Analysis of the population-level impact of co-administering ivermectin with albendazole or mebendazole for the control and elimination of Trichuris trichiura

Abstract

Introduction: Soil-transmitted helminth (STH) infections are predominately controlled by providing children with preventive chemotherapy with either albendazole or mebendazole. However, neither has a high efficacy against Trichuris trichiura. This low efficacy limits the overall effectiveness of the current STH control programmes against T. trichiura. It has been demonstrated that co-administering ivermectin with albendazole or mebendazole significantly increases the efficacy of current treatments, which may increase the overall effectiveness of control programmes.

Methods: Using a STH transmission mathematical model, we evaluated the potential impact of co-administering ivermectin with albendazole or mebendazole to treat T. trichiura within a preventive chemotherapy programme targeting children (2-15 year olds). We evaluated the impact in terms of reduction in prevalent infections, mean worm burden, and prevalence of heavy infections.

Results: Although the current treatment strategy reduced T. trichiura worm burden and prevalence of heavy infections, due to their poor efficacy the long term impact of preventive chemotherapy for children was smaller compared to the other STH. Co-administering ivermectin increased the projected impact of the preventive chemotherapy programme in terms of all three of the explored metrics, practically in high transmission settings. Furthermore, ivermectin co-administration greatly increased the feasibility of and timeframe for breaking transmission.

Conclusions: Co-administering ivermectin notably increased the projected impact of preventive chemotherapy in high transmission settings and increased the feasibility for breaking transmission. This has important implications for control programmes, some of which may be shifting focus from morbidity control to interruption of transmission, and some of which may be logistically unable to provide preventive chemotherapy twice a year as recommended. However, the benefit of co-administering ivermectin is limited by the fact that 2-5 year olds are often ineligible to receive treatment.

Keywords: ALB, albendazole; Control; ERRs, egg reduction rates; Elimination; IVM, ivermectin; Ivermectin co-administration; MBZ, mebendazole; Mass drug administration; Pre-SAC, preschool-aged; R0, basic reproductive number; SAC, school-aged children; STH, soil-transmitted helminth; Soil-transmitted helminth; Trichuris trichiura; WASH, water, sanitation and hygiene; WHO, World Health Organisation.

Fig. 1

Model fit to cross-sectional data from the St. Lucia study (Bundy et al., 1987). Note that the model fit was done to the individual data points and not the average data values shown here (see Supporting Information and Supporting Fig. 1).

Fig. 2

Projected impact of annual and biannual targeted preventive chemotherapy with and without ivermectin co-administration on the mean worm burden of T. trichiura. The solid and dotted line pertain to standalone albendazole, and albendazole–ivermectin co-administration respectively. Two different transmission settings were explored; lower (R₀ = 1.25), and higher (R₀ = 1.75 — fitted). Results assume 75% treatment coverage of Pre-SAC and SAC. The drug efficacy was assumed to be 50% for standalone albendazole (Vercruysse et al., 2011a), and 95% when co-administering ivermectin (Speich et al., 2015). Note that those under five years of age cannot receive ivermectin and would only be treated with albendazole. ALB; Albendazole, IVM; Ivermectin.

Fig. 3

Projected impact of annual and biannual targeted preventive chemotherapy with and without ivermectin co-administration on the prevalence of heavy T. trichiura infections in children. The solid and dotted line pertain to standalone albendazole, and albendazole–ivermectin co-administration respectively. Two different transmission settings were explored; lower (R₀ = 1.25), and higher (R₀ = 1.75 — fitted). Results assume 75% treatment coverage of Pre-SAC and SAC. The drug efficacy was assumed to be 50% for standalone albendazole (Vercruysse et al., 2011a), and 95% when co-administering ivermectin (Speich et al., 2015). Note that those under five years of age cannot receive ivermectin and would only be treated with albendazole. The results assume the lower intensity thresholds for heavy infection (presented in Table 1). The corresponding results using the higher intensity threshold are presented in Supporting Fig. S2. ALB; Albendazole, IVM; Ivermectin.

Fig. 4

Impact of a child-targeted preventive chemotherapy in terms of heavy case years averted with and without ivermectin co-administration. The bars are stratified by the host age-group (from the bottom up: Infants (0–2 year olds), Pre-SAC (2–5 year olds), SAC (5–15 year olds), and Adults (≥ 15 year olds)). Results pertain to the fitted (higher) transmission setting (R₀ = 1.75 — fitted) and assume 75% treatment coverage of Pre-SAC and SAC. The analysis was performed with a ten year time horizon (comparing ten years of standalone treatment to ivermectin co-administration). The drug efficacy was assumed to be 50% for standalone albendazole (Vercruysse et al., 2011a), and 95% when co-administering ivermectin (Speich et al., 2015). The results assume the lower intensity thresholds for heavy infection (presented in Table 1). The corresponding results using the higher intensity threshold are presented in Supporting Fig. S3. ALB; Albendazole, IVM; Ivermectin.

Fig. 5

Number of years of annual treatment to achieve elimination of T. trichiura as a function of coverage of children versus adults. Two different transmission settings were explored; lower (R₀ = 1.25), and higher (R₀ = 1.75 — fitted). Note that those under five years of age did not receive ivermectin and would only be treated with albendazole. ALB; Albendazole, IVM; Ivermectin. The corresponding results for mebendazole as shown in Supporting Fig. S4. Durations over ten years were not considered (marked as NA (not achievable)).

Fig. 6

Mean intensity of infection in different age groupings (A) and the number of years of annual treatment to achieve elimination of T. trichiura with and without Pre-SAC being eligible for ivermectin co-administration (B). The age profile of infection intensity used to parameterise the model (Fig. 1) is taken from (Bundy et al., 1987). ^†Accounting for both the age profile of infection intensity and the assumed demography (Truscott et al., 2014) yields an estimate of 25% of the worms occurring in Pre-SAC. Results in panel B) pertain to a fitted (higher) transmission setting (R₀ = 1.75). Durations over ten years were not considered (marked as NA (not achievable)). ALB; Albendazole, IVM; Ivermectin.

Fig. 7

Observed age profiles of T. trichiura infection intensity in Southeast Asia (A) and Southwest Cameroon (B). Panel A contains EPG data from 11 studies (18 areas in four different countries) identified by a systematic review of epidemiological surveys of STH in Southeast Asia (Dunn et al., 2016) (compared to data from the St. Lucia study (Bundy et al., 1987)). Panel B reproduces that data provided by a study from Cameroon (Mbuh et al., 2012). EPG: eggs per gramme of faeces.