Novel tools for the control of soil-transmitted helminthiasis : drug combinations, diagnostics, and meta-analyses on the effect of sanitation facilities

More than half of the world’s population is at risk of soil-transmitted helminthiasis, parasitic worm infections most commonly caused by the roundworm (Ascaris lumbricoides), the whipworm (Trichuris trichiura) and the hookworms (Ancylostoma duodenale and Necator americanus). Together these soil-transmitted helminths cause an estimated burden of 5 million disability-adjusted life years (DALYs), mostly affecting school-aged children living in the least developed settings, lacking clean water and sanitation facilities. To control soil-transmitted helminthiasis annual preventive chemotherapy is given to people at risk of infection. In 2012 a total of 212 million anthelmintic tablets were administered to school age-children. The most commonly used anthelmintics are albendazole and mebendazole. Both are highly effective in treating A. lumbricoides, while only albendazole has satisfactory efficacy against hookworm. Both drugs have only low efficacy against T. trichiura. Therefore an alternative treatment for T. trichiura infections is urgently required. However, even with an effective treatment, re-infection is common in endemic settings. Therefore other interventions besides preventive chemotherapy should be considered.
The primary goal of this PhD thesis was to find an alternative, effective treatment against T. trichiura and concomitant soil-transmitted helminth infections. Two compounds with potentially high trichuricidal activity are nitazoxanide and oxantel pamoate. Both of these compounds were tested on their efficacy and safety within two separate clinical trials conducted on Pemba Island, Tanzania in 2011 and 2012, respectively. Both drugs were evaluated alone as well as in combination with albendazole to broaden their spectrum of activity against concomitant soil-transmitted helminths. In a third clinical trial conducted in 2013, the drug combination albendazole-oxantel pamoate was compared to two other promising drug combinations (i.e. albendazole-ivermectin and albendazole-mebendazole) which were identified in recently conducted randomised controlled trials. Additional objectives were attached to these three randomised controlled trials which included the assessment of the prevalence of intestinal protozoa and the comparison of the performance of different diagnostic approaches. Further we conducted two systematic reviews and meta-analyses to generate evidence on the protective effect of sanitation facilities against soil transmitted helminths and intestinal protozoa infections.
In the first clinical trial conducted in 2011 we found no effect for single nitazoxanide (1,000 mg) against T. trichiura infections. Furthermore, children receiving nitazoxanide reported significantly more mild adverse events than children receiving a placebo. Hence we cannot recommend nitazoxanide for the treatment of T. trichiura and concomitant soil-transmitted helminths. The prevalence of intestinal protozoa assessed within this clinical trial was relatively high. In detail, 70% of the assessed children were infected with at least one of the (potentially) pathogenic intestinal protozoa Giardia intestinalis, Entamoeba histolytica/E. dispar and Blastocystis hominis. Nitazoxanide (1,000 mg) revealed moderate efficacy against intestinal protozoa, comparable to that of albendazole (400 mg). Within the same clinical trial, the sensitivity of a single, duplicate and quadruplicate Kato-Katz thick smear and the ether-concentration method was assessed for diagnosing soil-transmitted helminths. Quadruplicate Kato-Kato thick smears (duplicate Kato-Katz from two stool samples) revealed the highest sensitivity in general. We could further show that in clinical trials, relatively sensitive diagnostic approaches should be chosen (multiple stool samples); otherwise the efficacy of treatments might be overestimated.
In the second randomised controlled trial conducted in 2012, we examined the efficacy and safety of single oxantel pamoate (20 mg/kg) alone and in combination with albendazole (400 mg). Oxantel pamoate and albendazole were given on subsequent days. Oxantel pamoate was significantly more effective against T. trichiura compared to the standard drugs albendazole and mebendazole. The albendazole-oxantel pamoate combination was effective against all three soil-transmitted helminths. Therefore this promising combination was further evaluated within a third clinical trial.
In the third randomised controlled trial conducted in 2013 on Pemba Island, Tanzania, we identified two drug combinations (i.e. albendazole [400 mg]-oxantel pamoate [20 mg/kg], and albendazole [400 mg]-ivermectin [200 μg/kg]) with significantly higher efficacy against T. trichiura compared to the standard treatment mebendazole (500 mg). Additionally the albendazole-oxantel pamoate combination had superior efficacy compared to the albendazole-ivermectin treatment. We could not confirm the trichuricidal activity of the albendazole-mebendazole combination. Albendazole-ivermectin is already a commonly used drug combination which also has the advantage that ivermectin is the current standard treatment against Strongyloidiasis (probably the most neglected of the neglected tropical diseases) and lymphatic filariasis. But especially for settings highly endemic for T. trichiura, the albendazole-oxantel pamoate combination should be further investigated (i.e. dose finding-, safety-, pharmacokinetic-studies) to overcome the current lack of effective treatments and to expand the armamentarium against soil-transmitted helminths.
Prevalence often remains high even though regular preventive chemotherapy with an effective drug is conducted. In our meta-analyses we showed that the implementation of sanitation facilities is an important strategy for the control of soil-transmitted helminthiasis . Moreover we revealed that sanitation facilities and water treatment also have a positive effect on other diarrheal diseases (i.e. protozoa infections). Therefore, for successful control of soil-transmitted helminths, preventive chemotherapy programmes should be conducted with effective drugs and be accompanied by interventions involving sanitation facilities and safe water.