Onchocerciasis

Published on 16/03/2015 by admin

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Onchocerciasis

Michele E. Murdoch

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

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Onchocerciasis is a major tropical parasitic infection caused by the filarial worm Onchocerca volvulus and is transmitted by blood-sucking Simulium spp. blackflies, which breed near fast-flowing rivers. Global estimates suggest that 37 million people carry O. volvulus, most of whom live in Africa, and a total of 90 million people are considered at risk of infection because of where they live. The disease is endemic in 23 countries in sub-Saharan Africa; small foci also exist in the Yemen and Central and Southern America (Mexico, Guatemala, Ecuador, Venezuela, and Brazil). Mass invermectin treatment has now eliminated or interrupted transmission in ten of the thirteen foci in the Americas, and in 2011 Colombia became the first country to achieve certification for elimination of onchocerciasis. The first manifestation of infection is usually intense pruritus, and subsequently a wide variety of acute and chronic skin and eye changes develop. The socioeconomic consequences of onchocerciasis are most marked in hyperendemic areas in sub-Saharan Africa. Globally, approximately 270 000 people are blind and 500 000 have significant visual loss as a direct consequence of onchocerciasis. A multi-country study in Africa revealed that 42% of the adult population in endemic villages suffered from pruritus, and 28% of the population had onchocercal skin lesions.

Management strategy

The mainstay of treatment is ivermectin. Ivermectin is a safe, effective microfilaricide (i.e., it kills the immature larval stages of filarial worms), but it does not kill the adult worms. After a few months of dosing, the numbers of microfilariae in the skin gradually increase back towards pre-treatment levels and treatment has to be repeated throughout the lifespan of the adult worm (10–14 years).

Wolbachia spp. symbiotic endobacteria have been identified as essential for the filarial worms’ fertility, and offer novel targets for treatment. Additional treatment with doxycycline to sterilize the worms significantly enhances ivermectin-induced suppression of microfilaridermia.

The approach to treatment of onchocerciasis varies for (1) treatment of individuals outside of endemic areas, (2) treatment of individuals within endemic areas, and (3) mass treatment programs.

Mass treatment programs

Three regional programs have been established to coordinate global control. The Onchocerciasis Control Program (OCP, 1974–2002) successfully used aerial larviciding of rivers in West Africa to control the vector blackfly, and more recently it has distributed ivermectin to control any recrudescence. The Onchocerciasis Elimination Program in the Americas (OEPA), which started in 1991, uses 6-monthly mass ivermectin therapy and aims to eliminate onchocerciasis from the region by 2015. The largest program, the African Program for Onchocerciasis Control (APOC), commenced in 1995 and has been extended to run until 2015. It consists of large-scale annual community-directed treatment of ivermectin in 15 non-OCP countries and four ex-OCP countries. Its original aim was to reduce onchocerciasis until it was no longer a public health problem but this was revised in 2010 to aim for elimination. By 2015 the program intends to treat more than 90 million people.

In forested areas of central Africa and Sudan which are co-endemic with loiasis, ivermectin cannot be used because it causes serious neurological adverse reactions including encephalopathy. Whereas lengthy doxycycline regimes are deemed impractical for main large-scale treatment of onchocerciasis, in areas co-endemic with loiasis, doxycycline is a safe alternative as it is inactive against Loa loa because of the absence of Wolbachia.

First-line therapies

imageIvermectin A
imageIvermectin combined with doxycycline A

The effects of ivermectin on onchocercal skin disease and severe itching: results of a multicentre trial.

Brieger WR, Awedoba AK, Eneanya CI, Hagan M, Ogbuagu KF, Okello DO, et al. Trop Med Int Health 1998; 3: 951–61.

The effects of ivermectin were assessed in 3-monthly, 6-monthly, and annual doses in 4072 villagers in forest zones of Ghana, Nigeria, and Uganda who underwent interviews and clinical examinations at baseline and at five follow-up visits. Reactive skin lesions were categorized as acute papular onchodermatitis, chronic papular onchodermatitis, and lichenified onchodermatitis. From 6 months onwards there was a 40–50% reduction in the prevalence of severe itching after ivermectin treatment compared to the placebo group. Also, a greater reduction in prevalence and severity of reactive skin lesions over time was seen in those receiving ivermectin. The differences between the various ivermectin treatment regimens were not significant.

A trial of a three-dose regimen of ivermectin for the treatment of patients with onchocerciasis in the UK.

Churchill DR, Godfrey-Faussett P, Birley HDL, Malin A, Davidson RN, Bryceson ADM. Trans R Soc Trop Med Hyg 1994; 88: 242.

As ivermectin is also thought to suppress embryogenesis in adult worms, the efficacy of three doses of ivermectin given at monthly intervals was studied to determine whether such a regimen could lead to a greater suppression of microfilaridermia. Thirty-three patients (of whom 27 were European) with onchocerciasis were treated with a single dose of 150–200 µg/kg ivermectin and observed in hospital for 72 hours. Second and third doses were given as outpatient treatment respectively 1 and 2 months later. Patients were followed up at 3-, 6-, and 12-monthly intervals after the last dose of ivermectin. The patients with positive skin snips prior to treatment were compared with patients given a single dose of ivermectin in a previous study (Godfrey-Faussett P., et al., 1991, see below). Relapses occurred slightly less frequently after three doses. In contrast to studies in West Africa, where reactions to ivermectin are rare, 17 patients (52%) had reactions. The authors therefore recommend that the first dose of ivermectin for lightly infected expatriates be given in hospital.

Endosymbiotic bacteria in worms as targets for a novel chemotherapy in filariasis.

Hoerauf A, Volkmann L, Hamelmann C, Adjei O, Autenrieth IB, Fleischer B, et al. Lancet 2000; 355: 1242–3.

The activity of doxycycline against Wolbachia spp. and the fertility of adult female worms were assessed by examination of excised subcutaneous onchocercal nodules in 22 Ghanaian individuals treated with doxycycline 100 mg daily for 6 weeks and 14 untreated controls. Immunohistology with an antibody to bacterial heat shock protein-60 was used to assess the presence or absence of Wolbachia spp., and the morphology of female worms was examined. In addition, PCR reactions using, firstly, endobacterial primers, and, secondly, nematode primers, were performed. None of the treated worms had usual bacterial loads, and there was total suppression of normal embryonic worm development during early oocyte/morula stages, whereas nodules from untreated controls showed normal embryogenesis.

Depletion of Wolbachia endobacteria in Onchocerca volvulus by doxycycline and microfilaridermia after ivermectin treatment.

Hoerauf A, Mand S, Adjei O, Fleischer B, Büttner DW. Lancet 2001; 357: 1415–6.

The Ghanaian participants in this study were not randomized because this was not acceptable to the village elders. Instead, the first 55 patients were allocated to ivermectin and doxycycline, and the next 33 to ivermectin alone. Doxycycline 100 mg daily was given from the start of the study for 6 weeks. Subgroup A (31 doxycycline-treated and 24 controls) was given ivermectin 2.5 months after the start of the study and subgroup B (24 doxycycline-treated and nine controls) 6 months after the onset of the study. The results suggested a complete block in worm embryogenesis for at least 18 months after treatment with ivermectin and doxycycline.

The principle of targeting Wolbachia spp. with ivermectin in combination treatment offers the potential of interrupting transmission. Shorter anti-Wolbachia spp. regimens (either with other antibiotics or in combinations) are needed for mass treatment of endemic areas.

Second-line therapies

imageAlbendazole A

Other therapies

image Suramin D
image Future therapies: new macrofilaricides  

WHO researchers start trial on a new drug for river blindness.

Siva N. BMJ 2009; 339: b2755.

Moxidectin is a macrofilaricidal drug that shows a higher potency than ivermectin in animal models. A WHO-TDR/Wyeth phase III trial is currently underway in 15 000 people at four study sites in Ghana, Liberia, and the Democratic Republic of Congo comparing moxidectin with ivermectin. Since moxidectin has the same mode of action as ivermectin, whether it could replace ivermectin in the event of resistance is unknown.

The Bill and Melinda Gates Foundation is supporting research to optimize treatment regimens (Death of Onchocerciasis and Lymphatic Filariasis, DOLF; www.dolf.wustl.edu). Studies include attempts to reformulate flubendazole, a known effective macrofilaricide, in order to improve its bioavailability.

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