Onchocerciasis elimination: what`s left to do?

Onchocerciasis is a filarial disease caused by infection with Onchocerca volvulus, a vector-borne parasitic nematode transmitted via the bites of several Simulium black fly species. The disease is also known as river blindness because black flies breed in and bite near fast-flowing rivers, and because the most devastating sequela is irreversible loss of vision. High infection load, measured by the density of microfilariae (the larval progeny of adult worms) in the skin, is associated both with blindness incidence and excess human mortality. In addition to ocular sequelae, onchocerciasis is also responsible for skin disease and troublesome itching, which disturbs sleep and work patterns. Onchocerciasis represents a major public health problem in affected countries with up to 1.34 million disability adjusted life years (DALYs) lost in 2017. [1] This high number is driven by disease-induced disability and overall loss of economic productivity. The introduction of ivermectin in mass drug administration (MDA) has been extremely successful in reducing transmission and human morbidity. [2] However, treatment must be repeated at regular intervals (6 or 12 months) for 10-15 years and limitations exist in zones where Loa loa is co-endemic [3] due to severe adverse events, including fatalities, that may result from microfilaricidal treatment of individuals heavily infected with L. loa.

Mass drug administration: limitations

MDA with ivermectin has been extremely successful in reducing the onchocerciasis microfilarial burden resulting in reduction of clinical manifestations and interrupting transmission in some areas. The adult worm however is not permanently affected, and with a worm’s life span being 10-15 years, MDA campaigns need to continue for many years. Success of MDA is strongly related to 1) coverage of the population and 2) pre-intervention prevalence, making implementation of a sustainable MDA program extremely challenging in some areas. Thus, elimination of transmission appears feasible in low to moderate endemic areas with long-term MDA at high coverage (≥75%). [4] However, in other areas, this may be less successful because of high endemicity, low adherence, and lack of financial resources or political engagement.

Members of the NTD Modelling Consortium have used two mathematical models of onchocerciasis transmission dynamics and control (EPIONCHO and ONCHOSIM) to provide predictions of the elimination goals. [4] ONCHOSIM for example predicts there will be around fourteen million infected cases in the areas covered by the African Programme for Onchocerciasis Control (APOC) in 2025 with >4 million cases remaining with clinical manifestations. The total population at risk will be approximately 200 million in the countries formerly covered by APOC. [5] Success of MDA however continues to require extensive logistical efforts and financial commitments to ensure that treatment reaches all target recipients. Other drawbacks of MDA are inconvenience, loss of confidence in the elimination campaign, and possible drug resistance as described for ivermectin use in livestock. The effectiveness of MDA will therefore likely deviate from the model predictions and further delay the timeline to elimination.

The cost-effectiveness of current elimination strategies is currently being reconsidered and economic analyses are being conducted, [4] factoring in the expansion into currently untreated areas and prospects of more frequent rounds of MDA. This also includes support by additional tools such as the recently registered moxidectin, [6] the triple therapy with ivermectin, albendazole and diethylcarbamazine, [7] as well as a hypothetical macrofilaricide, enhanced surveillance or test and treat strategies. Given the current elimination goals, the additional benefit of optimized strategies and full engagement into a drug development pipeline for new treatments needs to be seriously considered.

Another aspect of MDA is that treatment of the entire population requires a careful risk-benefit analysis. In combatting infectious diseases, drug administration campaigns are important strategies for dealing with public health issues. There is however a balance between making MDA compulsory, which potentially limits the autonomy of an individual, and the possibility of opting out, which could jeopardize the entire effort of the campaign as onchocerciasis may be re-introduced to the treated community. [8] Unlike a vaccine, MDA does not provide an immediate benefit for an uninfected person. An individual may find repeated MDA inconvenient or may lose confidence in the MDA campaign. With effective MDA, the benefits for the entire population clearly exceed the risk, but if prevalence has been reduced, the risk/benefit ratio may be different.

Alternative approaches are needed

A macrofilaricidal drug that kills the adult worm or has a long-term sterilizing effect offers the advantage of reducing the number of MDA cycles and would be a powerful addition to the global strategy for eliminating onchocerciasis. A new and registered macrofilaricide or long-term sterilizing treatment would have considerable advantages and could be used for:

1. MDA, provided it is safe and well tolerated;
2. Test-and-treat (TNT) strategies for treatment of patients in endemic areas outside MDA campaigns if diagnostic tools are available, especially in “mop-up” campaigns after the disease burden has been reduced by MDA programs rendering them no longer cost effective, or in areas where regular ivermectin distribution is difficult;
3. Test-and-not-treat (TaNT) campaigns in areas where L. loa is co-endemic;
4. Appropriate case management.

The Drugs for Neglected Diseases initiative (DNDi) is a non-profit research and development organization based in Geneva, Switzerland that is committed to developing new treatments for patients with neglected tropical diseases, including those infected with onchocerciasis.

In general, helminth infections affect mostly poor and marginalized populations. Whereas the development of new treatment options is commercially not attractive, the development of anthelmintic drugs for animal health is lucrative. Commercially available animal health products should therefore be considered and evaluated for human indications to shorten drug development timelines. Two potential pathways are being considered, targeting the filarial parasite directly (a macrofilaricidal drug) or its endosymbiont (Wolbachia bacteria).

In collaboration with the Bayer AG pharmaceutical company, DNDi is currently developing emodepside, an anthelmintic veterinary product for cats and dogs. It inhibits parasite development and elicits profound impairment of neuromuscular function with broad-spectrum efficacy against gastrointestinal [9] as well as filarial nematodes, [10] which results in rapid paralysis (inhibition of locomotion, feeding and slowed development). The mechanism of action of emodepside is complex and not fully understood, but it predominantly exerts its anthelmintic activity through selective activation of the nematode isoform of a potassium channel called slowpoke (Slo-1). Emodepside has proven antifilarial potential in preclinical models, [10] warranting its further development.

Adult filarial worms causing onchocerciasis carry an obligate symbiotic endobacterium, Wolbachia, which is essential for development, fecundity, and ultimate survival. Clinical studies with doxycycline show that it depletes these endobacteria. Although it has no immediate effect on the adult worms, they will die in time. [11] It is effective in lowering microfilarial load in regions with suboptimal response to ivermectin. [3]

Although doxycycline is effective as a macrofilaricide via its anti-Wolbachia activity, it is contraindicated in pregnant women and children through the age of eight due to developmental toxicities. Furthermore, four to six weeks of daily therapy with doxycycline are required to lower the Wolbachia population sufficiently to produce a cidal effect in the adult worm. Consequently, doxycycline is unsuitable for MDA and far from ideal for patient management. Improved treatments are warranted.

The pharmaceutical company AbbVie has developed a tylosin analogue that has potent anti-Wolbachia and antifilarial activity. [12,13] In pre-clinical models, the compound (ABBV-4083) has demonstrated equal or superior efficacy to doxycycline with a shorter duration of treatment. In a collaboration with AbbVie, the DNDi and the Liverpool School of Tropical Medicine, ABBV-4083 is now further progressing into proof-of-concept studies in infected volunteers.

Summary

Years of experience have shown that current MDA with ivermectin has severe shortcomings in onchocerciasis control. New approaches are needed, such as development of macrofilarial drugs, to supplement current MDA in order to meet the sustainable development goals.

References

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