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      Mass drug administration of ivermectin, diethylcarbamazine, plus albendazole compared with diethylcarbamazine plus albendazole for reduction of lymphatic filariasis endemicity in Papua New Guinea: a cluster-randomised trial

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          Summary

          Background

          A single co-administered dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to be safe and more efficacious for clearing Wuchereria bancrofti microfilariae than the standard two-drug regimen of diethylcarbamazine plus albendazole in clinical trials. However, the effectiveness of mass drug administration with the triple-drug regimen compared with the two-drug regimen is unknown. We compared the effectiveness of mass drug administration with the triple-drug and two-drug regimens for reducing microfilariae prevalence to less than 1% and circulating filarial antigen prevalence to less than 2%, levels that are unlikely to sustain transmission of lymphatic filariasis, in Papua New Guinea.

          Methods

          This open-label, cluster-randomised study was done in 24 villages in a district endemic for lymphatic filariasis in Papua New Guinea. Villages paired by population size were randomly assigned to receive mass drug administration with a single dose of the triple-drug oral regimen of ivermectin (200 μg per kg of bodyweight) plus diethylcarbamazine (6 mg per kg of bodyweight) plus albendazole (400 mg) or a single dose of the two-drug oral regimen of diethylcarbamazine (6 mg per kg of bodyweight) plus albendazole (400 mg). This is a follow-on study of a previously reported safety study ( ClinicalTrials.govNCT02899936). All residents aged 5 years or older and non-pregnant women were asked to participate. After cross-sectional night blood microfilariae and circulating filarial antigen surveys, mass drug administration was provided at baseline and repeated 12 months later. The primary outcomes were mean prevalence of microfilariae and circulating filarial antigen at 12 months and 24 months, assessed in all residents willing to participate at each timepoint. This study is registered with ClinicalTrials.gov, NCT03352206.

          Findings

          Between Nov 18, 2016, and May 26, 2017, 4563 individuals were enrolled in 24 clusters; 12 clusters (2382 participants) were assigned to the triple-drug regimen and 12 clusters (2181 participants) to the two-drug regimen. Mean drug ingestion rates (of residents aged ≥5 years) were 66·1% at baseline and 63·2% at 12 months in communities assigned to the triple-drug regimen and 65·9% at baseline and 54·9% at 12 months in communities assigned to the two-drug regimen. Microfilariae prevalence in the triple-drug regimen group decreased from 105 (4·4%) of 2382 participants (95% CI 3·6–5·3) at baseline to nine (0·4%) of 2319 (0·1–0·7) at 12 months and four (0·2%) of 2086 (0·1–0·5) at 24 months. In the two-drug regimen group, microfilariae prevalence decreased from 93 (4·3%) of 2181 participants (95% CI 3·5–5·2) at baseline to 29 (1·5%) of 1963 (1·0–2·1) at 12 months and eight (0·4%) of 1844 (0·2–0·9) at 24 months (adjusted estimated risk ratio 4·5, 95% CI 1·4–13·8, p=0·0087, at 12 months; 2·9, 95% CI 1·0–8·8, p=0·058, at 24 months). The prevalence of circulating filarial antigen decreased from 523 (22·0%) of 2382 participants (95% CI 20·3–23·6) at baseline to 378 (16·3%) of 2319 (14·9–17·9) at 12 months and 156 (7·5%) of 2086 (6·4–8·7) at 24 months in the triple-drug regimen group and from 489 (22·6%) of 2168 participants (20·7–24·2) at baseline to 358 (18·2%) of 1963 (16·7–20·1) at 12 months and 184 (10·0%) of 1840 (8·7–11·5) at 24 months in the two-drug regimen group; after adjustment, differences between groups were not significant.

          Interpretation

          Mass administration of the triple-drug regimen was more effective than the two-drug regimen in reducing microfilariae prevalence in communities to less than the target level of 1%, but did not reduce circulating filarial antigen prevalence to less than 2%. These results support the use of mass drug administration with the triple-drug regimen to accelerate elimination of lymphatic filariasis.

          Funding

          Bill & Melinda Gates Foundation.

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          Most cited references22

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          A modified poisson regression approach to prospective studies with binary data.

          G Zou (2004)
          Relative risk is usually the parameter of interest in epidemiologic and medical studies. In this paper, the author proposes a modified Poisson regression approach (i.e., Poisson regression with a robust error variance) to estimate this effect measure directly. A simple 2-by-2 table is used to justify the validity of this approach. Results from a limited simulation study indicate that this approach is very reliable even with total sample sizes as small as 100. The method is illustrated with two data sets.
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            Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis.

            Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown.
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              A Randomized Trial of a New Triple Drug Treatment for Lymphatic Filariasis

              BACKGROUND The recommended drug regimen for elimination of lymphatic filariasis outside sub-Saharan Africa is single dose of diethylcarbamazine (DEC) plus albendazole (ALB). Multiple annual treatments are required for elimination since this regimen does not sustainably reduce blood microfilaria (Mf) counts below the threshold required to interrupt transmission. This study tested the efficacy of a single dose of ivermectin (IVM) combined with DEC/ALB. METHODS We conducted an open label, randomized clinical trial in which Wuchereria bancrofti-infected adults in Papua New Guinea were assigned to treatment with DEC/ALB once (n=61), DEC/ALB twice (n=61, baseline, 12 months) and IVM/DEC/ALB once (n=60). The primary outcome was complete clearance of blood Mf at 24 months. RESULTS At 24 months 96% of participants treated with IVM/DEC/ALB were amicrofilaremic compared to 56% after single dose DEC/ALB (relative risk for Mf+ = 0.08 [0.02-0.34, 95% CI], p<0.001) and 75% after two annual doses of DEC/ALB (relative risk for Mf+ = 0.15 [0.03-0.62, 95% CI], p=0.009). Filarial antigen levels decreased markedly and to a similar degree after treatment with all 3 regimens. Moderate adverse events were more common after the triple than the two-drug regimen (27% vs. 5%, p<0.001). There were no serious adverse events. CONCLUSIONS Treatment with a single dose of IVM/DEC/ALB was superior to a single dose or two annual doses of DEC/ALB for clearing Mf. There were no significant safety concerns. Widespread use of IVM/DEC/ALB could greatly accelerate elimination of lymphatic filariasis. (ClinicalTrials.gov, NCT01978771)
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                Author and article information

                Contributors
                Journal
                Lancet Infect Dis
                Lancet Infect Dis
                The Lancet. Infectious Diseases
                Elsevier Science ;, The Lancet Pub. Group
                1473-3099
                1474-4457
                1 August 2022
                August 2022
                : 22
                : 8
                : 1200-1209
                Affiliations
                [a ]Papua New Guinea Institute for Medical Research, Goroka, Papua New Guinea
                [b ]Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, QLD, Australia
                [c ]Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH, USA
                [d ]Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
                [e ]National Department of Health, Waigani, Papua New Guinea
                [f ]WHO Papua New Guinea, NTD Program, Waigani, Papua New Guinea
                [g ]Department of Medicine, Washington University, St Louis, MO, USA
                [h ]Burnet Institute, Melbourne, VIC, Australia
                [i ]Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
                [j ]Veterans Affairs Research Administration, Cleveland, OH, USA
                Author notes
                [* ]Correspondence to: Prof Christopher L King, Center for Global Health and Diseases, Case Western Reserve University, Cleveland, OH 44106, USA cxk21@ 123456case.edu
                [†]

                Contributed equally

                Article
                S1473-3099(22)00026-3
                10.1016/S1473-3099(22)00026-3
                9300473
                35533701
                715469fb-596a-47af-aaca-9cd6ac678b88
                © 2022 World Health Organization

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Infectious disease & Microbiology
                Infectious disease & Microbiology

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