Abstract
Preventive chemotherapy with albendazole or mebendazole remains one of the cornerstones of soil-transmitted helminth control. However, these drugs are less effective against Trichuris trichiura. Combined ivermectin-albendazole is a promising treatment alternative, yet robust evidence is lacking. We aimed to demonstrate superiority of co-administered ivermectin-albendazole over albendazole monotherapy in three distinct epidemiological settings. We conducted a double-blind, parallel-group, phase 3, randomised controlled trial in community members aged 6-60 years infected with T trichiura in Côte d'Ivoire, Laos, and Pemba Island, Tanzania, between Sept 26, 2018, and June 29, 2020. Participants with at least 100 T trichiura eggs per g of stool at baseline were randomly assigned (1:1) using computer-generated randomisation sequences in varying blocks of four, six, and eight, stratified by baseline T trichiura infection intensity, to orally receive either a single dose of ivermectin (200 μg/kg) plus albendazole (400 mg) or albendazole (400 mg) plus placebo. Patients, field staff, and outcome assessors were masked to treatment assignment. The primary outcome was cure rate against T trichiura, defined as the proportion of participants with no eggs in their faeces 14-21 days after treatment, assessed by Kato-Katz thick smears, and analysed in the available-case population according to intention-to-treat principles. Safety was a secondary outcome and was assessed 3 h and 24 h after drug administration. The trial is registered at ClinicalTrials.gov, NCT03527732. Between Sept 13 and Dec 18, 2019, Jan 12 and April 5, 2019, and Sept 26 and Nov 5, 2018, 3737, 3694, and 1435 community members were screened for trial eligibility in Côte d'Ivoire, Laos, and Pemba Island, respectively. In Côte d'Ivoire, Laos, and Pemba Island, 256, 274, and 305 participants, respectively, were randomly assigned to the albendazole group, and 255, 275, and 308, respectively, to the ivermectin-albendazole group. Primary outcome data were available for 722 participants treated with albendazole and 733 treated with ivermectin-albendazole. Ivermectin-albendazole showed significantly higher cure rates against T trichiura than albendazole in Laos (66% [140 of 213]vs 8% [16 of 194]; difference 58 percentage points, 95% CI 50 to 65, p<0·0001) and Pemba Island (49% [140 of 288]vs 6% [18 of 293], 43 percentage points, 36 to 49, p<0·0001) but had similar efficacy in Côte d'Ivoire (14% [32 of 232]vs 10% [24 of 235], 4 percentage points, -2 to 10, p=0·24). No serious adverse events were reported; observed events were mostly classified as mild (95% [266 of 279] in the albendazole group and 91% [288 of 317] in the ivermectin-albendazole group), and all were transient in nature. Treatment with ivermectin-albendazole resulted in higher efficacy against trichuriasis than albendazole alone in Laos and Pemba Island but not in Côte d'Ivoire. We recommend implementation of this combination therapy for soil-transmitted helminth control in countries with high T trichiura prevalence and proven enhanced efficacy of this treatment, particularly where ivermectin is beneficial against other endemic helminthiases. Bill & Melinda Gates Foundation.
Highlights
Soil-transmitted helminthiasis affects approximately one in five people in the world and disproportionally affects the most neglected populations.[1]
Our study showed higher efficacy against Trichuris trichiura if ivermectin–albendazole was used for treatment than if albendazole monotherapy was used in two settings
In Côte d’Ivoire, Laos, and Pemba Island, 256, 274, and 305 participants, respectively, were randomly assigned to and received albendazole co-administered with placebo, whereas 255, 275, and 308 participants, respectively, were randomly assigned to and received ivermectin–albendazole
Summary
Soil-transmitted helminthiasis affects approximately one in five people in the world and disproportionally affects the most neglected populations.[1]. Evidence before this study We searched PubMed, ISI Web of Science, ScienceDirect, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials. We used “ivermect* [AND] albendaz* [AND] (hookworm [OR] trichuri* [OR] ascari* [OR] soil-transmitted helminth*) [AND] (cure* [OR] trial)” as search terms for PubMed, ISI Web of Science, and ScienceDirect, and the keywords “ivermectin” and “albendazole” for CENTRAL and ClinicalTrials.gov. The latest evidence on the efficacy and safety of co-administered ivermectin plus albendazole against soil-transmitted helminths is presented in our systematic review, meta-analysis, and individual-patient data analysis, which was published in 2018. We identified four randomised controlled trials that investigated the standard dose of combined ivermectin (200 μg/kg) and albendazole (400 mg). The trials in the Philippines and Sri Lanka were done before 2000 and used a weak diagnostic approach, with only one stool sample analysed before and after treatment
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