Discussion
dermatitis, infections, blindness
BLINDNESS, ONCHOCERCIASIS, INFECTIONS, WORMS, DERMATITIS
The onchocerciasis elimination program focuses on periodic mass distribution of IVM. While this strategy has been effective for preventing blindness and controlling dermatitis, annual IVM has little or no ability to kill or permanently sterilize adult worms. Clinical trials that have assessed the potential macrofilaricidal effects of more frequent treatment with ivermectin have yielded mixed results (for example, [There were safety concerns regarding the use of IDA in this study, because DEC was linked to serious ocular AEs when it was used to treat onchocerciasis in the past. However, those AEs were mainly seen in persons with heavy infections and after many doses of DEC [Nodulectomy data suggest that a single dose or three daily doses of IDA killed or permanently sterilized about 40% of adult female worms relative to the number of living and fertile worms that were observed after the IA comparator treatment. However, this difference was not statistically significant for the predefined primary endpoint comparison (IA vs. IDA) when the analysis considered intraclass correlations of adult worm status within individual study participants. Secondary endpoint comparisons (IA vs. IDA3 or IA vs. combined IDA treatment groups) also suggested that IDA had significant macrofilaricidal activity relative to IA. The finding that calcified dead female worms were more common after IDA treatment than after IA provides additional evidence that IDA is more macrofilaricidal than the IA comparator treatment. The fact that many female worms remained alive and fertile after IDA1 and IDA3 probably explains why these treatments were not superior to IA for achieving long-lasting clearance of Mf from the skin.This study was powered for detecting a macrofilaricidal effect of 50% relative to the comparator treatment, and this assumed an ICC of 0.2 for worm fertility for multiple worms evaluated within individual study participants. Our ability to demonstrate a robust macrofilaricidal effect was hampered by the lower than expected health of adult female worms in the IA comparator group. Our power calculation assumed that 30% of females would be alive and fertile after IA treatment, but the observed percentage was only 22.7%, and the majority of living worms observed in nodules from all treatment groups were old. This suggests that transmission of IDA results from this study are novel, because this is the only short-course oral treatment studied to date that appears to have superior macrofilaricidal activity relative to the current MDA regimen of IA (which is not macrofilaricidal). This begs the question of whether this finding has any practical significance. Although a single treatment with IDA1 or IDA3 clearly did not kill or sterilize a majority of adult female worms in this study, any treatment with macrofilaricidal activity superior to IA or IVM alone might accelerate onchocerciasis elimination across Africa. Also, multiple doses of combination treatments separated in time may improve macrofilaricidal activity.MDA with IDA after IVM pretreatment would be more difficult to deploy than the currently recommended regimens (IA or IVM alone), but the extra effort could be justified if future studies demonstrate greater macrofilaricidal efficacy than that observed in this study. It is also important to mention that while there is a need for more effective MDA regimens, combination treatments could be very helpful for use cases other than MDA. For example, they might be used in endgame or mop-up situations, either as selective treatment of infected individuals (“test and treat”) or for focal MDA in hot-spot areas where routine MDA with IVM has failed to eliminate transmission.