Active substance: Doxycycline
This candidate molecule is well-positioned for onward development and has the potential to make a significant impact on communities affected by filariasis.
Onchocerciasis river blindness and lymphatic filariasis elephantiasis continue to inflict serious public health problems throughout tropical communities, globally affecting more than 38 million and 120 million people, respectively.
These two neglected tropical diseases are caused by the parasitic filarial nematodes Onchocerca volvulus onchocerciasis, Wuchereria bancrofti, Brugia malayi, and Brugia timori lymphatic filariasis 1. Global programs for control and elimination have been developed, but existing approaches target only microfilariae and require prolonged delivery with high treatment coverage to break the transmission cycle of the long-lived adult worm 2.
One of the major limitations occurs in areas that are co-endemic with another filarial infection caused by Loa loa, due to the risk of a rare severe adverse event associated with the rapid killing of L. There are also concerns over recent evidence of reduced efficacy of ivermectin and the possible development of resistance.
An alternative approach is to target the Wolbachia bacterial endosymbionts of Onchocerca volvulus with the antibiotic, doxycycline. In an area of Cameroon co-endemic for onchocerciasis and loiasis we conducted a trial comparing doxycycline with or without ivermectin treatment to ivermectin treatment alone.
The trial indicates that anti-wolbachial therapy is a feasible alternative to ivermectin in communities co-endemic for onchocerciasis and loiasis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Introduction Onchocerciasis also known as River Blindness is a chronic disease induced by the filarial nematode Onchocerca volvulus. An estimated 37 million individuals are infected worldwide with 90 million at risk of infection, mainly in Sub-Saharan Africa.
Adult worm infections establish within subcutaneous nodules onchocercomas and produce microfilariae mf, which parasitize skin and eye tissues.
Mf are the transmissive stage for black fly vectors and are also responsible for the major disease pathologies of onchocerciasis, including intense troublesome itching, dermatitis, atrophy, visual impairment and blindness.
Currently, the only drug available to treat onchocerciasis is ivermectin MectizanTM, Merck. Ivermectin is generally a safe and effective microfilaricide and has been used successfully in community-directed treatment programs aimed at both reducing the burden of disease and controlling transmission since 1987,.
Ivermectin has some macrofilaricidal activity against female adult worms after 6 years of exposure, or when given repeatedly at three-monthly intervals,. Higher doses of ivermectin do not improve on this activity and such regimens are contraindicated due to the occurrence of visual problems.
Another anti-filarial drug, diethylcarbamazine DEC, is also contraindicated due to the incidence of treatment-associated blindness and the frequent development of potentially life threatening adverse reactions, known as Mazzotti Reactions,.
There are three major limitations of a sole reliance on ivermectin for onchocerciasis control.
Firstly, its use in areas co-endemic with Loa loa, a tissue dwelling filariae that gives rise to blood circulating mf and found principally in forested regions in Africa.
Reports of severe adverse reactions SAE, including encephalopathy, coma and death, in the Central Africa region following mass distribution of ivermectin have introduced serious concerns and disruptions to onchocerciasis control programs.
Although the mechanism of ivermectin-associated SAE has not been fully elucidated.
The intensity of L. Secondly, because ivermectin principally targets the mf stage, continuous delivery of annual treatment is required for at least 15—17 years to interrupt transmission as demonstrated in some endemic areas of Africa.
In other endemic areas of Africa this strategy is unlikely to lead to the interruption of transmission due in part to civil strife and conflict, insufficient health infrastructure and political commitment to funding for sustained control programmes, which together compromise the eradicability of onchocerciasis in Africa.
The third limitation is that such a long term, community-based strategy based on a single drug intervention is potentially vulnerable to the development of drug resistance. Recent reports from Ghana show evidence of sub-optimal efficacy of ivermectin in communities receiving 6—18 rounds of treatment,,.
Parasites from these communities show genetic changes associated with resistance to ivermectin in other nematodes and increase the concern of resistance to ivermectin developing in onchocerciasis,.
Considering the absence of any safe alternative to ivermectin, there is an urgent need to identify novel anti-filarial drugs.