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Effects of ivermectin mass drug administration for malaria vector control on ectoparasites and soil-transmitted helminths: a cluster randomized trial

  • Christian Kositz
    Correspondence
    Corresponding author: Christian Kositz, Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom.
    Affiliations
    Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • Mariama Drammeh
    Affiliations
    Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • Hristina Vasileva
    Affiliations
    Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • Joanna Houghton
    Affiliations
    Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • James Ashall
    Affiliations
    Department of Infection Biology, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • Author Footnotes
    # Joint last author.
    Umberto D'Alessandro
    Footnotes
    # Joint last author.
    Affiliations
    Disease Control and Elimination, Medical Research Council Unit Gambia at London School of Hygiene and Tropical Medicine (MRCG at LSHTM), Bakau, The Gambia
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  • Author Footnotes
    # Joint last author.
    Michael Marks
    Footnotes
    # Joint last author.
    Affiliations
    Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • Author Footnotes
    # Joint last author.
    John Bradley
    Footnotes
    # Joint last author.
    Affiliations
    Department of Infectious Disease Epidemiology, Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom
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  • Author Footnotes
    # Joint last author.
Open AccessPublished:November 03, 2022DOI:https://doi.org/10.1016/j.ijid.2022.10.043

      Highlights

      • Ivermectin-specific mass drug administration for malaria control and its off-target effects on neglected tropical diseases.
      • The potential of combining malaria and neglected tropical disease control efforts with ivermectin.
      • High population mobility as a detriment for large-scale mass drug administration success.

      Abstract

      Objectives

      Ivermectin, used to control several neglected tropical diseases, may also reduce malaria transmission. Mass drug administration (MDA) for malaria control therefore might have off-target impacts on neglected tropical diseases.

      Methods

      In The Gambia, nested in a trial of ivermectin MDA, cross-sectional surveys measuring ectoparasites and soil-transmitted helminths in children aged 3 to 14 years took place in June and November 2019 and in November 2021.

      Results

      After MDA, scabies prevalence was 41.2% (237/576) in the control and 38.2% (182/476) in the intervention arm (odds ratio [OR] 0.89 (95% confidence interval [CI] 0 67-1.2), P-value = 0.471) but by 2021, had rebounded to 38.8% (180/464) in the control and 53.2% (245/458) in the intervention arm. After MDA, prevalence of Strongyloides stercoralis was 16.8% (87/518) in the control and 9.1% (40/440) in the intervention arm (OR 0.4 (95% CI 0.16-0.94), P-value = 0.039). In 2021, it was 9.2% (38/413) in the control and 11.3% (45/399) in the intervention arm (OR 1.31 (95% CI 0.74-2.28), P-value = 0.35).

      Conclusion

      Scabies prevalence was similar between the two study arms. S. stercoralis prevalence was reduced. However, this effect did not last long: the prevalence 2 years after MDA was similar between study arms.

      Keywords

      Background

      Despite substantial progress over the last 20 years, malaria remains an important cause of morbidity and mortality in many endemic countries (
      • World Health Organization
      World malaria report.
      ). Ivermectin has been identified as an additional tool for vector control due to its mosquitocidal properties against Anopheles spp. (The Ivermectin
      • Roadmappers The ivermectin
      • Billingsley P
      • Binka F
      • Chaccour C
      • Foy B
      • Gold S
      • et al.
      A roadmap for the development of ivermectin as a complementary malaria vector control tool.
      ). Mathematical modeling suggests that mass drug administration (MDA) of ivermectin at a dose of 300 mcg/kg for 3 days or 400 mcg for 1 day and with 70% coverage of those aged over 5 years would reduce malaria transmission (
      • Slater HC
      • Foy BD
      • Kobylinski K
      • Chaccour C
      • Watson OJ
      • Hellewell J
      • et al.
      Ivermectin as a novel complementary malaria control tool to reduce incidence and prevalence: a modelling study.
      ). These dosing regimens have been shown to be both safe and mosquitocidal (
      • Smit MR
      • Ochomo EO
      • Aljayyoussi G
      • Kwambai TK
      • Abong'o BO
      • Chen T
      • et al.
      Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial.
      ).
      In addition to its potential for vector control, ivermectin is already established as an effective drug against several neglected tropical diseases, particularly ectoparasites and soil-transmitted helminths (STH), which are a major cause of morbidity in lower- and middle-income countries. Ectoparasites occur at low levels in almost all countries but can be highly prevalent in hyperendemic foci in vulnerable or neglected populations (
      • Feldmeier H
      • Heukelbach J.
      Epidermal parasitic skin diseases: a neglected category of poverty-associated plagues.
      ;
      • Gbakima AA
      • Terry BC
      • Kanja F
      • Kortequee S
      • Dukuley I
      • Sahr F.
      High prevalence of bedbugs Cimex hemipterus and Cimex lectularis in camps for internally displaced persons in Freetown, Sierra Leone: a pilot humanitarian investigation.
      ;
      • Heukelbach J
      • van Haeff E
      • Rump B
      • Wilcke T
      • Moura RCS
      • Feldmeier H.
      Parasitic skin diseases: health care-seeking in a slum in north-east Brazil.
      ). STH, including Strongyloides stercoralis, Ascaris lumbricoides, Trichuris trichiura, and hookworms, are common intestinal parasites, with up to 3 billion individuals worldwide harboring at least one helminth (
      • Jourdan PM
      • Lamberton PHL
      • Fenwick A
      • Addiss DG.
      Soil-transmitted helminth infections.
      ). Moreover, unlike other STH, S. stercoralis is able to sustain itself within the host for life (
      • Gill GV
      • Welch E
      • Bailey JW
      • Bell DR
      • Beeching NJ.
      Chronic Strongyloides stercoralis infection in former British Far East prisoners of war.
      ).
      Ivermectin MDA, combined with permethrin, has been used successfully to reduce the prevalence of scabies in several settings (
      • Heukelbach J
      • Winter B
      • Wilcke T
      • Muehlen M
      • Albrecht S
      • de Oliveira FA
      • et al.
      Selective mass treatment with ivermectin to control intestinal helminthiases and parasitic skin diseases in a severely affected population.
      ;
      • Romani L
      • Whitfeld MJ
      • Koroivueta J
      • Kama M
      • Wand H
      • Tikoduadua L
      • et al.
      Mass drug administration for scabies control in a population with endemic disease.
      ,
      • Romani L
      • Marks M
      • Sokana O
      • Nasi T
      • Kamoriki B
      • Cordell B
      • et al.
      Efficacy of mass drug administration with ivermectin for control of scabies and impetigo, with coadministration of azithromycin: a single-arm community intervention trial.
      ). Similar studies also show reductions in other ectoparasites, including lice and bedbugs (
      • Coscione S
      • Esau T
      • Kekeubata E
      • Diau J
      • Asugeni R
      • MacLaren D
      • et al.
      Impact of ivermectin administered for scabies treatment on the prevalence of head lice in Atoifi, Solomon Islands.
      ;
      • Sheele JM
      • Anderson JF
      • Tran TD
      • Teng YA
      • Byers PA
      • Ravi BS
      • et al.
      Ivermectin causes Cimex lectularius (bedbug) morbidity and mortality.
      ). Similarly, ivermectin MDA has led to significant reductions in S. stercoralis prevalence in several studies (
      • Barda B
      • Albonico M
      • Buonfrate D
      • Ame SM
      • Ali S
      • Speich B
      • et al.
      Side benefits of mass drug administration for lymphatic filariasis on Strongyloides stercoralis prevalence on Pemba Island, Tanzania.
      ;
      • Forrer A
      • Khieu V
      • Schindler C
      • Schär F
      • Marti H
      • Char MC
      • et al.
      Ivermectin treatment and sanitation effectively reduce Strongyloides stercoralis infection risk in rural communities in Cambodia.
      ;
      • Kearns TM
      • Currie BJ
      • Cheng AC
      • McCarthy J
      • Carapetis JR
      • Holt DC
      • et al.
      Strongyloides seroprevalence before and after an ivermectin mass drug administration in a remote Australian Aboriginal community.
      ;
      • Marks M
      • Gwyn S
      • Toloka H
      • Kositz C
      • Asugeni J
      • Asugeni R
      • et al.
      Impact of community treatment with ivermectin for the control of scabies on the prevalence of antibodies to Strongyloides stercoralis in children.
      ) and is highly effective against A. lumbricoides. Efficacy for Trichuris and hookworms appears to be lower after a single dose of ivermectin, but the repeated application may be more effective (
      • Heukelbach J
      • Wilcke T
      • Winter B
      • Sales de Oliveira FA
      • Sabóia Moura RC
      • Harms G
      • et al.
      Efficacy of ivermectin in a patient population concomitantly infected with intestinal helminths and ectoparasites.
      ).
      We report the findings of a nested substudy evaluating the potential for the synergistic impact of a large-scale ivermectin MDA conducted for malaria control on the prevalence of ectoparasites and STH.

      Methods

      Background trial

      The MASSIV trial (NCT03576313) was a cluster randomized trial implemented in the Upper River Region (URR), eastern Gambia, with 32 clusters (villages) randomized into control or intervention arms. The URR has a rainy season from July to November, followed by a longer dry season. MDA with ivermectin and dihydroartemisinin-piperaquine was implemented in intervention villages at the beginning of the malaria transmission season for over 2 years (2018 and 2019). Each year, three monthly rounds were implemented, in August-October 2018, and in July-September 2019. Ivermectin was given at a dose of 300-400 mcg/kg body weight and dihydroartemisinin-piperaquine at 320/40 mg and 160/20 mg depending on body weight, daily for 3 days. Control villages received standard malaria control measures. Individuals under 15 kg in weight or 90 cm in height, as well as those who were pregnant and breastfeeding did not receive ivermectin. The full details of the MASSIV trial have been previously reported (
      • Dabira ED
      • Soumare HM
      • Conteh B
      • Ceesay F
      • Ndiath MO
      • Bradley J
      • et al.
      Mass drug administration of ivermectin and dihydroartemisinin–piperaquine against malaria in settings with high coverage of standard control interventions: a cluster-randomised controlled trial in the Gambia.
      ).

      Study design

      Cross-sectional surveys for scabies were carried out in June 2019 (before the implementation of the 2nd year of MDA) and for both scabies and STH in November 2019 (after the 2019 MDA), and in November 2021 (>2 years after the last MDA). No standardized scabies survey was done before implementing the first MDA in 2018. No STH survey was conducted in June 2019 due to logistical and time constraints. The November 2021 survey was originally planned for 2020 but its implementation was delayed due to the COVID-19 pandemic. The surveys measured the prevalence of ectoparasites and STH in children aged 3-14 years.
      Ivermectin was administered by the MASSIV trial field team under direct observation. Women of childbearing age were tested for pregnancy before ivermectin treatment and were excluded if positive. Body weight was measured by the MASSIV trial field team with a scale using kilogram units.

      Sample size calculation

      Because there was no information on the prevalence of ectoparasites and STH in URR, available data from other areas of The Gambia was used. Assuming a 15% prevalence for each ectoparasite and for all STH, and an intracluster correlation coefficient of 0.5, 30 children per cluster would allow the detection of a 75% decrease of prevalence to 6%, with over 80% power.

      Study population

      The study population was all children aged 3-14 years, living in the 32 study villages, and whose parents/guardians provided a written informed consent. A simple random selection process was used to select children in each cluster. If a household or compound was not willing to participate, moved away, or was not available for any other reason, new participants were randomly selected.

      Study procedures

      For the June 2019 survey, there were a total of 1322 children randomly selected from the MASSIV trial database. The same list of participants was used for the November 2019 survey, except for one village, in which two compounds had moved out in the meantime. For this village, there were two new compounds randomly selected from the original dataset, increasing the total number of children to 1331 for the November survey. For the November 2021 survey, a new list of 1378 participants from the MASSIV trial database was established because some previous participants were outside the targeted age group. Because no further interventions took place in the MASSIV trial after 2019, we ensured that the children diagnosed with scabies in 2021 received appropriate treatment with benzyl benzoate cream as part of the survey.
      Each village was visited between two to five times, at different times of the day, over the course of 5 weeks to account for public holidays and for children being absent during the day. Children that moved away, died, or were otherwise lost to follow-up, were recorded. Investigators were blinded to which arm the respective village was allocated to and did not participate in the distribution of the MDA. All findings were collected using a standardized electronic case report form using REDCap® software in 2019 and Open Data Kit.

      Clinical investigation

      Scabies

      Clinical examination for scabies was carried out by an experienced clinician familiar with the diagnosis of scabies. If possible, a full body examination was conducted, respecting the communities’ cultural and societal norms. The electronic case report form questions were structured according to the International Alliance for the Control of Scabies criteria for scabies (
      • Engelman D
      • Yoshizumi J
      • Hay RJ
      • Osti M
      • Micali G
      • Norton S
      • et al.
      The 2020 international alliance for the control of scabies consensus criteria for the diagnosis of scabies.
      ). Because dermatoscopy and parasitological testing were not available, patients were diagnosed using clinical criteria. For the purpose of the study, we considered the International Alliance for the Control of Scabies categories B1, B2, B3, and C1 to be cases of scabies (
      • Engelman D
      • Yoshizumi J
      • Hay RJ
      • Osti M
      • Micali G
      • Norton S
      • et al.
      The 2020 international alliance for the control of scabies consensus criteria for the diagnosis of scabies.
      ) (Table S1).

      Head lice and bedbugs

      Examination for head lice consisted of direct visual inspection at the sites predilected for nits located behind the ear, the temples, and the neck using standardized methods used in the previous survey in The Gambia (
      • Lindsay SW
      • Snow RW
      • Armstrong JR
      • Greenwood BM.
      Permethrin-impregnated bednets reduce nuisance arthropods in Gambian houses.
      ). For bedbugs, the sleeping quarters of participants were physically inspected based on a previous survey conducted in The Gambia (
      • Lindsay SW
      • Snow RW
      • Armstrong JR
      • Greenwood BM.
      Permethrin-impregnated bednets reduce nuisance arthropods in Gambian houses.
      ).

      Sample collection for STH

      Participants and/or their caregivers received a 60-ml container and spoons, as well as instructions on how to scoop the feces into the container and the amount needed. Instructions included storing the sample in a cold, dark place, and preferably taking a morning stool sample to reduce the time between sample production and collection. Samples produced at the time of a study visit were collected the same day. Collected samples were aliquoted into a 7-ml Bijou container containing 98% ethanol to preserve DNA and prevent bacterial overgrowth at a 1 : 2 to 1 : 4 ratio, avoiding larger objects. Samples were then transported into the research facility and aliquoted into 1.8-ml cryotubes for further cold storage at -20C.

      STH detection by quantitative polymerase chain reaction (qPCR)

      Stool samples in 98% ethanol were thawed at ambient temperature and processed as previously described (
      • Farrant O
      • Marlais T
      • Houghton J
      • Goncalves A
      • Teixeira da Silva Cassama ETda S
      • Cabral MG
      • et al.
      Prevalence, risk factors and health consequences of soil-transmitted helminth infection on the Bijagos Islands, Guinea Bissau: a community-wide cross-sectional study.
      ). Due to the potentially low prevalence and therefore, lack of sensitivity, no microscopy was done (
      • Farrant O
      • Marlais T
      • Houghton J
      • Goncalves A
      • Teixeira da Silva Cassama ETda S
      • Cabral MG
      • et al.
      Prevalence, risk factors and health consequences of soil-transmitted helminth infection on the Bijagos Islands, Guinea Bissau: a community-wide cross-sectional study.
      ). qPCR was performed on a Rotorgene 3000 platform, using previously evaluated STH qPCR protocols (
      • Farrant O
      • Marlais T
      • Houghton J
      • Goncalves A
      • Teixeira da Silva Cassama ETda S
      • Cabral MG
      • et al.
      Prevalence, risk factors and health consequences of soil-transmitted helminth infection on the Bijagos Islands, Guinea Bissau: a community-wide cross-sectional study.
      ). Briefly, S. stercoralis was analyzed using a singleplex qPCR (
      • Verweij JJ
      • Canales M
      • Polman K
      • Ziem J
      • Brienen EAT
      • Polderman AM
      • et al.
      Molecular diagnosis of Strongyloides stercoralis in faecal samples using real-time PCR.
      ), whereas A. lumbricoides, Necator americanus, Ancylostoma duodenale, and T. trichiura were analyzed together using a multiplex qPCR (
      • Basuni M
      • Muhi J
      • Othman N
      • Verweij JJ
      • Ahmad M
      • Miswan N
      • et al.
      A pentaplex real-time polymerase chain reaction assay for detection of four species of soil-transmitted helminths.
      ;
      • Mejia R
      • Vicuña Y
      • Broncano N
      • Sandoval C
      • Vaca M
      • Chico M
      • et al.
      A novel, multi-parallel, real-time polymerase chain reaction approach for eight gastrointestinal parasites provides improved diagnostic capabilities to resource-limited at-risk populations.
      ). For both qPCRs described, 3 µl of target DNA template was used in a total volume of 25 µl reaction. Table S2 in supplementary materials shows primer and probe sequences.

      Statistical analysis

      The co-primary outcomes were the prevalence of each ectoparasite and a composite end point of overall STH prevalence. For adjusted analyses, age was stratified into three groups, 3-6 years, 7-10 years, and 11-14 years, roughly corresponding to preschool, primary school, and secondary school children, respectively. To compare between arms, a logistic regression model with fixed effects for age and sex, and with random effects for the study cluster was fitted.
      The statistical analysis was conducted using STATA 14. Figures containing statistical data were made using R software with R studio version 4.0.2 (June 22, 2020).

      Role of the funding source

      The Wellcome Trust did not have any involvement in data collection, analysis, or interpretation; trial design; patient recruitment; or any aspect pertinent to the study.

      Results

      Using the MASSIV trial census, 1342 children were randomly selected in July 2019, 1321 in November 2019, and 1378 in November 2021; 81.7 % (1096/1342) of these children were identified in July 2019, 79.6 % (1052/1321) in November 2019, and 66.9 % (922/1378) in November 2021 (Fig. 1, Fig. 2). Stool samples were provided by 72.5% (957/1321) children in November 2019, and 58.9% (812/1378) in November 2020. Baseline demographic details by the survey are described in Tables 1 and 2.
      Fig. 1:
      Fig. 1Participants and their whereabouts in 2019
      STH, soil-transmitted helminths.
      Fig. 2:
      Fig. 2Participants and their whereabouts in 2021
      STH, soil-transmitted helminths.
      Table 1Baseline characteristics of the study participants for scabies surveys.
      Demography (scabies)July-19November-19November-21
      ControlInterventionControlInterventionControlIntervention
      Age groupN (%)N (%)N (%)
      3-6 years244 (22.3)217 (19.7)215 (20.4)172 (16.4)184 (19.9)175 (18.9)
      7-10 years210 (19.2)183 (16.7)215 (20.4)172 (16.4)176 (19.1)180 (19.5)
      11-14 years113 (10.3)129 (11.8)146 (13.9)132 (12.5)104 (11.3)103 (11.2)
      Sex
      Female280 (25.5)272 (24.8)278 (26.4)257 (24.4)250 (27.1)206 (19.6)
      Male287 (26.2)257 (23.5)298 (28.3)219 (20.8)214 (20.3)252 (23.9)
      Arm567 (51.7)529 (48.3)576 (54.8)476 (45.2)464 (50.3)458 (49.7)
      Total10961052922
      Table 2Baseline characteristics of the study participants for soil-transmitted helminths surveys.
      Demography (soil-transmitted helminths)November-19November-21
      ControlInterventionControlIntervention
      Age groupN (%)N (%)
      3-6 years195 (20.4)161 (16.8)162 (19.9)154 (18.9)
      7-10 years207 (21.6)165 (17.2)161 (19.8)162 (19.9)
      11-14 years116 (12.1)114 (11.9)90 (11.2)83 (10.3)
      Sex
      Female254 (26.5)226 (23.6)228 (28.1)166 (20.4)
      Male264 (25.6)214 (22.3)185 (22.8)233 (28.7)
      Arm518 (54.1)440 (45.9)413 (50.8)399 (49.1)
      Total958812

      Head lice and bedbugs

      During the June 2019 survey, no bedbugs were found. Only eight (0.7%) individuals, four in each study arm, had nits with no living head lice detected. Therefore, no further search for these ectoparasites was carried out in the following surveys.

      Scabies

      In June 2019, the overall prevalence of scabies was 43.7% (478/1096); 38.8 % (205/529) in the intervention, and 48.2% (273/567) in the control arm (Table S3). After adjustment for clustering, scabies prevalence was significantly lower in intervention villages (odds ratio [OR]: 0.64; 95% confidence interval [CI]: 0.43-0.95, P-value = 0.027).
      In the second survey in November 2019, the overall prevalence was 39.9% (419/1052); 41.2 % (237/576) in the intervention and 38.2 % (182/476) in the control arm (OR: 0.88; 95% CI: 0.66-1 8, P-value = 0.406).
      In November 2021, 2 years after MDA, the overall prevalence of scabies was 46.5% (425/922); 53.3% (245/458) in the intervention, and 38.7% (180/464) in the control arm (OR: 1.94; 95% CI: 1.1-3.43, P-value = 0.022) (Table 3).
      Table 3OR and P-values for all three scabies surveys; adjusted for sex and age.
      Scabies
      SurveyPrevalenceUnadjusted OR (95% CI)P-valueAdjusted OR (95% CI)P-value
      July-19
      Control273/567 (48.2%)11
      Intervention205/529 (38.8%)0.64 (0.43-0.95)0.0270.65 (0.44-0.97)0.037
      November-19
      Control237/576 (41.2%)11
      Intervention182/476 (38.2%)0.88 (0.66-1.8)0.4060.89 (0.67-1.2)0.471
      November-21
      Control180/464 (38.8%)11
      Intervention245/458 (53.2%)1.94 (1.1-3.43)0.0221.89 (1.07-3.37)0.029
      OR, odds ratio.

      STH 2019 and 2021

      In November 2019, the overall prevalence of STH was 20.2% (193/958). S. stercoralis was the most prevalent STH (13.3%; 127/958), followed by N. americanus (4.8%; 46/958), and A. lumbricoides (4.1%; 39/958). No T. trichiura or A. duodenale were detected (Table S4, supplementary material).
      No evidence of an effect of the intervention on the overall STH prevalence was detected (adjusted OR: 0.63; 95% CI 0.34-1.21, P-value = 0.169). There was evidence of an effect of the intervention on S. stercoralis, with 16.9% in the control and 9.1% in the intervention arm, with an adjusted OR: 0.4 (95% CI 0.17-0.96, P-value = 0.039) (Table 4).
      Table 4OR and P-values for both STH surveys and S. stercoralis surveys; adjusted for sex and age.
      Soil-transmitted helminths
      SurveyPrevalenceUnadjusted OR (95% CI)P-valueAdjusted OR (95% CI)P-value
      November-19
      Control121 (23.4%)11
      Intervention72 (16.4%)0.63 (0.33-1.19)0.1580.63 (0.34-1.21)0.169
      November-21
      Control57 (13.8%)11
      Intervention75 (18.7%)1.47 (0.86-2.52)0.1571.51 (0.86-2.63)0.149
      Strongyloides
      SurveyPrevalenceUnadjusted OR (95% CI)P-valueAdjusted OR (95% CI)P-value
      November-19
      Control87 (16.8%)11
      Intervention40 (9.1%)0.40 (0.16-0.95)0.0370.4 (0.17-0.96)0.039
      November-21
      Control38 (9.2%)11
      Intervention45 (11.3%)1.26 (0.72-2.17)0.411.31 (0.74-2.28)0.35
      OR, odds ratio.
      In November 2021, the overall STH prevalence was 16.3% (132/812). In 2019, S. stercoralis was the most prevalent STH with 10.2% (83/812), followed by N. americanus 4.8% (40/812) and A. lumbricoides 1.2% (10/812). The prevalence for A. duodenale and T. trichiura were 0.24 and 0.12%, respectively (Table S4).
      No evidence of an effect of the intervention on overall STH prevalence was detected with an unadjusted OR of 1.47 (95% CI 0.86-2.52, P-value = 0.15) and an adjusted OR of 0.63 (95% CI 0.34-1.21; P-value = 0.169). In the case of S. stercoralis, no evidence for a long-term effect was seen, with an OR of 1.26 (95% CI 0.72-2.17, P-value = 0.41) and an adjusted OR of 1.31 (95% CI 0.74-2.28; P-value =0.35) (Table 4).

      Discussion

      In this study, we did not show any clear evidence of the impact of ivermectin MDA conducted in the context for malaria control on either scabies or STH prevalence, except for S. stercoralis. The prevalence of scabies was relatively high in all three surveys, whereas the STH prevalence varied around 15-20%, most of the infections caused by S. stercoralis. The prevalence of other STH was low and comparable to that of a survey carried out in 2015 among Gambian school children; however, this survey did not include S. stercoralis (
      • Camara Y
      • Sanneh B
      • Joof E
      • Sanyang AM
      • Sambou SM
      • Sey AP
      • et al.
      Mapping survey of schistosomiasis and soil-transmitted helminthiases towards mass drug administration in the Gambia.
      ).
      The study results initially suggested a change in scabies prevalence in July 2019. However, this effect was not seen again after the second MDA in 2019, and the effect appeared to be reversed in the following survey in 2021. This is probably explained by the lack of substantial impact of the MDA on scabies combined with local fluctuations in prevalence (see Fig. S1) because the survey, a few months after the MDA, showed no change in prevalence. Our results differ from most of the previous studies. A lack of impact on scabies has been shown in a study in an area with high population movement (
      • Kearns TM
      • Speare R
      • Cheng AC
      • McCarthy J
      • Carapetis JR
      • Holt DC
      • et al.
      Impact of an ivermectin mass drug administration on scabies prevalence in a remote Australian Aboriginal community.
      ;
      • Lake SJ
      • Kaldor JM
      • Hardy M
      • Engelman D
      • Steer AC
      • Romani L.
      Mass drug administration for the control of scabies: a systematic review and meta-analysis.
      ). One of the strongest contributors to our results is probably the presence of a substantial untreated reservoir of study participants, including individuals with >15 kg body weight and pregnant and breastfeeding women. The MDA conducted for MASSIV differed importantly from most of the previous studies, where MDA was conducted for scabies. In studies conducted specifically for scabies, individuals who remained untreated due to ineligibility for ivermectin would have been offered treatment with permethrin. In addition, there is a potential of children who were treated being reinfected in schools or while visiting other villages outside the study area or due to contamination between clusters. Using larger clusters might have avoided this risk but is not as statistically robust, and cluster randomized trials have been successfully used for scabies control programs elsewhere. Furthermore, it may be that the coverage reported by the MASSIV trial is enough to impact malaria, but not enough to impact scabies.
      The lack of detection for head lice is probably caused by the local habit of shaving the boys’ heads, as well as braiding of girl's hair, thus denying lice the necessary living space. In the case of bedbugs, it is possible that, based on temperature data, the climate is too hot in the URR to establish a perennial presence (
      • How YF
      • Lee CY.
      Effects of temperature and humidity on the survival and water loss of Cimex hemipterus (Hemiptera: Cimicidae).
      ).
      The intervention did not have any effect on the overall STH prevalence. In the 2019 survey, we did detect an impact on S. stercoralis, which represented more than half of all STH infections. Of note, only three of 16 intervention villages had two-thirds of all individuals infected with Strongyloides (see Fig. S2). Whether this clustered higher burden was due to differences in coverage in these villages is unknown. Despite this initial impact, the effect of ivermectin was not detectable 2 years after MDA. This absence of effect may be due to reinfection from individuals who were untreated within MASSIV or from environmental sources.
      This study faced several limitations. The STH survey in 2021 had less than the expected number of participants. Secondly, the prevalence of A. lumbricoides, N. americanus, A. duodenale, and T. trichiura were much lower than anticipated, resulting in reduced statistical power to detect differences between arms. Unfortunately, this negated the opportunity to shine more light on the potential effect of this repeated ivermectin MDA on T. trichiura and hookworm species. Also, not every selected individual provided a stool sample, which may have introduced a bias into the data. In addition, we observed a high level of population movement, either by people moving away to different areas for better job opportunities or seasonal workers migration, which may have impacted the observed efficacy of the intervention (see Figs. 1 and 2).
      Finally, although study clusters are all from within the same region of The Gambia and we are not aware of any other factors outside the trial itself that could have influenced scabies prevalence in the control clusters but not the intervention clusters, we cannot completely exclude the possibility that an unidentified external factor influenced the prevalence of scabies in the control villages. Because routine socioeconomic and health interventions are not typically delivered to some villages, we believe that external secular changes are unlikely to account for the lack of effect seen.
      Overall, the results of the study were mixed with no effect shown for scabies and only S. stercoralis being significantly impacted. Further work is required to investigate the effect of MDA with ivermectin when implemented for malaria control on ectoparasites and STH because this may depend on both the intensity of the MDA coverage and local parasite prevalence.

      Funding

      CK was supported by Wellcome Trust Clinical Research Fellowship Programme (217357/Z/19/Z). The MASSIV trial was sponsored by the Joint Global Health Trials Scheme and Wellcome Trust.

      Ethical approval

      This study was nested within the MASSIV trial, and all participants were consented for the main study. The communities and local authorities were informed about these surveys and only consented participants were included. Parents consented for their children and additional written assent was obtained for children aged ≥12 years. Ethical clearance was given by the ethics board of the London School of Hygiene and Tropical Medicine and the Gambian government/Medical Research Council Unit Gambia Joint Ethics Committee (Ethics Ref. Nr. 17123).

      Author contributions

      Conceptualization: CK, JB, MM, JH; review & editing: JB, HV, AL, UD, MM; methodology: HV, JH, JA; original draft: CK; analysis and interpretation of data: CK, JB, HV, JH, JA, UD, MM; read and approved final version: CK, MD, JB, HV, JH, JA, UD, MM.
      For the purpose of Open Access, the author has applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission.

      Data sharing

      After publication, trial data will be made available on reasonable request to the corresponding author. A proposal with a detailed description of study objectives and a statistical analysis plan is needed for assessment of requests. Additional materials might also be required during the process. Deidentified participant data will be provided after approval by the sponsor and trial management group.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Acknowledgments

      The authors thank the staff of the Medical Research Council the Gambia microbiology laboratory in Basse for their support and their fieldworker team; without their support, hard work, and endurance, this study would not have been possible. The authors are also grateful for the support of communities’ leaders and village health workers who supported them throughout.

      Appendix. Supplementary materials

      References

        • Barda B
        • Albonico M
        • Buonfrate D
        • Ame SM
        • Ali S
        • Speich B
        • et al.
        Side benefits of mass drug administration for lymphatic filariasis on Strongyloides stercoralis prevalence on Pemba Island, Tanzania.
        Am J Trop Med Hyg. 2017; 97: 681-683
        • Basuni M
        • Muhi J
        • Othman N
        • Verweij JJ
        • Ahmad M
        • Miswan N
        • et al.
        A pentaplex real-time polymerase chain reaction assay for detection of four species of soil-transmitted helminths.
        Am J Trop Med Hyg. 2011; 84: 338-343
        • Camara Y
        • Sanneh B
        • Joof E
        • Sanyang AM
        • Sambou SM
        • Sey AP
        • et al.
        Mapping survey of schistosomiasis and soil-transmitted helminthiases towards mass drug administration in the Gambia.
        PLoS Negl Trop Dis. 2021; 15e0009462
        • Coscione S
        • Esau T
        • Kekeubata E
        • Diau J
        • Asugeni R
        • MacLaren D
        • et al.
        Impact of ivermectin administered for scabies treatment on the prevalence of head lice in Atoifi, Solomon Islands.
        PLoS Negl Trop Dis. 2018; 12e0006825
        • Dabira ED
        • Soumare HM
        • Conteh B
        • Ceesay F
        • Ndiath MO
        • Bradley J
        • et al.
        Mass drug administration of ivermectin and dihydroartemisinin–piperaquine against malaria in settings with high coverage of standard control interventions: a cluster-randomised controlled trial in the Gambia.
        Lancet Infect Dis. 2022; 22: 519-528
        • Engelman D
        • Yoshizumi J
        • Hay RJ
        • Osti M
        • Micali G
        • Norton S
        • et al.
        The 2020 international alliance for the control of scabies consensus criteria for the diagnosis of scabies.
        Br J Dermatol. 2020; 183: 808-820
        • Farrant O
        • Marlais T
        • Houghton J
        • Goncalves A
        • Teixeira da Silva Cassama ETda S
        • Cabral MG
        • et al.
        Prevalence, risk factors and health consequences of soil-transmitted helminth infection on the Bijagos Islands, Guinea Bissau: a community-wide cross-sectional study.
        PLoS Negl Trop Dis. 2020; 14e0008938
        • Feldmeier H
        • Heukelbach J.
        Epidermal parasitic skin diseases: a neglected category of poverty-associated plagues.
        Bull World Health Organ. 2009; 87: 152-159
        • Forrer A
        • Khieu V
        • Schindler C
        • Schär F
        • Marti H
        • Char MC
        • et al.
        Ivermectin treatment and sanitation effectively reduce Strongyloides stercoralis infection risk in rural communities in Cambodia.
        PLoS Negl Trop Dis. 2016; 10e0004909
        • Gbakima AA
        • Terry BC
        • Kanja F
        • Kortequee S
        • Dukuley I
        • Sahr F.
        High prevalence of bedbugs Cimex hemipterus and Cimex lectularis in camps for internally displaced persons in Freetown, Sierra Leone: a pilot humanitarian investigation.
        West Afr J Med. 2002; 21: 268-271
        • Gill GV
        • Welch E
        • Bailey JW
        • Bell DR
        • Beeching NJ.
        Chronic Strongyloides stercoralis infection in former British Far East prisoners of war.
        Qjm. 2004; 97: 789-795
        • Heukelbach J
        • van Haeff E
        • Rump B
        • Wilcke T
        • Moura RCS
        • Feldmeier H.
        Parasitic skin diseases: health care-seeking in a slum in north-east Brazil.
        Trop Med Int Health. 2003; 8: 368-373
        • Heukelbach J
        • Wilcke T
        • Winter B
        • Sales de Oliveira FA
        • Sabóia Moura RC
        • Harms G
        • et al.
        Efficacy of ivermectin in a patient population concomitantly infected with intestinal helminths and ectoparasites.
        Arzneimittelforschung. 2004; 54: 416-421
        • Heukelbach J
        • Winter B
        • Wilcke T
        • Muehlen M
        • Albrecht S
        • de Oliveira FA
        • et al.
        Selective mass treatment with ivermectin to control intestinal helminthiases and parasitic skin diseases in a severely affected population.
        Bull World Health Organ. 2004; 82: 563-571
        • How YF
        • Lee CY.
        Effects of temperature and humidity on the survival and water loss of Cimex hemipterus (Hemiptera: Cimicidae).
        J Med Entomol. 2010; 47: 987-995
        • Jourdan PM
        • Lamberton PHL
        • Fenwick A
        • Addiss DG.
        Soil-transmitted helminth infections.
        Lancet. 2018; 391: 252-265
        • Kearns TM
        • Speare R
        • Cheng AC
        • McCarthy J
        • Carapetis JR
        • Holt DC
        • et al.
        Impact of an ivermectin mass drug administration on scabies prevalence in a remote Australian Aboriginal community.
        PLoS Negl Trop Dis. 2015; 9e0004151
        • Kearns TM
        • Currie BJ
        • Cheng AC
        • McCarthy J
        • Carapetis JR
        • Holt DC
        • et al.
        Strongyloides seroprevalence before and after an ivermectin mass drug administration in a remote Australian Aboriginal community.
        PLoS Negl Trop Dis. 2017; 11e0005607
        • Lake SJ
        • Kaldor JM
        • Hardy M
        • Engelman D
        • Steer AC
        • Romani L.
        Mass drug administration for the control of scabies: a systematic review and meta-analysis.
        Clin Infect Dis. 2022; 75: 959-967
        • Lindsay SW
        • Snow RW
        • Armstrong JR
        • Greenwood BM.
        Permethrin-impregnated bednets reduce nuisance arthropods in Gambian houses.
        Med Vet Entomol. 1989; 3: 377-383
        • Marks M
        • Gwyn S
        • Toloka H
        • Kositz C
        • Asugeni J
        • Asugeni R
        • et al.
        Impact of community treatment with ivermectin for the control of scabies on the prevalence of antibodies to Strongyloides stercoralis in children.
        Clin Infect Dis. 2020; 71: 3226-3228
        • Mejia R
        • Vicuña Y
        • Broncano N
        • Sandoval C
        • Vaca M
        • Chico M
        • et al.
        A novel, multi-parallel, real-time polymerase chain reaction approach for eight gastrointestinal parasites provides improved diagnostic capabilities to resource-limited at-risk populations.
        Am J Trop Med Hyg. 2013; 88: 1041-1047
        • Romani L
        • Whitfeld MJ
        • Koroivueta J
        • Kama M
        • Wand H
        • Tikoduadua L
        • et al.
        Mass drug administration for scabies control in a population with endemic disease.
        N Engl J Med. 2015; 373: 2305-2313
        • Romani L
        • Marks M
        • Sokana O
        • Nasi T
        • Kamoriki B
        • Cordell B
        • et al.
        Efficacy of mass drug administration with ivermectin for control of scabies and impetigo, with coadministration of azithromycin: a single-arm community intervention trial.
        Lancet Infect Dis. 2019; 19: 510-518
        • Sheele JM
        • Anderson JF
        • Tran TD
        • Teng YA
        • Byers PA
        • Ravi BS
        • et al.
        Ivermectin causes Cimex lectularius (bedbug) morbidity and mortality.
        J Emerg Med. 2013; 45: 433-440
        • Slater HC
        • Foy BD
        • Kobylinski K
        • Chaccour C
        • Watson OJ
        • Hellewell J
        • et al.
        Ivermectin as a novel complementary malaria control tool to reduce incidence and prevalence: a modelling study.
        Lancet Infect Dis. 2020; 20: 498-508
        • Smit MR
        • Ochomo EO
        • Aljayyoussi G
        • Kwambai TK
        • Abong'o BO
        • Chen T
        • et al.
        Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial.
        Lancet Infect Dis. 2018; 18: 615-626
        • Roadmappers The ivermectin
        • Billingsley P
        • Binka F
        • Chaccour C
        • Foy B
        • Gold S
        • et al.
        A roadmap for the development of ivermectin as a complementary malaria vector control tool.
        Am J Trop Med Hyg. 2020; 102: 3-24
        • Verweij JJ
        • Canales M
        • Polman K
        • Ziem J
        • Brienen EAT
        • Polderman AM
        • et al.
        Molecular diagnosis of Strongyloides stercoralis in faecal samples using real-time PCR.
        Trans R Soc Trop Med Hyg. 2009; 103: 342-346
        • World Health Organization
        World malaria report.
        World Health Organization, Geneva2021: 2021