Assessing the Safety and Efficacy of a Combination Therapy for STH in PSAC in Bangladesh

Description of the Research Project

Background of the Project including Preliminary Observations:

Epidemiology of Soil-transmitted helminthiasis Soil-transmitted helminthiasis (STH) infections are a group of parasitic infections caused by Ascaris lumbricoides (AL), Trichuris trichiura (TT), Ancylostoma duodenale (AD) and Necator americanus (NA) (hookworms). This infection is transmitted to humans by contaminated soil by human faeces containing parasite eggs. These infections impact the most impoverished and marginalized communities that lack access to clean water, sanitation, and proper hygiene, particularly in tropical and subtropical regions. At the same time, the highest prevalence is documented in sub-Saharan Africa, China, South America, and Asia. STH is a significant public health threat, with an estimated 1.5 billion people or 24% of the world population resulting in a loss of two million disability-adjusted life years.

The nutritional status of STH-infected children is often affected, eventually leading to impaired health, growth, cognition, and educational outcomes. High helminth intensity and polyparasitism may cause malnourishment and morbidity, which may result in death. Because of physical barrier and/or competition for food, helminths may make human hosts' malnutrition worse. Insufficient absorption of micronutrients and intestinal blood loss are more intricately linked to anaemia through an unknown process. The overall effect may change the children's cognitive development, including memory, reaction time, learning, and intrinsic intelligence. Children in preschool are not currently included in regular deworming programs for STH. However, the research indicates that children get infected soon after weaning and continue to be infected throughout childhood and adolescence. Children are negatively impacted by infections long before attending school, which exacerbates the long-term health risks of STH infection. Epidemiological research conducted among SACs demonstrated that STHs had a direct impact on student performance and absenteeism. So, deworming may play vital roles for preschool-aged children before entering school.

Several demographic groups are considered eligible for routine deworming, including preschool-aged children (PSAC) and school-aged children (SAC). In Bangladesh, STH was prevalent among 79.8% of school-age children (SAC) in 2005, which dropped to 14% in recent times. The prevalence is higher in slums or low socio-economic clusters (around 50.54%) due to poor hygiene and malnutrition, despite homogenous mass drug administration, MDA. More than one-third (36.3%) of SAC are re-infected with at least one helminth within six months of the MDA, with the highest prevalence of TT (27.5%) and 12.4 % of multiple helminth infections, which indicates the inefficiency of current PC.

Bangladesh Ministry of Health \& Family Welfare (MOHFW) and Children Without Worms (CWW) conducted the Integrated Community-based Survey for Program Monitoring" (ICSPM) in 4 districts in 2016 and 10 districts from 2017-2020. According to both surveys, the moderate-to-high intensity infection of STH (MHII) was one of the highest in Sirajganj (7.1%) and it was above the WHO-recommended target of \<1%. A. lumbricoides was the most common STH parasite followed by T. trichiura and hookworm. A. lumbricoides was most prevalent among SAC (n = 139,8.9% ), followed by PSAC (n = 114, 8.1% ) and adults n = 99, 7.4%,). All polyparasitism was due to A. lumbricoides and T. trichiura (n = 14,0.3% ) and was only identified in Sirajganj District. Sirajganj subdistricts of concern included Belkuchi (STH prevalence in SAC: 57.1%, 20.0% MHII) and Kamarkhanda (STH prevalence in SAC: 50.0%, 28.6% MHII). Belkuchi had the highest STH prevalence in PSAC (n = 23, 60.5% ), SAC (n = 20, 57.1% ), and adults (n = 15, 50.0% ). Belkuchi had the highest MHII among PSAC \[(n = 9, 23.7%) and adults (n = 6, 20.0%), and Kamarkhanda had the highest MHII among SAC.

Treatment of STH- Bangladesh perspective The latest WHO roadmap for neglected tropical diseases aims to eliminate STHs as a public health concern in 96% of endemic countries by 2030. To combat STH the WHO suggests four medications for treating STH infections: pyrantel, levamisole, mebendazole, and albendazole. WHO introduced routine preventive chemotherapy (PC) for preschool and school-aged children, using benzimidazoles (albendazole or mebendazole) in 2001. The benzimidazole medications, such as albendazole and mebendazole, work by disrupting the parasitic worms' microtubular system to treat a range of parasitic infections. These are the most common medications used to treat roundworm and hookworm. These are inexpensive, secure, and simple to use as children do not need to be weighed. Both adults and children receive the same dosage. However, Albendazole and mebendazole, commonly dispensed against soil-transmitted helminths (STH), are frequently utilized in combination with other medications to establish an integrated approach.

The widespread use of these medications for treatment and preventative chemotherapy is a result of the excellent efficacy demonstrated by the applications of scientific knowledge. Through WHO, national health ministries in endemic countries get donations of albendazole and mebendazole to treat school-age children. Bangladesh implemented a national deworming program in 2008, which involves MDA at primary schools for age groups 6-12 years with Mebendazole/Albendazole (ALB) monotherapy as preventive chemotherapy (PC), conducted at six-month intervals. The deworming program had reached a national treatment coverage increasing from 86.4% to 98.3% in the four years 2015-2019; however, only 76.2% of PSAC were found to be dewormed through self-prescribed locally purchased deworming medicines.

Current Treatment Review Since 1982, Albendazole has been used extensively to treat intestinal parasites. High cure rates for lumbricoides infections are attained with a single dosage of albendazole. The cure rates attained in various trials, however, vary. The efficacy of ALB against AL infection is well established with a 94%-100% egg reduction rate (ERR), while it has proved inefficient in curbing TT infections (ERR: 39%-60%). A single oral dose of albendazole, mebendazole, and pyrantel pamoate effectively treats infections caused by Ascaris lumbricoides, but a single dose of mebendazole was ineffective in combating hookworm infections in school children in Zanzibar and Vietnam. A quick re-infection, especially in the case of AL and TT, was found in another study aiming to assess patterns and dynamics of STH reinfection after drug treatment. However, treating infections from Trichuris trichiura with the current anthelmintics in a single oral dose is unsatisfactory. The side effects of albendazole include headache, leukopenia, and temporary gastrointestinal distress.

Scope of Repurposing Ivermectin in STH Ivermectin (IVM) is a safe and widely used macrocyclic lactone due to its broad-spectrum anti-infective and anti-parasitic activity against ecto- and endoparasites. Ivermectin is mostly used to treat strongyloidiasis, loiasis, onchocerciasis, and lymphatic filariasis. Additionally, it has been licensed to treat human ascariasis and has a beneficial effect on Trichuris trichiura. It paralyzes adult worms and appears to be dormant. Indirect evidence suggests a decreased burden of soil-transmitted helminths in regions where albendazole and ivermectin have been jointly administered. While ivermectin alone is recognized for having less-than-optimal efficacy against hookworm and TT infections, available data indicates that the combined administration of ivermectin and albendazole may exhibit greater efficacy compared to single-drug regimens. The co-administration of ivermectin and albendazole significantly outperformed albendazole alone in clearing TT infections, with a relative risk (RR) of 0.44 (95% CI = 0.31-0.62) for post-treatment infection. Patients receiving the combination treatment demonstrated higher individual egg reduction rates (ERRs) ranging from 91% to 100%, a cumulative cure rate (CR) of 45.8%, and an overall ERR of 84.5%, surpassing the efficacy of albendazole alone (ERR = 59.1%) and Ivermectin alone (ERR = 72.1%) (p \< 0.001). Ivermectin-treated patients have not seen any significant side effects, according to safety trials. Adverse effects of ivermectin included abdominal pain, headache, and diarrhoea .

Relevance for assessing new treatment regimen The two benzimidazole medications mebendazole (500 mg) and albendazole (400 mg) are currently used primarily to treat STH infections. Both medications are highly effective against A. lumbricoides (cure rate (CR) = 96% with albendazole and CR = 96% with mebendazole), according to a 2017 meta-analysis. However, these are less effective against hookworm (CR = 80% with albendazole and CR = 33% with mebendazole), and less effective against T. trichiura (CR = 31% with albendazole and CR = 42% with mebendazole). Given the enormous drug pressure imposed by widespread usage and dependence on these two medications, it is imperative to step up efforts to investigate alternative medicines to both improve efficacy for trichuriasis and postpone the establishment of potential drug resistance.

In regions where albendazole and ivermectin have been co-administered, there is indirect evidence of a lower burden of STH. Data suggests that ivermectin and albendazole administered together can be more effective than single-drug regimens, even though ivermectin alone is thought to have inadequate efficacy against hookworm and T. trichiura infections . As a result, the WHO Essential Medicines List now includes ivermectin and albendazole together for the treatment of STH infection. Future MDA campaigns are expected to support the use of ivermectin-albendazole co-treatment since it is listed in the WHO Model List of Essential Medicines to treat STH.

As the WHO suggested revising the frequency of MDA treatments, the discovery of therapy to increase efficacy, delay the reinfection time, and halt the emergence of potential drug resistance is paramount. Evidence does exist that PSAC benefits from deworming, and others have advocated for PSAC inclusion in MDA. Deworming of PSAC will help to address the infections at the earlier stages, potentially preventing the progression of disease and associated complications. Besides that, the upscaling of PC over the past years has increased the selective drug pressure on STH-affected populations, posing the risk of triggering anthelmintic drug resistance. In addition, deworming PSAC complements efforts to break the cycle of transmission within communities, reducing the overall burden of STH infections.

Research Design and Methods

Research plan/experimental design:

Study Site The research will be conducted in rural settings in the Belkuchi sub-district (upazila) of Sirajganj district, which had the highest STH prevalence among PSACs (60.5%). The investigators will set up a field office there for conducting patient screening, enrolment, microscopic examination, treatment, and follow-up.

Study Population In this study, the investigators will screen about 300 preschool-aged children (PSAC) by household visits to the study site, and then the investigators will randomly select 110 pre-SACs following all the inclusion and exclusion criteria and put them into randomization for selecting treatment arm.

Screening and enrolment of the patients:

The study will be done in a rural area (Belkuchi Sub-district) of Sirajganj District of Bangladesh. The investigators will set up a field office in the study area with a radius of about 5 km from the office. At the initiation phase of the project, a household (HH) survey will be conducted in the study area after obtaining consent from the HH head(s). Trained field assistants will visit every house of the study site and enlist childr

• Determine statistically significant effect of combination therapy on patient's nutritional status based on z-scores [Срок оценки: 3 months, 6 months, 9 months, 12 months after baseline enrolment]
• Correlate and compare changes in CR and ERR at different time points [Срок оценки: 3 weeks, 3 months, 6 months, 9 months, 12 months after baseline enrolment]
• Determine statistically significant effect of combination therapy on patient's clinical condition (anaemia) based on haemoglobin count [Срок оценки: At Baseline and 3 months after baseline enrolment]