Deworming and adjuvant interventions for children in low and middle income countries: systematic review and network meta-analysis Vivian Welch, Chris Cameron, Shally Awasthi, Chisa Cumberbatch, Robert Fletcher, Jessie McGowan, Shari Krishnaratne, Salim Sohani, Peter Tugwell, George Wells

Canadian Institutes of Health Research Knowledge Synthesis Acknowledgements Canadian Institutes of Health Research Knowledge Synthesis

Geohelminths and schistosomiasis Necator americanus and Ancylostoma duodenale (hookworm) Ascaris lumbricoides (roundworm) Schistosomiasis Trichuris Trichiura (whipworm)

Ascaris lumbricoides Necator Americanus Trichuris trichiura   Infection Process Light Infection Symptoms Heavy Infection Symptoms Approximate # of people infected Ascaris lumbricoides swallows food or soil   Often no symptoms Cough, fever, discomfort passing worms 800 million Necator Americanus absorbed through skin. diarrhea, cramps and weight loss that can lead to anorexia. anaemia   500-600 million Ancylostama Duodenale contact of skin with soil contaminated with larvae Light infection causes abdominal pain, loss of appetite protein deficiency or iron-deficiency anaemia 100 million Trichuris trichiura Ingestion of eggs iron-deficiency anaemia, Vitamin A loss. Schistosomiasis swimming or playing in infected water. anaemia, stunting and reduced ability to learn 243 million

The greatest burden of STH occurs in Sub-Saharan Africa (SSA) The greatest burden of STH occurs in Sub-Saharan Africa (SSA). This map shows the predicted distribution of STHs in SSA with Ascaris Lumbricoides. Source: Global Atlas of Helminth Infections

WHO Guidelines for Deworming, 2011 For soil-transmitted helminths, annual treatment in areas where prevalence rate of soil-transmitted helminthiases is between 20% and 50%, and, a bi-annual treatment in areas with prevalence rates of over 50%. For schistosomiasis, annual treatment with praziquantel in high risk communities (>50%), once every two years in medium risk (>10% and <50%), twice during primary school in low risk communities (<10%)

What do we know about effects of deworming?

Deworm the World School-based deworming identified as one of the most efficient and cost-effective solutions to the global challenges facing us today (Copenhagen Consensus Meeting) School-based deworming proven to reduce school absenteeism by 25%, and can lead to an additional year of attendance for only $3.50. Children regularly dewormed are shown to earn over 20% more and work 12% more hours as adults Children less than one year old at the time of school-based deworming in their communities are shown to have large cognitive improvements equivalent to half a year of schooling. Source: www.Dewormtheworld.org; Kremer and Miguel 2004, Ozier 2011, Baird 2011

Taylor-Robinson et al 2012, Cochrane Aimed to summarize the effects of deworming to children to treat soil-transmitted intestinal worms (nematode geohelminths) on weight, haemoglobin, and cognition; and the evidence of impact on physical well being, school attendance, school performance, and mortality 42 randomized and quasi-randomized trials satisfied eligibility criteria Author’s conclusion: “it is probably misleading to justify contemporary deworming programmes based on evidence of consistent benefit on nutrition, haemoglobin, school attendance or school performance as there is simply insufficient reliable information to know whether this is so”

DEVTA- “largest trial ever” 1 million children in India, aged 1-6 years No difference in mortality (deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·00 (SE 0·07) albendazole versus 3·16 (SE 0·09) control, difference 0·16 (SE 0·11, mortality ratio 0·95, 95% CI 0·89 to 1·02, p=0·16))

Why such discordant conclusions?

Possible reasons for discordance… Spillover effects/positive externalities All intestinal worms are not the same Not all intestinal worms respond to the same deworming medication. Only moderate and heavy intestinal helminth infections typically cause measurable disease. Reinfection Underlying host and environment factors Non-standard measures of school attendance and cognitive performance Heterogeneity within and between studies mebendazole produces only a 15% cure rate against hookworm infection, and indeed the Smith and Brooker analysis confirmed that mebendazole does not improve anemia whereas albendazole does

Mechanism of action of selected drugs Name of drug Mechanism of Action Target Disease Praziquantel Allows rapid entrance of Calcium ions into cell membrane of worm. Leads to parasitic death Schistosomiasis Levamisole Causes muscle paralysis and parasitic death Ascariasis Pyrantel Causes paralysis in worms. They detach from the host’s intestinal walls. Necatoriasis Trichinosis Ivermectin Disrupts the permeability of the cell membrane to chloride ions. Leads to paralysis then death of parasite Onchocerciasis Strongyloidiasis Soil-transmitted helminths Mebendazole Gradually kills the larvae secreted by adult worms More effective when used in combination therapy Albendazole Inhibits assembly of tubulin into microtubles , inhibits uptake of glucose, worm immobilized, then dies

Campbell review on deworming: a network meta-analysis IDCG review

Research questions Effect of deworming according to the WHO guidelines compared to placebo (or control)? Effect of deworming for STH vs. schistosomiasis vs. combined approaches? Effect of adding hygiene education, sanitation, micronutrients or feeding programs compared to deworming alone What factors contribute to heterogeneity of effect (e.g. endemicity, child age, baseline nutritional status, infection intensity)?

Hygiene promotion and/or sanitation Vectors: soil drinking water washing water feces hands food Reduced reinfection Deworming (STH treatment +/ or schistoso-miasis treatment) Reduced symptoms 3 (eg. diarrhoea, abdominal pain, general malaise, weakness, intestinal blood loss, anemia, fever, dysuria, intestinal obstruction, haematuria, and organ damage) Improved longer term outcomes Reduced proportion of wasted children Improved weight and height Improved social, physical, emotional and cognitive functioning Effects of improved health outcomes Improved overall well-being Increased school attendance and achievement Improved labour market outcomes Target Population Children (1-16 yrs) in worm endemic areas [Ascaris lumbricoides Trichuris trichura Ancylostoma duodenale,Necator americanus, and Schistosoma] Decreased worm burden in treated children 1 Improved short term outcomes Improved nutrient absorption nutritional status Spillover decreased worm burden in control children 2 Nutritional therapy (eg. micronutrient, feeding, iron) Decreases the gap between the poor and least poor Improves health equity Risk factors/conditions for implementation and up-take: Individual Environment Intervention anaemia, high worm burden, supervision, dosage, time of day, place of administration undernutrition, high endemicity of other infectious disease, poor sanitation, poor hygiene, poverty low socioeconomic status LEGEND Intermediary outcomes Final outcomes Interventions/ co-interventions Causal pathway Cyclical effect

Mixed treatment comparisons Assessment of heterogeneity due to multiple components (i.e. hygiene, sanitation, micronutrients, feeding and type of deworming); Identification of areas where evidence is limited Meta-regression allows more complete consideration of covariates (such as age, study duration, nutritional status and intensity of worm infection)

What is a network meta-analysis?

Methods Bayesian Mixed Treatment Comparison Network Meta-analysis using WinBUGS software Normal likelihood model which allows for the use of multi-arm trials Both fixed and random-effects Bayesian network meta-analyses were conducted Choice of model was based on assessment of the Deviance Information Criterion (DIC) and comparison of residual deviance to number of unconstrained data points Compared deviance and DIC statistics in fitted consistency and inconsistency models Vague or flat priors were assigned for basic parameters throughout Bayesian analyses

PICO Population: 6 months- 16 years of age Intervention: Mass drug administration for chemoprevention of STH or schistosomiasis, alone or in combination with cointerventions Comparison: placebo, control, active Outcomes: anthropometry, educational status, cognition, well-being, adverse events

Eligible studies Randomized and quasi-randomized controlled trials Quasi-experimental studies which use statistical methods to account for confounding and sample selection bias

Search strategy LILACS, Social Services Abstracts, Econlit, Database name and coverage Search date Total Retrieved Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present 1946 to April 18, 2013 5664 Ovid Embase Classic+Embase 1947 to 2013 January 16 1947 to April 18, 2013 1582 Wiley Cochrane Library , Issue 2 of 12, Feb 2013 April 18, 2013 260 EbscoHost CINAHL, 1982-March 2013 1982- April 18, 2013 95 LILACS, 316 Social Services Abstracts, 2 Econlit, 11 Public Affairs Information Service 1 Global Health CABI and CAB Abstracts 4455   Total without Duplicates 9790

PRISMA Flow diagram 9,790 identified through database searching Impact evaluation databases remain to be searched 9790 screened for eligibility 9,619 Excluded Studies retrieved in full text (n=171) 143 Excluded 7 awaiting data from authors RCTs included in quantitative synthesis (n=21)

Characteristics of studies # arms: 14 two arm, 5 three arm, 2 four arm Age range: < 6 months: 1; 12-60 month: 9; >60 month: 11 Endemicity: low: 8; moderate: 5; high: 8 Size of study: <100: 3; 100-500: 7; >500: 7; >1000: 4 Study duration: <6 months: 3; 6 months-1 year: 11; > 1 year: 7 # cluster RCTs: 7 out of 21

Evidence Network – Deworming-Weight gain (Kg) 21 RCTs 16 Treatments N=42,197

Results vs. Placebo – Weight gain in Kg Pyrantel Pamoate Albendazole Albendazole-high dose Albendazole+iron iron Mebendazole vitamin A Albendazole + vitamin A Levamisole Piperazine Metronizadole (anti giardia) Piperazine+metronizadole Albendazole + Praziquantel Praziquantel (for schistosomiasis) Metrifonate (also for schistosomiasis) 0.19(0.01,0.37) 0.24(-0.43,0.92)   0.15(0.11,0.19) 0.28(-0.01,0.57) 0(-0.35,0.34) 0.09(-0.84,1.02) 0.06(-0.21,0.33) -0.07(-0.89,0.67) 0.09(-0.04,0.23) 0.12(-0.48,0.69) 0.02(-0.09,0.14) -0.08(-0.62,0.45) 0.43(0.13,0.74) 0.38(-0.48,1.26) 1.42(1.06,1.79) 1.38(0.12,2.64) 0.93(0.71,1.16) 0.93(0.02,1.85) 0.03(-0.32,0.37) 0.02(-0.92,0.97) 0.22(-0.11,0.55) 0.22(-0.73,1.16) 0.35(-0.31,1.01) 0.35(-0.75,1.44) 0.2(-0.22,0.62) 0.2(-0.78,1.18) 1.2(0.92,1.48) 1.2(0.27,2.13) 1.4(1.09,1.7) 1.41(0.47,2.35) FE: Resdev=161 vs 51; DIC=60.65 RE: Resdev=52.7 vs 51; DIC=-35.9

Results vs. Placebo, RE Model– Weight gain in Kg Pyrantel Pamoate Albendazole Albendazole-high dose Albendazole+iron iron Mebendazole vitamin A Albendazole + vitamin A Levamisole Piperazine Metronizadole (anti giardia) Piperazine+metronizadole Albendazole + Praziquantel Praziquantel (for schistosomiasis) Metrifonate (also for schistosomiasis) 0.24(-0.43,0.92) 0.28(-0.01,0.57) 0.09(-0.84,1.02) -0.07(-0.89,0.67) 0.12(-0.48,0.69) -0.08(-0.62,0.45) 0.38(-0.48,1.26) 1.38(0.12,2.64) 0.93(0.02,1.85) 0.02(-0.92,0.97) 0.22(-0.73,1.16) 0.35(-0.75,1.44) 0.2(-0.78,1.18) 1.2(0.27,2.13) 1.41(0.47,2.35) 0.20(-0.01,0.41), I2-na 0.31(0.10, 0.53), i2, 94% na 0.14 (-0.04, 0.32), I2=0% 0.10 (-0.07, 0.26), i2=0% -0.07 (-0.41, 0.28), i2=87% 0.14 (-0.20, 0.49), i2=0% 0.93 (0.71, 1.15), i2-na 0.03 (-0.32, 0.37), i2=na 0.22 (-0.11, 0.55), i2=na 0.35 (0.02, 0.68), i2=na 0.20 (-0.21, 0.61), i2=na 1.2(0.92, 1.47), i2-=na 1.40 (1.09, 1.71), i2=na Deworming 0.29 (0.13, 0.45) Overall I2=92%

Next steps Hand searching reference lists, impact evaluation databases, contacting authors Educational outcomes Quasi-experimental studies Risk of bias Causal pathway analysis Covariate analysis to explore heterogeneity and improve consistency of model

Questions? Vivian.welch@uottawa.ca