Reference Citation Analysis: Find an Article, Find a Category, Find a Journal, Find a Scholar

For: Barda B, Ame SM, Ali SM, Albonico M, Puchkov M, Huwyler J, Hattendorf J, Keiser J. Efficacy and tolerability of moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial. The Lancet Infectious Diseases 2018;18:864-873. [DOI: 10.1016/s1473-3099(18)30233-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/23/2018] [Accepted: 03/26/2018] [Indexed: 12/26/2022]

For:	Barda B, Ame SM, Ali SM, Albonico M, Puchkov M, Huwyler J, Hattendorf J, Keiser J. Efficacy and tolerability of moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial. The Lancet Infectious Diseases 2018;18:864-873. [DOI: 10.1016/s1473-3099(18)30233-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/23/2018] [Accepted: 03/26/2018] [Indexed: 12/26/2022]

Number

Cited by Other Article(s)

Sprecher VP, Coulibaly JT, Hürlimann E, Hattendorf J, Keiser J. Efficacy and Safety of Moxidectin-Albendazole and Ivermectin-Albendazole Combination Therapy Compared to Albendazole Monotherapy in Adolescents and Adults Infected with Trichuris trichiura: A Randomized, Controlled Superiority Trial. Clin Infect Dis 2023;77:1294-1302. [PMID: 37357904 DOI: 10.1093/cid/ciad387] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/18/2023] [Accepted: 06/21/2023] [Indexed: 06/27/2023] Open

Abstract

BACKGROUND

The currently recommended benzimidazole monotherapy is insufficiently effective to control infection with the soil-transmitted helminth Trichuris trichiura. Ivermectin-albendazole combination has shown promising, but setting-dependent efficacy, with therapeutic underperformance in Côte d'Ivoire. We evaluated whether moxidectin-albendazole could serve as an alternative to albendazole monotherapy in Côte d'Ivoire.

METHODS

In this community-based, randomized, placebo-controlled, parallel-group superiority trial, individuals aged 12-60 years were screened for T. trichiura eggs in their stool using quadruplicate Kato-Katz thick smears. Diagnostically and clinically eligible participants were randomly assigned (1:1:1) to receive single oral doses of moxidectin (8 mg) and albendazole (400 mg), ivermectin (200 µg/kg) and albendazole (400 mg), or albendazole (400 mg) and placebo. The primary outcome was proportion cured, ie, cure rate (CR), assessed at 2-3 weeks post-treatment. Safety endpoints were assessed pre-treatment and at 3 and 24 hours post-treatment.

RESULTS

For the 210 participants with primary outcome data, we observed CRs of 15.3% in the moxidectin-albendazole arm and 22.5% in the ivermectin-albendazole arm, which did not differ significantly from the CR of 13.4% in the albendazole arm (differences: 1.8%-points [95% confidence interval: -10.1 to 13.6] and 9.1%-points [-3.9 to 21.8], respectively). Most common adverse events were abdominal pain (range across arms: 11.9%-20.9%), headache (4.7%-14.3%), and itching (5.8%-13.1%), which were predominantly mild and transient.

CONCLUSIONS

All therapies showed similar low efficacy in treating trichuriasis in Côte d'Ivoire. Alternative treatment options need to be evaluated, and further analyses should be conducted to understand the lack of enhanced activity of the combination therapies in Côte d'Ivoire.

CLINICAL TRIALS REGISTRATION

NCT04726969.

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Pfarr KM, Krome AK, Al-Obaidi I, Batchelor H, Vaillant M, Hoerauf A, Opoku NO, Kuesel AC. The pipeline for drugs for control and elimination of neglected tropical diseases: 2. Oral anti-infective drugs and drug combinations for off-label use. Parasit Vectors 2023;16:394. [PMID: 37907954 PMCID: PMC10619278 DOI: 10.1186/s13071-023-05909-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/31/2023] [Indexed: 11/02/2023] Open

Abstract

In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.

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Chhonker YS, Bjerum C, Bala V, Ouattara AF, Koudou BG, Gabo TP, Alshehri A, Meïté A, Fischer PU, Weil GJ, King CL, Budge PJ, Murry DJ. Pharmacokinetics of Moxidectin combined with Albendazole or Albendazole plus Diethylcarbamazine for Bancroftian Filariasis. PLoS Negl Trop Dis 2023;17:e0011567. [PMID: 37616301 PMCID: PMC10482275 DOI: 10.1371/journal.pntd.0011567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 09/06/2023] [Accepted: 08/01/2023] [Indexed: 08/26/2023] Open

Abstract

Moxidectin (MOX) is a milbemycin endectocide recently approved by the U.S. FDA for the treatment of onchocerciasis in persons at least 12 years of age. MOX has been shown to have a good safety profile in recent clinical trials. The efficacy of MOX for the treatment of lymphatic filariasis (LF) and its potential use in mass drug administration protocols for the elimination of LF is currently under evaluation. In the context of a clinical trial, we investigated the pharmacokinetics and drug interactions of a combination of MOX plus albendazole (ALB) with or without diethylcarbamazine (DEC) compared to ivermectin (IVM) plus ALB with or without DEC in the following four different treatment arms: (I) IVM (0.2mg/kg) plus DEC (6 mg/kg) and ALB (400mg); (II) IVM plus ALB; (III) MOX (8 mg) plus DEC and ALB; and (IV) MOX plus ALB. Drug concentrations were determined using validated liquid chromatography-mass spectrometric methods. Pharmacokinetic parameters were determined using standard non-compartmental analysis methods. Statistical analysis was performed using JMP software. Fifty-eight of 164 study participants (53 men and five women) were included with ages ranging from 18 to 63 yrs (mean = 37). MOX apparent oral clearance (Cl/F) ranged from 0.7 to 10.8 L/hr with Cmax values ranging from 20.8 to 314.5 ng/mL. The mean (range) area under the curve (AUC)0-∞ for MOX, 3405 ng*hr/mL (742-11376), and IVM 1906 ng*hr/mL (692-5900), varied over a ~15.3 and ~8.5-fold range, respectively. The geometric mean ratio for Cmax, AUC0-t, and AUC0-∞ were within the no-drug interaction range of 80-125% for all drugs. This indicates that the addition of MOX to ALB alone or ALB plus DEC for LF therapy did not alter the drug exposure of co-administered drugs compared to IVM combinations. Clinical Trial Registration: NCT04410406, https://clinicaltrials.gov/.

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Affiliation(s)

Yashpal S. Chhonker Clinical Pharmacology Laboratory, Dept of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
Catherine Bjerum Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
Veenu Bala Clinical Pharmacology Laboratory, Dept of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
Allassane F. Ouattara Centre Suisse de Recherche Scientifique en Côte d’Ivoire (CSRS), Abidjan, Ivory Coast
Benjamin G. Koudou Centre Suisse de Recherche Scientifique en Côte d’Ivoire (CSRS), Abidjan, Ivory Coast
Toki P. Gabo Centre Hospitalier Regional d’Agboville, Côte d’Ivoire
Abdullah Alshehri Clinical Pharmacology Laboratory, Dept of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
Abdoulaye Meïté Programme National de la Lutte Contre la Schistosomiase, les Geohelminthiases et la Filariose Lymphatique, Ivory Coast
Peter U. Fischer Infectious Diseases Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
Gary J. Weil Infectious Diseases Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
Christopher L. King Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America Veterans Affairs Research Service, Cleveland Veterans Affairs Medical Center, Cleveland, Ohio, United States of America
Philip J. Budge Infectious Diseases Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America
Daryl J. Murry Clinical Pharmacology Laboratory, Dept of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, Nebraska, United States of America Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, United States of America

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Hürlimann E, Hofmann D, Keiser J. Ivermectin and moxidectin against soil-transmitted helminth infections. Trends Parasitol 2023;39:272-284. [PMID: 36804383 DOI: 10.1016/j.pt.2023.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/19/2023] [Accepted: 01/20/2023] [Indexed: 02/19/2023]

Welsche S, Mrimi EC, Hattendorf J, Hürlimann E, Ali SM, Keiser J. Efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole coadministration in adolescents infected with Trichuris trichiura in Tanzania: an open-label, non-inferiority, randomised, controlled, phase 2/3 trial. THE LANCET. INFECTIOUS DISEASES 2023;23:331-340. [PMID: 36354034 PMCID: PMC9946839 DOI: 10.1016/s1473-3099(22)00589-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/02/2022] [Accepted: 09/05/2022] [Indexed: 02/18/2023]

Abstract

BACKGROUND

Control efforts against soil-transmitted helminths focus on preventive chemotherapy with albendazole and mebendazole, however these drugs yield unsatisfactory results against Trichuris trichiura infections. We aimed to assess the efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole against T trichiura in adolescents living on Pemba Island, Tanzania.

METHODS

This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done in four secondary schools (Kilindi, Kwale, Ndagoni [Chake Chake District], and Kiuyu [Wete District]) on Pemba Island, Tanzania. Adolescents aged 12-19 years who tested positive for T trichiura in at least two of four Kato-Katz slides with a mean infection intensity of 48 eggs per gram (EPG) of stool or higher were considered for inclusion. Participants were randomly assigned (21:21:2:2:8) to five treatment groups (8 mg moxidectin and 400 mg albendazole [group 1], 200 μg/kg ivermectin and 400 mg albendazole [group 2], 400 mg albendazole [group 3], 200 μg/kg ivermectin [group 4], or 8 mg moxidectin [group 5]) using a computer-generated randomisation code, stratified by baseline T trichiura infection intensity. Study site investigators and participants were not masked to study treatment; however, allocation was concealed to participants. The primary outcome was egg reduction rate (ERR) of T trichiura 14-21 days after treatment in the available case population. Moxidectin and albendazole was considered non-inferior to ivermectin and albendazole (control group) when the lower limit of the two-sided 95% CI of the difference was higher than the non-inferiority margin of -2 percentage points. This study is registered with ClinicalTrials.gov, NCT04700423.

FINDINGS

Between March 1 and April 30, 2021, 771 participants were assessed for eligibility. 221 (29%) of 771 participants were ineligible and a further 14 (2%) were excluded. 207 (39%) of 536 participants were randomly assigned to moxidectin and albendazole, 211 (39%) to ivermectin and albendazole, 19 (4%) to albendazole, 19 (4%) to ivermectin, and 80 (15%) to moxidectin. Primary outcome data were available for all 536 participants. The geometric mean ERR of T trichiura after 14-21 days was 96·8% (95% CI 95·8 to 97·6) with moxidectin and albendazole and 99·0% (98·7 to 99·3) with ivermectin and albendazole (difference of -2·2 percentage points [-4·2 to -1·4]). No serious adverse events were reported during the study. The most reported adverse events were headache (160 [34%] of 465), abdominal pain (78 [17%]), itching (44 [9%]), and dizziness (26 [6%]).

INTERPRETATION

Our findings show inferiority of moxidectin and albendazole to ivermectin and albendazole against T trichiura. However, given the high efficacy, moxidectin coadministration might complement treatment progammes, particularly in areas in which ivermectin is not available FUNDING: Bill and Melinda Gates Foundation, reference number OPP1153928.

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Pfarr KM, Krome AK, Al-Obaidi I, Batchelor H, Vaillant M, Hoerauf A, Opoku NO, Kuesel AC. The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration. Parasit Vectors 2023;16:82. [PMID: 36859332 PMCID: PMC9979492 DOI: 10.1186/s13071-022-05581-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/05/2022] [Indexed: 03/03/2023] Open

Abstract

The World Health Organization 'Ending the neglect to attain the Sustainable Development Goals: A road map for neglected tropical diseases 2021-2030' outlines the targets for control and elimination of neglected tropical diseases (NTDs). New drugs are needed to achieve some of them. We are providing an overview of the pipeline for new anti-infective drugs for regulatory registration and steps to effective use for NTD control and elimination. Considering drugs approved for an NTD by at least one stringent regulatory authority: fexinidazole, included in WHO guidelines for Trypanosoma brucei gambiense African trypanosomiasis, is in development for Chagas disease. Moxidectin, registered in 2018 for treatment of individuals ≥ 12 years old with onchocerciasis, is undergoing studies to extend the indication to 4-11-year-old children and obtain additional data to inform WHO and endemic countries' decisions on moxidectin inclusion in guidelines and policies. Moxidectin is also being evaluated for other NTDs. Considering drugs in at least Phase 2 clinical development, a submission is being prepared for registration of acoziborole as an oral treatment for first and second stage T.b. gambiense African trypanosomiasis. Bedaquiline, registered for tuberculosis, is being evaluated for multibacillary leprosy. Phase 2 studies of emodepside and flubentylosin in O. volvulus-infected individuals are ongoing; studies for Trichuris trichuria and hookworm are planned. A trial of fosravuconazole in Madurella mycetomatis-infected patients is ongoing. JNJ-64281802 is undergoing Phase 2 trials for reducing dengue viral load. Studies are ongoing or planned to evaluate oxantel pamoate for onchocerciasis and soil-transmitted helminths, including Trichuris, and oxfendazole for onchocerciasis, Fasciola hepatica, Taenia solium cysticercosis, Echinococcus granulosus and soil-transmitted helminths, including Trichuris. Additional steps from first registration to effective use for NTD control and elimination include country registrations, possibly additional studies to inform WHO guidelines and country policies, and implementation research to address barriers to effective use of new drugs. Relative to the number of people suffering from NTDs, the pipeline is small. Close collaboration and exchange of experience among all stakeholders developing drugs for NTDs may increase the probability that the current pipeline will translate into new drugs effectively implemented in affected countries.

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Fabara SP, Patel G, Jain N, Bishev D, Tama B, Caputi A, Zarrate D, Al-Tawfiq JA, Tirupathi R. Can Moxidectin Be an Anthelmintic Alternative for Trichuris trichiura and Strongyloides stercoralis: A Systematic Review. Cureus 2022;14:e27074. [PMID: 36000107 PMCID: PMC9390862 DOI: 10.7759/cureus.27074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/20/2022] [Indexed: 11/06/2022] Open

Bakajika D, Kanza EM, Opoku NO, Howard HM, Mambandu GL, Nyathirombo A, Nigo MM, Kennedy KK, Masembe SL, Mumbere M, Kataliko K, Bolay KM, Attah SK, Olipoh G, Asare S, Vaillant M, Halleux CM, Kuesel AC. Effect of a single dose of 8 mg moxidectin or 150 μg/kg ivermectin on O. volvulus skin microfilariae in a randomized trial: Differences between areas in the Democratic Republic of the Congo, Liberia and Ghana and impact of intensity of infection. PLoS Negl Trop Dis 2022;16:e0010079. [PMID: 35476631 PMCID: PMC9084535 DOI: 10.1371/journal.pntd.0010079] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/09/2022] [Accepted: 03/13/2022] [Indexed: 11/21/2022] Open

Abstract

Background

Our study in CDTI-naïve areas in Nord Kivu and Ituri (Democratic Republic of the Congo, DRC), Lofa County (Liberia) and Nkwanta district (Ghana) showed that a single 8 mg moxidectin dose reduced skin microfilariae density (microfilariae/mg skin, SmfD) better and for longer than a single 150μg/kg ivermectin dose. We now analysed efficacy by study area and pre-treatment SmfD (intensity of infection, IoI).

Methodology/Principal findings

Four and three IoI categories were defined for across-study and by-study area analyses, respectively. We used a general linear model to analyse SmfD 1, 6, 12 and 18 months post-treatment, a logistic model to determine the odds of undetectable SmfD from month 1 to month 6 (UD1-6), month 12 (UD1-12) and month 18 (UD1-18), and descriptive statistics to quantitate inter-interindividual response differences. Twelve months post-treatment, treatment differences (difference in adjusted geometric mean SmfD after moxidectin and ivermectin in percentage of the adjusted geometric mean SmfD after ivermectin treatment) were 92.9%, 90.1%, 86.8% and 84.5% in Nord Kivu, Ituri, Lofa and Nkwanta, and 74.1%, 84.2%, 90.0% and 95.4% for participants with SmfD 10–20, ≥20-<50, ≥50-<80, ≥80, respectively. Ivermectin’s efficacy was lower in Ituri and Nkwanta than Nord Kivu and Lofa (p≤0.002) and moxidectin’s efficacy lower in Nkwanta than Nord Kivu, Ituri and Lofa (p<0.006). Odds ratios for UD1-6, UD1-12 or UD1-18 after moxidectin versus ivermectin treatment exceeded 7.0. Suboptimal response (SmfD 12 months post-treatment >40% of pre-treatment SmfD) occurred in 0%, 0.3%, 1.6% and 3.9% of moxidectin and 12.1%, 23.7%, 10.8% and 28.0% of ivermectin treated participants in Nord Kivu, Ituri, Lofa and Nkwanta, respectively.

Conclusions/Significance

The benefit of moxidectin vs ivermectin treatment increased with pre-treatment IoI. The possibility that parasite populations in different areas have different drug susceptibility without prior ivermectin selection pressure needs to be considered and further investigated.

Clinical Trial Registration

Registered on 14 November 2008 in Clinicaltrials.gov (ID: NCT00790998).

Onchocerciasis or river blindness is a parasitic disease primarily in sub-Saharan Africa and Yemen. It can cause debilitating morbidity including severe itching, skin changes, visual impairment and even blindness. Many years of control efforts, today primarily based on mass administration of ivermectin (MDA) in endemic communities, have reduced morbidity and the percentage of infected individuals so that elimination of parasite transmission is now planned. WHO estimated that in 2020 more than 239 million people required MDA. Ivermectin may not be sufficiently efficacious to achieve elimination everywhere. Our study in areas in Liberia, Ghana and the Democratic Republic of the Congo where MDA had not been implemented yet showed that one treatment with 8 mg moxidectin reduced parasite levels in the skin better and for longer than one treatment with 150 μg/kg ivermectin, the dose used during MDA. Here we show that people with higher numbers of parasites in the skin benefited more from moxidectin treatment than those with lower numbers and that the efficacy of ivermectin and moxidectin differed between study areas. Provided WHO and countries include moxidectin in guidelines and policies, this information could help decisions on when and where to use moxidectin.

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Affiliation(s)

Didier Bakajika Centre de Recherche en Maladies Tropicale de l’Ituri, Hôpital Générale de Référence de Rethy, Ituri, Democratic Republic of the Congo Democratic Republic of the Congo (DRC)
Eric M. Kanza Centre de Recherche Clinique de Butembo, Université Catholique du Graben, Site Horizon, Butembo, Nord Kivu, Democratic Republic of the Congo (DRC)
Nicholas O. Opoku Onchocerciasis Chemotherapy Research Center, Hohoe, Ghana
Hayford M. Howard Clinical Research Center, Liberia Institute for Biomedical Research, Bolahun, Liberia
Germain L. Mambandu Centre de Recherche en Maladies Tropicale de l’Ituri, Hôpital Générale de Référence de Rethy, Ituri, Democratic Republic of the Congo Democratic Republic of the Congo (DRC)
Amos Nyathirombo Centre de Recherche en Maladies Tropicale de l’Ituri, Hôpital Générale de Référence de Rethy, Ituri, Democratic Republic of the Congo Democratic Republic of the Congo (DRC)
Maurice M. Nigo Centre de Recherche en Maladies Tropicale de l’Ituri, Hôpital Générale de Référence de Rethy, Ituri, Democratic Republic of the Congo Democratic Republic of the Congo (DRC)
Kambale Kasonia Kennedy Centre de Recherche Clinique de Butembo, Université Catholique du Graben, Site Horizon, Butembo, Nord Kivu, Democratic Republic of the Congo (DRC)
Safari L. Masembe Centre de Recherche Clinique de Butembo, Université Catholique du Graben, Site Horizon, Butembo, Nord Kivu, Democratic Republic of the Congo (DRC)
Mupenzi Mumbere Centre de Recherche Clinique de Butembo, Université Catholique du Graben, Site Horizon, Butembo, Nord Kivu, Democratic Republic of the Congo (DRC)
Kambale Kataliko Centre de Recherche Clinique de Butembo, Université Catholique du Graben, Site Horizon, Butembo, Nord Kivu, Democratic Republic of the Congo (DRC)
Kpehe M. Bolay Clinical Research Center, Liberia Institute for Biomedical Research, Bolahun, Liberia
Simon K. Attah Onchocerciasis Chemotherapy Research Center, Hohoe, Ghana
George Olipoh Onchocerciasis Chemotherapy Research Center, Hohoe, Ghana
Sampson Asare Onchocerciasis Chemotherapy Research Center, Hohoe, Ghana
Michel Vaillant Competence Center for Methodology and Statistics, Luxembourg Institute of Health, Strassen, Grand Duchy of Luxembourg
Christine M. Halleux UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR), World Health Organization, Geneva, Switzerland
Annette C. Kuesel UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR), World Health Organization, Geneva, Switzerland * E-mail:

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Barda B. Ivermectin and albendazole against Trichuris trichiura: a long and winding road. THE LANCET. INFECTIOUS DISEASES 2022;22:10-12. [PMID: 34856182 DOI: 10.1016/s1473-3099(21)00498-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/06/2021] [Indexed: 06/13/2023]

Welsche S, Mrimi EC, Keller L, Hürlimann E, Hofmann D, Hattendorf J, Ali SM, Keiser J. Efficacy and safety of moxidectin and albendazole compared to ivermectin and albendazole co-administration in adolescents infected with Trichuris trichiura: a randomized controlled trial protocol. Gates Open Res 2021;5:106. [PMID: 34632308 PMCID: PMC8488464 DOI: 10.12688/gatesopenres.13299.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2021] [Indexed: 11/20/2022] Open

Abstract

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The trial will be open-label with blinded outcome assessors. The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations' superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections ( Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment and pharmacokinetic/ pharmacodynamic parameters will also be assessed. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021).

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Welsche S, Mrimi EC, Keller L, Hürlimann E, Hofmann D, Hattendorf J, Ali SM, Keiser J. Efficacy and safety of moxidectin and albendazole compared to ivermectin and albendazole co-administration in adolescents infected with Trichuris trichiura: a randomized controlled trial protocol. Gates Open Res 2021;5:106. [PMID: 34632308 PMCID: PMC8488464 DOI: 10.12688/gatesopenres.13299.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2021] [Indexed: 08/17/2024] Open

Abstract

Background: Infections with soil-transmitted helminths (STHs) predominantly affect impoverished populations in tropical environments. The periodic administration of single dose benzimidazoles (i.e., albendazole, mebendazole) to at-risk individuals in endemic regions is at the center of STH control strategies. Given the low efficacy of these drugs against trichuriasis, investigation of drug combinations including moxidectin and ivermectin has recently been initiated, yet the identification of the best treatment option requires more research. We present the protocol for a trial investigating the efficacy and safety of co-administered moxidectin and albendazole compared to co-administered ivermectin and albendazole against Trichuris trichiura. Methods: We will conduct a randomized controlled trial enrolling 540 T. trichiura-infected adolescents aged 12-19 years on Pemba Island (Tanzania). The primary objective is to demonstrate non-inferiority of orally co-administered single-dose moxidectin (8 mg)/albendazole (400 mg) compared to orally co-administered single-dose ivermectin (200 µg/kg)/albendazole (400 mg) in terms of egg reduction rates (ERRs) against T. trichiura infections assessed by Kato-Katz at 14-21 days post-treatment. Secondary objectives include the assessment of the drug combinations' superiority compared to their respective monotherapies, of the cure rates (CRs) against T. trichiura, and the safety and tolerability of all treatments, as well as CRs and ERRs against concomitant STH infections ( Ascaris lumbricoides and hookworm). Potential effects of the treatment regimens on follow-up prevalences of STH at 5-6 weeks and 3 months post-treatment, infection status derived by quantitative polymerase chain reaction (qPCR), and pharmacokinetic/ pharmacodynamic parameters will also be assessed. Furthermore, a subsample of stool specimens will be analyzed by an updated version of the FECPAK G2 platform. Conclusions: Results from this trial will help to inform decision- and policymakers on which anthelminthic combination therapy might improve existing deworming programs and provide a valuable adjunct tool for interrupting STH transmission. Clinicaltrials.gov registration: NCT04700423 (07/01/2021).

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Palmeirim MS, Specht S, Scandale I, Gander-Meisterernst I, Chabicovsky M, Keiser J. Preclinical and Clinical Characteristics of the Trichuricidal Drug Oxantel Pamoate and Clinical Development Plans: A Review. Drugs 2021;81:907-921. [PMID: 33929716 PMCID: PMC8144136 DOI: 10.1007/s40265-021-01505-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 12/31/2022]

Partridge F, Bataille CJ, Forman R, Marriott AE, Forde-Thomas J, Häberli C, Dinsdale RL, O’Sullivan JD, Willis NJ, Wynne GM, Whiteland H, Archer J, Steven A, Keiser J, Turner JD, Hoffmann KF, Taylor MJ, Else KJ, Russell AJ, Sattelle DB. Structural Requirements for Dihydrobenzoxazepinone Anthelmintics: Actions against Medically Important and Model Parasites: Trichuris muris, Brugia malayi, Heligmosomoides polygyrus, and Schistosoma mansoni. ACS Infect Dis 2021;7:1260-1274. [PMID: 33797218 PMCID: PMC8154432 DOI: 10.1021/acsinfecdis.1c00025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Indexed: 02/07/2023]

Affiliation(s)

Frederick A. Partridge Centre for Respiratory Biology, UCL Respiratory, Division of Medicine, University College London, London WC1E 6JF, United Kingdom
Carole J.R. Bataille Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom
Ruth Forman Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom
Amy E. Marriott Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom
Josephine Forde-Thomas Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, Wales SY23 3DA, United Kingdom
Cécile Häberli Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland University of Basel, Petersplatz 1, Basel CH-4001, Switzerland
Ria L. Dinsdale Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom
James D.B. O’Sullivan Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom Henry Royce Institute, The University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
Nicky J. Willis Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom Alzheimer’s Research UK UCL Drug Discovery Institute, University College London, Gower Street, London WC1E 6BT, United Kingdom
Graham M. Wynne Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom
Helen Whiteland Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, Wales SY23 3DA, United Kingdom
John Archer Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom
Andrew Steven Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom
Jennifer Keiser Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse 57, Basel CH-4002, Switzerland University of Basel, Petersplatz 1, Basel CH-4001, Switzerland
Joseph D. Turner Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom Centre for Neglected Tropical Diseases, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom
Karl F. Hoffmann Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth, Wales SY23 3DA, United Kingdom
Mark J. Taylor Centre for Drugs and Diagnostics, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom Centre for Neglected Tropical Diseases, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom
Kathryn J. Else Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom
Angela J. Russell Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom
David B. Sattelle Centre for Respiratory Biology, UCL Respiratory, Division of Medicine, University College London, London WC1E 6JF, United Kingdom

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Hofmann D, Sayasone S, Sengngam K, Chongvilay B, Hattendorf J, Keiser J. Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial. THE LANCET. INFECTIOUS DISEASES 2021;21:1151-1160. [PMID: 33798487 DOI: 10.1016/s1473-3099(20)30691-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/30/2020] [Accepted: 07/30/2020] [Indexed: 01/30/2023]

Abstract

BACKGROUND

Strongyloidiasis represents a major public health issue, particularly in resource-limited countries. Preliminary studies suggest that moxidectin might serve as an alternative to the only available treatment option, ivermectin. We aimed to evaluate the efficacy and safety of ascending doses of moxidectin in Strongyloides stercoralis-infected patients.

METHODS

We did a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial in four villages in northern Laos. Eligible adults (aged 18-65 years) with S stercoralis infection intensities of at least 0·4 larvae per g of stool in at least two stool samples were randomly assigned (1:1:1:1:1:1:1) by use of computerised, stratified, block randomisation into seven treatment groups: 2 mg of moxidectin, 4 mg of moxidectin, 6 mg of moxidectin, 8 mg of moxidectin, 10 mg of moxidectin, 12 mg of moxidectin, or placebo. Participants and primary outcome assessors were masked to treatment allocation, but study site investigators were not. Participants received a single oral dose of their allocated dose of moxidectin in 2 mg tablets, or four placebo tablets. Three stool samples were collected at baseline and two stool samples were collected 28 days after treatment from each participant. A Baermann assay was used to quantify S stercoralis infection and Kato-Katz thick smears were used to qualitatively identify coinfections with additional helminths species. The primary endpoint was cure rate against S stercoralis and was analysed in an available case analysis set, defined as all randomly assigned participants with primary endpoint data. Predicted cure rates and associated CIs were estimated with hyperbolic E_max models. Safety was evaluated in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04056325, and is complete.

FINDINGS

Between Nov 27, 2019, and March 15, 2020, 785 adults were screened for trial eligibility. Of these, 223 participants were randomly assigned to treatment groups and 209 completed the study and were analysed for the primary outcome. 2 mg of moxidectin had a predicted cure rate of 75% (95% CI 59-87; 22 [73%] of 30 cured) against S stercoralis compared with a predicted cure rate of 14% (5-31; four [14%] of 29 cured) for placebo. With escalating doses, the probability of cure increased from 83% (95% CI 76-88; 26 [90%] of 29 cured) at 4 mg to 86% (79-90; 27 [84%] of 32 cured) at 6 mg, and to 87% (80-92; 24 [83%] of 29 cured) at 8 mg, levelling off at 88% (80-93; 29 [97%] of 30 cured) at 10 mg and 88% (80-93; 26 [87%] of 30 cured) at 12 mg. Moxidectin was well tolerated across all treatment groups, with no serious adverse events being recorded and all reported symptoms being classified as mild.

INTERPRETATION

4-12 mg of moxidectin showed promising tolerability and efficacy profiles in the treatment of S stercoralis infections in adults. Because 8 mg of moxidectin is used for the treatment of onchocerciasis and has been evaluated for other helminth infections, we recommend this dose for phase 2b and phase 3 trials of strongyloidiasis therapy.

FUNDING

Fondazione Adiuvare.

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Jawahar S, Tricoche N, Bulman CA, Sakanari J, Lustigman S. Drugs that target early stages of Onchocerca volvulus: A revisited means to facilitate the elimination goals for onchocerciasis. PLoS Negl Trop Dis 2021;15:e0009064. [PMID: 33600426 PMCID: PMC7891776 DOI: 10.1371/journal.pntd.0009064] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open

Hansen TVA, Cirera S, Neveu C, Courtot E, Charvet CL, Calloe K, Klaerke DA, Martin RJ. The narrow-spectrum anthelmintic oxantel is a potent agonist of a novel acetylcholine receptor subtype in whipworms. PLoS Pathog 2021;17:e1008982. [PMID: 33544769 PMCID: PMC7891710 DOI: 10.1371/journal.ppat.1008982] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 02/18/2021] [Accepted: 01/13/2021] [Indexed: 12/28/2022] Open

Abstract

In the absence of efficient alternative strategies, the control of parasitic nematodes, impacting human and animal health, mainly relies on the use of broad-spectrum anthelmintic compounds. Unfortunately, most of these drugs have a limited single-dose efficacy against infections caused by the whipworm, Trichuris. These infections are of both human and veterinary importance. However, in contrast to a wide range of parasitic nematode species, the narrow-spectrum anthelmintic oxantel has a high efficacy on Trichuris spp. Despite this knowledge, the molecular target(s) of oxantel within Trichuris is still unknown. In the distantly related pig roundworm, Ascaris suum, oxantel has a small, but significant effect on the recombinant homomeric Nicotine-sensitive ionotropic acetylcholine receptor (N-AChR) made up of five ACR-16 subunits. Therefore, we hypothesized that in whipworms, a putative homolog of an ACR-16 subunit, can form a functional oxantel-sensitive receptor. Using the pig whipworm T. suis as a model, we identified and cloned a novel ACR-16-like subunit and successfully expressed the corresponding homomeric channel in Xenopus laevis oocytes. Electrophysiological experiments revealed this receptor to have distinctive pharmacological properties with oxantel acting as a full agonist, hence we refer to the receptor as an O-AChR subtype. Pyrantel activated this novel O-AChR subtype moderately, whereas classic nicotinic agonists surprisingly resulted in only minor responses. We observed that the expression of the ACR-16-like subunit in the free-living nematode Caenorhabditis elegans conferred an increased sensitivity to oxantel of recombinant worms. We demonstrated that the novel Tsu-ACR-16-like receptor is indeed a target for oxantel, although other receptors may be involved. These finding brings new insight into the understanding of the high sensitivity of whipworms to oxantel, and highlights the importance of the discovery of additional distinct receptor subunit types within Trichuris that can be used as screening tools to evaluate the effect of new synthetic or natural anthelmintic compounds.

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Hofmann D, Sayasone S, Keiser J. Development and validation of an LC-MS/MS method for the quantification of the anthelmintic drug moxidectin in a volumetric absorptive microsample, blood, and plasma: Application to a pharmacokinetic study of adults infected with Strongyloides stercoralis in Laos. J Chromatogr B Analyt Technol Biomed Life Sci 2021;1166:122556. [PMID: 33535101 DOI: 10.1016/j.jchromb.2021.122556] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/05/2021] [Accepted: 01/14/2021] [Indexed: 02/04/2023]

Abstract

Moxidectin is a promising candidate for addition to the lean repertoire of drugs against neglected tropical diseases (NTD) including strongyloidiasis. Pharmacokinetic (PK) and -dynamic studies are required to support its clinical development. Microsampling approaches enable PK studies in the challenging environments where NTDs are most prevalent, due to simplified collection and processing. We developed a liquid chromatography tandem mass spectrometry method for the sensitive quantification of moxidectin in human blood obtained by capillary sampling with the microsampling device Mitra® compared to blood and plasma obtained by venous sampling. Sample preparation consisted of protein precipitation, evaporation and reconstitution and also included phospholipid filtration for blood and plasma. Moxidectin was detected by multiple reaction monitoring (640.4 → 528.5 m/z) using a Luna C8(2) (30 × 2.0 mm, 3 µm particle size, 100 Å) analytical column with a gradient program of 6 min duration. Validation was performed with respect to accuracy, precision, sensitivity, selectivity, linearity, stability, recovery, and haematocrit influence with a limit of quantification of 0.5 and 2.5 ng/mL, for venous and capillary blood respectively. Moxidectin was stable up to 2 months at storage condition (blood and plasma: -20 °C, microsamples: room temperature), 3 cycles of temperature shift, for at least 4 h on the bench-top and 24 h in the autosampler (4 °C). Deviations of inter- and intra-assay accuracy and precision were smaller than 12.6% and recoveries were in the range of 80.7-111.2%. The method was applied to samples obtained from nine Strongyloides stercoralis-infected adults from northern Laos. A good agreement in the time-concentration profiles of moxidectin and a high consistency in PK parameters was found between the different matrixes and sampling strategies: e.g. identical time to reach maximal concentration of 4.0 h and a similar maximal concentration of 83.9-88.5 ng/mL of moxidectin. The simple and practical capillary procedure using Mitra® microsampling has been demonstrated to be suitable for PK studies of moxidectin and will pave the way for future PK studies.

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Keller L, Palmeirim MS, Ame SM, Ali SM, Puchkov M, Huwyler J, Hattendorf J, Keiser J. Efficacy and Safety of Ascending Dosages of Moxidectin and Moxidectin-albendazole Against Trichuris trichiura in Adolescents: A Randomized Controlled Trial. Clin Infect Dis 2021;70:1193-1201. [PMID: 31044235 DOI: 10.1093/cid/ciz326] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 04/22/2019] [Indexed: 11/12/2022] Open

Kaji MD, Geary TG, Beech RN. A Functional Comparison of Homopentameric Nicotinic Acetylcholine Receptors (ACR-16) Receptors From Necator americanus and Ancylostoma ceylanicum. Front Mol Neurosci 2020;13:601102. [PMID: 33324163 PMCID: PMC7725692 DOI: 10.3389/fnmol.2020.601102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 11/04/2020] [Indexed: 12/24/2022] Open

Barda B, Schindler C, Wampfler R, Ame S, Ali SM, Keiser J. Comparison of real-time PCR and the Kato-Katz method for the diagnosis of soil-transmitted helminthiasis and assessment of cure in a randomized controlled trial. BMC Microbiol 2020;20:298. [PMID: 33008301 PMCID: PMC7531123 DOI: 10.1186/s12866-020-01963-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 09/01/2020] [Indexed: 02/05/2023] Open

Abstract

Background

Diagnosis of soil-transmitted helminths (STHs) in developing countries is commonly based on microscopic detection of eggs in stool samples, using the Kato-Katz (KK) method, which has a poor sensitivity for detecting light intensity infections. We compared the performance of the KK method and real-time PCR in the framework of a randomized trial, which evaluated four novel treatments against Trichuris trichiura and concomitant STH infections.

Results

Two stool samples obtained from 320 participants were examined at baseline and follow-up with quadruplicate KK and PCR analyses of one of the two samples using “bead-beating” for DNA extraction. At follow-up, 80 samples were negative according to both PCR and KK and 173 were positive with both methods for any of the STHs. Relative to PCR, the calculated sensitivity of KK at follow-up was 83.6%, 43.0% and 53.8% for T. trichiura, for hookworm and for Ascaris lumbricoides, respectively. The sensitivity of PCR compared with KK at this time point was 89.1% for T. trichiura, 72.7% for hookworm and 87.5% for A. lumbricoides. Cure rates (CRs) for T. trichiura and A. lumbricoides were slightly lower with the PCR method. For hookworm CRs with KK were mostly significantly lower, namely 36.7%, 91.1%, 72.2% and 77.8% for moxidectin, moxidectin in combination with tribendimidine, moxidectin in combination with albendazole and albendazole in combination with oxantel pamoate, respectively, whereas with PCR the CRs were 8.3%, 82.6%, 37.1% and 57.1%, respectively.

Conclusions

In conclusion, a single real-time PCR is as sensitive as quadruplicate KK for T. trichiura and A. lumbricoides detection but more sensitive for hookworm, which has an influence on the estimated treatment efficacy. PCR method with DNA extraction using the “bead-beating protocol” should be further promoted in endemic areas and laboratories that can afford the needed equipment.

The study is registered at ISRCTN (no. 20398469).

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Boussinesq M, Enyong P, Chounna-Ndongmo P, Njouendou AJ, Pion SD, Rech A, Roberge C, Gaudriault G, Wanji S. Effects of an injectable long-acting formulation of ivermectin on Onchocerca ochengi in zebu cattle. ACTA ACUST UNITED AC 2020;27:36. [PMID: 32420864 PMCID: PMC7233116 DOI: 10.1051/parasite/2020036] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 05/05/2020] [Indexed: 11/14/2022]

Getachew B, Tizabi Y. Antidepressant effects of moxidectin, an antiparasitic drug, in a rat model of depression. Behav Brain Res 2019;376:112220. [PMID: 31513828 PMCID: PMC6783392 DOI: 10.1016/j.bbr.2019.112220] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/13/2019] [Accepted: 09/06/2019] [Indexed: 12/31/2022]

Wagner-Hattler L, Québatte G, Keiser J, Schoelkopf J, Schlepütz CM, Huwyler J, Puchkov M. Study of drug particle distributions within mini-tablets using synchrotron X-ray microtomography and superpixel image clustering. Int J Pharm 2019;573:118827. [PMID: 31756443 DOI: 10.1016/j.ijpharm.2019.118827] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 10/23/2019] [Accepted: 10/25/2019] [Indexed: 12/19/2022]

Schwartz RA, Al-Qubati Y, Zieleniewski Ł, Shah R, Kapila R. Onchocerciasis (river blindness): larva-induced eczema (onchodermatitis) from an important oculocutaneous tropical disease spilling over into North America and Europe. Int J Dermatol 2019;59:1065-1070. [PMID: 31513297 DOI: 10.1111/ijd.14614] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/05/2019] [Accepted: 08/09/2019] [Indexed: 11/28/2022]

Dunn JC, Bettis AA, Wyine NY, Lwin AMM, Tun A, Maung NS, Anderson RM. Soil-transmitted helminth reinfection four and six months after mass drug administration: results from the delta region of Myanmar. PLoS Negl Trop Dis 2019;13:e0006591. [PMID: 30768602 PMCID: PMC6395004 DOI: 10.1371/journal.pntd.0006591] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 02/28/2019] [Accepted: 01/24/2019] [Indexed: 12/26/2022] Open

Abstract

BACKGROUND

Mass drug administration (MDA), targeted at school-aged children (SAC) is the method recommended by the World Health Organization for the control of morbidity induced by soil-transmitted helminth (STH) infection in endemic countries. However, MDA does not prevent reinfection between treatment rounds and research suggests that only treating SAC will not be sufficient to bring prevalence to low levels and possibly interrupt transmission of STH. In countries with endemic infection, such as Myanmar, the coverage, who is targeted, and rates of reinfection will determine how effective MDA is in suppressing transmission in the long-term.

METHODS/PRINCIPAL FINDINGS

In this paper, data from an epidemiological study on STH, comprising three surveys conducted between June 2015 and June 2016 in the delta region of Myanmar, are analysed to determine how STH prevalence and intensity in the study community changes over the course of a year, including reinfection after two MDA rounds in which the whole study sample (all age groups, n = 523) were treated with albendazole. Prevalence in the first survey (August 2015) was 27.92% for any STH, 5.54% for Ascaris lumbricoides, 17.02% for Trichuris trichiura and 9.75% for hookworm. Over the year (survey one to survey three), prevalence of any STH decreased by 8.99% (P < 0.001) and mean EPG significantly decreased for T. trichiura (P < 0.01) and hookworm (P < 0.001). Risk ratios (RRs) for a four-month reinfection period (August to December) were statistically significant and were below one, indicating that STH prevalence had not bounced back to the prevalence levels recorded immediately prior to the last round of treatment (any STH RR = 0.67, 95% CI 0.56-0.81; A. lumbricoides RR = 0.31, 95% CI 0.16-0.59; T. trichiura RR = 0.70, 95% CI 0.55-0.88; hookworm RR = 0.69, 95% CI 0.50-0.95). The only statistically significant RR for the six-month reinfection period (December to June) was for A. lumbricoides infection in SAC (RR = 2.67, 95% CI 1.37-5.21). All six-month RRs were significantly higher than four-month RRs (P < 0.05). Evidence of predisposition to infection (low and high), as measured by the Kendall Tau-b statistic, was found for all species overall and within most age groups stratifications, except for hookworm infection in preschool-aged children.

CONCLUSIONS/SIGNIFICANCE

This study demonstrates that, for certain demographic groups, a six-month gap between MDA in these communities is enough time for STH infection to return to STH prevalence levels recorded immediately before the previous MDA round, and that on average the same individuals are being consistently infected between MDA rounds.

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Drug Combinations Against Soil-Transmitted Helminth Infections. ADVANCES IN PARASITOLOGY 2019;103:91-115. [PMID: 30878060 DOI: 10.1016/bs.apar.2018.08.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]

Tanjong Ghogomu E, Suresh S, Rayco-Solon P, Hossain A, McGowan J, Peña-Rosas JP, Welch V. Deworming in non-pregnant adolescent girls and adult women: a systematic review and meta-analysis. Syst Rev 2018;7:239. [PMID: 30572948 PMCID: PMC6300900 DOI: 10.1186/s13643-018-0859-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 10/29/2018] [Indexed: 01/12/2023] Open

Abstract

BACKGROUND

The impact of deworming on parasite load, nutritional status and other health outcomes of non-pregnant adolescent girls and adult women is uncertain.

METHODS

MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, the WHO International Clinical Trials Registry Platform, the Cochrane Database of Systematic Reviews and Food and Technology Abstracts databases were searched until 24 September 2018. Studies were included if they were randomised controlled trials (RCTs), controlled before and after studies or interrupted time studies comparing deworming with no intervention or placebo in non-pregnant adolescent girls and women 10 to 49 years old. Outcomes of interest included parasite load, reinfection, anaemia, severe anaemia, iron deficiency, diarrhoea or all-cause morbidity. Risk of bias was assessed using the Cochrane risk of bias tool.

RESULTS

We included four RCTs of mass deworming involving 1086 participants, in the analyses. Mass deworming probably reduces the prevalence of roundworm infection (RR 0.29; 95% CI 0.14 to 0.62; 2 trials; 1498 participants, moderate certainty evidence), prevalence of hookworm infection (RR 0.32; 95% CI 0.18 to 0.59; 2 trials; 1498 participants, moderate certainty evidence), prevalence of whipworm infection (RR 0.77; 95% CI 0.65 to 0.91; 2 trials; 1498 participants, moderate certainty evidence) compared to the control group. Deworming may make little or no difference in prevalence of anaemia (RR 0.82; 95% CI 0.60 to 1.11, 3 studies, 683 participants, low certainty evidence) and prevalence of iron-deficiency (RR 0.89; 95% CI 0.64 to 1.23, 1 study, 186 participants, low certainty evidence) compared to control. We are uncertain whether deworming reduces the prevalence of severe anaemia compared to control as the certainty of evidence was very low. None of the included studies assessed screen and treat deworming or reported reinfection, diarrhoea or adverse events.

CONCLUSIONS

Mass deworming probably reduces the prevalence of soil-transmitted helminth infections but may have little or no effect on anaemia and iron-deficiency in adolescent girls and non-pregnant women in comparison to no intervention or placebo. We are uncertain about the effect on severe anaemia. These results are limited by sparse data and the moderate to very low quality of evidence available.

SYSTEMATIC REVIEW REGISTRATION

The protocol was registered in PROSPERO (registration number: CRD42016039557 ). Primary source of funding: Evidence and Programme Guidance unit, Department of Nutrition for Health and Development, World Health Organization (WHO).

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Maheu-Giroux M, Joseph SA. Moxidectin for deworming: from trials to implementation. THE LANCET. INFECTIOUS DISEASES 2018;18:817-819. [DOI: 10.1016/s1473-3099(18)30270-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 04/11/2018] [Indexed: 12/17/2022]

Schulz JD, Moser W, Hürlimann E, Keiser J. Preventive Chemotherapy in the Fight against Soil-Transmitted Helminthiasis: Achievements and Limitations. Trends Parasitol 2018;34:590-602. [DOI: 10.1016/j.pt.2018.04.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 04/26/2018] [Accepted: 04/27/2018] [Indexed: 02/06/2023]