An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana

Abstract

If ivermectin-based programmes for the control of human onchocerciasis are to be successful, the drug must remain effective for as long as necessary. In an open, case-control study, an attempt was made to determine if the persistent, significant, Onchocerca volvulus microfilaridermias seen in some individuals who had received at least nine treatments with ivermectin were the result of the development of drug resistance in the parasite. Twenty-one of these 'sub-optimal' responders (cases) were matched, by age, weight, number of treatments, locality and skin microfilarial counts, with seven amicrofilaridermic responders and 14 ivermectin-naive subjects. The number of treatments taken, any potential drug interactions and significant underlying disease were determined from detailed clinical and laboratory studies. Each subject was treated with ivermectin during the study, so that plasma concentrations of the drug could be determined for 72 h from the time of dosage. The microfilarial and adult-worm responses to this treatment were assessed from skin microfilarial counts (obtained before the treatment and at days 8, 90 and 365 post-treatment), day-90 embryogrammes, and the results of fly-feeding experiments. Parasite-sensitivity criteria for various time-points were derived from earlier data on skin microfilaridermias and the effects of ivermectin on the adult worms. The results indicate that the significant microfilaridermias that persist despite multiple treatments with ivermectin are mainly attributable to the non-response of the adult female worms and not to inadequate drug exposure or other factors. The possibility that some adult female worms have developed resistance to ivermectin cannot be excluded. These results justify the routine monitoring of treatment efficacy in any ivermectin-based programme of disease control.

Repositioning of an existing drug for the neglected tropical disease Onchocerciasis

“…Ivermectin targets the O. volvulus microfilariae and has an embryostatic effect on the adult female worms (8,31). Although issues exist with this drug, including resistance development (10,(32)(33)(34), its success validates the importance of drug repositioning toward the discovery of therapeutics against NTDs. One untapped pathway for the discovery of new therapeutic avenues is chitin metabolism.…”

Complex dynamics and stability of resistance to antimalarial drugs

“…Helminth parasites frequently exhibit intense intrahost competition and selection, a phenomenon known as the ' crowding ' effect (Anderson and May, 1992) equivalent to the GI regulation described above ; their sexual life-cycle means that recombinational loss of resistance gene combinations will occur ; and the mechanisms of drug action and parasite resistance suggest that fitness costs will plausibly be associated with resistance (Wolstenholme et al 2004). Drug resistance is a major concern in human microscopic helminth infections such as schistosomiasis (Coles et al 1987 ;Doenhoff et al 2002 ;Hagan et al 2004) and onchocerciasis (Dadzie, Neira and Hopkins, 2003 ;Awadzi et al 2004). The incorporation of the complex dynamics, identified above, caused by intrahost effects may therefore be usefully incorporated into these discussions and have a wider impact on our understanding of drug resistance in other important human infections.…”

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness

“…This latter effect may (13) or may not (14) be cumulative with each subsequent treatment. Recently, faster than expected skin repopulation rates have been reported in villages treated for prolonged periods, particularly in Ghana (4,5,8), raising controversy as to whether these observations are indicative of emerging resistance to ivermectin's effect on the release of microfilariae by the adult female worm (embryostatic effect) or due to other causes (15)(16)(17).…”

“…drug resistance ͉ helminth parasites ͉ Onchocerca volvulus ͉ overdispersion T he recent dramatic increase in the use of mass drug administration for the control of helminth infections in humans has raised the possibility that anthelmintic drug resistance may impede the success of such control programs. Anthelmintic resistance is already a major problem in veterinary parasitic nematodes (1), and suboptimal responses to treatment have been reported in a number of human helminthiases (2)(3)(4)(5)(6)(7)(8).…”