Preventive chemotherapy as the main strategy for STH morbidity control heavily relies on two benzimidazole drugs: albendazole and mebendazole^11,15. These two drugs have been extensively used worldwide for more than 50 years; however, their efficacy varies against all three STH species, with T. trichiura still remaining as the main challenge^13,16. Numerous studies have reported low efficacy of a single dose of 400 mg albendazole as recommended by the WHO against T. trichiura¹³. Despite the absence of effective alternative treatment against T. trichiura, only a few studies are available comparing the efficacy of different doses and regimens of albendazole¹⁴. This study aims to evaluate the effect of two rounds of single-dose albendazole 400 mg treatments administered 4 weeks apart on CR and ERR of STH infections, particularly T. trichiura.

As expected in this present study, single-dose albendazole resulted in a high level of efficacy in the treatment of A. lumbricoides (92.5% CR); however, the CRs were only 63.1% and 5.1% for hookworm and T. trichiura infections, respectively. These findings are comparable to the recent network meta-analysis of randomized controlled trials¹³, demonstrating single-dose albendazole to be highly efficacious against Ascaris and moderately efficacious for hookworm infection, but not for Trichuris. Based on the recent meta-analysis, considering time interactions, a single dose of 400 mg albendazole has shown a limited efficacy against T. trichiura, with CRs having decreased from 38.6% in 1999 to 16.4% in 2015¹³. It is interesting to note that the reported efficacy of 6.3% for T. trichiura in this present study is by far the lowest observed following two doses compared to the average CR (30.7%) reported in the aforementioned network meta-analysis¹³.

With regard to ERRs, single-dose albendazole resulted in an outstanding efficacy for A. lumbricoides with ERRs approaching 100%. Single-dose albendazole was also associated with an 87.9% ERR for hookworm. Compared to the other two STH species, a markedly lower ERR (41.4%) was observed for T. trichiura. For hookworm, the ERR reported from this study was higher than the ERR values reported from the meta-analysis of Moser et al.¹³, while below the reference ERRs for the benzimidazoles published by WHO in 2013. The ERR for T. trichiura derived in this study was lower compared to the pooled ERR reported in the recent systematic review and meta-analysis¹³ and the reference ERR by WHO¹⁷. It is noteworthy that treatment efficacy may vary across hookworm species¹⁸, but we were unable to ascertain that here due to the use of KK and not molecular diagnostics.

With the second round of albendazole treatment, the observed CRs slightly increased against A. lumbricoides (98.9% CR), markedly increased against hookworm (92.2% CR), and remained low against T. trichiura (6.3% CR). The difference in CRs between first and second round regimens was statistically significant for A. lumbricoides and hookworm but not for T. trichiura in our study. The two repeated rounds (400 mg) did not offer improved efficacy (in terms of CR) against T. trichiura. In contrast to our study, Horton et al. in 2000 reported that increasing the single dosage and using repeated doses improves the efficacy of albendazole against T. trichiura¹². However, in a recent trial investigating the feasibility of interrupting STH transmission using biannual albendazole community-based MDA (cMDA) compared to annual school-based MDA, repeated rounds of albendazole treatment led to interruption of hookworm (N. americanus) and any STH transmission, although there was no impact on A. lumbricoides and T. trichiura infections after 3 years of cMDA¹⁹. These differences could be attributed to decreasing efficacy over the last two decades and differing study design or geographic area.

The ERR for all three species after the administration of the second single-dose albendazole increased to 99.6%, 99.8% and 74.1% for A. lumbricoides, hookworm, and T. trichiura, respectively. These ERRs were above the ERR values for each species put forth by the meta-analysis of Moser et al.¹³, and the reference ERRs by WHO¹⁷. The benefit of repeated doses is further shown in the significant reduction of moderate and heavy infections for A. lumbricoides and T. trichiura. The near 100% ERR for A. lumbricoides is reflected in the change in intensity category distribution, with heavy infections being completely eliminated at FU1 and light/moderate infections being nearly completely eliminated at FU2. At baseline, approximately 37.6% of participants had moderate/heavy T. trichiura infections. Moderate infection was reduced to approximately 21.4% at FU1 and 9.3% at FU2, and heavy infections were completely eliminated at FU2. Based on this result, from the public health perspective, it looks, therefore, that the two rounds of albendazole are effective in reducing infection intensity for T. trichiura, although the low CR found in this study is still worrying.

We acknowledge that this study lacks a comparison group as a limitation, which means no direct measure for comparative effectiveness. The current study was conducted to assess the added benefit of a second 400 mg dose of albendazole in addition to the standard regimen (single round 400 mg dose) in the context of a public health deworming program in a highly endemic setting, thus assignment of a control group (placebo) was unattainable and unethical to implement.

Although the KK technique is a widely used tool by control programs for assessing MDA effectiveness, it is not the most sensitive diagnostic test for STH infections^20,21,22,23. The KK may fail to detect low-intensity infections, which could lead to underestimation of the actual prevalence. In the context of efficacy trials, this could result in falsely elevated CRs due to undetected residual low egg counts post treatment²². Despite these limitations, the current study considered the KK technique using multiple stools and slides as the appropriate procedure of choice since the polymerase chain reaction (PCR) technique was being optimized at the time of the study. In contrast to KK, PCR is semi-quantitative, which poses a limitation for measuring ERRs. It is well recognized that the sensitivity of KK improves with the use of additional stool samples and slides²⁴, therefore, employing two stool samples and triplicate slides per sample in this study likely enhanced the accuracy for STH detection.

The goal of preventive chemotherapy against STH, however, is to eliminate moderate and heavy infection intensities, with the aim of reducing morbidity. Currently, there is an ongoing discussion on the validity of CR as an indicator for assessing drug efficacy and the impact of preventive chemotherapy²⁵. It has been pointed out that CR is an efficient indicator of drug efficacy against bacterial diseases (for which it was originally developed) but less efficient for helminth infections because CR is influenced by the intensity of infection at baseline and by the sensitivity of the parasitological technique used. These concerns may be of less significance in relation to the present study, as the majority of the STH-positive individuals at baseline were in the low infection intensity category.

The most notable finding of the study was the poor efficacy of albendazole against T. trichiura, resulting in only 6.3% efficacy even after the second round. This provides further evidence for the poor efficacy of albendazole against T. trichiura and reinforces the need for new STH treatments. There has been a growing body of research over the past 5 years advocating the use of ivermectin or oxantel pamoate as an alternative or supplementary treatment for STH infections. Both drugs have shown high efficacy against T. trichiura in humans^{13,26,27,28,29,30,31}. In 2017, the WHO included the co-administration of ivermectin with albendazole in their List of Essential Medicines to treat STH infections^28,32. Moreover, recent studies reported that the use of moxidectin in combination with albendazole has shown enhanced efficacy against T. trichiura, and could be a potential alternative or complementary drug in STH control^30,33,34,35. Further research should explore the co-administration of albendazole with oxantel pamoate or moxidectin to improve current STH treatments. Additionally, drug administration alone is not enough to effectively control STH infections; an integrated approach combining improved water, sanitation, and health and hygiene education will be required for long-term sustainable control and elimination of STH infections.