Could Nitazoxanide Be Added to Other Essential Medicines for Integrated Neglected Tropical Disease Control and Elimination

In 2011, the World Health Organization (WHO) determined that more than 700 million people were treated with at least one essential medicine for neglected tropical diseases (NTDs) under the auspices of a global preventive chemotherapy initiative [1,2]. However, a total of at least 1.9 billion people require annual preventive chemotherapy [1,2], so these efforts will need to be greatly expanded in order to meet NTD control and elimination targets as outlined in the 2012 London Declaration and the 2013 World Health Assembly resolution for these diseases [3]. The original ‘‘rapid-impact’’ package of NTD interventions targeted up to seven NTDs highly endemic to sub-Saharan Africa, including the three soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis, onchocerciasis, and trachoma, and was comprised of up to four essential NTD medicines that could include a benzimidazole anthelminthic drug (i.e., mebendazole or albendazole), ivermectin, praziquantel, and/or azithromycin [4,5]. However, it was quickly noted that either the entire rapid-impact package or some component thereof had applicability outside of Africa (with modifications depending on the specific NTDs being targeted) [6]. By controlling or eliminating the seven major NTDs, this approach could potentially effect a global disease burden reduction almost as important as HIV/ AIDS, tuberculosis, or malaria control [7,8]. As global preventive chemotherapy efforts expanded, it also became apparent that they could produce important collateral public health benefits that were not originally anticipated, including overall reductions in child mortality from the azithromycin component [9] and coverage for additional NTDs such as food-borne trematodiases, scabies, and yaws [3,10,11]. There are equally important efforts underway to broaden the interventions to include water, sanitation, and hygiene (WASH) initiatives [12]. Thus, in the decade since rapid impact was originally proposed, there are new uses and approaches for preventive chemotherapy. In the last year, two important studies were published that could alter how we think about current preventive chemotherapy approaches. The first, known as the Global Enteric Multicenter Study (GEMS) for diarrheal diseases, made the surprising finding that cryptosporidiosis is one of the most important causes of infectious diarrhea in children in developing countries [13]. The second is the Global Burden of Disease Study 2010 (GBD 2010), which found that, together, cryptosporidiosis and amoebiasis exceed the disease burden–as measured in disability-adjusted life years (DALYs) or in deaths—of any helminth infection now currently being targeted for preventive chemotherapy (Table 1) [14,15]. Although there are important disagreements in the NTD community about whether the DALYs for helminth infections (and other NTDs) were underestimated [16], both GEMS and GBD 2010 provide important information to our community that we need to consider in deciding whether it is possible to add coverage for cryptosporidiosis and amoebiasis as part of global preventive chemotherapy efforts. A potential candidate drug for use in mass drug administration programs to target intestinal protozoa is the nitrothiazole benzamide drug, nitazoxanide (Figure 1) [17]. The development program for nitazoxanide was led by Jean Francois Rossignol in the 1970s, initially as a veterinary anthelminthic agent, but the drug was subsequently shown to be active against intestinal protozoa and some human helminths, as well as anaerobic bacteria [17]. It was approved in 2002 by the United States Food and Drug Administration, initially as an oral suspension for pediatric use (100 mg/5 ml) against cryptosporidiosis and giardiasis, and subsequently as 500 mg tablets for adults [17]. According to The Medical Letter, the recommended therapeutic dosage is administered over three days [18]. Although the initial indication for nitazoxanide was for cryptosporidiosis and giardiasis, subsequent investigative research has revealed that the drug is effective for amoebiasis caused by Entamoeba histolytica and could be used to treat both invasive intestinal amoebiasis and colonization with E. histolytica [19]. Moreover, nitazoxanide is active against a number of nonprotozoan parasites, including the