Something old, something new: is praziquantel enough for schistosomiasis control?

In recent years, more people living in schistosomiasis endemic areas are receiving treatment with praziquantel. The combination of the World Health Assembly’s resolution 54.19, the WHO preventive chemotherapy strategy for neglected tropical diseases, and the recognition of the considerable health impact of schistosomiasis even in persons who do not have severe fibrotic disease led financial donors and drug companies to provide the resources that have allowed availability of a much higher number of treatments for at risk individuals [1]. However, the available resources to provide treatment still are insufficient for the vast number of people who need it. The WHO treatment guidelines for schistosomiasis were drafted before sufficient quantities of praziquantel were available to make mass drug administration (MDA) a realistic possibility and were therefore primarily focused on treatment strategies to reduce morbidity. Now that praziquantel MDA has been implemented more widely, there is also a push for elimination of schistosomiasis [2]. Efforts to evaluate the efficacy of a single intervention, praziquantel MDA, are underway; however, there is growing evidence that once yearly MDA, the highest frequency of treatment in the current guidelines, will not by itself be sufficient to lower prevalence in high risk communities to rates where elimination of transmission is feasible [3–5]. There are many critical questions concerning the current and future treatment of schistosomiasis that need to be addressed. Current schistosomiasis control programs rely on one drug, praziquantel. Praziquantel has clear advantages over the schistosomiasis treatment drugs that preceded it and no widespread resistance has developed despite its use for over 30 years. Paradoxically, the general success of praziquantel may have reduced the impetus for drug companies to pursue development of new drugs to treat schistosomiasis. But praziquantel does have a number of limitations. First, it is only effective against adult parasites and a single treatment may not kill all worms, especially in individuals with high-intensity infections. Similarly, for persons with heavy worm burdens, the side effects of treatment can be very unpleasant, even if somewhat short lived [6]. The side effects and bitter taste that some people experience have contributed to reduced compliance, leading to decreased coverage of treatment in the population targeted by the MDA [7]. Young children, who are increasingly recognized as at high risk of infection, are excluded from most control program because of these factors as well as the large size of the tablets. Fortunately, efforts are underway to develop pediatric formulations of praziquantel. Control programs should consider including pharmacovigilance in the monitoring and evaluation of praziquantel MDA, a critical need that has mostly been ignored to date. Including pharmacovigilance in routine MDA evaluations would mean that factors affecting coverage, such as reasons for poor participant compliance, as well as data to evaluate potential drug efficacy problems are systematically collected. Targeting the specific issues behind poor coverage levels and identifying the possible development of schistosome resistance to praziquantel promptly are critically important to efficiently manage schistosomiasis control programs. Despite its key role in schistosomiasis treatment, how praziquantel works as well as putative resistance mechanisms in drug tolerant parasites remain essential areas of investigation. By better understanding how praziquantel affects schistosomes, it may be possible to refine the molecular structure to be more effective or less unpleasant in terms of taste or side effects. For example, the R-enantiomer of praziquantel is the active form of the drug while the S-enantiomer may contribute to the bitter taste and side effects of treatment [8,9]. If these observations are true and it is possible to produce the R-enantiomer in a cost-effective manner, several of the current concerns about praziquantel, such as the size of the tablets, could be moderated. Similarly, it may be possible to make small alterations in drug structure to overcome resistance. Real progress in this area has not been possible as evidence for development of praziquantel resistance is still mostly indirect and no field-derived clinically resistant isolates are available for detailed study. However, if and when they become available, the elegant approach that has recently been described for identification of the oxamniquine resistance mechanism could similarly be applied for praziquantel and praziquantel structural modifications explored [10,11]. Another critical consideration for schistosomiasis control programs is decision making about treatment approaches in the context of more sensitive diagnostic tools. Egg detection has long been the mainstay of schistosomiasis diagnosis and provides most of the basis for treatment strategies in the current WHO guidelines. However, these methods have known sensitivity limitations as well as challenges with respect to sample collection and handling, especially for detection of Schistosoma mansoni or S. japonicum eggs in stool. Many groups are working to identify new methods that are cost effective and technologically appropriate; these efforts are challenging given the lack of a gold standard for active infection to determine a new test’s sensitivity and specificity. Coupled with a shift in goals from morbidity control to elimination, changing the guidelines from parasitological detection of infection to DNA-, antigen- or antibody-based tests will require a commitment to extensive operational research that is well coordinated among program managers, researchers and donors. Fortunately, recent funding initiatives promote increased collaboration among these groups and while much work remains, the schistosomiasis community is beginning to better align research priorities with program needs. Additional field studies using standardized methods and reporting should provide the evidence base for development of new guidelines. Annual treatment with praziquantel will continue as the backbone of most control programs for the foreseeable future but new interventions will likely be needed to achieve control or elimination of schistosomiasis in many areas. For persons with S. japonicum infection, annual MDA may not even be sufficient for morbidity control [5]. Improved interventions could include development and implementation of new treatment drugs or protective vaccines, more frequent treatment with praziquantel, or coupling treatment with interventions that interrupt the role cercaria-contaminated fresh water plays in transmission [12]. A great deal of effort has gone into identifying new compounds and vaccines for schistosomiasis and these efforts should continue. However, as there are no ongoing clinical trials, these new tools are still many years away from incorporation into control or elimination programs. Derivatives and rational drug design for modified praziquantel and oxamniquine may be useful in the event of clinical resistance and may require less time for approval due to experience with the parent compounds. The antimalarial drugs artesunate and mefloquine have some activity against schistosomes, but their use alone or in combination with praziquantel does not seem to improve efficacy compared with praziquantel alone [13]. New strategies for praziquantel MDA may improve the drug’s impact. Double treatments of praziquantel within a short time period yield an incremental improvement on cure rate and reduction in infection intensity but at a relatively high cost for the amount of health benefit realized and with no apparent benefit for reduced transmission the following year [14–16]. Studies on MDA at 6 month intervals are needed to evaluate any greater impact than once annual MDA for reducing force of transmission and could be performed immediately as no preclinical testing is required. Other operational research needs for praziquantel include evaluation of the efficiency and safety when used in conjunction with drugs for other neglected tropical diseases in integrated MDAs. In addition, with the recognition that schistosomiasis may increase risk of infection with malaria or HIV [17,18], the benefits of treating schistosomiasis on reducing the transmission or manifestations of these and other coinfecting agents should be considered. Combining praziquantel treatment with environmental improvements such as access to clean water, sanitation or control of the intermediate snail host are critical needs that are only beginning to be addressed [19]. Improved water and sanitation typically requires behavioral change as well as significant infrastructure investment and broad political and community commitment. Community-led total sanitation efforts have expanded in some schistosomiasis endemic areas, with encouraging reports of progress [20]. The continued expansion and adoption of these programs hopefully will supplement drug-based control efforts. The momentum for control and elimination of schistosomiasis is greater than it has ever been and is growing. More resources and stronger commitments make this an exciting time for schistosomiasis research but also reveal the magnitude of the current knowledge gaps and the need for new tools. Additional work toward finding new drugs and interventions as well as better utilization of the existing tools are both needed and should be viewed as partners for accomplishing the same goals rather than competitors. Furthermore, collaboration across disparate fields ranging from basic chemistry and immunology to operational and behavioral research, all with an eye toward program needs, will be necessary to achieve control and elimination of schistosomiasis.