New findings in animal models

One focus of this symposium was the impact of filarial infections on other parasitic diseases. A now well-known feature of the former is the ability to dampen the host's immune responses in order to increase parasite survival chances. Rick Maizels summarized the results of studies indicating the induction of regulatory T cells by excretory–secretory products of Heligmosomoides polygyrus, termed HES. These products were found to contain an activity similar to mammalian transforming growth factor-beta (TGF-β), a known inducer of regulatory T cells. Many laboratory and field studies are currently addressing how these regulatory or other mechanisms influence co-infections. Filarial co-infection experiments, presented in this symposium, have shown two very different sides of the coin, reflecting the current literature, with a wide range of different outcomes dependent on the host, the parasite and the sequence of infection. Sabine Specht addressed the protective effect of murine filarial infection on a subsequent Plasmodium infection, with a sterile protection, i.e. absence of P. berghei parasitaemia, seen only after filarial infection and correlating with the presence of filarial offspring (microfilariae) (Fernandez Ruiz et al., Reference Fernandez Ruiz, Dubben, Saeftel, Endl, Deininger, Hoerauf and Specht2008). Coralie Martin, on the other hand, showed data obtained when two nematode infections (filariae and oxyurids) were inoculated at the same time into a murine host. This apparently leads to competition, resulting in a reduced number of parasites of both species.

Control strategies for onchocerciasis

Attempts to eliminate human filarial infections have been implemented for more than 25 years. In the Onchocerciasis Control Programme (OCP) in West Africa insecticides were used to kill the larvae of Simulium spp. Since the closing of OCP in 2002, control of onchocerciasis relies almost exclusively on antiparasitic mass drug administration (MDA) within the African Programme for Onchocerciasis Control (APOC), launched in 1995. This became possible as a result of the donation of ivermectin (IVM, Merck & Co.), which had been used successfully since 1987 for the treatment of onchocerciasis and lymphatic filariasis (LF) in humans, effectively reducing the number of microfilariae. Onchocerca volvulus microfilarial densities decreased by 92–99% during the first month after ivermectin treatment. It is assumed that adult female worms, after losing their fecundity, gradually resume microfilarial production over 11 months, reaching a new production level that is on average 35% lower than before treatment (Basanez et al., Reference Basanez, Pion, Boakes, Filipe, Churcher and Boussinesq2008). Many years of IVM distribution successfully reduced transmission of infective larvae and cutaneous and ocular morbidity.

Despite progress towards elimination of onchocerciasis, early hopes that mass treatment with IVM would eradicate the disease by breaking transmission have not been realized (Borsboom et al., Reference Borsboom, Boatin, Nagelkerke, Agoua, Akpoboua, Alley, Bissan, Renz, Yameogo, Remme and Habbema2003). This is due in part to socio-economic reasons, but mainly to the biology and transmission of O. volvulus. In this symposium, Odile Bain reported that vectors ingesting low numbers of Mf, which would be the situation in an area after MDA, have higher transmission efficacy when compared to vectors with high numbers of Mf. For example, after uptake of 1–3 Mf by Simulium sirbanum, a savanna vector of O. volvulus, 33% of the parasites can develop up to the stage of infective larvae in the haemocoel, accounting for the larvae most likely to be transmitted, whereas only 5% can be found, when 20–75 microfilariae are ingested. Thus, the reduction in microfilarial density in the human population does not result in the expected reduction of the transmission rate, because both parameters are not proportionally related, but rather inversely correlated (density-dependent limitation) (Bain, Reference Bain1971; Churcher & Basanez, Reference Churcher and Basanez2008). Another observation related to MDA is that of Ben Makepeace and Sandy Trees, who showed that cattle infected with Onchocerca ochengi become more susceptible to infection after ivermectin treatment (Njongmeta et al., Reference Njongmeta, Nfon, Gilbert, Makepeace, Tanya and Trees2004). In addition, macrofilaricidal activity of ivermectin is rather limited, making repeated treatment necessary, increasing the potential for the development of resistance, as indicated by recent data (Ardelli & Prichard, Reference Ardelli and Prichard2004; Awadzi et al., Reference Awadzi, Attah, Addy, Opoku, Quartey, Lazdins-Helds, Ahmed, Boatin, Boakye and Edwards2004; Bourguinat et al., Reference Bourguinat, Pion, Kamgno, Gardon, Duke, Boussinesq and Prichard2007).

The density-dependent mechanisms taking place in the biology of Onchocerca transmission, coupled with the fact that treatment relies on only one drug that does not kill the adult worm, make it likely that it will be impossible to eliminate O. volvulus from Africa with the current tools used in MDA. Therefore what is needed is the development of a safe and effective macrofilaricide or long-term sterilizing drug, and/or a vaccine. Vaccination is the most cost-effective means of disease control. However, taking into account that the filarial genome encodes for 15,000–18,000 proteins with, until now, only a handful tested, finding those proteins that are able to stimulate the host's immune system requires intensive investigation. The appropriate priming of an antifilarial immune response has been discussed by Simon Babayan. New approaches, such as proteomics and transcriptomics, will support the search for promising candidates in the future.

Sabine Specht (for Achim Hoerauf) summarized the current developments of antiwolbachial therapy. This recently developed treatment principle relies on the efficacy of tetracycline antibiotics to deplete the Wolbachia endosymbionts, which are essential for larval moulting, adult female worm fertility and adult survival in those filarial species that harbour them. This was first shown in several models of filariasis in vitro and in vivo (Bandi et al., Reference Bandi, McCall, Genchi, Corona, Venco and Sacchi1999; Hoerauf et al., Reference Hoerauf, Nissen-Pähle, Schmetz, Henkle-Dührsen, Blaxter, Büttner, Gallin, Al-Qaoud, Lucius and Fleischer1999, Reference Hoerauf, Volkmann, Paehle, Schmetz, Autenrieth, Büttner and Fleischer2000b; Langworthy et al., Reference Langworthy, Renz, Mackenstedt, Henkle-Dührsen, Bronsvoort, Tanya, Donnelly and Trees2000; Townson et al., Reference Townson, Hutton, Siemienska, Hollick, Scanlon, Tagboto and Taylor2000). In humans, the use of doxycycline provides a new tool to induce long-term sterility of adult female worms (Hoerauf et al., Reference Hoerauf, Volkmann, Hamelmann, Adjei, Autenrieth, Fleischer and Buttner2000a). In a more recent study, in addition to long-term sterility, a macrofilaricidal activity of 60–70% against O. volvulus was also achieved with doxycycline (Hoerauf et al., Reference Hoerauf, Specht, Buttner, Pfarr, Mand, Fimmers, Marfo-Debrekyei, Konadu, Debrah, Bandi, Brattig, Albers, Larbi, Batsa, Taylor, Adjei and Buttner2008), thus rendering this drug the only non-toxic macrofilaricidal compound against this parasite. However, since treatment has to be repeated daily for 4–6 weeks, this regimen is currently considered to be too long for application as part of mass administration programmes.

Community-directed treatment

To circumvent this, transfer of treatments to the responsibility of the village through community-directed treatment (ComDT) could make antiwolbachial therapy possible, as Samuel Wanji reported. Initially, the development of ComDT strategy was a response to the need for a cost-effective and sustainable method for the mass treatment with ivermectin in endemic areas in Africa, many of which still have weak healthcare infrastructures. This strategy, which could be used as a model for the development of other control programmes, is a potential entry point in the fight against other diseases of public health importance (Homeida et al., Reference Homeida, Braide, Elhassan, Amazigo, Liese, Benton, Noma, Etya'ale, Dadzie, Kale and Seketeli2002). In order to explore the feasibility of a community-directed approach in the treatment of onchocerciasis using doxycycline, Wanji's group carried out a study in an area where Loa loa is co-endemic. This area was chosen because several studies pointed out that high microfilaraemia is associated with severe and sometimes fatal encephalopathic reactions in L. loa infected patients who had taken ivermectin against onchocerciasis (Gardon et al., Reference Gardon, Gardon-Wendel, Demanga, Kamgno, Chippaux and Boussinesq1997; Boussinesq et al., Reference Boussinesq, Gardon, Gardon-Wendel, Kamgno, Ngoumou and Chippaux1998), giving a further reason for alternative treatment strategies. The treatment was conducted by the community itself after introduction of health processes and ComDT concepts, in order to encourage community ownership from the beginning. In 35 participating communities a total of 190 health implementers were trained for the population census and the distribution of drugs. Of the individuals being eligible for treatment, about two-thirds started the 6-week doxycycline treatment, with over 90% completing it. Community health implementers also reported that a reasonable number of those who took the treatment were very satisfied, as the drug has relieved them from many health problems, such as skin manifestations, body pains and improvement of appetite. In addition, no severe adverse reactions were reported. Individuals who refused treatment at the beginning or who took herbal medication, are now requesting doxycycline treatment, after positive feedback by others.

These promising results therefore indicate that a community-directed approach can be used to carry out a 6-week doxycycline treatment in onchocerciasis endemic areas. The observed high compliance, associated with the high treatment completion rate, good coverage of the eligible population and absence of severe adverse reactions are important indicators of acceptability of the treatment by the population (Wanji et al., manuscript in preparation).

In parallel, antiwolbachial chemotherapy of onchocerciasis (and LF) is becoming established as an additional approach for treatment of individuals who have left an area of high transmission or need a drug that reduces disease symptoms. A detailed overview of this issue has been published (Hoerauf, Reference Hoerauf2008). As endemic countries develop economically, so do health programmes that will allow better care of individuals (e.g. establishment of a health insurance system in Ghana). Doxycycline may also be applied in areas where a sub-optimal performance of IVM has been indicated, as for example in the Asubende focus in Ghana (Osei-Atweneboana et al., Reference Osei-Atweneboana, Eng, Boakye, Gyapong and Prichard2007). Worm populations that might have acquired some degree of resistance may thus be eliminated with an existing drug to prevent resistance from spreading further. Doxycycline without IVM may also be used in areas where onchocerciasis and loiasis are co-endemic and where IVM treatment has resulted in the occurrence of encephalopathy (Mackenzie et al., Reference Mackenzie, Geary, Prichard and Boussinesq2007). In addition, the Onchocerciasis Elimination Program for the Americas is contemplating ‘end-game’ scenarios where transmission has apparently been interrupted and where only a limited number of people remain infected with O. volvulus (WHO, 2007). For this scenario, doxycycline treatment is being considered and is currently awaiting authority approval (F. Richards, Atlanta, USA, personal communication).

The potential of chemotherapy with antibiotics is far from being fully exploited; new combinations of registered drugs are currently being investigated or already being used in human trials, and the list of potentially active compounds is growing rapidly. High-throughput assays are being set up in order to analyse several thousands of compounds, newly synthesized and already registered for human use, but yet not tested in various combinations for antibiotic activity (www.a-wol.com). As for now, doxycycline has fulfilled the requirements of a macrofilaricidal drug. While the treatment duration still makes it not useful for MDA, it is being administered in increasing numbers in cases where the patients seek individual treatment and doctors are charged with delivering the best possible medication.

Currently an alternative to IVM is under investigation. Moxidectin (MOX), a milbemycin with a structure similar to that of IVM, is being tested in a phase II trial funded by Tropical Disease Research (a special programme run by the WHO and the World Bank) in collaboration with Wyeth in Ghana. This drug has not demonstrated macrofilaricidal activity in bovine onchocerciasis; however, it does have a longer half-life than IVM, so that a more sustained effect on microfilariae was observed (summarized by Trees et al., Reference Trees, Graham, Renz, Bianco and Tanya2000; Boussinesq, Reference Boussinesq2008). Results of the human trial will show whether MOX can be used as alternative for IVM in MDA.