Long-term outcomes of ivermectin-albendazole versus albendazole alone against soil-transmitted helminths: Results from randomized controlled trials in Lao PDR and Pemba Island, Tanzania

Abstract

Background: Preventive chemotherapy is the cornerstone of soil-transmitted helminth (STH) control. Long-term outcomes and adequate treatment frequency of the recently recommended albendazole-ivermectin have not been studied to date.

Methodology/principal findings: Double-blind randomized controlled trials were conducted in Lao PDR, Pemba Island, Tanzania and Côte d'Ivoire between 2018 and 2020 to evaluate the efficacy and safety of ivermectin-albendazole versus albendazole-placebo in Trichuris trichiura-infected individuals aged 6 to 60. In the framework of this study, in Lao PDR 466 and 413 participants and on Pemba Island, 558 and 515 participants were followed-up six and 12 months post-treatment, respectively. From each participant at least one stool sample was processed for Kato-Katz diagnosis and cure rates (CRs), egg reduction rates (ERRs) and apparent reinfection rates were calculated. If found helminth-positive at six months, participants were re-treated according to their allocated treatment. Long-term outcomes against T. trichiura based on CRs and ERRs of ivermectin-albendazole compared to albendazole were significantly higher at six months in Lao PDR (CR, 65.8 vs 13.4%, difference; 52.4; 95% CI 45.0-60.0; ERRs, 99.0 vs 79.6, difference 19.4; 95% CI 14.4-24.4) and Pemba Island (CR, 17.8 vs 1.4%, difference; 16.4; 95% CI 11.6-21.0; ERRs, 84.9 vs 21.2, difference 63.8; 95% CI 50.6-76.9) and also at 12 months in Lao PDR (CR, 74.0 vs 23.4%, difference; 50.6; 95% CI 42.6-61.0; ERRs, 99.6 vs 91.3, difference 8.3; 95% CI 5.7-10.8) and Pemba Island (CR, 19.5 vs 3.4%, difference; 16.1; 95% CI 10.7-21.5; ERRs, 92.9 vs 53.6, difference 39.3; 95% CI 31.2-47.4) respectively. Apparent reinfection rates with T. trichiura were considerably higher on Pemba Island (100.0%, 95% CI, 29.2-100.0) than in Lao PDR (10.0%, 95% CI, 0.2-44.5) at 12 months post-treatment for participants treated with albendazole alone.

Conclusions/significance: The long-term outcomes against T. trichiura of ivermectin-albendazole are superior to albendazole in terms of CRs and ERRs and in reducing infection intensities. Our results will help to guide decisions on how to best use ivermectin-albendazole in the context of large-scale PC programs tailored to the local context to sustainably control STH infections.

Trial registration: ClinicalTrials.gov registered with clinicaltrials.gov, reference: NCT03527732, date assigned: 17 May 2018.

Fig 1. Study design flow chart for Lao PDR (A) and Pemba Island (B).

Abbreviations: T. trichiura, Trichuris trichiura; ALB, albendazole monotherapy; IVM-ALB, ivermectin-albendazole combination therapy. In Lao PDR “helminth positive” includes infections with Strongyloides stercoralis

Fig 2. Proportion of infection intensities of T. trichiura at baseline, 14–21 days, six and 12 months post-treatment in Lao PDR (A) and Pemba Island (B) for ivermectin-albendazole above and albendazole-placebo below.

315 participants in Lao PDR and 492 participants on Pemba Island had a complete data set. Red dashed lines at baseline and follow up represent treatment time points. Abbreviations: BL, baseline assessment; N, number of participants with a complete data set; 3wk, 14–21 days post-treatment follow-up; 6m, 6 months post-treatment follow-up; 1yr, 12 months post-treatment follow-up.

Fig 3. Proportion of infection intensities of A. lumbricoides at baseline, 14–21 days, six and 12 months post-treatment in Lao PDR (A) and Pemba Island (B) for ivermectin-albendazole above and albendazole-placebo below.

114 participants in Lao PDR and 127 participants on Pemba Island were initially infected with A. lumbricoides and had a complete data set. Red dashed lines at baseline and follow up represent treatment time points. Abbreviations: BL, baseline assessment; N, number of participants with a complete data set; 3wk, 14–21 days post-treatment follow-up; 6m, 6 months post-treatment follow-up; 1yr, 12 months post-treatment follow-up.

Fig 4. Proportion of infection intensities of hookworm at baseline, 14–21 days, six and 12 months post-treatment in Lao PDR (A) and Pemba Island (B) for ivermectin-albendazole above and albendazole-placebo below.

289 participants in Lao PDR and 40 participants on Pemba Island were initially infected with hookworm and had a complete data set. Red dashed lines at baseline and follow up represent treatment time points. Abbreviations: BL, baseline assessment; N, number of participants with a complete data set; 3wk, 14–21 days post-treatment follow-up; 6m, 6 months post-treatment follow-up; 1yr, 12 months post-treatment follow-up.