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Community-wide versus school-based targeted deworming for soil-transmitted helminth control in school-aged children in Vietnam: the CoDe-STH cluster-randomised controlled trial
research-article
Author(s):
Clare E.F. Dyer
a
,
l ,
Dinh Ng-Nguyen
b
,
l ,
Naomi E. Clarke
a
,
l ,
Sze Fui Hii
c ,
Hieu Quoc Nguyen
b ,
Van-Anh Thi Nguyen
b ,
Thai Van Nguyen
b ,
Trong Van Nguyen
b ,
Tam Thi Ngo
d ,
H.M.P. Dilrukshi Herath
c ,
Handan Wand
a ,
Luc E. Coffeng
e ,
Justine C. Marshall
a ,
Darren J. Gray
f
,
g ,
Roy M. Anderson
h ,
Archie C.A. Clements
i
,
j
,
k ,
John M. Kaldor
a ,
Rebecca J. Traub
c ,
Susana Vaz Nery
a
,
∗
Publication date (Electronic):
11 October 2023
Publisher:
Elsevier
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Summary
Background
Soil-transmitted helminth (STH) infection control programs typically consist of school-based preventive chemotherapy (PC) targeted to school-aged children. STH reservoirs in untreated community members contribute to ongoing transmission in children. The CoDe-STH (Community Deworming against STH) trial, conducted in Dak Lak province, Vietnam, between October 2019 and November 2020, aimed to determine whether community-wide mass drug administration (MDA) is more effective than school-based targeted PC in reducing STH prevalence and intensity in children.
Methods
In this two-arm cluster randomised controlled trial, 64 primary schools were randomly assigned 1:1 to receive either school-based targeted PC (“school arm”) or community-wide MDA (“community arm”). A single dose of albendazole 400 mg was used for deworming. The primary outcome was hookworm prevalence in schoolchildren, measured using quantitative real-time PCR. We also measured infection intensity for Necator americanus only, using qPCR cycle threshold (Ct) values converted into eggs per gram of faeces (EPG). Analysis was by intention to treat. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619000309189).
Findings
The analysis included 4955 children in the school arm and 5093 children in the community arm. N. americanus was the dominant STH species. The relative reduction in hookworm prevalence was not significantly different between the school arm (30.1%, 95% confidence interval [CI] 20.5–36.9) and the community arm (34.6%, 95% CI 19.9–49.4). Due to lower baseline prevalence than expected, the study was underpowered to detect a difference in prevalence reduction between the study arms. The community arm showed significantly greater relative reduction in N. americanus infection intensity (56.0%, 95% CI 39.9–72.1) compared to the school arm (3.4%, 95% CI −24.7 to 31.4). The community arm also showed greater relative reduction in prevalence of moderate-to-heavy intensity (≥2000 EPG) N. americanus infections (81.1%; 95% CI 69.7–92.6) compared to the school arm (39.0%, 95% CI 13.7–64.2).
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Most cited references21
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Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protocol
Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial. Trial registration ClinicalTrials.gov NCT03014167
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Soil-Transmitted Helminth Reinfection after Drug Treatment: A Systematic Review and Meta-Analysis
Tie-Wu Jia, Sara Melville, Jürg Utzinger … (2012)
Introduction Infections with soil-transmitted helminths (STHs) affect more than 1 billion people, particularly the rural poor of the developing world [1], [2]. The four most common STHs are the roundworm (Ascaris lumbricoides), the whipworm (Trichuris trichiura), and two hookworm species (Ancylostoma duodenale and Necator americanus) [2]. The greatest number of STH infections occur in Central and South America, People's Republic of China (P.R. China), Southeast Asia, and sub-Saharan Africa [2], [3]. Warm climates and adequate moisture are essential for the hatching or embryonation of STH eggs in the environment or development of larvae. Important contextual determinants for human infection are poverty, lack of sanitation, and inadequate hygiene (e.g., absence of hand washing with soap after defecation and before eating, and walking barefoot) [4]–[6]. In such social-ecological systems, multiple species STH infections are common [7]. Transmission of STHs occurs via contact with contaminated soil (hookworm) or consumption of egg-contaminated foods (A. lumbricoides and T. trichiura) [4]. An important epidemiological feature is their highly aggregated distribution: the majority of patients harbor low intensity infections, while only few individuals harbor very heavy infections [8]. People infected with STHs may suffer from anemia, growth stunting, diminished physical fitness, and impaired cognitive development [7], representing a persistent drain on social and economic development of low-income countries [9], [10]. The current global strategy to control STH infections is preventive chemotherapy, that is the repeated large-scale administration of anthelmintic drugs to at-risk populations, most importantly school-aged children [11], [12]. A shortcoming of this strategy is failure to prevent reinfection after effective deworming [6], [7], [13], [14]. Hence, identifying factors that determine reinfection risk is crucial to improving the effectiveness of this strategy [15]. To foster the design of more effective integrated control strategies, the objectives of this systematic review and meta-analysis were to assess available evidence on global patterns of STH reinfection after drug treatment, and to identify, through pooled risk estimates, the frequency and leading determinants of STH reinfection. Methods This systematic review was developed in line with the PRISMA guidelines (see Checklist S1) [16]. A protocol was prospectively registered in PROSPERO [17], registration number: CRD42011001678; available from http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001678. Selection Criteria We aimed to include all published studies in English or Chinese in which reinfection with STH was measured, for the period January 1, 1900 to December 31, 2010. Both observational studies and trials were eligible for inclusion. We excluded the following studies: (i) data without rate of infection after preventive chemotherapy; (ii) where time of follow-up was less than 2 months or more than 3 years; (iii) hospital-based or case studies in which the representativeness of the sample for the general population was unknown; and (iv) duplicate publication or extended analysis of previously published studies (see Figure 1 for selection flow of included studies). Additional exclusion criteria were: low adherence (loss rate of subjects at follow-up >30%), low initial prevalence ( 80%) [24], even after exclusion of five studies due to poor quality (three with low adherence rates [32], [36], [39], two with poor CR [13], [28]; for details, see Table S3). Publication and selection bias were not detected visually using funnel plots in eight pooled estimates with the exception of A. lumbricoides at the 3 months posttreatment follow-up time point. Re-Acquired Prevalence of STH at 3 Months Posttreatment For A. lumbricoides, we found a random pooled RR of reinfection, based on five studies, of 0.26 (95% CI: 0.16–0.43) [29], [31], [42]–[44]. The estimates from the individual studies are listed in Figure 2. CRs ranged from 89.7% to 97.7% for three studies [31], [42], [43]. The remaining two studies applied an excluding or retreatment procedure to the uncured [29], [44]. The study carried out by Liu et al. (2006) [44] showed that even after four rounds of treatment with pyrantel pamoate (10 mg/kg per dose given at 3 months interval for a year), the prevalence of A. lumbricoides reached 47% of the original prevalence at 3 months after the final treatment. We also performed a subgroup analysis of school-aged children (6–15 years) after excluding one population-based study [44]. Their pooled RR from four studies was 0.22 (95% CI: 0.13–0.39) [29], [31], [42], [43], slightly less than the value obtained using all age groups. We performed another pooled estimate in view of the detected publication bias caused by one large study (n = 1017) [42]. After excluding this study, the pooled RR changed slightly, rising from 0.26 to 0.29 (95% CI: 0.17–0.51) [29], [31], [43], [44]. 10.1371/journal.pntd.0001621.g002 Figure 2 Forest plot of prevalence of Ascaris lumbricoides 3, 6, and 12 months posttreatment. A random relative risk (RR) value of less than 1 indicates a lower infection rate after treatment compared to the initial level. Diamonds represent the pooled estimate across studies. See Table S1 for full references. *The infection rate 3 or 6 months after the last round of treatment was abstracted (Table S3). Due to low CR, only a few studies were included in our evaluation of reinfection with T. trichiura or hookworm at the 3 months posttreatment follow-up. In this review only two studies of T. trichiura and hookworm were included, which is insufficient for pooling [31], [42]. If the threshold of CR was set at 50%, then the resulting RR 3 months after treatment was 0.36 (95% CI: 0.28–0.47) for T. trichiura [31], and 0.30 (95% CI: 0.26–0.34) for hookworm (Table S3) [42]. Re-Acquired Prevalence of STH 6 Months Posttreatment For A. lumbricoides, the random pooled RR derived from nine studies was 0.68 (95% CI: 0.60–0.76) [29], [34], [40]–[44], [46], [47]. Estimates of the individual studies are given in Figure 2. CRs ranged from 92% to 100% in four studies [34], [40], [41], [43], while the remaining five studies applied an excluding or retreatment procedure to the uncured, and hence resulted in a higher CR [29], [42], [44], [46], [47]. We also performed a subgroup analysis of children aged 2–15 years after excluding two population-based studies and obtained a pooled estimate of 0.69 (95% CI: 0.60–0.79) [34], [44]. After three outlier studies were removed [40], [42], [43], the fixed RR was estimated to be 0.71 (95% CI: 0.68–0.75) (I 2 = 0%; χ2 = 3.22, P = 0.67) [29], [34], [41], [44], [46], [47]. For T. trichiura, four studies were included in the pooled estimate, two with moderate CRs (>67%) [34], [47], and two with poor CRs (30–40%), even after two rounds of treatment at 6-month intervals in 1 year (Table S3) [40], [42]. Poor CRs caused two outlier results and a higher pooled estimate without a significant difference from 1 (RR = 0.67; 95% CI: 0.42–1.08) (Figure 3) [34], [40], [42], [47]. When these two outlier studies were excluded [40], [42], the random RR dropped to 0.54 (95% CI: 0.41–0.71) [34], [47]. For hookworm, there were only two studies included with high CR (>90%) [41], [42], and the random RR was 0.55 (95% CI: 0.34–0.87). 10.1371/journal.pntd.0001621.g003 Figure 3 Forest plot of prevalence of Trichuris trichiura or hookworm after treatment. A random relative risk (RR) value of less than 1 indicates a lower infection rate after treatment compared to the initial level. Diamonds represent the pooled estimate across studies. See Table S1 for full references. *The infection rate 6 months after the last round of treatment was abstracted (Table S3). Re-Acquired Prevalence of STH 12 Months Posttreatment Generally, the heterogeneity effect caused by CR, treatment regimen, subpopulation, and variability in study design decreased gradually over the posttreatment follow-up time and became non-significant. STH prevalence tended to regress to the pretreatment level in A. lumbricoides and T. trichiura, and persisted at approximately half the level in the case of hookworm. However, poor adherence in some studies was a major source of heterogeneity, which could introduce an influential outlier. This effect was evaluated for a study in which the adherence rate for A. lumbricoides was relatively high (74%; 724/977), but considerably lower for T. trichiura (56%; 548/977) and hookworm (60%; 588/977) (Table S3) [22]. For A. lumbricoides, eight studies were included, resulting in a random RR of 0.94 (95% CI: 0.88–1.01) (Figure 2 and Table S3) [19], [22], [30], [33], [37], [44], [46], [47]. Removal of two outlier studies [19], [37], resulted in a fixed RR of 0.96 (95% CI: 0.93–0.98) (I 2 = 49%; χ2 = 9.85, P = 0.08). For T. trichiura, there were three studies included with a random RR of 0.82 (95% CI: 0.62–1.07) (Figure 3 and Table S3) [19], [37], [47]. One study was excluded from this pooling due to poor adherence of the T. trichiura cohort (56%; 548/977), of which the individual RR was 0.42 (95% CI: 0.35–0.51) [22]. If combined into the random-effects model, the pooled estimate dropped to 0.69 (95% CI: 0.45–1.05). We ultimately removed this cohort of T. trichiura from the pooled estimate based on our exclusion criteria (Table S3) [22]. For hookworm, there were five studies included with a random RR of 0.57 (95% CI: 0.49–0.67) (Figure 3 and Table S3) [19], [27], [35], [37], [45]. After removing two outlier studies [35], [45], we obtained a fixed RR of 0.57 (95% CI: 0.52–0.62) from three studies (I 2 = 0%; χ2 = 0.32, P = 0.85) [19], [27], [37]. In contrast to A. lumbricoides and T. trichiura, the re-acquired prevalence of hookworm returned to only about half of the initial level. We also removed a cohort of hookworm from the pooled estimate due to poor adherence (Table S3) [22]. Including that study would have resulted in a slightly lower pooled estimate (RR = 0.53; 95% CI: 0.44–0.64). Figure 4 shows the rapidity of re-acquiring soil-transmitted helminth (STH) infections at the 3, 6, and 12 months posttreatment follow-up time points. 10.1371/journal.pntd.0001621.g004 Figure 4 Summary of the rapidity of re-acquiring soil-transmitted helminth (STH) infections after treatment. Determinants of Predisposition to Reinfection Most studies focused on the risk of A. lumbricoides reinfection, particularly reinfection predisposition relating to the initial infection status, age, and sex. Seven studies were included into the pooled estimate of effect of initial infection status on A. lumbricoides reinfection, with a fixed RR of 1.95 (95% CI: 1.62–2.34) (I 2 = 0%, χ2 = 3.63, P = 0.73) (Figure S1) [31], [44], [48], [50], [51], [53], [54]. This means that 6 months after treatment, risk of reinfection in the pretreatment-positive group was almost twice as high than that of the pretreatment-negative group (P<0.001). The pooled estimates of the risk ratios of STH reinfection between subgroups are summarized in Table 2. Overall, males had a significantly lower risk of A. lumbricoides reinfection (P<0.001), and those with heavy intensity pretreatment infection with hookworm predisposed to re-acquiring high numbers of worm after therapy (P = 0.04) [63]. 10.1371/journal.pntd.0001621.t002 Table 2 Summary estimates of the risk of soil-transmitted helminth (STH) reinfection by determinants of predisposition.* Subgroups in comparison Risk ratios (RR) of reinfection, stratified by STH species (95% CI) (number of studies) [Reference] A. lumbricoides T. trichiura Hookworm Initial infection (present vs. absent) 1.95 (1.62–2.34) (n = 7)F [31], [44], [48], [50], [51], [53], [54] 1.07 (0.41–2.80) (n = 4)R [31], [51], [53], [54] 1.57 (0.74–3.37) (n = 3)F [31], [51], [54] Initial intensity (heavy vs. light) 3.65 (1.03–12.96, P = 0·05) (n = 2)R [52], [63] 2.82 (0.62–12.75) (n = 1) [63] 2.55 (1.02,6.37) (n = 1) [63] Age (adults vs. children) 0.76 (0.52–1.12) (n = 5)R [44], [51], [54], [57], [65] 0.93 (0.31–2.81) (n = 2)R [51], [54] 1.15 (0.58–2.28) (n = 2)F [51], [54] Sex (male vs. female) 0.71 (0.61–0.83) (n = 4)F [44], [51], [54], [65] 1.06 (0.67–1.68) (n = 2)F [51], [54] 1.42 (0.91–2.19) (n = 2)F [51], [54] *: Meta-analysis of nutrient supplementation, malnutrition, health promotion, individual behavior, and family and community environment was restricted because of small sample size (i.e., number of available studies for inclusion), or because of inconsistent measures used to assess infection and/or reinfection. F Pooled estimate of fixed-effects model. R Pooled estimate of random-effects model. For some important outcome measures, it was not possible to perform meta-analyses because of the low number of studies addressing such outcomes and the broad differences in the measures and statistical methods used to assess them [79]. Of 16 studies reporting the predisposition to heavy or light intensity of infection after treatment, 15 provided significant statistics and one was depicted by column chart without any statistics [49]. Only two provided data of subgroups categorized by intensity level and could be pooled (Table 2) [52], [63]. Statistical tests in 15 studies consistently found a positive relationship between the intensity of infection pre- and posttreatment. Eleven were tested by Kendall's correlation [32], [35], [49], [52], [55]–[59], [62], [64], two by Pearson's [50], [53], one by Spearman [61], and one by χ2 [63]. Among nine studies reporting reinfection risk of infected individuals, two could not be combined due to discordant or absent statistics [49], [52]. Two studies indicated that growth-retarded children were more susceptible to STH reinfection in comparison to children with normal development [21], [39]. One randomized controlled trial indicated that multi-micronutrient fortification significantly enhanced deworming efficacy [69]. However, two randomized controlled trials separately demonstrated that supplementation of iron or multi-micronutrients in children had no significant effect, neither on prevalence nor on intensity of reinfection [19], [22], and one cross-sectional cohort study in 1- to 5-year-old children identified possible transitory benefit of vitamin A supplementation [68]. One longitudinal study in Kenyan women during pregnancy reported a positive relationship between earth-eating and STH reinfection [72]. One controlled trial in Chinese pupils assessed and quantified the impact of hand washing with soap on A. lumbricoides infection [71]. Four studies assessed the effect of sanitation to control STH reinfection [21], [27], [50], [73]. Three studies observed the seasonal fluctuations of A. lumbricoides reinfection, indicating transmission is highest when rainfall is minimal and lowest when rainfall is at its highest [29], [48]. Discussion Investigation of STH reinfection patterns following drug therapy dates back to the early 1920s [27]. However, nearly 90% (45/51) of studies included in the meta-analysis reported here were pursued in the past 30 years, suggesting their relevance to current deworming strategies and programs. Our broad-based meta-analysis shows that after targeted or mass drug administration, the prevalence of STH infections recovers rapidly in most endemic areas. Indeed, 6 months posttreatment, the prevalence of all three species reached or exceeded half the initial level; and at 12 months posttreatment follow-up, the prevalence of A. lumbricoides and T. trichiura usually returned to levels close to the initial pretreatment, while levels of hookworm reinfection continued to fluctuate at about half pretreatment level (Figure 4). The rate and intensity of initial pretreatment infection status were positively correlated with reinfection, although such predisposing effects were not as clear-cut for T. trichiura and hookworm due to limited data or discordant statistics. Publication and Selection Bias We report relatively conservative pooled effect sizes, as demonstrated through sensitivity analysis. Had case studies with poor CR, low adherence with follow-up, or low coverage for treatment been included, the projected prevalence at around 6 months posttreatment would be higher than the presented pooled estimates (Table S3) [13], [28], [32], [36], [39]. One study included in our review, but not included in pooled estimates due to the difference in follow-up interval, showed that by 9 months posttreatment, re-acquired prevalence of A. lumbricoides and T. trichiura almost reached pre-intervention levels [38]. We acknowledge that some potentially relevant studies reported in Thai, Korean, Japanese, and Portuguese, identified by hand searching reference lists of included studies, were omitted. However, we are confident that excluding these studies and unpublished studies (‘grey literature’) would not impact our conservative pooled estimates (Figure 1). Our claim is substantiated by only a modest publication bias detected by funnel plots. Assessment of Quality of Included Studies For our analysis, it was important to include the broadest range of data (i.e., covering a large time period and multiple locations) from field-based studies to develop a more general and inclusive assessment of the risk of STH reinfection after treatment. There was potential heterogeneity of individual study inclusion criteria, initial prevalence and intensity levels, CR, drug administration strategies, adherence, and coverage rates, as well as sanitation and risk behavior. During the process of heterogeneity testing and sensitivity analysis, it was found that a low adherence rate created outliers with a large effect on the pooled estimate. For this reason, the final exclusion threshold for adherence was set conservatively at 70%. A low initial prevalence of STH infections (<10%) also created outliers (but with little influence on estimates), while a low CR could directly limit effective measurement of reinfection rates within 6 months after drug administration. We therefore removed such cohorts from our final pooled estimates. Most studies on reinfection of STH are based on the infected cohort (sometimes along with the uninfected cohort). Restricted by the methods of pooled analysis, the reinfection rate of such a cohort could not be combined and compared among studies. We therefore selected PRR between posttreatment and pretreatment as the indicator for estimating risk of reinfection after drug administration, which balanced the heterogeneity of studies and made them comparable. For some pooled estimates (Figure 2), we removed several outlier studies to compare the difference between fixed- and random-effects models. We found that the random estimate was similar to that of the fixed model, with wider 95% CIs than the fixed-effects model. Main Outcomes In May 2001, at the 54th World Health Assembly, member states were urged to pursue preventive chemotherapy to control morbidity due to STH infections and schistosomiasis, mainly among school-aged children [9], [80]–[82]. Our study indicates that in endemic areas where the prevalence of STH infections is above 10%, biannual treatment might be indicated against A. lumbricoides and T. trichiura and at least one treatment per year against hookworm. The seasonality of transmission of STHs is an important factor to consider in planning and timing of preventive chemotherapy, so that the effectiveness of this control strategy can be enhanced [13], [29], [40], [48], [83]. Our study shows that the rate and intensity of reinfection are positively correlated with the initial pretreatment infection status (Table 2). Although the dynamics of STH transmission may be intricate, reinfection levels should be expected to be similar over repeated treatments if the factors responsible for predisposition to light or heavy infection are stable through time [84]. For example, in view of PRR, there was only a modest decrease after a second-round treatment compared to the initial treatment (50.6% vs. 61.8% of the initial level of pretreatment for A. lumbricoides, 33.5% vs. 46.0% for T. trichiura [34] (for details, see Table S3). Overall, the ultimate objective of preventive chemotherapy is to control morbidity rather than to interrupt transmission of STH infections [15], [52], [81]. Limitations There are limitations to this systematic review and meta-analysis, which are offered for consideration. First, epidemiological and statistical heterogeneity between studies allows possible confounding of the observed results. For example, differences in age, sex, socioeconomic and nutritional status could modify the risk of STH reinfection, which could then confound estimation of the effects of these determinants. However, details of these potentially modifying factors were not available in most of the studies included in our analysis, so adjustment was not attempted in the summary statistics. Other factors, such as diagnostic method, the frequency, approach, and efficacy of anthelmintic drugs, and length and adherence of follow-up, also varied between studies. Second, for continuous distributions, relatively large changes in average worm load could have been related to only small changes in overall prevalence such that prevalence, and hence CR, may not be the best indicator to monitor the impact of anthelmintic treatment in highly endemic areas [33], [40], [52], [76]. Indeed, it has been argued that egg reduction rate (ERR) rather than CR should be used for anthelmintic drug efficacy evaluations [85]–[87], and perhaps for studying patterns of reinfection after treatment. Intensity of infection is an important aspect of all helminthiases, but could not be well addressed in our pooled estimates. Similarly, the significant relationships between STH reinfection and socioeconomic factors could not be definitively assessed [4]. Finally, the generalized estimates from our study will probably not apply to low endemicity areas, characterized by prevalence estimates below 10%. Concluding, preventive chemotherapy with the current drugs of choice against STHs, while showing good results on morbidity reduction, does not prevent rapid reinfection [88]. Decision-makers have to make tradeoffs between benefits, cost (selected vs. mass treatment), acceptability, and harms (e.g., drug resistance) of preventive chemotherapy according the local settings [89]–[92]. Our results therefore support recommendations for integrated control approaches, complementing preventive chemotherapy with information, education, and communication (IEC) strategies, and sanitation improvement, in order to control STH infections more durably [6], [93]–[95]. The experience from the southern parts of the United States of America almost 100 years ago, as well as the Republic of Korea, P.R. China, and some parts of sub-Saharan Africa indicates that control strategies must be adapted to the prevailing social-ecological setting, and require long-term political commitment [95], [96]. In resource-limited settings, regular deworming of school-aged children is considered to be a cost-effective intervention for control of morbidity due to STH infections [9], [80], [96]. More intense treatment (e.g., twice yearly) is likely to further impact on morbidity, as seen for schistosomiasis [90], but might bear the risk of drug resistance development [91], [97]. If resources allow, efforts should be made to promote clean water, improved sanitation, health promotion in schools, and these efforts should ultimately aim at behavioral change [6], [98]–[101]. Communities living in newly industrialized countries such as P.R. China, should benefit from an integrated treatment and sanitation strategy. Hence, rather than solely being restricted to preventive chemotherapy targeting STHs and other neglected tropical diseases [102], comprehensive control requires inter-programmatic and intersectoral action for health and development [103], [104]. Supporting Information Figure S1 Forest plot of reinfection risk of individuals initially infected with Ascaris lumbricoides , 6–12 months posttreatment. Notes: A random relative risk (RR) of less than 1 indicates a lower infection rate after treatment compared to the initial level. Diamonds represent the pooled estimate across studies. See Table S1 for full references. (PDF) Click here for additional data file. Table S1 Included studies. (DOC) Click here for additional data file. Table S2 Excluded studies. (DOC) Click here for additional data file. Table S3 Studies included in our meta-analysis pertaining to reinfection patterns of soil-transmitted helminths (STHs) 3–12 months posttreatment.* (DOC) Click here for additional data file. Checklist S1 PRISMA checklist. (DOC) Click here for additional data file.
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Should the Goal for the Treatment of Soil Transmitted Helminth (STH) Infections Be Changed from Morbidity Control in Children to Community-Wide Transmission Elimination?
Roy Anderson, Hugo C. Turner, James Truscott … (2015)
Introduction Morbidity induced by infection with the major soil transmitted infections (STH—Ascaris lumbricoides, Trichuris trichiura, and hookworms) results in an estimated 5.19 million disability-adjusted life years (DALYs) [1]. The World Health Organization’s (WHO) policy for control centres on three groups, preschool aged children (pre-SAC), school-aged children (SAC), and women of child bearing age, on the basis that heavy infection in these groups will have a detrimental impact on anaemia, child growth, and development. The current WHO guidelines focus on school-aged children, both for monitoring infection and as a target for treatment, although treatment of pre-SAC and women of childbearing age is also recommended where sustainable delivery mechanisms exist, especially in areas of intense transmission [2,3]. The guidelines recommend treating SAC annually where any STH prevalence falls between 20% and 50% and twice a year where it exceeds 50% [3]. The London Declaration on Neglected Tropical Diseases in 2012 endorsed WHO goals to scale up mass drug administration (MDA) for STH, so that by 2020, 75% of the pre-SAC and SAC in need will be treated regularly [4]. Building on an existing roadmap, WHO announced an intention to meet the target [2,5,6]. Progress has been good in some areas, but less so in others. In 2012, global coverage of those in need was 37% for SAC and 29% for pre-SAC [5]. Data for the more recent years is as yet to be published by WHO [5], but a huge gain in coverage is not expected, despite increased drug donations from the pharmaceutical companies who manufacture the main anthelmintics. This is due in part to the logistical challenges in getting even donated drugs to these populations, who are often beyond “the end of the road.” At present, many countries with endemic STH infections are not availing themselves of the freely donated drugs to treat children. We are still a long way from the 2020 target of 75%. Even if this target is reached, will it be enough to eliminate transmission and the disease arising from heavy infections with STH? If not, how should the guidelines be changed to push towards morbidity control, and ideally, the eventual elimination of transmission? Basing Policy on Quantitative Calculations To answer these questions, calculations are required to assess the impact of MDA targeted at particular age groupings, especially pre-SAC and SAC, on overall transmission in communities with differing levels of infection exposure. In many areas of infectious disease epidemiology and the design of interventions, the impact of control is today assessed by simulations based on mathematical models using parameter estimates from epidemiological studies (e.g., HIV and Plasmodium falciparum [7,8]). The neglected tropical disease (NTD) field lags behind, in the sense of largely basing target treatment levels on discussion and consensus, without detailed calculations. Much of the basic framework for the study of the transmission dynamics of helminth infections was laid down in the 1960s and 1980s [9,10]). Rather little has been achieved since that time in model development and parameter estimation. Concomitantly, little use has been made of the insights gained from these analyses in the design of public health policy for the control of STH and schistosome infections. The tools now available can rectify this shortcoming, and they can easily be adapted to include costs and benefits as outlined in this article. They should be used to refine WHO policy on treatment to aim for a robust framework that will eliminate transmission. Demography and Epidemiology A key issue concerns demography in sub-Saharan Africa and other areas with endemic infection. Typically, there are as many adults as there are pre-SAC and SAC [11]. This implies that, depending on the distribution of worms across the age classes, the adults themselves may be able to sustain transmission within a community, even when a very high fraction of the children are treated effectively. This is especially the case for hookworm where adults typically harbour the majority of worms (in some areas, more than 80% of the total population of parasites, (Fig 1—see inset in graph C)), but also applies for Ascaris and Trichuris, where up to 30% of worms and egg counts are in those older than 15 years of age [11], irrespective of the intensity of transmission in a defined area. 10.1371/journal.pntd.0003897.g001 Fig 1 Cross-sectional surveys of the mean intensity of infection in different age groupings for A. lumbricoides (A), T. trichiura (B), and hookworm (C) based on worm expulsion studies. These are typical age intensity profiles for the three most important STH species, where the colours denote the age groupings: pre-SAC (blue), SAC (red), and adults (orange). Data for A from [25], data for B [26], and data for C [27]. The inset in Graph C represents five worm expulsion studies of Necator americanus showing consistent patterns in a rise in burden with age in different geographical locations [28]. The impact of this substantial reservoir of infection in adults on reinfection in children can be better illuminated using deterministic and stochastic models of STH transmission, based on parameter estimates derived from cross-sectional and longitudinal worm expulsion studies and observations on demography and the mean intensity distribution across the major age groupings (pre-SAC, SAC, and adults—see Fig 1 [12,13]). A series of general conclusions emerge that support the observational studies based on demography and cross-sectional epidemiological data on age specific intensities of infection. Impact of Current Treatment Strategies We focus on three major issues concerning MDA, namely: who to treat, how frequently to treat, and how long to treat. In our calculations, we use a fully aged structured deterministic STH transmission model (described in [12,13]). Stochastic individual-based models for the mean worm burden give identical results to the deterministic predictions. For illustration, we compare the impact of annual and biannual treatment of pre-SAC and SAC, with annual mass treatment, in communities with Ascaris and hookworm. As a case study, we focus on an area of medium transmission (R0 values around 2–3, true prevalence (not adjusted for diagnostic sensitivity) around 70% in SAC). As illustrated in Fig 2, which records simulated MDA strategies focusing on once and twice yearly treatment of pre-SAC and SAC combined (at a coverage level of 75%), compared with community-wide treatment (at the same coverage level). Increasing the frequency of MDA in children is predicted to be marginally more effective than annual mass treatment, in terms of reducing the overall burden of Ascaris. In contrast, for hookworm, the analyses illustrate that increasing the frequency of MDA for pre-SAC and SAC alone has limited additional impact. Expanding the annual treatment programme to also include adults actually reduces the intensity of hookworm infections both in children and the community as a whole (Fig 2). This occurs because the adults have the majority share of the infectious reservoir (i.e., are a core group), and consequently, treating children alone does not significantly impact the level of transmission. The children get reinfected after treatment because of the reservoir in adults. This suggests that WHO guidelines to increase treatment to twice a year in high prevalence areas is unlikely to have the desired impact in areas with high hookworm prevalence. The best treatment strategy is highly dependent on the local age distribution of infection of the different STH species. 10.1371/journal.pntd.0003897.g002 Fig 2 Impact of different treatment stratgies on the mean number of worms in different age groupings. The coloured lines represent different treatment strategies: green—annual community-wide MDA (75% coverage of all age groupings (pre-SAC, SAC, and adults) and 95% drug efficacy); red—biannual age group targeted MDA (pre-SAC and SAC with 75% coverage and 95% drug efficacy); and blue—annual age group targeted MDA (pre-SAC and SAC with 75% coverage and 95% drug efficacy). Graphs A–C and D–F correspond to Hookworm and Ascaris respectively. Graphs A and D record the overall mean number of worms across all ages. Graphs B and E record the mean number of worms in children (pre-SAC and SAC, 2–15-year-olds). Graphs C and F record the mean number of worms in adults (>15 year olds). Calculations based on a basic reproductive number, Ro, of 2.5 (medium to high transmission setting). Model parameters described in [13]. It is important to note that monitoring and evaluation programmes that only measure the impact of a school-based hookworm treatment programme in the treated age group record a much bigger impact on the children (Fig 2b) than the true impact on the entire population, as reflected by persisting worm burdens in adults (Fig 2c). School-age group-based surveillance programmes can give good estimates of the reduced morbidity in children but can lead to misleading estimates of the impact of these programmes on overall transmission in the community. A revision in the monitoring and evaluation (M & E) guidelines is required to address this problem. Current guidelines recommend that monitoring is conducted in schools, as school children are the main targets of control [14]. More recently, transmission assessment surveys (TAS) for lymphatic filariasis have been proposed as an alternative platform for monitoring STH infection [15], and the implementation of TAS in the wider community provides the opportunity to reliably track STH across a range of age classes [16]. To cross the transmission “breakpoint” [10], where transmission is eliminated, requires many years of continual treatment (Fig 2b) at moderate to high coverage (>75%), depending on the intensity of transmission (the value of R0). Elimination requires the treatment of adults for hookworm, and the time required to achieve this is accelerated (and required in areas of high transmission) for Ascaris. This conclusion also applies for Trichuris, and in most circumstances for the schistosome infections for which praziquantel is employed in MDA. Pre-SAC treatment for the control of morbidity induced by schistosome infections has been suggested by Stothard [17]. The practical feasibility of providing mass treatment to adults in addition to pre-SAC and SAC is demonstrated by the mass treatment campaigns for onchocerciasis and lymphatic filariasis (LF), which provide albendazole plus ivermectin or diethylcarbamazine citrate to entire communities, using community drug distributors [16]. The albendazole and ivermectin used in these programmes are also highly effective against STH [18,19], although there has been no systematic attempt to quantify the impact of the global onchocerciasis and LF control programmes on the transmission of STH despite the potential insight they afford into the impact of expanding current school-based deworming programmes. Costs of Different Strategies A key issue in scaling up treatment to the whole community is cost, and this in turn depends on demography (the proportions of the population in each age grouping), who is treated, at what coverage level, how often, and for how long. If transmission is not interrupted by only focusing on pre-SAC and SAC, treatment must continue forever if no other conditions change [13]. Water, sanitation, and hygiene (WASH) programmes have the potential to radically change the picture, if they can be designed to permanently supress transmission, but progress has been limited in many areas of endemic infection [20]. Hopefully, this situation may change in the coming decades as economic growth improves in parts of Africa and Asia, leading to better sanitation and hygiene. Under the pessimistic assumption that treating adults is twice as expensive as treating children (many studies reporting a much lower difference [21]), we calculate that the total costs of community-wide treatment over a 20 year period (discounting at 3% per year) are much less (approximately 60%) than that for repeated annual treatment of pre-SAC and SAC, given that the former has only to continue for three years (with the assumptions in Fig 2), while the latter must continue beyond the 20-year time horizon in hookworm transmission areas of intermediate intensity (Turner et al. manuscript in preparation). New Treatment Guidelines and a New Strategy Our calculations suggest that the current guidelines need modification, particularly regarding the recommendation to increase treatment frequency if the prevalence of any STH is greater than 50% in SAC. Calculations suggest that in most areas where hookworm is the dominate infection, it is better to broaden treatment across all age classes instead of treating children twice a year. This leads to the more efficient use of limited resources in the longer term. For high transmission Ascaris areas, the best option is both increasing frequency and broadening coverage across all age classes. Drug efficacy for Trichuris is known to be low with monotherapy using either Albendazole or Mebendazole (the standard treatments for STH) [22], and hence in settings where Trichuris is the dominant STH, alternative approaches will be required. One such approach that has been shown to notably increase the treatment efficacy against Trichuris is coadministering Ivermectin with the benzimidazoles or using other drug combinations [23]. With dual therapy, broadening the coverage of age groupings to include adults may also be beneficial (depending on the local age intensity profile [Fig 1]). What are the barriers to changing the quidelines for treatment, monitoring and evaluation? The school has many advantages for treatment delivery since high treatment coverage can be achieved for regular attenders and for surveillance as schools provide a ready sampling frame. In contrast, in some settings it has proven difficult to achieve high coverage (and good surveillance) in adults for STH (although the experience with MDA for lymphatic filariasis argues that it can be achieved [24]), and the cost of treating one adult may at times be higher when compared with treating children in a school setting. Community-wide coverage also requires an increase in drug donations. Despite this, the longer term cost calculations are compelling, given that one strategy has to be continued forever while the other offers the hope of interrupting transmission permanently. On this basis, it would seem highly desirable to change the WHO guidelines, with a concomitant emphasis on education, sustainability of current WASH programmes (to reduce transmission intensity and thereby enhance the impact of MDA), communication to encourage high treatment uptake amongst adults and better integration of STH control with that of LF where community-wide coverage has been a target for some time. The coverage levels predicted to eliminate LF transmission are much less stringent than those required for hookworm or Ascaris, so integrated STH and LF control is desirable, but reported coverage and frequency of treatment with Albendazole for LF must be increased to stop STH transmission. A revision of the guidelines is especially desirable when hookworm is the dominant infection, since most worms are typically harboured by adults. The cross-sectional age intensity profiles for Ascaris and Trichuris (Fig 1), and for the schistosomes, suggest that in high transmission areas, infections across the community may be maintained by adults even when children are effectively treated twice a year at high coverage levels. Of course, treating the whole community will also lead to more rapid reductions in transmission. But the effect will not be as extreme as for hookworm. To achieve the 2020 goals, treatment coverage in children must be increased significantly, but in many areas reductions in morbidity, and the highly desirable goal of stopping transmission, would both be more likely and much more rapid, if coverage is broadened to encompass adults. The debate on what is the best strategy to manage STH infection should shift from morbidity control to transmission interruption. Concomitantly, there is a need to broaden the scope of research to investigate the cost-effectiveness and feasibility of alternative treatment strategies in achieving the interruption of transmission across a range of settings. Linked to any shift from age group targeting to community-wide control is the risk of enhancing selection for drug resistant strains of the parasites, where the refugium of untreated adults no longer dilutes the gene pool of those parasites exposed to selection. But the experience with community-wide control in LF programmes, where the Albendazole drug also impacts STH, suggests this concern may not materialize in practice. However, this needs careful monitoring.
Author and article information
Contributors
Susana Vaz Nery
Journal
Journal ID (nlm-ta): Lancet Reg Health West Pac
Journal ID (iso-abbrev): Lancet Reg Health West Pac
Title:
The Lancet Regional Health: Western Pacific
Publisher:
Elsevier
ISSN
(Electronic):
2666-6065
Publication date PMC-release: 11
October
2023
Publication date Collection:
December
2023
Publication date
(Electronic):
11
October
2023
Volume: 41
Electronic Location Identifier: 100920
Affiliations
[c
]Faculty of Science, Melbourne Veterinary School, The University of Melbourne, Melbourne,
Vic, Australia
Author notes
[∗
]Corresponding author. The Kirby Institute, University of New South Wales, Level 6,
Wallace Wurth Building High Street, Kensington, NSW 2052, Australia.
snery@
123456kirby.unsw.edu.au
Article
Publisher Item ID: S2666-6065(23)00238-9 Publisher ID: 100920DOI: 10.1016/j.lanwpc.2023.100920
PMC ID: 10583164
PubMed ID: 37860203
SO-VID: 70a1f3ea-0ca7-4a40-a01d-9efc189b7c07
Copyright © © 2023 The Authors
License:
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
History
Date
received
: 20
August
2023
Date
accepted
: 15
September
2023
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