Individual responses to a single oral dose of albendazole indicate reduced efficacy against soil-transmitted helminths in an area with high drug pressure

Abstract

Background: Albendazole (ALB) is administered annually to millions of children through global deworming programs targeting soil-transmitted helminths (STHs: Ascaris lumbricoides, Trichuris trichiura and hookworms, Necator americanus and Ancylostoma duodenale). However, due to the lack of large individual patient datasets collected using standardized protocols and the application of population-based statistical methods, little is known about factors that may affect individual responses to treatment.

Methodology/principal findings: We re-analyzed 645 individual patient data from three standardized clinical trials designed to assess the efficacy of a single 400 mg oral dose of ALB against STHs in schoolchildren from different study sites, each with varying history of drug pressure based on duration of mass drug administration programs: Ethiopia, low; Lao People's Democratic Republic (PDR), moderate; Pemba Island (Tanzania), high. Using a Bayesian statistical modelling approach to estimate individual responses (individual egg reduction rates, ERRi), we found that efficacy was lower in Pemba Island, particularly for T. trichiura. For this STH, the proportion of participants with a satisfactory response (ERRi ≥50%), was 65% in Ethiopia, 61% in Lao PDR but only 29% in Pemba Island. There was a significant correlation between ERRi and infection intensity prior to drug administration (ERRi decreasing as a function of increasing infection intensity). Individual age and sex also affected the drug response, but these were of negligible clinical significance and not consistent across STHs and study sites.

Conclusions/significance: We found decreased efficacy of ALB against all the STHs analyzed in Pemba Island (Tanzania), an area with high drug pressure. This does not indicate causality, as this association may also be partially explained by differences in infection intensity prior to drug administration. Notwithstanding, our results indicate that without alternative treatment regimens, program targets will not be achievable on Pemba Island because of inadequate efficacy of ALB.

Trial registration: The study was registered on Clinicaltrials.gov (ID: NCT03465488) on March 7, 2018.

Fig 1. Mean fecal egg count per individual before and after administration of a single oral dose albendazole.

The mean number of eggs counted across duplicate Kato-Katz slides from one stool sample for each individual (mean fecal egg count) before (baseline) and after administration of a single 400 mg oral dose of albendazole (follow-up) for Ascaris lumbricoides (panel A), Trichuris trichiura (panel B) and hookworm (panel C) in Ethiopia, Lao PDR and Pemba Island (Tanzania). The boxplots show the median, interquartile range, 5^th and 95^th percentiles of the data. Grey lines join mean fecal egg counts measured from the same individual.

Fig 2. Individual therapeutic efficacy of albendazole against soil-transmitted helminth infections estimated in three study sites.

The individual-based therapeutic efficacy is expressed as the reduction in fecal egg counts (FECs) following drug administration (egg reduction rate, ERR_i) and was estimated by fitting the Bayesian model [15,16,21] to FEC data on Ascaris lumbricoides (panel A), Trichuris trichiura (panel B) and hookworm (panel C) collected before and after administration of a single 400 mg oral dose of albendazole in three study sites, Ethiopia, Lao PDR and Pemba Island (Tanzania). Each cross denotes the posterior median of ERR_i and horizontal lines denote 95% credible intervals. The estimates are ordered according to the percentile of the estimated median ERR_i. The areas shaded in orange, yellow and blue denote, respectively, the World Health Organization categories for ‘reduced’, ‘doubtful’ and ‘satisfactory’ population-based therapeutic efficacy (ERR_P, which differ for each infection). Negative estimates of ERR_i correspond to FECs that increased after administration of albendazole.

Fig 3. Coefficients of fixed effects terms associated with the efficacy of albendazole against soil-transmitted helminth infections.

Coefficients were estimated by fitting the Bayesian model [15,16,21] to fecal egg count data on Ascaris lumbricoides (panel A), Trichuris trichiura (panel B) and hookworm (panel C) collected before and after administration of a single 400 mg oral dose of albendazole in three study sites, Ethiopia, Lao PDR and Pemba Island (Tanzania). Points, horizontal thick and thin lines indicate the median, the 50% and the 95% credible interval respectively. The reference category of each variable is indicated by a point on the vertical line (Ethiopia; female; age 6–9 years; follow up >2 weeks and no coinfection). Positive coefficients indicate a lower individual egg reduction rate, ERR_i. Negative coefficients indicate a higher ERR_i.

Fig 4. Influence of fixed effects coefficients on the efficacy of albendazole against soil-transmitted helminth infections.

Individual egg reduction rates, ERR_i, were estimated by fitting the Bayesian model [15,16,21] to fecal egg count data on Ascaris lumbricoides (panel A), Trichuris trichiura (panel B) and hookworm (panel C) collected before and after administration of a single 400 mg oral dose of albendazole in three study sites, Ethiopia, Lao PDR and Pemba Island (Tanzania). Points, horizontal thick and thin lines indicate the median, the 50% and the 95% credible interval respectively. The reference ERR_i (i.e., with fixed effects set to the reference categories of Ethiopia, female, age 6–9 years, follow up >2 weeks and no coinfection) is indicated by the solid vertical line. All estimates correspond to the ERR_i associated with a ‘typical individual’ (i.e., with random effects terms set to 0).

Fig 5. Correlation between the intensity of infection before drug administration and the efficacy of albendazole against soil-transmitted helminth infections.

Correlation coefficients were estimated by fitting the Bayesian model [15,16,21] to fecal egg count data on Ascaris lumbricoides (panel A), Trichuris trichiura (panel B) and hookworm (panel C) collected before and after administration of a single 400 mg oral dose of albendazole in three study sites, Ethiopia, Lao PDR and Pemba Island (Tanzania).