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Schistosomiasis control: keep taking the tablets
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Vol.20 No.2 February 2004
Schistosomiasis control: keep taking the tablets Paul Hagan1, Christopher C. Appleton2, Gerald C. Coles3, John R. Kusel4 and Louis-Albert Tchuem-Tchuente´5 1
Division of Infection and Immunity, Institute of Biomedical and Life Sciences, Joseph Black Building (B4-09d), University of Glasgow, G12 8QQ, UK 2 University of Natal, School of Life and Environmental Sciences, Biology Division, George Campbell Building, 4041 Durban, South Africa 3 Department of Clinical Veterinary Science, University of Bristol, Langford House, Langford, Bristol BS40 5DU, UK 4 Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Davidson Building, Lab 502, University of Glasgow, G12 8QQ, UK 5 Centre for Schistosomiasis and Parasitology, PO Box 7244, Yaounde´, Cameroon
Despite the limited reports of praziquantel resistance, the relative success of chemotherapy-based control programmes for schistosomiasis has prompted overdue efforts to expand the use of cheap, generic, praziquantel in sub-Saharan Africa. The likely impact of such programmes on the development and spread of praziquantel resistance is uncertain, but this possibility reinforces the need for monitoring the spectrum of praziquantel sensitivity of schistosome populations and for an improved knowledge of the precise targets for the action of the drug. The search for alternatives to praziquantel and other tools for control of schistosomiasis must continue. Despite success with control programmes in Egypt [1], China [2], Brazil [3] and Morocco [4], schistosomiasis remains a major public health problem [5]. Treatment and control of infection depends largely upon the use of praziquantel, which is now cheaper, easier to use and more readily available than other schistosomicides [6]. The renewed impetus for extending schistosomiasis control throughout sub-Saharan Africa will probably result in greater use of praziquantel than ever before [7 – 9]. This welcome development is set against the background of limited knowledge on many aspects of praziquantel. Here, we summarize the current status of praziquantel and its interactions with the parasites. The praziquantel puzzle Treatment failures are often the first indication of the end of the effective life of a drug. In the case of praziquantel, the report of treatment failure in 1995 [10] was attributed principally to the peculiar stage-specific efficacy of the drug [11]. Praziquantel is active against schistosomula in the first two days after their penetration of the skin. After this time, and for a period of approximately four weeks, the parasites lose their susceptibility and can continue their development, progressing to mature egg-producing paired
adult worms [12,13]. The excretion of eggs from the worms that develop after giving praziquantel can give the impression of failed treatment (Box 1). When repeated
Box 1. Key concepts in schistosomiasis control Defining resistance ‘A population of Schistosoma is resistant when either a susceptible population shows a significant decrease in its response to a schistosomicide or it is significantly less responsive than a fully susceptible population. The change is due to an increase in the proportion of worms unresponsive to the drug and may be partial or complete. It is complete when the maximum dose tolerated by the host has no effect on the parasite population. The resistance will be heritable.’ [26].
Action of praziquantel Praziquantel appears to exert multiple effects on schistosomes (see main text). At this time, it is not known whether these effects are the result of the drug’s action on a single target or multiple targets in the worms. If multiple targets are involved, then the situation with regard to heritability of susceptibility or resistance to praziquantel could be complex.
In vitro testing For in vitro testing, there is as yet no internationally agreed standard for classifying schistosomes as resistant or susceptible to praziquantel based on the level of drug that the parasites can tolerate. However, as more work is done, a consensus might begin to emerge (see main text).
Treatment failure Treatment failures are cases where repeated treatments with the standard dose of praziquantel fail to eliminate egg-producing adult worms. Following treatment failures, eggs can still be detected in the urine (Schistosoma haematobium) or faeces (Schistosoma mansoni, Schistosoma japonicum). The peculiar stage-specificity of praziquantel means that some immature parasites are unaffected by the drug. These can later mature to give egg-producing adult worms and thus an apparent treatment failure. This problem occurs most often in areas of high transmission when individuals harbour large numbers of maturing worms that escape the effects of praziquantel. Treatment failures could arise if drug-resistant parasites are present, but the difference between these two situations can usually be resolved by repeated chemotherapy [11].
Corresponding author: Paul Hagan ([email protected]). www.sciencedirect.com 1471-4922/$ - see front matter q 2003 Published by Elsevier Ltd. doi:10.1016/j.pt.2003.11.010
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treatments were given, this increased the relative effectiveness of the drug compared with a single dose and confirmed that immature worms were capable of surviving exposure to praziquantel [11,14]. Reports of the isolation of praziquantel-resistant parasites from both Egypt [15– 17] and Senegal [18,19], together with the ability to select for praziquantel-resistant schistosomes in the laboratory [20], have ensured that concerns about the possible emergence and spread of praziquantel-resistant parasites have remained prominent. But, rather than heralding the end of the praziquantel era, the findings have galvanized research and control efforts. Public health priority Confronted by the awareness that 25 years after it first entered the market, praziquantel is still not reaching the majority of those who most need it, many national and international agencies have promoted the control of schistosomiasis (and other helminth diseases) on their public health agendas [8,21]. Dramatic reductions in the cost of praziquantel from manufacturers of generic product have facilitated the process [22]. At ,US$0.07 per tablet, praziquantel has become an affordable, costeffective, public health tool. There are no excuses not to use it, although some poorer nations will still need external support to allow them to purchase praziquantel and to include schistosomiasis in their portfolio of control priorities. If they needed any further encouragement, evidence of the capacity for praziquantel to control schistosomiasis is available from its success in underpinning the prolonged and largely successful control effort in Egypt [23]. As the control effort gathers pace across sub-Saharan Africa, the wider availability of praziquantel could exacerbate the risk of the emergence of drug-resistant parasites, providing an incentive to extend monitoring and surveillance, and continued investigations of the biology of resistant parasites. But what is the current situation regarding praziquantel [24] and the development of resistant schistosomes? Status of resistance In the early 1990s, the treatment failures reported from Northern Senegal caused widespread alarm [10,25]. In part, this was because there was no agreed definition of resistance to praziquantel. While this remains the case, Coles and Kinoti have proposed that a population of Schistosoma is resistant when either a susceptible population shows a significant decrease in its response to a schistosomicide or is significantly less responsive than a fully susceptible population [26]. Resistance results from an increase in the proportion of worms unresponsive to the drug might be partial or complete. It is complete when the maximum dose tolerated by the host has no effect on the parasite population. The resistance will be heritable Box 1). This definition of resistance requires some knowledge of the natural variation in praziquantel susceptibility of worms, but one of the difficulties highlighted by the situation in Senegal was that there was little information on the levels of susceptibility (or resistance) in naturally www.sciencedirect.com
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occurring populations of schistosomes. Some of the parasites isolated from Senegal demonstrated reduced susceptibility to praziquantel when compared with parasites that had been maintained in the laboratory for many years [19]. In Egypt, schistosomes that had survived three doses of praziquantel were isolated and shown to have a lower susceptibility to praziquantel than either freshly isolated schistosomes that could be eliminated with a single treatment or long-term laboratory-passaged parasites. However, there are as yet no reports of praziquantelresistant parasites from other locations. Some of the resistant parasites (50% of the resistant isolates) from Egypt maintained their resistance to praziquantel after multiple passages in the laboratory over several years (S. Botros, pers. commun.). The community from which these parasites were isolated was included in the national schistosomiasis control programme. Despite years of drug pressure in a focus where resistance has been recorded, there is now no evidence that the proportion of resistant parasites has increased. Two treatments with a standard dose of 40 mg kg21 of praziquantel, a protocol designed to identify resistant schistosomes [27], effectively cleared most infections. Schistosome variations Limited knowledge of the extent of natural variations in susceptibility to praziquantel from different epidemiological settings is a major drawback when attempting to identify the emergence of true praziquantel resistance. The reality is that we know very little about any natural variations in schistosome populations or how any of the variations influence the biology of the parasite and its clinical impact on humans or animals [28]. Over the past 40 years, schistosome research has been over-dependent on laboratory-reared parasites repeatedly passaged through a variety of mouse strains (Figure 1). Furthermore, there has been no systematic comparison of the current status of the ‘old’ isolates from different
Figure 1. Schistosoma egg granuloma formation. Small-sized fibrocellular granuloma surrounding a central egg in a mouse infected with praziquantel-sensitive Schistosoma mansoni isolate. Scale bar ¼ 25 mm. Image kindly supplied by Sanaa Botros.
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schistosome laboratories. All this is about to change. A major effort has been launched to investigate the natural variations in schistosome susceptibility to praziquantel. As a first step, standard operating procedures (SOPs) are being defined by an European Community-funded group of researchers to aid the collection of biological material from the field and to run comparable tests in each laboratory. The SOPs are designed to ensure detailed information is available for each isolate, including the geographical location and treatment and infection history of the patient. Such information is particularly important when biological material is being collected from treatment failures when praziquantel-resistant parasites might be present. Collection of biological material will be followed by laboratory characterization of the parasites, wherever possible, also using the standardized methodologies. At present, there are no molecular probes for praziquantel resistance and, perhaps more important at this time, no agreed criteria for assessing the degree of susceptibility or resistance of schistosomes to drugs either in vitro or in vivo. This prevents valid comparisons between the findings from different laboratories, and undermines attempts to assess the true extent of the threat, or otherwise, of praziquantel resistance in the field. Laboratory studies have provided valuable insights into the differences between parasites that are susceptible and resistant to praziquantel, although the precise target(s) for the action of praziquantel have yet to be defined. Testing for resistance A variety of assays has been used to test for resistance (Box 1), but are they good indicators of the susceptibility or resistance status of parasites? Perhaps the most reliable measure is direct drug testing with a range of doses in infected animals (normally mice). When comparing four susceptible isolates with ten praziquantel-insensitive isolates, the adult worms from susceptible isolates could be removed from infected mice with a dose of , 100 mg kg21, whereas all ten insensitive isolates required between 100 and 225 mg kg21. The mean ED50 (effective dose that kills 50% of the worms) was 75 mg kg21 for sensitive isolates and 200 mg kg21 for insensitive isolates (D. Cioli, pers. commun.) The most obvious effects of praziquantel on worms include damage to the tegumental membrane, changes in calcium flux and muscular contraction. As might be expected, membrane damage is easily detected by electron microscopy, and is more extensive in susceptible worms [29,30]. Muscle tension after exposure also correlates with susceptibility to praziquantel [31] but, surprisingly, Ca2þuptake appeared not to be directly associated with susceptibility. This, despite some preliminary in vitro evidence that chemicals which inhibit calcium release from internal stores (e.g. Nifedipine), could protect worms from the effects of praziquantel (D. Cioli, pers. commun.). When biological factors were considered, no differences were found among isolates in worm burdens and faecal egg counts [32], but granulomas were larger and levels of circulating worm antigen were lower in resistant isolates [29,33]. Adult worms from resistant isolates had fewer www.sciencedirect.com
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surface-bound antibodies, perhaps reflecting enhanced membrane turnover [34]. In sensitive isolates, the worms showed greatest sensitivity to the effects of praziquantel when male and female worms were paired. Single sex males were less sensitive, and unmated females were insensitive to praziquantel. In vitro experiments confirmed that single sex worms were less sensitive than paired parasites. This suggests that at least some praziquantel-sensitive sites could develop on pairing (D. Cioli, pers. commun.). The method of Grevelding and co-workers in which cultured worm pairs are separated and tested for gene activity, and re-paired to examine genetic and metabolic consequences could help study this phenomenon [35]. Of course, none of these assays is of much practical value in a field setting. A simpler test involving an assessment of muscular contraction visualized by a change of shape of miracidia after exposure to praziquantel has been developed, but still needs wider testing before its utility can be properly assessed [19,36]. Genetics of resistance One key factor for the development and spread of resistance is its heritability. Until now, we knew little about the genetics of praziquantel resistance (Box 1). However, novel studies are being carried out in vivo and in vitro with resistant isolates that are crossed with susceptible isolates using surgical implantation of worms. The resulting eggs are passaged through snail and mouse hosts, and subsequently tested for praziquantel sensitivity. It will be of interest to see whether the resistance trait shows clear dominance or recessive characteristics (D. Cioli, pers. commun.). Veterinary experiences The public health priority for sub-Saharan Africa is to ensure praziquantel reaches those who most need it. But, by rapidly expanding the scale of praziquantel use, drug pressure on schistosomes is likely to increase dramatically. What lessons have been learned from the veterinary experience and are any being applied in the renewed assault on schistosomes? There are no plans to use combination therapy or for the use of different drugs in alternate years. Combination therapy would be costly and logistically difficult. In any case, the success of praziquantel has had an indirect negative effect on the availability of the other schistosomicidal drugs, oxamniquine and metrifonate. More extensive treatment of high risk groups is likely to increase the chances of the development of resistance as, by extending the target worm population for praziquantel use, the chances of encountering and selecting for worms with the potential for resistance increases. From what limited knowledge we have, such variation in susceptibility to praziquantel is to be expected. Veterinarians are aware of the dangers of selecting for resistance by under-dosing. There have been concerns for some time about whether or not the standard praziquantel dose use in humans (40 mg kg21) is sub-curative [37], although it is not known if this is important. This catalogue of potential weakness in the planned approach for schistosomiasis control should in normal circumstances be a cause for
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concern, but one other lesson from the veterinary field could preserve the activity of praziquantel for a prolonged period. It is now recognized that leaving a percentage of nematodes untreated (in refugia) will delay the development of resistance [38,39]. By leaving batches of animals untreated, or by staggering treatment schedules, it is possible to ensure that a proportion of susceptible parasites is maintained in the worm population and can interbreed with any resistant parasite, thus theoretically slowing the spread of the resistance genes. Leaving people untreated would be ethically unacceptable. However, few drug intervention programmes for helminths would claim 100% coverage, even when mass chemotherapy is employed. In addition, most control interventions are targeted at high-risk groups and in particular at children of school age, thus leaving a relatively large proportion of individuals (and worms, including larval stages in snails) unexposed to praziquantel. This is refugia by default. This could be one reason why the prolonged use of praziquantel in the control programme in Egypt has not led to widespread praziquantel resistance. While the control programme effectively reached its target group (schoolchildren), there was less of an impact of the programme on infection levels found in each new annual intake to primary schools. In other words, transmission of infection continued at a level sufficient to ensure a large population of worms was not being exposed to praziquantel. New drugs It would be foolish to depend on refugia or on a single agent for the sustainable control of schistosomiasis. Ideally, a range of treatment options should be available, preferably with different classes of drugs being used. The development of new classes of drugs with schistosomicidal activity seems unlikely at this stage. One promising development is that novel approaches in organic chemistry are being exploited for the synthesis of praziquantel [40], including solid phase synthesis and combinatorial chemistry. It might be possible to produce a variety of novel analogues with antischistosome activity. Work is also under way to generate fluorescent and radioactive derivatives of praziquantel that can be used for determining the in vivo target of the drug (which would finally allow rational drug design) and for drug excretion studies. Labelled derivatives would also facilitate investigations into whether praziquantel can be synthesized cost-effectively as its single active enantiomer (M. Todd, pers. commun.). The continuing market dominance of praziquantel might explain the relative disinterest of the pharmaceutical industry in developing new drugs against schistosomes. Given this challenging situation, the identification and licensing of any new schistosomicide might be seen as a significant advance. Artemisinin derivatives, now seen as important antimalarials, have been shown to have an effect on schistosomes. In China, artemether has been used successfully for acute S japonicum infections in times of flood [41]. Artemisinin derivatives are expensive and, in areas where these drugs are underpinning malaria treatment and control programmes, their use for schistosomiasis treatment is likely to be restricted [42– 45]. www.sciencedirect.com
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Figure 2. The launch of the Bill and Melinda Gates Foundation supported Schistosomiasis Control Initiative (http://www.schisto.org)/Ministry of Health control programme in Uganda. Image kindly supplied by Alan Fenwick.
Another natural product, an extract of Commiphora molmol (myrrh) has been licensed and marketed (as Mirazid) for clinical use against Fasciola and schistosome infections in Egypt [46]. Despite early reports indicating its efficacy, more recent formal testing in humans has yielded no evidence that the extract has any impact on infection (S. Botros, pers. commun.). Schistosomiasis control activities Praziquantel and albendazole (to control gastrointestinal nematodes at the same time) are the major weapons used by the Schistosomiasis Control Initiative (SCI; http://www. schisto.org) in its attempts to facilitate the implementation of more extensive helminth control programmes in sub-Saharan Africa (Figure 2) [9]. SCI has the benefit of the lessons gained from the successful National Schistosomiasis Control Programme in Egypt and, wherever possible, it will build on existing control activities. The Egyptian success can be attributed to political will, the determination, dedication and skills of the programme management team and the availability of resources, that from 1988 allowed praziquantel to be provided free of charge. In Morocco, the preparatory phase of the national control programme was started in 1976 with the operational phase being implemented in all provinces with endemic schistosomiasis in 1982. Praziquantel was introduced in 1987. Rigorous treatment and post-treatment follow-up, coupled with environmental management, has reduced cumulative incidence to , 1%. Since 1994, the policy has shifted from transmission control to elimination. In Cameroon, the national survey conducted from 1985 to 1987 indicated that . 1.7 million people were infected with schistosomes. Schistosoma haematobium and Schistosoma mansoni were widely distributed, whereas Schistosoma intercalatum had a very restricted distribution [47]. A series of laboratory and field studies has indicated that, where co-infections occur, there are sexual and other interactions among these schistosome species. This has resulted in a high prevalence of ectopic eliminations of S. haematobium (eggs in faeces, when they are normally found in urine) and S. mansoni (eggs in
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urine, when they are normally found in faeces), as a consequence of heterospecific pairings between these two species [47]. As a result of introgressive hybridization with S. haematobium, or possibly competitive exclusion by S. mansoni, S. intercalatum has been eliminated from several foci and is now an endangered species in Cameroon [47]. Control measures using praziquantel have been very effective against all three species, and now the national control programme is being boosted. Launched in 1981, the schistosomiasis control programme in Mali is integrated into the primary health care system. Free treatment is available at community and district health centers, and this is being supplemented by improvement of dam and irrigation systems. The national schistosomiasis survey in Nigeria in 1990– 1992 revealed that all states in the Federation had infected cases. Praziquantel has been on the essential drug list in all 37 states since 1994. It is coadministered with other drugs such as ivermectin, albendazole or chloroquine as appropriate. However, the percentage coverage of the population remains low, at , 10%. There have been positive developments in South Africa where, in 1998, the Parasite Control Programme (PCP) was instigated in KwaZulu-Natal to target S. haematobium and geohelminths. Not surprisingly with the difficult political and economic situation in that country, the national control effort in Zimbabwe has been in decline. In 2001, schistosomiasis dropped out of the top ten health priorities. This could be seen as a worrying development because co-infections with S. haematobium and S. mansoni remain relatively common, but faced with HIV, TB and malaria, harsh choices on control priorities must be made. One way in which control programmes are likely to change in the future is in their approach to the treatment of young women of childbearing age, and pregnant and lactating women. A recent review of the issues surrounding praziquantel use has resulted in the clear recommendation that young women of childbearing age should be included in control programmes and that pregnant and lactating women need not automatically be excluded from receiving treatment [48,49]. What about vaccines? Diminishing drug efficacy might have served to stimulate the search for alternative approaches to control, but the surge in interest in praziquantel has come at a time when the vaccine effort is stalled. The leading vaccine candidate antigens gave relatively poor levels of protection when assessed in independent laboratories. Technical difficulties with the production of S. mansoni paramyosin Sm97, S. japonicum paramyosin Sj97, and S. mansoni triosephosphate isomerase as a multiple antigenic peptide (MAP4) have delayed their progression to Phase I clinical trials [50 – 52]. The leading vaccine candidate, S. haematobium glutathione-s-transferase (Sh28GST) has completed Phase I and Phase II clinical trials, but has yet to progress to Phase III trials [53]. This is not the forum to argue the relative merits of vaccines and drugs; ideally, the control toolbox should contain both. However, the revival of interest in praziquantel and the prospects for its use on a wider scale could increase the pressure for scarce www.sciencedirect.com
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resources to be focused on the implementation of existing tools, rather than on the development of new tools [54]. Importantly, recent developments in schistosome genome analysis offer hope for the development of new tools for control [55,56]. Expectations Those responsible for generating the wave of enthusiasm for the control of schistosomiasis that is sweeping through health ministries and public health departments in many countries should be satisfied that their efforts are beginning to be translated into potentially long-term control programmes. These new programmes might not be on the scale of that in Egypt but, given the background to their launch, they probably have as much chance of success. With the drive for control comes the expectation particularly among those infected, that schistosomiasis might be banished as a significant health problem. Spectacular progress in the control of onchocerciasis and dracunculiasis and promising preliminary results with lymphatic filariasis indicate that a new era has dawned in helminth disease control. But, until we have some evidence of widespread, sustained and successful schistosomiasis control across sub-Saharan Africa, it would be premature to abandon the research efforts that generate the tools that make control possible. The case for caution is clear, in 2000 [5], it was estimated that 200 million people were infected with schistosomes, the same figure as in 1973 [57]. Dedication This article is dedicated to the memory of Professor Magdi Ismail who was one of the first people to identify and isolate praziquantel-resistant schistosomes. Acknowledgements This article is based on a summary of the deliberations of the EC Concerted Action on ‘Praziquantel: its central role in the chemotherapy of schistosome infection’ at their meeting held 23rd to 25th March 2003 in Cape Town, South Africa. We thank the EC for its support. Thanks are due to Jillian Bryce who organized the meeting.
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immature worm surface immunoglobulins in mice harbouring a praziquantel -resistant Schistosoma mansoni isolate. APMIS (in press). Grevelding, C.G. et al. (1997) Female-specific gene expression in Schistosoma mansoni is regulated by pairing. Parasitology 115, 635– 640 Kenworthy, J.D. et al. (2003) Field evaluation of a test for praziquantel resistance in Schistosoma sp. Vet. Parasitol. 113, 83 – 87 Doenhoff, M.J. (1998) Is schistosomicidal chemotherapy sub-curative? Implications for drug resistance. Parasitol. Today 14, 434 – 435 Van Wyk, J.A. (2001) Refugia- overlooked as probably the most potent factor concerning the development of anthelmintic resistance. Onderstepoort J. Vet. Res. 68, 55 – 67 Coles, G.C. (2002) Sustainable use of anthelmintics in grazing animals. Vet. Rec. 151, 165– 169 Todd, M.H. et al. (2002) Amino acid-derived heterocycles: Lewis acidcatalysed and radical cyclizations from peptide acetals. J. Org. Chem. 67, 3985 – 3988 Xiao, S.H. et al. (2000) The prophylactic effects of artemether against Schistosoma japonicum infections. Parasitol. Today 16, 122 – 126 De Clercq, D. et al. (2002) Efficacy of artesunate and praziquantel in Schistosoma haematobium infected schoolchildren. Acta Trop. 82, 61 – 66 De Clercq, D. et al. (2000) Efficacy of artesunate against Schistosoma mansoni infections in Richard Toll. Senegal. Trans. R. Soc. Trop. Med. Hyg. 94, 90 – 91 Shuhua, X. et al. (2002) Recent investigations of artemether, a novel agent for the prevention of schistosomiasis japonica, mansoni and haematobium. Acta Trop. 82, 175 – 181 N’Goran, E.K. et al. (2003) Randomized, double-blind, placebocontrolled trial of oral artemether for the prevention of patent Schistosoma haematobium infections. Am. J. Trop. Med. Hyg. 68, 24 – 32 Sheir, Z. et al. (2001) A safe, effective, herbal antischistosomal therapy derived from myrrh. Am. J. Trop. Med. Hyg. 65, 700 – 704 Tchuem Tchuente´, L.A. et al. (2003) Schistosoma intercalatum: an endangered species in Cameroon? Trends Parasitol. 19, 389– 396 Olds, G.R. (2003) Administration of praziquantel to pregnant and lactating women. Acta Trop. 86, 185 – 195 World Health Organization (2003) Report of the WHO Informal Consultation on the Use of Praziquantel During Pregnancy/Lactation and Albendazole/Mebendazole in Children Under 24 Months. Geneva (WHO/CDS/CPE/PVC/2002.4). Bergquist, R. et al. (2002) Blueprint for schistosomiasis vaccine development. Acta Trop. 82, 183 – 192 McManus, D.P. et al. (2001) Recombinant paramyosin (rec-Sj-97) tested for immunogenicity and vaccine efficacy against Schistosoma japonicum in mice and water buffaloes. Vaccine 20, 870 – 878 Reynolds, S.R. et al. (1994) T and B epitope determination and analysis of multiple antigenic peptides for the Schistosoma mansoni experimental vaccine triose-phosphate isomerase. J. Immunol. 152, 193– 200 Capron, A. et al. (2001) Vaccine strategies against schistosomiasis: from concepts to clinical trials. Int. Arch. Allergy Immunol. 124, 9 – 15 Hagan, P. and Sharaf, O. Schistosomiasis vaccines. Expert Opin. Biol. Ther. (in press). Hu, W. et al. (2003) Evolutionary and biomedical implications of a Schistosoma japonicum complementary DNA resource. Nat. Genet. 35, 139– 147 Verjovski-Almeida, S. et al. (2003) Transcriptome analysis of the acoelomate human parasite Schistosoma mansoni. Nat. Genet. 35, 148– 157 World Health Organization, (1973) Schistosomiasis control report of the WHO expert committee. Tech. Rep. Ser., 515
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Schistosomiasis control: keep taking the tablets Paul Hagan1, Christopher C. Appleton2, Gerald C. Coles3, John R. Kusel4 and Louis-Albert Tchuem-Tchuente´5 1
Division of Infection and Immunity, Institute of Biomedical and Life Sciences, Joseph Black Building (B4-09d), University of Glasgow, G12 8QQ, UK 2 University of Natal, School of Life and Environmental Sciences, Biology Division, George Campbell Building, 4041 Durban, South Africa 3 Department of Clinical Veterinary Science, University of Bristol, Langford House, Langford, Bristol BS40 5DU, UK 4 Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Davidson Building, Lab 502, University of Glasgow, G12 8QQ, UK 5 Centre for Schistosomiasis and Parasitology, PO Box 7244, Yaounde´, Cameroon
Despite the limited reports of praziquantel resistance, the relative success of chemotherapy-based control programmes for schistosomiasis has prompted overdue efforts to expand the use of cheap, generic, praziquantel in sub-Saharan Africa. The likely impact of such programmes on the development and spread of praziquantel resistance is uncertain, but this possibility reinforces the need for monitoring the spectrum of praziquantel sensitivity of schistosome populations and for an improved knowledge of the precise targets for the action of the drug. The search for alternatives to praziquantel and other tools for control of schistosomiasis must continue. Despite success with control programmes in Egypt [1], China [2], Brazil [3] and Morocco [4], schistosomiasis remains a major public health problem [5]. Treatment and control of infection depends largely upon the use of praziquantel, which is now cheaper, easier to use and more readily available than other schistosomicides [6]. The renewed impetus for extending schistosomiasis control throughout sub-Saharan Africa will probably result in greater use of praziquantel than ever before [7 – 9]. This welcome development is set against the background of limited knowledge on many aspects of praziquantel. Here, we summarize the current status of praziquantel and its interactions with the parasites. The praziquantel puzzle Treatment failures are often the first indication of the end of the effective life of a drug. In the case of praziquantel, the report of treatment failure in 1995 [10] was attributed principally to the peculiar stage-specific efficacy of the drug [11]. Praziquantel is active against schistosomula in the first two days after their penetration of the skin. After this time, and for a period of approximately four weeks, the parasites lose their susceptibility and can continue their development, progressing to mature egg-producing paired
adult worms [12,13]. The excretion of eggs from the worms that develop after giving praziquantel can give the impression of failed treatment (Box 1). When repeated
Box 1. Key concepts in schistosomiasis control Defining resistance ‘A population of Schistosoma is resistant when either a susceptible population shows a significant decrease in its response to a schistosomicide or it is significantly less responsive than a fully susceptible population. The change is due to an increase in the proportion of worms unresponsive to the drug and may be partial or complete. It is complete when the maximum dose tolerated by the host has no effect on the parasite population. The resistance will be heritable.’ [26].
Action of praziquantel Praziquantel appears to exert multiple effects on schistosomes (see main text). At this time, it is not known whether these effects are the result of the drug’s action on a single target or multiple targets in the worms. If multiple targets are involved, then the situation with regard to heritability of susceptibility or resistance to praziquantel could be complex.
In vitro testing For in vitro testing, there is as yet no internationally agreed standard for classifying schistosomes as resistant or susceptible to praziquantel based on the level of drug that the parasites can tolerate. However, as more work is done, a consensus might begin to emerge (see main text).
Treatment failure Treatment failures are cases where repeated treatments with the standard dose of praziquantel fail to eliminate egg-producing adult worms. Following treatment failures, eggs can still be detected in the urine (Schistosoma haematobium) or faeces (Schistosoma mansoni, Schistosoma japonicum). The peculiar stage-specificity of praziquantel means that some immature parasites are unaffected by the drug. These can later mature to give egg-producing adult worms and thus an apparent treatment failure. This problem occurs most often in areas of high transmission when individuals harbour large numbers of maturing worms that escape the effects of praziquantel. Treatment failures could arise if drug-resistant parasites are present, but the difference between these two situations can usually be resolved by repeated chemotherapy [11].
Corresponding author: Paul Hagan ([email protected]). www.sciencedirect.com 1471-4922/$ - see front matter q 2003 Published by Elsevier Ltd. doi:10.1016/j.pt.2003.11.010
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treatments were given, this increased the relative effectiveness of the drug compared with a single dose and confirmed that immature worms were capable of surviving exposure to praziquantel [11,14]. Reports of the isolation of praziquantel-resistant parasites from both Egypt [15– 17] and Senegal [18,19], together with the ability to select for praziquantel-resistant schistosomes in the laboratory [20], have ensured that concerns about the possible emergence and spread of praziquantel-resistant parasites have remained prominent. But, rather than heralding the end of the praziquantel era, the findings have galvanized research and control efforts. Public health priority Confronted by the awareness that 25 years after it first entered the market, praziquantel is still not reaching the majority of those who most need it, many national and international agencies have promoted the control of schistosomiasis (and other helminth diseases) on their public health agendas [8,21]. Dramatic reductions in the cost of praziquantel from manufacturers of generic product have facilitated the process [22]. At ,US$0.07 per tablet, praziquantel has become an affordable, costeffective, public health tool. There are no excuses not to use it, although some poorer nations will still need external support to allow them to purchase praziquantel and to include schistosomiasis in their portfolio of control priorities. If they needed any further encouragement, evidence of the capacity for praziquantel to control schistosomiasis is available from its success in underpinning the prolonged and largely successful control effort in Egypt [23]. As the control effort gathers pace across sub-Saharan Africa, the wider availability of praziquantel could exacerbate the risk of the emergence of drug-resistant parasites, providing an incentive to extend monitoring and surveillance, and continued investigations of the biology of resistant parasites. But what is the current situation regarding praziquantel [24] and the development of resistant schistosomes? Status of resistance In the early 1990s, the treatment failures reported from Northern Senegal caused widespread alarm [10,25]. In part, this was because there was no agreed definition of resistance to praziquantel. While this remains the case, Coles and Kinoti have proposed that a population of Schistosoma is resistant when either a susceptible population shows a significant decrease in its response to a schistosomicide or is significantly less responsive than a fully susceptible population [26]. Resistance results from an increase in the proportion of worms unresponsive to the drug might be partial or complete. It is complete when the maximum dose tolerated by the host has no effect on the parasite population. The resistance will be heritable Box 1). This definition of resistance requires some knowledge of the natural variation in praziquantel susceptibility of worms, but one of the difficulties highlighted by the situation in Senegal was that there was little information on the levels of susceptibility (or resistance) in naturally www.sciencedirect.com
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occurring populations of schistosomes. Some of the parasites isolated from Senegal demonstrated reduced susceptibility to praziquantel when compared with parasites that had been maintained in the laboratory for many years [19]. In Egypt, schistosomes that had survived three doses of praziquantel were isolated and shown to have a lower susceptibility to praziquantel than either freshly isolated schistosomes that could be eliminated with a single treatment or long-term laboratory-passaged parasites. However, there are as yet no reports of praziquantelresistant parasites from other locations. Some of the resistant parasites (50% of the resistant isolates) from Egypt maintained their resistance to praziquantel after multiple passages in the laboratory over several years (S. Botros, pers. commun.). The community from which these parasites were isolated was included in the national schistosomiasis control programme. Despite years of drug pressure in a focus where resistance has been recorded, there is now no evidence that the proportion of resistant parasites has increased. Two treatments with a standard dose of 40 mg kg21 of praziquantel, a protocol designed to identify resistant schistosomes [27], effectively cleared most infections. Schistosome variations Limited knowledge of the extent of natural variations in susceptibility to praziquantel from different epidemiological settings is a major drawback when attempting to identify the emergence of true praziquantel resistance. The reality is that we know very little about any natural variations in schistosome populations or how any of the variations influence the biology of the parasite and its clinical impact on humans or animals [28]. Over the past 40 years, schistosome research has been over-dependent on laboratory-reared parasites repeatedly passaged through a variety of mouse strains (Figure 1). Furthermore, there has been no systematic comparison of the current status of the ‘old’ isolates from different
Figure 1. Schistosoma egg granuloma formation. Small-sized fibrocellular granuloma surrounding a central egg in a mouse infected with praziquantel-sensitive Schistosoma mansoni isolate. Scale bar ¼ 25 mm. Image kindly supplied by Sanaa Botros.
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schistosome laboratories. All this is about to change. A major effort has been launched to investigate the natural variations in schistosome susceptibility to praziquantel. As a first step, standard operating procedures (SOPs) are being defined by an European Community-funded group of researchers to aid the collection of biological material from the field and to run comparable tests in each laboratory. The SOPs are designed to ensure detailed information is available for each isolate, including the geographical location and treatment and infection history of the patient. Such information is particularly important when biological material is being collected from treatment failures when praziquantel-resistant parasites might be present. Collection of biological material will be followed by laboratory characterization of the parasites, wherever possible, also using the standardized methodologies. At present, there are no molecular probes for praziquantel resistance and, perhaps more important at this time, no agreed criteria for assessing the degree of susceptibility or resistance of schistosomes to drugs either in vitro or in vivo. This prevents valid comparisons between the findings from different laboratories, and undermines attempts to assess the true extent of the threat, or otherwise, of praziquantel resistance in the field. Laboratory studies have provided valuable insights into the differences between parasites that are susceptible and resistant to praziquantel, although the precise target(s) for the action of praziquantel have yet to be defined. Testing for resistance A variety of assays has been used to test for resistance (Box 1), but are they good indicators of the susceptibility or resistance status of parasites? Perhaps the most reliable measure is direct drug testing with a range of doses in infected animals (normally mice). When comparing four susceptible isolates with ten praziquantel-insensitive isolates, the adult worms from susceptible isolates could be removed from infected mice with a dose of , 100 mg kg21, whereas all ten insensitive isolates required between 100 and 225 mg kg21. The mean ED50 (effective dose that kills 50% of the worms) was 75 mg kg21 for sensitive isolates and 200 mg kg21 for insensitive isolates (D. Cioli, pers. commun.) The most obvious effects of praziquantel on worms include damage to the tegumental membrane, changes in calcium flux and muscular contraction. As might be expected, membrane damage is easily detected by electron microscopy, and is more extensive in susceptible worms [29,30]. Muscle tension after exposure also correlates with susceptibility to praziquantel [31] but, surprisingly, Ca2þuptake appeared not to be directly associated with susceptibility. This, despite some preliminary in vitro evidence that chemicals which inhibit calcium release from internal stores (e.g. Nifedipine), could protect worms from the effects of praziquantel (D. Cioli, pers. commun.). When biological factors were considered, no differences were found among isolates in worm burdens and faecal egg counts [32], but granulomas were larger and levels of circulating worm antigen were lower in resistant isolates [29,33]. Adult worms from resistant isolates had fewer www.sciencedirect.com
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surface-bound antibodies, perhaps reflecting enhanced membrane turnover [34]. In sensitive isolates, the worms showed greatest sensitivity to the effects of praziquantel when male and female worms were paired. Single sex males were less sensitive, and unmated females were insensitive to praziquantel. In vitro experiments confirmed that single sex worms were less sensitive than paired parasites. This suggests that at least some praziquantel-sensitive sites could develop on pairing (D. Cioli, pers. commun.). The method of Grevelding and co-workers in which cultured worm pairs are separated and tested for gene activity, and re-paired to examine genetic and metabolic consequences could help study this phenomenon [35]. Of course, none of these assays is of much practical value in a field setting. A simpler test involving an assessment of muscular contraction visualized by a change of shape of miracidia after exposure to praziquantel has been developed, but still needs wider testing before its utility can be properly assessed [19,36]. Genetics of resistance One key factor for the development and spread of resistance is its heritability. Until now, we knew little about the genetics of praziquantel resistance (Box 1). However, novel studies are being carried out in vivo and in vitro with resistant isolates that are crossed with susceptible isolates using surgical implantation of worms. The resulting eggs are passaged through snail and mouse hosts, and subsequently tested for praziquantel sensitivity. It will be of interest to see whether the resistance trait shows clear dominance or recessive characteristics (D. Cioli, pers. commun.). Veterinary experiences The public health priority for sub-Saharan Africa is to ensure praziquantel reaches those who most need it. But, by rapidly expanding the scale of praziquantel use, drug pressure on schistosomes is likely to increase dramatically. What lessons have been learned from the veterinary experience and are any being applied in the renewed assault on schistosomes? There are no plans to use combination therapy or for the use of different drugs in alternate years. Combination therapy would be costly and logistically difficult. In any case, the success of praziquantel has had an indirect negative effect on the availability of the other schistosomicidal drugs, oxamniquine and metrifonate. More extensive treatment of high risk groups is likely to increase the chances of the development of resistance as, by extending the target worm population for praziquantel use, the chances of encountering and selecting for worms with the potential for resistance increases. From what limited knowledge we have, such variation in susceptibility to praziquantel is to be expected. Veterinarians are aware of the dangers of selecting for resistance by under-dosing. There have been concerns for some time about whether or not the standard praziquantel dose use in humans (40 mg kg21) is sub-curative [37], although it is not known if this is important. This catalogue of potential weakness in the planned approach for schistosomiasis control should in normal circumstances be a cause for
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concern, but one other lesson from the veterinary field could preserve the activity of praziquantel for a prolonged period. It is now recognized that leaving a percentage of nematodes untreated (in refugia) will delay the development of resistance [38,39]. By leaving batches of animals untreated, or by staggering treatment schedules, it is possible to ensure that a proportion of susceptible parasites is maintained in the worm population and can interbreed with any resistant parasite, thus theoretically slowing the spread of the resistance genes. Leaving people untreated would be ethically unacceptable. However, few drug intervention programmes for helminths would claim 100% coverage, even when mass chemotherapy is employed. In addition, most control interventions are targeted at high-risk groups and in particular at children of school age, thus leaving a relatively large proportion of individuals (and worms, including larval stages in snails) unexposed to praziquantel. This is refugia by default. This could be one reason why the prolonged use of praziquantel in the control programme in Egypt has not led to widespread praziquantel resistance. While the control programme effectively reached its target group (schoolchildren), there was less of an impact of the programme on infection levels found in each new annual intake to primary schools. In other words, transmission of infection continued at a level sufficient to ensure a large population of worms was not being exposed to praziquantel. New drugs It would be foolish to depend on refugia or on a single agent for the sustainable control of schistosomiasis. Ideally, a range of treatment options should be available, preferably with different classes of drugs being used. The development of new classes of drugs with schistosomicidal activity seems unlikely at this stage. One promising development is that novel approaches in organic chemistry are being exploited for the synthesis of praziquantel [40], including solid phase synthesis and combinatorial chemistry. It might be possible to produce a variety of novel analogues with antischistosome activity. Work is also under way to generate fluorescent and radioactive derivatives of praziquantel that can be used for determining the in vivo target of the drug (which would finally allow rational drug design) and for drug excretion studies. Labelled derivatives would also facilitate investigations into whether praziquantel can be synthesized cost-effectively as its single active enantiomer (M. Todd, pers. commun.). The continuing market dominance of praziquantel might explain the relative disinterest of the pharmaceutical industry in developing new drugs against schistosomes. Given this challenging situation, the identification and licensing of any new schistosomicide might be seen as a significant advance. Artemisinin derivatives, now seen as important antimalarials, have been shown to have an effect on schistosomes. In China, artemether has been used successfully for acute S japonicum infections in times of flood [41]. Artemisinin derivatives are expensive and, in areas where these drugs are underpinning malaria treatment and control programmes, their use for schistosomiasis treatment is likely to be restricted [42– 45]. www.sciencedirect.com
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Figure 2. The launch of the Bill and Melinda Gates Foundation supported Schistosomiasis Control Initiative (http://www.schisto.org)/Ministry of Health control programme in Uganda. Image kindly supplied by Alan Fenwick.
Another natural product, an extract of Commiphora molmol (myrrh) has been licensed and marketed (as Mirazid) for clinical use against Fasciola and schistosome infections in Egypt [46]. Despite early reports indicating its efficacy, more recent formal testing in humans has yielded no evidence that the extract has any impact on infection (S. Botros, pers. commun.). Schistosomiasis control activities Praziquantel and albendazole (to control gastrointestinal nematodes at the same time) are the major weapons used by the Schistosomiasis Control Initiative (SCI; http://www. schisto.org) in its attempts to facilitate the implementation of more extensive helminth control programmes in sub-Saharan Africa (Figure 2) [9]. SCI has the benefit of the lessons gained from the successful National Schistosomiasis Control Programme in Egypt and, wherever possible, it will build on existing control activities. The Egyptian success can be attributed to political will, the determination, dedication and skills of the programme management team and the availability of resources, that from 1988 allowed praziquantel to be provided free of charge. In Morocco, the preparatory phase of the national control programme was started in 1976 with the operational phase being implemented in all provinces with endemic schistosomiasis in 1982. Praziquantel was introduced in 1987. Rigorous treatment and post-treatment follow-up, coupled with environmental management, has reduced cumulative incidence to , 1%. Since 1994, the policy has shifted from transmission control to elimination. In Cameroon, the national survey conducted from 1985 to 1987 indicated that . 1.7 million people were infected with schistosomes. Schistosoma haematobium and Schistosoma mansoni were widely distributed, whereas Schistosoma intercalatum had a very restricted distribution [47]. A series of laboratory and field studies has indicated that, where co-infections occur, there are sexual and other interactions among these schistosome species. This has resulted in a high prevalence of ectopic eliminations of S. haematobium (eggs in faeces, when they are normally found in urine) and S. mansoni (eggs in
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urine, when they are normally found in faeces), as a consequence of heterospecific pairings between these two species [47]. As a result of introgressive hybridization with S. haematobium, or possibly competitive exclusion by S. mansoni, S. intercalatum has been eliminated from several foci and is now an endangered species in Cameroon [47]. Control measures using praziquantel have been very effective against all three species, and now the national control programme is being boosted. Launched in 1981, the schistosomiasis control programme in Mali is integrated into the primary health care system. Free treatment is available at community and district health centers, and this is being supplemented by improvement of dam and irrigation systems. The national schistosomiasis survey in Nigeria in 1990– 1992 revealed that all states in the Federation had infected cases. Praziquantel has been on the essential drug list in all 37 states since 1994. It is coadministered with other drugs such as ivermectin, albendazole or chloroquine as appropriate. However, the percentage coverage of the population remains low, at , 10%. There have been positive developments in South Africa where, in 1998, the Parasite Control Programme (PCP) was instigated in KwaZulu-Natal to target S. haematobium and geohelminths. Not surprisingly with the difficult political and economic situation in that country, the national control effort in Zimbabwe has been in decline. In 2001, schistosomiasis dropped out of the top ten health priorities. This could be seen as a worrying development because co-infections with S. haematobium and S. mansoni remain relatively common, but faced with HIV, TB and malaria, harsh choices on control priorities must be made. One way in which control programmes are likely to change in the future is in their approach to the treatment of young women of childbearing age, and pregnant and lactating women. A recent review of the issues surrounding praziquantel use has resulted in the clear recommendation that young women of childbearing age should be included in control programmes and that pregnant and lactating women need not automatically be excluded from receiving treatment [48,49]. What about vaccines? Diminishing drug efficacy might have served to stimulate the search for alternative approaches to control, but the surge in interest in praziquantel has come at a time when the vaccine effort is stalled. The leading vaccine candidate antigens gave relatively poor levels of protection when assessed in independent laboratories. Technical difficulties with the production of S. mansoni paramyosin Sm97, S. japonicum paramyosin Sj97, and S. mansoni triosephosphate isomerase as a multiple antigenic peptide (MAP4) have delayed their progression to Phase I clinical trials [50 – 52]. The leading vaccine candidate, S. haematobium glutathione-s-transferase (Sh28GST) has completed Phase I and Phase II clinical trials, but has yet to progress to Phase III trials [53]. This is not the forum to argue the relative merits of vaccines and drugs; ideally, the control toolbox should contain both. However, the revival of interest in praziquantel and the prospects for its use on a wider scale could increase the pressure for scarce www.sciencedirect.com
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resources to be focused on the implementation of existing tools, rather than on the development of new tools [54]. Importantly, recent developments in schistosome genome analysis offer hope for the development of new tools for control [55,56]. Expectations Those responsible for generating the wave of enthusiasm for the control of schistosomiasis that is sweeping through health ministries and public health departments in many countries should be satisfied that their efforts are beginning to be translated into potentially long-term control programmes. These new programmes might not be on the scale of that in Egypt but, given the background to their launch, they probably have as much chance of success. With the drive for control comes the expectation particularly among those infected, that schistosomiasis might be banished as a significant health problem. Spectacular progress in the control of onchocerciasis and dracunculiasis and promising preliminary results with lymphatic filariasis indicate that a new era has dawned in helminth disease control. But, until we have some evidence of widespread, sustained and successful schistosomiasis control across sub-Saharan Africa, it would be premature to abandon the research efforts that generate the tools that make control possible. The case for caution is clear, in 2000 [5], it was estimated that 200 million people were infected with schistosomes, the same figure as in 1973 [57]. Dedication This article is dedicated to the memory of Professor Magdi Ismail who was one of the first people to identify and isolate praziquantel-resistant schistosomes. Acknowledgements This article is based on a summary of the deliberations of the EC Concerted Action on ‘Praziquantel: its central role in the chemotherapy of schistosome infection’ at their meeting held 23rd to 25th March 2003 in Cape Town, South Africa. We thank the EC for its support. Thanks are due to Jillian Bryce who organized the meeting.
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