Improved treatment options for the control of soil-transmitted helminthiasis: From repurposed drugs to reinfection patterns

Background: Soil-transmitted helminths (STHs) are a group of intestinal dwelling parasitic nematode worms that disproportionally affect socio-economically deprived populations in warm and tropical environments living with inadequate sanitation, poor hygiene and unsatisfactory educational coverage. Intestinal helminths are transmitted through contamination of soil with human feces and by subsequent accidental ingestion of soil with parasite eggs (Ascaris lumbricoides, Trichuris trichiura and occasionally Ancylostoma duodenale) or by penetration of the worm larvae (hookworm) into the skin and body of the human host. Soil-transmitted helminths are responsible for the largest burden of neglected tropical diseases, with about 1.5 billion infected people worldwide. Although most infections are asymptomatic and of light intensity, heavier intensity infections can cause severe morbidity. Chronic high-intensity manifestations caused by STH infections can lead to physical and intellectual growth retardation, perpetuating a vicious cycle of poor health and poverty. The World Health Organization (WHO) has advocated targeted preventive chemotherapy (PC), the periodic mass drug administration (MDA) of single dose benzimidazoles (i.e., albendazole and mebendazole) to at-risk population groups, without prior diagnosis. The main goal of this strategy is to reduce morbidity by decreasing infection intensities and to ultimately eliminate STH infections as a public health problem. This is defined as the decrease of prevalence of moderate and heavy infection intensities to below 2% as assessed in preschool- and school-aged children by 2030. However, several factors might jeopardize the success of PC, including the low efficacy of the currently used benzimidazoles, its inability to prevent reinfections and the potential emergence of anthelmintic resistance due to mounting drug pressure. On Pemba Island, Tanzania, STH infections were recognized as a major public health problem in the early 1990s. Since then, PC has been widely implemented (coverage rate >80%), but STH prevalence remains high to date. Hence, development of new and safe broad-spectrum drugs, repurposing of available drugs or the use of drug combinations to expand the armamentarium of treatment options is of paramount importance to help control and eliminate STH infections.
Goal and specific objectives: The first objective of my PhD was to test the efficacy and safety of ascending doses of moxidectin alone or combined with albendazole (400 mg) against trichuriasis. The second objective was to evaluate the short-term and long-term outcomes 14-21 days, six and 12 months post-treatment of ivermectin-albendazole and albendazole alone in an expanded study population (6-60 years) aiming to inform and update STH control guidelines and programs. The third objective was to compare the performance of the microscopic Kato-Katz method to the molecular polymerase chain reaction (qPCR) and its impact on drug efficacy and day-to-day variation. The fourth objective was to test fecal calprotectin (FC) and fecal occult blood (FOB) as potential surrogate markers for STH attributable morbidity. Insights gained from the ivermectin-albendazole trial on trial methodology, trial procedures and mitigation strategies to overcome challenges faced during clinical research taking place in resource-limited environments is presented as fifth objective.
Methods: This PhD work consisted of two clinical trials. The first was a phase II, randomized, placebo-controlled, dose-finding study on moxidectin in adolescents aged between 16 and 18 years on Pemba Island in 2018. Screened individuals were asked to provide two stool samples at baseline to assess STH ova by the Kato-Katz method. Eligible adolescents were physically examined and questioned for clinical symptoms by a trial physician prior to treatment administration. Trichuris trichiura-infected adolescents were randomly assigned to seven treatment arms: 8, 16, or 24 mg of moxidectin monotherapy; 8, 16, or 24 mg of moxidectin plus 400 mg of albendazole combination therapy; or placebo. The primary outcome was cure rate (CR) against T. trichiura, analyzed 13 to 20 days post-treatment. Adverse events were assessed 3h, 24h, 48h, 72h and 13-20 days after treatment, graded on severity, relatedness and expectedness as specified in the trial protocol. The second study was a Phase III, multi-country, randomized, standard of care-controlled, blinded, parallel group, single dose, superiority trial on ivermectin-albendazole in Côte d’Ivoire, Lao People’s Democratic Republic (Lao PDR) and on Pemba Island, Tanzania between 2018 and 2020. The study was conducted in communities aged 6-60 years. Screened individuals provided two stool samples at baseline, 14-21 days, six and 12 months post-treatment. Similar to the first study, the Kato-Katz method was employed for STH diagnosis and, in addition, an aliquot of stool (~1 g) was mixed with 80% ethanol and preserved at 4°C and later shipped at room temperature to Swiss Tropical and Public Health Institute in Basel, Switzerland for subsequent qPCR analyses. Furthermore, fecal rapid tests (FC and FOB), were used as potential proxy markers for STH attributable morbidity. Hence, a semi-quantitative chromatographic immunoassay (Actim® Fecal Calprotectin test/Actim® Fecal Blood test, Medix Biochemica, Finland) was applied for FC and FOB detection from participants diagnosed positive for T. trichiura and concomitant STH infections and identified STH negative participants as controls. Before treatment administration, all participants underwent a physical examination and a rapid diagnostic test for hemoglobin levels, pregnancy in all female participants (≥12 years), malaria (Côte d’Ivoire and Lao PDR) and lymphatic filariasis (Côte d’Ivoire and on Pemba Island, Tanzania) was applied. Drug efficacies (in terms of egg reduction rates (ERRs) and CRs), reinfections and new infections were assessed 14-21 days, six and 12 months post-treatment. Adverse events were captured 3h, 24h and 14-21 days after treatment, graded on severity, relatedness and expectedness as specified in the trial protocol.
Results: We found that 8 mg of moxidectin (the lowest tested dose) performed as well as 16 mg and 24 mg, and that the combination of moxidectin and albendazole was significantly more efficacious against T. trichiura than albendazole alone. Likewise, we revealed superiority of the ivermectin-albendazole combination therapy compared to albendazole alone against T. trichiura infections in Lao PDR and on Pemba Island. Similarly, the ivermectin-albendazole combination therapy led to a larger reduction of moderate and heavy T. trichiura infections and successfully reduced the prevalence of these infections to below 1.5% within 12 months. However, ivermectin-albendazole was not found to be superior to albendazole alone in Côte d’Ivoire. Moreover, we observed a higher sensitivity of qPCR compared to quadruple Kato-Katz, revealing significantly lower CRs for ivermectin-albendazole, when two qPCR samples were assessed pre- and post-treatment. In addition, we did not find an association between the presence of intestinal inflammation or mucosal bleeding, assessed with FC and FOB as respective proxy markers, and STH infection status or infection intensity.
Conclusion: Promising efficacies and safety for moxidectin-albendazole and ivermectin-albendazole against T. trichiura were found. Hence, both drug combinations might be valuable alternatives in PC programs. The combination of 8 mg moxidectin and 400 mg albendazole should be further investigated in younger age groups, with longer follow-up periods and in different settings to help guiding recommendations for future STH control. Prior to MDA implementation with ivermectin-albendazole, careful decisions on the frequency of deworming adapted to the epidemiological parasite profile in each setting have to be made, while variations in treatment responses should be considered. In addition to that, standardized and accurate molecular diagnostic tools, which are applicable in peripheral field settings for the assessment of drug efficacy and for future monitoring within STH control and/or elimination programs, should be developed. Further studies are needed to identify suitable, standardized, low-cost proxy markers of STH attributable morbidity to monitor the clinical impact of STH control interventions. A strategic plan adapted to each setting with a distinct focus on community engagement and workforce is crucial for successful preparation, screening and implementation of randomized controlled trials. Gained knowledge on improvements of trial methodology, trial procedures and mitigation strategies to overcome challenges faced during clinical research in resource-constrained healthcare environments are valuable information that should be made available to the related research network. Moreover, potential drug donors and preferably local anthelmintic drug production facilities will need to be identified to meet the demand for STH control programs.