drugs 4.1.1 Microfilaricidal Agents 4.1.2 Macrofilaricidal Agents.

861 862 862 862 862 863 864 864 864 864 864 865 865 866 866 866 867 867 868 868

4.2 Ivermectin . . . . . . . . . . . . 4.2.1 Identifying Who Needs to Be Treated. 4.2.2 Dose ......... . 4.2.3 Frequency . . . . . . . 4.2.4 Duration of Treatment 4.2.5 Adverse Effects .... 4.2.6 Resistance to Ivermectin .

4.3 Nodulectomy 5. Follow-Up . 6. Conclusion ....

Summary Onchocerciasis (,river blindness') has for several centuries been the scourge of people living in certain areas of the world where the disease is endemic. The treatment available up to 10 years ago, diethylcarbamazine, had very severe secondary effects. The availability of ivermectin - a well tolerated and highly effective microfilaricidal drug - has completely changed this scenario. Ivermectin is now considered to be the drug of choice for the treatment of onchocerciasis.

The prognosis for people with onchocerciasis has changed greatly. It is now possible to avoid the heavy infection loads seen previously, and patients, especially expatriates, may have their symptoms relieved by treatment. Ivermectin, used in mass treatment, may also improve the epidemiological situation, reducing the level of microfilariae in the skin of infected people and thus reducing the source for vector infestation. However, the treatment has to be repeated because the drug has no macrofilaricidal effect. Research today is focused on the finding of a drug able to destroy the adult worms that go on producing microfilariae for the length of their lives.

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1. Overview

1.1 Epidemiology

Onchocerciasis occurs predominantly in West Africa, but endemic areas stretch across the African continent, and there are foci of infection in Central and South America. 85 million people live in areas where onchocerciasis is endemic and thus are at risk for infection.[l] 18 million people are infected with onchocerciasis, 99% of them in AfricaP1 6 million are estimated to be in need of urgent treatment. Of those infected, 3 to 4 million have skin disease, and 1 to 2 million are blind or visually impaired. [31

Infection begins early in childhood, and more than 80% of the population are affected in some parts of West Africa; 30% have impaired vision and 10% are blind.l41 Onchocerciasis is therefore one of the leading causes of blindness in the developing world, leading to a mean reduction in life expectancy of 13 years.[51

The pattern of socioeconomic liability that has emerged as a result of human onchocerciasis in Africa has been particularly damaging. Because of debilitation and blindness, the patient is unable to maintain any type of productive activity for long. The desertion of many river valleys in the savannah zone that are agriculturally fertile has been attributed mainly to the effects of this disease.[61

It has been said that the microfilariae of the savannah form of the parasite are a great deal more pathogenic than those of the forest form. Its apparently increased corneal pathogenicity might be one of the factors causing the high blindness rates in the savannah, much of which is attributable to sclerosing keratitis.

1 .2 The Parasite

Onchocerca volvulus is spread by blackflies belonging to the genus Simulium, usually S. damnosum. These blackflies breed in fast-flowing rivers, and humans get bitten extensively when working near or washing in these rivers.

With its meal of blood, the blackfly ingests skindwelling microfilaria which then go through 2 fur-

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Van Laethem & Lopes

ther larval stages in the fly, completing their development over some 6 to 8 days until they become infective larvae in the proboscis. When the blackfly bites again, the larvae of O. volvulus escape through the membranous labrum into the wound, and penetrate the tissues to develop into adult filaria which are found clinically in nodules scattered around the body.

80% of the nodules, which may vary from the size of a split pea to that of a golf ball, contain 1 or 2 male and 2 or 3 female worms;P1 in exceptional cases, more than 50 worms may accumulate in 1 nodule. The females are very long and thin (20 to 80cm x 0.25 to 0.45mm), and they can live for about 9 to 14 years. During this time they produce many millions ofliving embryos (each about 220-300llm long) known as microfilariae.l81 Each day, 700 to 900 microfilariae are actively released one by one by the female worm.l91 Development to the point when the female worms begin to produce microfilariae takes about 1 year (10 to 16 months).

2. The Disease

It must be emphasised that many infected individuals in endemic areas are asymptomaticP1 Onchocerciasis - clinical disease from infection by O. volvulus - takes 3 predominant forms: eye disease, subcutaneous nodules (onchocercomata) and a pruritic, hypopigmented or hyperpigmented papular dermatitis. In addition, lymphadenopathy, mostly sclerosing, may also occur. Most of those manifestations are chronic, acute skin and eye symptoms being the exception.

The lesions seem to be due to the dead and degenerating microfilariae, their death occurring naturally or after treatment. Indeed, when they are alive, microfilariae (as well as adult worms) appear to be unaffected by the immune response of the host. [101

Blindness is the most important effect of the disease. However, dermatitis is also very distressing for numerous patients, and may lead to serious psychological effects and social isoiationP1

The dermatitis begins when dead microfilaria degenerate in the dermis. Pruritus is the most com-

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Treatment of Onchocerciasis

mon early manifestation of onchocerciasis; itching and scratching may be mild and intermittent or severe and unremitting. It may lead to excoriation and secondary infection. Pruritus may be the sole manifestation of the disease, especially in lightly infected individuals, and may be especially troublesome in expatriates.

3. Diagnosis

Four methods are available for the diagnosis of onchocerciasis. The most widely used and easiest method of diagnosis is the detection of microfilariae in a bloodless skin biopsy.£2l This 'skin snip' can be obtained by lifting the skin with the tip of a needle and excising a disk of dermis and epidermis with a razor blade, or, preferably, by using a corneoscleral punch.

Snips are usually taken from one or more standard sites (buttocks, iliac crests, scapula or lower calf) depending on where the clinical manifestations are most severe. For instance, in Latin America, where most lesions are located above the shoulders, snip tests are customarily performed on the shoulders, whereas in Africa, lesions and diagnostic procedures are done mostly on the iliac crests and buttocks. It may be necessary to take multiple skin snips from patients with light infection (up to six are usually well tolerated).

The snips, weighing up to 5mg, are then placed in distilled water or saline solution to allow microfilariae to emerge. Some authors suggest that tissue culture media may be useful, but there is no proven advantage. Most agree that examination under the microscope should be dony after 30 to 60 minutes, but a 3- to 4-hour waiting time may be usefuUlll If nothing is found at this time, another examination performed after 24 hours of incubation may improve the sensitivity of the test. This may be particularly valuable in patients with a low density of microfilariae in the skin (<3.5/mg of skin) as demonstrated by Taylor,l3l

Identification of the microfilariae is 100% specific. However, in some forest regions of equatorial Africa, differentiation from Mansonella streptocerca must be done, by measurements or by stain-

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ing the preparation. This is also sometimes the case with M. perstans (in Africa and South America) and M. ozzardi (in Central and South America).

The clinical detection of a typical nodule is good presumptive evidence of onchocerciasis. A definitive diagnosis can be made if adult worms can be identified in an excised nodule. Ultrasonography is a suitable noninvasive technique in the differential diagnosis of the nodules; however, its use is limited in endemic areas.

The clinical recognition of intraocular microfilariae is diagnostic of onchocerciasis. This research must be performed with a slit lamp. A useful method consists of getting the patient to sit with head between the knees for;;::2 minutes. Normally, the micro filariae are settled at the bottom of the anterior chamber, where they are not detectable with the slit lamp. When the sitting patient bends their head the microfilariae are resuspended in the chamber, but settle again when the head is raised. The microfilariae in the process of settling to sediment can be shown for several minutes when using a slit lamp. In developed countries, this easy-toperform and noninvasive technique may be the first step in the diagnosis. Obviously, if this research remains negative, snip tests must be performed to try to confirm the diagnosis.

In the future, immunological tests may help in the diagnosis. A recently cloned OV-16 antigen has performed extremely well in field testing in Africa, with a high level of specificity and, importantly, a higher level of sensitivity than skin positivity.[lll A 'cocktail' of 3 antigens (OV-16 plus OV-7 and OVU) has also been studied.[7] However, their definitive place is still to be characterised. Similarly, DNA probes are currently of limited help in the field.[7l

Use of the Mazzotti test (administration of diethylcarbamazine 50mg) is controversial in the modern literature. Most authors believe that this test, which is at least of great discomfort for most patients, is often dangerous and should not be used for diagnostic purposes. However, some specialists still use it in patients strongly suspected of onchocercial infection with repeated negative skin

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snips and eye examination. A modification of the test, with local application of 1 to 10% of diethylcarbamazine in anhydrous lanolin, is reported by some authors to provoke a typical local erythema in infected patients without systemic reactions.[12] Its use seems very confidential; more data concerning the sensitivity and specificity of this test are still needed.

4. Treatment

The primary aim of treatment in the individual patient is to reduce the number of microfilariae, which represent the tissue-damaging stage of O. volvulus.

The treatment of onchocerciasis has been radically improved by the introduction of ivermectin, an effective microfilaricidal drug causing few adverse reactions.

4.1 Older Drugs

4.1.1 Microfilaricidal Agents Diethylcarbamazine was introduced in the late

1940s. It is predominantly a microfilaricide affecting the neuromuscular system of the parasites, but it also promotes cellular cytotoxicity mediated by immune factors.

Despite its efficacy proved in several clinical trials and field studies, the adverse effects are numerous and frequent. Accelerated impairment of visual capacity has been reported because of aggravation of chorioretinallesions. Indeed, this inflammatory reaction may accelerate optic nerve disease, leading to permanent loss of visual function.[l3]

There is a highly significant relationship between the intensity of the infection and the incidence of most adverse reactions: hypotension, fever, adenitis and pruritus. However, arthralgia and tachycardia are not correlated with the intensity of the infection.l141

The Mazzotti reaction starts within 2 hours after administration of diethylcarbamazine and can be very unpleasant. Hence, it is impossible to treat patients on a community-wide scale using this drug. Diethylcarbamazine is therefore no longer


Van Laethem & Lopes

recommended for the treatment of onchocerciasis by the WHO.[7] In addition, accessibility to ivermectin has been greatly simplified by the Mectizan Donation Program, which will provide the drug free of charge for as long as necessary to treat everyone with the infection.

4. 1.2 Macrofilaricidal Agents Over 70 years ago, suramin was introduced into

clinical practice for sleeping sickness. Van Hoof et al. in 1947 were the first to report its use for onchocerciasis. It acts by damaging the intestinal epithelium of the worms and it is very effective in killing the adults.

However, this drug must be given intravenously, and its therapeutic index is narrow, often causing serious adverse reactions. Some patients exhibit a marked idiosyncrasy with digestive and neurological manifestations. Renal impairment and exfoliate dermatitis are other serious complications. The treatment of onchocerciasis with suramin is also associated with exacerbation of ocular lesions, occurring more frequently in patients with the more severe ocular manifestations.

For these reasons, treatment with suramin has been withheld by most clinicians, and should be restricted, as recommended by the WHO, to curative treatment of selected patients in nonendemic areas and for severe hyperreactive onchodermatitis uncontrolled by repeated ivermectin treatmentsPl In these cases, a total dose of 4g (or 66.7 mg/kg) should be given as follows to a 60kg adult: week 1, 200mg; week 2, 400mg; week 3, 600mg; week 4, 800rpg; weeks 5 and 6, 1000mg. A detailed review of adverse effects and patient monitoring has been published by the WHO, and must be consulted before using this drug.[2]

4.2 Ivermectin

Ivermectin ('Mectizan') is the current drug of choice, and is provided free of charge by the manufacturer, not only in multinational health programmes but also for compassionate use in the field and in developed countries.D5]

Ivermectin is a synthetic derivative of a macrocyclic lactose produced by the actinomycete Strep-

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tomyces avermitilis. It has broad spectrum antiparasitic activity against nematodes.[l6] It appears to be effective via its action as an agonist at yaminobutyric acid (GABA) receptors, impairing the neuromuscular function of the parasites and leading to paralysis.l17]

Although it is rapidly microfilaricidal, ivermectin does not cause a severe reaction in the eyes or skin, as seen with diethylcarbamazine.l 18]

Ivermectin does not kill the adult worm but appears to impair the release of micro filariae from the gravid female adult worm, which occurs after the first dose.[l9,20] However, after multiple doses at 3-month intervals, a one-third excess mortality of female worms over and above the levels in controls has been demonstrated in one studyPl]

Ivermectin also affects embryonic development in O. volvulus, which occurs after multiple dosesp2] Other potential mechanisms of action are still controversiaU23] Two recent papers have shown a gradual restitution of the cellular immune response of patients treated with ivermectin. These immunological changes may explain the long term suppression of skin microfilariae in previously chronically infected patients.[24,25]

The effect of repeated administration of ivermectin (150 Ilg/kg given annually or semiannually) may be summarised as follows:[7] a 90% decrease in the prevalence of ocular microfilarial loads after 2 to 4 years; 50 and 30% reductions, respectively, in the prevalence of early iridocyclitis and sclerosing keratitis after the same period; a less marked impact on posterior segment lesions (in one study, however, optical atrophy was reduced by one-third); no significant benefit in terms of visual acuity or blindness.

4.2. 1 Identifying Who Needs to Be Treated Because of the high efficacy and few adverse

effects of ivermectin, every patient proved to be infected and living in nonendemic areas must be treated. In the same areas, empirical therapy must also be considered for patients who are strongly suspected of infection on the basis of history and biological parameters, but having negative sniptests and normal ophthalmological examinations.


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In endemic areas, the practitioner should treat on an individual basis all patients presenting at health centres with (acute) onchodermatitis, symptomatic visual impairment or lesions discovered during ophthalmological examinations (with the possible exception of cases of isolated chorioretinal changes). There is still some controversy concerning the potential usefulness of quantitative microfilarial counting in the different parts of the eye as a criterion for treatment. All forms of acute onchodermatitis respond adequately to ivermectin; however, pruritus is not systematically reduced. [26,27]

In hyperendemic areas, according to Whitworth,[28] the drug will need to be given to all individuals (except those meeting the exclusion criteria; see section 4.2.5) at intervals of 6 months or longer, regardless of whether they have symptoms of the disease. This strategy is considered urgent where the prevalence of infection is >60% (or where the prevalence of palpable nodules is >40% in men) and highly desirable where the prevalence exceeds 40% (or palpable nodules >20%).[7] Should the resources be available, such a policy of large scale treatment has no clearly defined lower limit. It is often considered that an ideal threshold should be the prevalence below which the disease is sporadic, i.e. 15 to 30% for onchocerciasis.

It has been shown that regular treatment with ivermectin reduced the incidence of optic nerve disease in patients with microfilarial loads above 1Olmg, but had little effect in those with lower loadsp9] Nevertheless, all these patients should be treated.

4.2.2 Dose The optimal dose of ivermectin is 150 Ilglkg,

despite the fact that studies have demonstrated no significant difference in terms of efficacy when comparing doses of 100, 150 and 200 Ilg/kg.l30]

For most patients, the treatment consists of 2 tablets in the morning, fasting. The patients should remain fasting for 2 hours postdose to facilitate absorption of the drug.

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4.2.3 Frequency The frequency of administration is still very

controversial. Several different schemes of administration are advocated: • A single dose of 150 /lg/kg given annually.£31] • Therapy given 6-monthly.[32] • A single dose of ivermectin, repeated every 3 to

6 months as necessary. This regimen is likely to be the treatment of choice for patients in nonendemic areas, until a safer macrofilaricidal drug emerges.lll ]

• Three doses of ivermectin given at monthly intervals. A study in the UK has suggested that this regimen may be slightly better than a single dose in terms of suppression of microfilariae over 12 months.[33] Different objectives may justify such different

regimens. Most authors recommend administration once or twice a year, at least in endemic countries.

4.2.4 Duration of Treatment

In nonendemic areas, the number of retreatments is still not established. Nor is the need for retreatment throughout the full length of life of the macrofilariae (12 to 15 years) proven; indeed, at least one-third of patients treated by a single dose of ivermectin may be cured.[34]

After several doses of ivermectin (the number is still to be determined), strict follow-up of the clinical picture and biological parameters may be sufficient to determine the need for retreatment.

Obviously, the availability of a macrofilaricidal drug would shorten the duration of treatment. Different drugs are currently under investigation, the most promising being amocarzine (CGP 6140).[35]

In hyperendemic areas, retreatment every 6 months may be necessary (at least for the first year of treatment), as ivermectin does not kill the adult worm, which goes on producing micro filariae throughout its life.[36] Therefore, long term treatment is likely to be necessary, until the achievement of control of the vector and/or until a cheaper and safer macrofilaricidal drug becomes available. However, according to published papers, experience of annual or biannual treatment is limited to a period of 5 years.[37]


Van Laethem & Lopes

It is thought that pauses of several years in the treatment will be feasible, as several studies have demonstrated the high efficacy of multiple doses of ivermectin in reducing microfilaraemia. [38] It seems likely that alternate therapy could be administered. However, scientific data supporting this assumption are still lacking.

There is no proof that severe cases of onchocerciasis need more frequent retreatment.

4.2.5 Adverse Effects There is no doubt that ivermectin is a better tol

erated and more effective microfilaricidal agent than diethylcarbamazine for the treatment of onchocerciasis.

Adverse reactions after large scale treatment with ivermectin (a total of 50 929 persons treated and monitored for 72 hours) were reported in 9% of the patients; 2.4% had moderate reactions and 0.24% had severe reactions.[39]

The adverse effects recorded following the first treatment with ivermectin were, with decreasing frequency: oedema (limbs and face), fever, pruritus, generalised body pains, lymphadenitis and severe symptomatic postural hypotension (SSPH). Following subsequent treatments, these reactions were generally milder.[32] Oedema was the adverse reaction of greatest concern to patients, and this most commonly involved the face.l40] It could be explained by the predominantly lymphatic location of microfilarial death; indeed, the microfilariae density shows an increase by a factor of 1000 after treatment. [41]

Most reactions were reported during the first day of follow-up, the most severe being SSPH. However, this needed only simple symptomatic treatment, such as adopting the Trendelenburg position and, in limited cases, providing plasma expanders. The patients should also be advised to lie down when feeling dizzy. No deaths were attributable to ivermectin.

The incidence, but not the severity, of reactions after the fIrst dose of ivermectin was related to the pretreatment density of microfilariae in the skin,[42] except for cutaneous reactions.l43]

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There is still some controversy concerning the need for supervision of the treatment.

As severe adverse effects mainly appear after the initial dose, and most adverse reactions appear within 48 hours, it is commonly stated that the first treatment with ivermectin should take place under strict medical supervision.l44] However, in the field, ivermectin is considered to be sufficiently safe for large scale treatment, but monitoring by resident nurses for at least 24 hours is recommended. [39]

Davidson et al.[45] described a higher rate (61 %) of adverse reactions in expatriates treated with ivermectin. This could be a result of a more vigorous immune response than in indigenous adults with longstanding infection. As there is no increased frequency of adverse reactions to ivermectin in children, Whitworth et al.[46] concluded that this higher rate of reactions to treatment was likely to result from the different monitoring system used (policy of observation in hospital for 72 hours).

Ivermectin should not be used in pregnant women, in the first month of lactation, in children under 5 years of age or weighing <15kg, and in patients with very poor health - hence, only 60% of the total population in areas endemic for onchocerciasis are eligible for treatment when these criteria are applied.l8]

In areas endemic for Loa loa, heavy microfilariaemia with this parasite should be excluded. Ivermectin is also active against L. loa, and severe inflammatory reactions including eNS involvement with encephalitis leading to coma have been described, at least with diethylcarbamazine. Nothing has been shown to date during ivermectin therapy.

Some authors also advocate a restricted use during endemic periods of meningococcal meningitis, and in areas where sletlping sickness is endemic, because of potential neurological toxicity, as shown in animal models when the blood-brain barrier was impaired.

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4.2.6 ReSistance to Ivermectin Ivermectin resistance is well recognised in vet

erinarian practice. It has been detected in nematodes of goats and sheep.[47] Schoop[47] argues that onchocerciasis control programmes should administer ivermectin at the highest dose tolerable to kill as many microfilariae as possible, and decrease the risk of emergence of resistant forms. However, the life cycle of O. volvulus makes survival of ivermectin-resistant forms improbable in the short term. We also need to establish sensitive, easily interpretable in vitro methods to detect this resistance.[48]

4.3 Nodulectomy

A question that has always intrigued those interested in the pathophysiology of onchocerciasis is whether palpable nodules represent the majority of active parasites in a particular individual.

In Latin America, according to the studies done by Guderian et al.,[49] deep nodules in light to moderate infections may be the exception rather than the rule. Deep nodules would occur more frequently in chronic infections. These authors found a strong relationship between palpable nodules in onchocerciasis and O. volvulus microfilarial loads in the skin. They concluded that nodulectomy is a procedure beneficial to O. volvulus-infected patients in Ecuador, by reducing both microfilarial loads and the degree of pathology. [49]

In Guatemala, a national nodulectomy campaign has been carried out since 1935. The nodule prevalence declined from the decade 1940-1949 to the decade 1970-1979 in most of the selected areas.l50]

According to Guderian et al.,[49] again, the efficacy of this therapeutic measure could vary as a function of onchocerciasis prevalence. In hypoendemic areas, nodulectomy had a positive effect in reducing the intensity of infections and contributed to control of the advancement of the disease. In hyperendemic areas a positive effect was also observed, but new nodules developed rapidly.l51] However, nodulectomy is of clinical relevance

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only in Latin America, where most nodules are located on the head, in contrast with Africa.

5. Follow-Up

In nonendemic areas, follow-up is indicated to decide when there is no more need to treat, or when to re-treat. In endemic areas the only reason for such follow-up should be for scientific or epidemiological purposes. Patients in endemic areas will receive treatment, regardless of their symptoms, every 6 to 12 months.

6. Conclusion

The treatment of onchocerciasis has changed radically since the introduction of ivermectin. Although ivermectin is still far from being the 'final solution' for onchocerciasis, it has greatly simplified and improved the quality of patient treatment and the burden of this disease. However, the lack of an acceptable macrofilaricidal drug implies the repeated use of ivermectin in most infected patients.

In sporadic cases found in nonendemic areas ivermectin constitutes a good therapeutic tool, with a high efficacy and good tolerance. In endemic areas, it is generally an easily accessible drug, which avoids the progressive deterioration previously seen in highly infected cases.

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Correspondence and reprints: Dr Yves Van Laethem, SaintPierre University Hospital, Department of Infectious Diseases, 322 rue Haute (PL5), B-IOOO Brussels, Belgium.

Vol. 52, No.3, page 450: The list of those who reviewed the manuscript should have included O. Tajuma, Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan. The Editor regrets the omission.

[Fulton B, Benfield P. Moclobemide: an update of its pharmacological properties and therapeutic use. Drugs 1996 Sep; 52 (3): 450-74J

© Adis Intemational Limited. All rights reserved. Drugs 1996 Dec; 52 (6)

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