Efficacy and Safety of a Single Dose of Ivermectin, Diethylcarbamazine, and Albendazole for Treatment of Lymphatic Filariasis in Côte d'Ivoire: An Open-label Randomized Controlled Trial

Catherine M Bjerum, Allassane F Ouattara, Méité Aboulaye, Olivier Kouadio, Vanga K Marius, Britt J Andersen, Gary J Weil, Benjamin G Koudou, Christopher L King, Catherine M Bjerum, Allassane F Ouattara, Méité Aboulaye, Olivier Kouadio, Vanga K Marius, Britt J Andersen, Gary J Weil, Benjamin G Koudou, Christopher L King

Abstract

Background: Improved drug regimens are needed to accelerate elimination of lymphatic filariasis in Africa. This study determined whether a single co-administered dose of ivermectin plus diethylcarbamazine plus albendazole [IDA] is noninferior to standard 3 annual doses of ivermectin plus albendazole (IA) used in many LF-endemic areas of Africa.

Methods: Treatment-naive adults with Wuchereria bancrofti microfilaremia in Côte d'Ivoire were randomized to receive a single dose of IDA (n = 43) or 3 annual doses of IA (n = 52) in an open-label, single-blinded trial. The primary endpoint was the proportion of participants who were microfilaria (Mf) negative at 36 months. Secondary endpoints were Mf clearance at 6, 12, and 24 months; inactivation of adult worm nests; and safety.

Results: At 36 months posttreatment with IDA, 18/33 (55%; 95% CI, 38-72%) cleared Mf versus 33/42 (79%; 67-91%) with IA (P = .045). At 6 and 12 months IDA was superior to IA in clearing Mf (89% [77-99%] and 71% [56-85%]), respectively, versus 34% (20-48%) and 26% (14-42%) (P < .001). IDA was equivalent to IA at 24 months (61% [45-77%] vs 54% [38-72%]; P = .53). IDA was superior to IA for inactivating adult worms at all time points. Both treatments were well tolerated, and there were no serious adverse events.

Conclusions: A single dose of IDA was superior to 2 doses of IA in reducing the overall Mf burden by 24 months. Reinfection may have contributed to the lack of sustained clearance of Mf with IDA.

Clinical trials registration: NCT02974049.

Keywords: albendazole; diethylcarbamazine; efficacy; ivermectin; lymphatic filariasis.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Trial profile. Abbreviations: ALB, albendazole; DEC, diethylcarbamazine; IDA, ivermectin plus diethylcarbamazine plus albendazole; IVM, ivermectin; LFT, liver function tests, aspartate aminotransferase and alanine aminotransferase with one or both >85 international unit representing >1.5 fold above normal values; Mf, microfilaria; oncho, Onchocerca volvulus; Rx, treatment. * The albendazole alone arms are part of a different study.
Figure 2.
Figure 2.
Mean percent decrease (95% CI) in microfilaremia levels at 6, 12, and 24 months after treatment for the 2 treatment arms, as determined by microfilaria (Mf) counts at each time point divided by baseline Mf count for each participant. The numbers of participants for each time point are shown in Table 2. Participants without detectable Mf are included in the analysis and considered to have 100% clearance. ***P < .001 using Mann–Whitney test (2-sided) comparing individuals at 6 and 12 months. Abbreviations: ALB, albendazole; CI, confidence interval; DEC, diethylcarbamazine; IVM, ivermectin; Mf, microfilaria.
Figure 3.
Figure 3.
Changes in circulating filarial antigen (CFA) relative to baseline as determined by enzyme-linked immunosorbent assay (A) or Filariasis Test Strip (FTS) score (B). A, The mean (±standard error of the mean [SEM]) percentage of persisting CFA levels relative to baseline (CFA levels at 6 or 12 months/CFA levels at baseline) is shown (ivermectin plus albendazole [IA] arm: n = 30, 28, and 15 at baseline and 6 and 12 months, respectively; ivermectin plus diethylcarbamazine plus albendazole [IDA] arm: n = 26, 24, and 14 at the same time points). B, Mean (±SD) FTS score results for all individuals for which a microfilarial level was determined. *P < .05, **P < .01, ***P < .001 using Mann–Whitney U test for comparisons between IA and IDA groups. Abbreviations: ALB, albendazole; CFA, circulating filarial antigen; DEC, diethylcarbamazine; FTS, Filariasis Test Strip; IA, ivermectin plus albendazole; IDA, ivermectin plus diethylcarbamazine plus albendazole; IVM, ivermectin; SD, standard deviation; SEM, standard error of the mean.
Figure 4.
Figure 4.
The effect of treatment on the number of adult worm nests detected by ultrasonography. The mean (±SEM) number of worm nests in scrotal lymphatics pretreatment and at 6, 12, 24, and 36 months posttreatment is shown. Only men with detectable worm nests in the scrotal lymphatics at baseline were examined at follow-up. Annual ivermectin plus albendazole (IA) treatment significantly reduced worm nests from baseline at 12, 24, and 36 months (P = .015, P < .001, and P < .001; paired Wilcoxon rank sum test). A single treatment with ivermectin plus diethylcarbamazine plus albendazole (IDA) resulted in significantly greater reductions in worm nest counts relative to annual treatment with IA for all time points posttreatment (P < .001). The significance of this difference was determined by the Mann–Whitney U test. The 5 participants in the IDA arm who were retreated with IDA at 24 months were included in the worm nest analysis, because the additional round of treatment had almost no additional effect on worm nests (see text). Abbreviations: ALB, albendazole; DEC, diethylcarbamazine; IA, ivermectin plus albendazole; IDA, ivermectin plus diethylcarbamazine plus albendazole; IVM, ivermectin; SEM, standard error of the mean.

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