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Microbes and Infection xx (2014) 1e10 www.elsevier.com/locate/micinf
Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications Q8
Marianette T. Inobaya a,b, Remigio M. Olveda b, Veronica Tallo b, Donald P. McManus c, Gail M. Williams d, Donald A. Harn e, Yuesheng Li c, Thao N.P. Chau e,f, David U. Olveda a, Allen G. Ross a,* a
b
Griffith Health Institute, Griffith University, Gold Coast Campus, Australia Research Institute for Tropical Medicine, Department of Health, The Philippines c QIMR Berghofer Medical Research Institute, Australia d School of Population Health, University of Queensland, Australia e Department of Infectious Diseases, College of Veterinary Medicine and Center for Tropical and Emerging Global Diseases, University of Georgia, USA f Discipline of Public Health, Flinders University, Australia Received 23 July 2014; accepted 17 October 2014
Abstract Schistosomiasis was first reported in the Philippines in 1906. A variety of treatments have been deployed to cure infection and to control the disease in the long-term. We discuss the journey to combat the disease in the Philippines and the lessons learnt which have implications for schistosomiasis control globally. © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
Keywords: Schistosomiasis; Treatment; Mass drug administration; Control
Q1
1. Introduction Schistosomiasis is an intravascular disease caused by trematode worms of the genus Schistosoma. As of 2011, the disease was endemic in 78 countries [1]. The World Health Organization (WHO) estimated in 2012 that 249 million people are at risk of infection and in need of preventive chemotherapy [2]. The burden of schistosomiasis caused by Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni was estimated at 24e29 million disability adjusted life years [3]. Considerable optimism surrounds Mass Drug Administration (MDA) for the control of schistosomiasis globally, for * Corresponding author. E-mail address: [email protected] (A.G. Ross).
which praziquantel (PZQ) has served as the cornerstone since its inception in 1979. Numerous studies have claimed that preventive chemotherapy (i.e. 40 mg/kg of praziquantel), given annually or biannually, can significantly reduce the prevalence and intensity of infection, and control morbidity in the long-term [4e13]. In the last decade, close to one billion US dollars has been raised for MDA campaigns for neglected tropical diseases largely from international donors and delivered vertically to local endemic communities through national health care services largely using unpaid volunteers [5,14]. Praziquantel (PZQ), a pyrazinoisoquinoline derivative (Fig. 1), is a safe and highly effective oral drug that is active against all schistosome species. PZQ is the mainstay of treatment and a critical part of community-based schistosomiasis control programs globally, including those in the Philippines [15e17]. Since its discovery in the mid-1970s, its
http://dx.doi.org/10.1016/j.micinf.2014.10.006 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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M.T. Inobaya et al. / Microbes and Infection xx (2014) 1e10
Fig. 1. The chemical structure of the drug praziquantel (Biltricide) used for the mass drug administration of schistosomiasis globally.
safety and efficacy have ensured its widespread use. It is absorbed well but undergoes extensive first-pass hepatic clearance [15]. PZQ is secreted in breast milk and is metabolized by the liver, and its (inactive) metabolites are excreted in the urine [15]. Side effects of PZQ treatment are minimal, and PZQ can be used to treat young children and pregnant women [16]. PZQ acts within one hour of ingestion, although its precise action on adult worms is unknown. It appears to cause tetanic contractions and tegumental vacuoles, causing worms to detach from the wall of the vein and die [15]. Schistosome calcium ion channels have been suggested as the molecular target of PZQ, but the evidence remains indirect and a recent study implicated myosin light chain as an alternative target of PZQ [17]. Standard treatment of chronic schistosomiasis is 60 mg/kg of PZQ in divided doses; for mass chemotherapy a single dose of 40 mg/kg is used [16]. There is also some evidence, albeit very controversial, that resistance to PZQ may be emerging in Africa, where there has been heavy exposure to PZQ and there are reports of S. mansoni and S. haematobium infections that are not responsive [17]. There have been no reports of the development of resistance of S. japonicum to PZQ in the clinical treatment of patients in the Philippines [17]. Periodic treatment of bovines (water buffalos [called Carabao in the Philippines], cattle) with PZQ, managed by local veterinarians, is now being considered for control programs for S. japonicum in the Philippines. This is because they are large animals (water buffaloes often exceed 300 kg in weight), they deposit considerable amounts of excreta near or in surface water, live for 10e12 years, and can carry large parasite burdens and develop hepato-intestinal disease. In China bovines have been successfully treated and in some localities have been removed to halt transmission. In agricultural areas in the Philippines, where S. japonicum is endemic, 10e80% of bovines are infected [18]. PZQ is curative, but the animals become reinfected. In most areas of endemicity, a large proportion (70%) of the environmental contamination may be traced back to bovine defecation and a high proportion of schistosome eggs [17]. The treatment doses (25 mg/kg for water buffaloes and 30 mg/kg for cattle) are lower than that used for humans because the collateral effects may be fatal, which is thought to result from portal occlusion by dead worms in heavily infected animals, as noted in other forms of
cattle schistosomiasis [17]. Older buffaloes tend to excrete fewer viable eggs than those less than 18 months old; this could reflect self-cure, decreased egg viability, or decreased egg production by female worms, and all have been described for other forms of bovine schistosomiasis [17]. 2. History of MDA for schistosomiasis control in the Philippines Schistosomiasis (Schistosoma japonicum) was first reported in the Philippines in 1906. Approximately 12 million people living in 28 endemic provinces located in 12 different regions of the country are at risk of infection (Fig. 2) [19,20]. Overall, a total of 190 municipalities and 20 cities are affected by the infection. Villages in Gonzaga, Cagayan province and municipality of Calatrava in Negros Occidental (northern and central parts of the Philippines, respectively) were the most recently identified endemic foci, confirmed in 2004 and 2006, respectively [21]. Control of schistosomiasis in the Philippines was initially focused on snail control due to the lack of an effective, nontoxic and economical drug that could be used for mass treatment [19,22]. Use of antimonials, Fuadin and tartar emeric, for treatment of schistosomiasis was introduced in the country during the outbreak of the disease among United States (US) and allied forces in 1944 in the island of Leyte. The efficacy of the drugs was low as 31% of the cases remained stool-positive when the soldiers were tested back in US hospitals [23]. After the liberation of the Philippines, Stibophen, a trivalent antimonial preparation, was introduced in a trial with a course of nine intramuscular injections that resulted to a cure rate of 78.2% [24]. Following the trial, the Schistosomiasis Control Pilot Project (SCPP) used it as part of the support strategy for agro-engineering methods of snail control together with environmental sanitation and health education. SCPP was implemented in Palo, Leyte in collaboration with WHO starting in 1953 [19]. After three years of implementation, the snail population was almost eradicated and the human prevalence of infection was reduced from 38.9% to 32.0% [25]. These strategies were tried in the towns of Mayorga, La Paz and Burauen in Leyte before being formally implemented nationwide under the National Schistosomiasis Control Program in 1961 [19]. Further trials were conducted with an
Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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3
Fig. 2. Map of the current endemic areas in the Philippines highlighted in blue. The red dot represents a new focus of infection Luzon.
increased dosage of 10 and 15 injections that resulted in cure rates of 61.2% and 86.7%, respectively, after one month. But the proportion of cured patients dropped to 38.3% among those given 10 injections and 48.6% in patients with 15 doses six months after treatment. Almost half of those who participated in the trial dropped out due to pain at the site of injection or to drug reactions. Reactions to the drug, such as dizziness, vomiting, body weakness, nausea, anorexia, and joint and muscular pains, were observed in 83.9% of the patients [24]. In middle of the 1960s use of another anti-schistosome drug, parasoniline pamoate, a complex azo dye from gentian violet which comes in oral preparation as gelatine capsules, was started in the Philippines. A clinical trial on this drug was conducted in San Lazaro Hospital and the Bureau of Research Laboratories in Manila, while the field study was done in the municipalities of Palo and Tanauan in Leyte. Results of these trials proved parasoniline pamoate to be safe and effective, but the course of treatment was long, 52 treatment days spread
over 203 days, and the number of capsules to be taken was numerous (3e4 capsules 3 per day) [26]. Another antimonial, sodium antimony dimethylcysteine tatrate, was introduced later in 1960s. In a preliminary trial, a dose of 400 mg per day for 5 days was administered intramuscularly and resulted in negative stool results for six months in all trial subjects. However, patients suffered from severe adverse reactions. Aside from common drug reactions like anorexia, malaise, vomiting, pain at the site of injection, fine vesicular eruptions, fever and nausea, patients were also hospitalized with signs of myocardial injury. In a further trial wherein patients were given a lower dosage, 48.5% of patients showed myocardial toxicity [24]. In 1979, PZQ was introduced in the country and a preliminary clinical trial on the tolerance and efficacy of the drug was conducted in Palo, Leyte (Table 1). The cure rate among patients given a single dose of 50 mg/kg PZQ was 71% on the sixth month after treatment, which was reduced to 54% one
Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Author
Study type Year of publication
Site
Santos AT et al.
Clinical trial
Palo, Leyte 1975
Nosenas JS et al.
Santos AT
Clinical trial
Clinical trial
1979
1984
1984
Year of study
Q7
No. Baseline No. Treated PZQ dose Enrolled prevalence cases
Leyte
Oriental Mindoro, Sorsogon, Leyte, Davao del Norte Misamis Occidental, Leyte, Davao del Norte Irosin, Sorsogon
42.7
Cohort study
1996
PHDP Report
1997 Case finding and treatment survey
Leyte
1981
Regions 4, 1989 5, 7, 8, 9, 11, 12 and ARMM
5122
25.0e44.0
7.5
Cure rate Egg Proportion Post-treatment Other findings Duration from prevalence reduction with treatment rate adverse to post-treatment events assessment
56
3 20 mg/kg
2 aliquots of each of the 3 stool samples
6 months
84.0
96.5
53.3
30
1 50 mg/kg
2 aliquots of each of the 3 stool samples
6 months
65.5
93.0
70.0
26
3 20 mg/kg
6 months
72.0
89.7
61.5
12
1 50 mg/kg
2 aliquots of each of the 3 stool samples 2 aliquots of each of the 3 stool samples
6 months
83.3
97.1
58.3
75
1 40 mg/kg
6 months
76.5
95.9
52.0
75 74 6751
2 35 mg/kg 3 25 mg/kg 2 30 mg/kg
6 months 6 months 6 months
80.0 80.0 88.5
98.9 99.5 95.4
64.0 35.5 67.9
933
2 20 mg/kg
6 months
91.6
99.0
782
50e60 mg/kg
1 year
667 488 Olveda RM et al.
No. of slides and stool samples
50e60 mg/kg 50 mg/kg in 2 divided doses
2 years 3 years 2 slides per stool; 1 3e4 years stool sample
3 years
Subjects without advanced disease Subjects without advanced disease Subjects with hepatosplenic involvement Subjects with hepatosplenic involvement
16.8 13.7 15.2 4.0e13.0
3.9
Prevalence and incidence did not increase despite deferment of treatment in years 6 and 7 The target of reducing the prevalence to 1% was not attained nor the expected 10% decrease in prevalence per year.
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Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
Table 1 Summary of praziqantel treatment campaigns since 1979 in the Philippines.
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Mass treatment campaign Coutinho HM et al. Cohort study
2007
Caraga
1999
18.0
3 years
3.0
2006
Leyte
2000
982
61.6
477
60 mg/kg
2 slides per sample; 4 weeks 3 stool samples
94.1
Subjects were 7e20 years old; 41.6% had higher egg counts at follow-up on 6th month as compared to the third month indicating a high rate of reinfection Subjects were 7e30 years old Subjects were 7e30 years old; 82.7% were reinfected after 12 months,; 89.3% after 18 months
Kurtis JD et al.
Cohort study
2006
Leyte
2000
1262
60.0
616
60 mg/kg
2 slides per sample; 4 weeks 3 stool samples
83.1
Leenstra T et al.
Cohort study
2006
Leyte
2000
1262
60.0
550
60 mg/kg
2 slides per sample; 4 weeks 3 stool samples
93.2
Olliaro PL et al.
Clinical trial
2011
Agusan del 2005e2006 1848 Sur
32.0
101
40 mg/kg
92.2
90.1
99
60 mg/kg
2 slides per sample; 3 weeks 2 stool samples 2 slides per sample; 3 weeks 2 stool samples
97.0
90.8
Note: Blanks spaces indicate no data was available.
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DOH AO-20070015
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M.T. Inobaya et al. / Microbes and Infection xx (2014) 1e10
year after treatment. PZQ given at a dosage of 3 20 mg/kg resulted in cure rates of 80% and 76% after six and 12 months, respectively. This dosage also resulted in a large decrease in egg counts, with egg reduction rates reported at 96% at six months and 95% at 12 months. Unfortunately, there was a high incidence of adverse reactions to PZQ such as: abdominal discomfort, recurrent diarrhea, fever, drowsiness, syncope, headache, malaise, sweating, and urticarial. It is noteworthy that the same symptoms were noted prior to drug intake in a subset of patients and this may have been a manifestation of Schistosome infection [27] (Fig. 3). Subsequent clinical trials for PZQ were conducted in the Philippines (Table 1). A Phase II trial of different doses of PZQ was conducted in Leyte and resulted in cure rates of 70.7e80.0% and egg reduction rates of >95.0% six months after treatment [28]. In a Phase III trial undertaken in Oriental Mindoro, Sorsogon, Leyte and Davao del Norte, a dosage of 2 30 mg/kg PZQ was used and cure rates were high, ranging from 84.3% to 97.4% [28]. However, episodes of severe adverse reactions in 1.3% of the cases caused concern in using this dosage in selective mass treatments, especially in rural areas where access to medical services was a challenge. Hence, further trials were performed using 2 20 mg/kg PZQ which resulted in a cure rate of 91.6% (range 85.3e92.2%) which was comparable to that obtained using the higher dose of 3 20 mg/kg [28]. A study by the Schistosomiasis Control and Research Services (SCRS) of the Philippines Ministry of Health in 1979 influenced a shift from snail control to morbidity reduction using PZQ [29]. This was done in Irosin, Sorsogon in order to determine the effect of chemotherapy on the transmission of schistosomiasis. Stool examinations were done in two villages and positive cases in one village were treated with 60 mg/kg PZQ divided in two doses and with a single dose of 50 mg/kg PZQ in the other village. Follow-up stool examinations of the general population were conducted annually for three years and all positive cases were treated. This case finding resulted in a significant decrease in prevalence from 42.71% at baseline to 16.79%, 13.73% and 15.17% after one, two and three years of treatment, respectively. The decrease in infection led to subsequent egg output reduction which ultimately lowered snail infection rates. More specifically, infection rates in
Oncomelania hupensis quadrasae snails dropped from 5.54% at baseline to 0.97% in year two and to 0.21% in year three. Infection in sentinel snails also decreased from 2.67% to 0.20% after two years of treatment. Morbidity involving liver (95.7%), spleen (12.9%) and liver-spleen (12.9%) also significantly changed over the course of treatments to 69.8%, 7.8% and 7.8%, respectively. In sum, the repeated selective mass treatment had a significant impact on the disease prevalence, morbidity and transmission [30]. Additional studies were carried out to assess the impact of case finding and treatment with PZQ on S. japonicum prevalence, intensity of infection and associated morbidity. A combination of case finding and treatment with environmental sanitation, health education and mollusciciding was also conducted [23]. A study on the long-term impact of case finding and treatment with PZQ on the prevalence, intensity and morbidity of S. japonicum infection was carried out from 1981 to 1989. Annual screening and treatment of positive cases with praziquantel were performed in three rural villages in Leyte with low, moderate and high prevalence of infection. Compliance rates for both case finding and treatment were >85%. Although the prevalence and incidence of infection in the study areas dropped dramatically after 3 years of intensive case finding and treatment, the levels of infection remained at around 50% compared with the baseline for the rest of the study period suggesting that community-based chemotherapy alone with PZQ was unable to eliminate schistosomiasis in the Philippines. The authors also concluded that relaxation in the chemotherapy-based approach would result in rebound of prevalence, intensity and morbidity of S. japonicum infection [31]. In 1990, under the Philippine Health Development Plan, the Philippine National Schistosomiasis Control Program received a loan from the World Bank that allowed the authorities to increase the target to 95% case finding and 100% treatment. This move resulted in a decrease in the prevalence from greater than 10% before the implementation of the program to less than 5% in 1995 [32]. The subsequent decrease in funding that followed resulted in inadequate manpower to sustain active case finding and treatment. The Department of Health (DOH) modified the strategy in 1996 from case finding to mass drug administration (MDA). In all endemic areas, school
Fig. 3. Delivering ‘preventive chemotherapy’ on foot to a remote endemic village in Northern Samar, The Philippines. Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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children were tested, and the prevalence rates used to determine intervention. If the prevalence rate was less than 10%, passive case finding and treatment of positive cases would be implemented in the area whereas with prevalence rates of 10% and higher, mass treatment of all those 6 years and older was indicated [33]. Floods in the schistosome-endemic region of Caragain the latter part of the 1990s brought about the concern that there may be an increase in the number of cases of schistosomiasis. Hence, an administrative order (AO) was issued by the DOH to implement mass treatment among the population of individuals 5 years and older in the region for three consecutive years [34]. The mass treatment successfully reduced the prevalence from 18% to 3%. Hence, this strategy was implemented for all endemic areas nationwide through the issuance of AO 55 s. 2000 [35]. This was ordered by DOH in order to attain the target of disease elimination or a disease prevalence of less than 1% [36]. After the issuance of AO 55 s. 2000, a PZQ treatment study was undertaken in Leyte in 2002e2003 whereby Coutinho and colleagues [37] enrolled children and adolescent participants from three rural villages to assess the magnitude of improvement in nutritional status after treatment with a split dose of 60 mg/kg. The split dose treatment resulted in a 94.1% cure rate and a significant improvement in nutritional status. The negative effect of reinfection on hemoglobin level improvement and reduction in absolute growth due to high intensity of infection at 18 month followup indicated the need for annual treatment to prevent nutritional morbidities [37]. Another study was performed in the same region involving individuals aged 7e30 years [38]. This study aimed to evaluate the impact of host pubertal development on the prevalence and intensity of infection of S. japonicum in a crosssectional sample and the intensity of reinfection following PZQ treatment. The cure rate observed at four weeks posttreatment was 83.1%, while an additional 9.4% and 0.97% were negative on stool examination after three and six months, respectively. Leenstra et al. [39] assessed the effect of reinfection after PZQ treatment on hemoglobin levels, and the occurrence of iron deficiency anemia and non-iron deficiency anemia among residents of three villages. PZQ treatment resulted in a cure rate of 93.2%, but a remarkable 89.3% were reinfected 18 months post-treatment. The median time from treatment to reinfection was 13.5 months [39]. A further study on 7e19 year olds in Leyte revealed that control of schistosome infection using PZQ and simultaneous deworming against soil-transmitted helminths had a significant impact on cognitive performance [40]. In 2007, DOH released revised guidelines for the management and prevention of schistosomiasis whereby mass treatment would only be implemented in endemic areas where prevalence exceeded 10%. Without stool examination, all residents aged 5e65 years would be given a single dose of 40 mg/kg PZQ. For selective mass treatment or treatment of cases seen during active or passive surveillance, cases would be identified by stool examination. Confirmed cases would be
7
treated with PZQ at a dosage of 60 mg/kg given at two divided doses 4e6 h apart. A repeat of treatment would be done 2e3 weeks after the first to ensure that all the worms had been killed by the PZQ [35]. Aside from the goal of eliminating schistosomiasis as a public health problem as stated in the National Objectives for Health Year 2005e2010, the DOH has also recognized the need to protect the exposed population from the consequent development of chronic infection by providing them with ‘preventive chemotherapy’. Through issuance AO 2009-0013, the DOH declared the month of July as mass treatment and awareness month for schistosomiasis. Mass treatment of the population aged 5e65 years old is conducted in 24 endemic provinces, targeting at least 85% coverage for at least three years or until elimination (prevalence
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MODEL
Microbes and Infection xx (2014) 1e10 www.elsevier.com/locate/micinf
Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications Q8
Marianette T. Inobaya a,b, Remigio M. Olveda b, Veronica Tallo b, Donald P. McManus c, Gail M. Williams d, Donald A. Harn e, Yuesheng Li c, Thao N.P. Chau e,f, David U. Olveda a, Allen G. Ross a,* a
b
Griffith Health Institute, Griffith University, Gold Coast Campus, Australia Research Institute for Tropical Medicine, Department of Health, The Philippines c QIMR Berghofer Medical Research Institute, Australia d School of Population Health, University of Queensland, Australia e Department of Infectious Diseases, College of Veterinary Medicine and Center for Tropical and Emerging Global Diseases, University of Georgia, USA f Discipline of Public Health, Flinders University, Australia Received 23 July 2014; accepted 17 October 2014
Abstract Schistosomiasis was first reported in the Philippines in 1906. A variety of treatments have been deployed to cure infection and to control the disease in the long-term. We discuss the journey to combat the disease in the Philippines and the lessons learnt which have implications for schistosomiasis control globally. © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
Keywords: Schistosomiasis; Treatment; Mass drug administration; Control
Q1
1. Introduction Schistosomiasis is an intravascular disease caused by trematode worms of the genus Schistosoma. As of 2011, the disease was endemic in 78 countries [1]. The World Health Organization (WHO) estimated in 2012 that 249 million people are at risk of infection and in need of preventive chemotherapy [2]. The burden of schistosomiasis caused by Schistosoma haematobium, Schistosoma japonicum and Schistosoma mansoni was estimated at 24e29 million disability adjusted life years [3]. Considerable optimism surrounds Mass Drug Administration (MDA) for the control of schistosomiasis globally, for * Corresponding author. E-mail address: [email protected] (A.G. Ross).
which praziquantel (PZQ) has served as the cornerstone since its inception in 1979. Numerous studies have claimed that preventive chemotherapy (i.e. 40 mg/kg of praziquantel), given annually or biannually, can significantly reduce the prevalence and intensity of infection, and control morbidity in the long-term [4e13]. In the last decade, close to one billion US dollars has been raised for MDA campaigns for neglected tropical diseases largely from international donors and delivered vertically to local endemic communities through national health care services largely using unpaid volunteers [5,14]. Praziquantel (PZQ), a pyrazinoisoquinoline derivative (Fig. 1), is a safe and highly effective oral drug that is active against all schistosome species. PZQ is the mainstay of treatment and a critical part of community-based schistosomiasis control programs globally, including those in the Philippines [15e17]. Since its discovery in the mid-1970s, its
http://dx.doi.org/10.1016/j.micinf.2014.10.006 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved. Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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M.T. Inobaya et al. / Microbes and Infection xx (2014) 1e10
Fig. 1. The chemical structure of the drug praziquantel (Biltricide) used for the mass drug administration of schistosomiasis globally.
safety and efficacy have ensured its widespread use. It is absorbed well but undergoes extensive first-pass hepatic clearance [15]. PZQ is secreted in breast milk and is metabolized by the liver, and its (inactive) metabolites are excreted in the urine [15]. Side effects of PZQ treatment are minimal, and PZQ can be used to treat young children and pregnant women [16]. PZQ acts within one hour of ingestion, although its precise action on adult worms is unknown. It appears to cause tetanic contractions and tegumental vacuoles, causing worms to detach from the wall of the vein and die [15]. Schistosome calcium ion channels have been suggested as the molecular target of PZQ, but the evidence remains indirect and a recent study implicated myosin light chain as an alternative target of PZQ [17]. Standard treatment of chronic schistosomiasis is 60 mg/kg of PZQ in divided doses; for mass chemotherapy a single dose of 40 mg/kg is used [16]. There is also some evidence, albeit very controversial, that resistance to PZQ may be emerging in Africa, where there has been heavy exposure to PZQ and there are reports of S. mansoni and S. haematobium infections that are not responsive [17]. There have been no reports of the development of resistance of S. japonicum to PZQ in the clinical treatment of patients in the Philippines [17]. Periodic treatment of bovines (water buffalos [called Carabao in the Philippines], cattle) with PZQ, managed by local veterinarians, is now being considered for control programs for S. japonicum in the Philippines. This is because they are large animals (water buffaloes often exceed 300 kg in weight), they deposit considerable amounts of excreta near or in surface water, live for 10e12 years, and can carry large parasite burdens and develop hepato-intestinal disease. In China bovines have been successfully treated and in some localities have been removed to halt transmission. In agricultural areas in the Philippines, where S. japonicum is endemic, 10e80% of bovines are infected [18]. PZQ is curative, but the animals become reinfected. In most areas of endemicity, a large proportion (70%) of the environmental contamination may be traced back to bovine defecation and a high proportion of schistosome eggs [17]. The treatment doses (25 mg/kg for water buffaloes and 30 mg/kg for cattle) are lower than that used for humans because the collateral effects may be fatal, which is thought to result from portal occlusion by dead worms in heavily infected animals, as noted in other forms of
cattle schistosomiasis [17]. Older buffaloes tend to excrete fewer viable eggs than those less than 18 months old; this could reflect self-cure, decreased egg viability, or decreased egg production by female worms, and all have been described for other forms of bovine schistosomiasis [17]. 2. History of MDA for schistosomiasis control in the Philippines Schistosomiasis (Schistosoma japonicum) was first reported in the Philippines in 1906. Approximately 12 million people living in 28 endemic provinces located in 12 different regions of the country are at risk of infection (Fig. 2) [19,20]. Overall, a total of 190 municipalities and 20 cities are affected by the infection. Villages in Gonzaga, Cagayan province and municipality of Calatrava in Negros Occidental (northern and central parts of the Philippines, respectively) were the most recently identified endemic foci, confirmed in 2004 and 2006, respectively [21]. Control of schistosomiasis in the Philippines was initially focused on snail control due to the lack of an effective, nontoxic and economical drug that could be used for mass treatment [19,22]. Use of antimonials, Fuadin and tartar emeric, for treatment of schistosomiasis was introduced in the country during the outbreak of the disease among United States (US) and allied forces in 1944 in the island of Leyte. The efficacy of the drugs was low as 31% of the cases remained stool-positive when the soldiers were tested back in US hospitals [23]. After the liberation of the Philippines, Stibophen, a trivalent antimonial preparation, was introduced in a trial with a course of nine intramuscular injections that resulted to a cure rate of 78.2% [24]. Following the trial, the Schistosomiasis Control Pilot Project (SCPP) used it as part of the support strategy for agro-engineering methods of snail control together with environmental sanitation and health education. SCPP was implemented in Palo, Leyte in collaboration with WHO starting in 1953 [19]. After three years of implementation, the snail population was almost eradicated and the human prevalence of infection was reduced from 38.9% to 32.0% [25]. These strategies were tried in the towns of Mayorga, La Paz and Burauen in Leyte before being formally implemented nationwide under the National Schistosomiasis Control Program in 1961 [19]. Further trials were conducted with an
Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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3
Fig. 2. Map of the current endemic areas in the Philippines highlighted in blue. The red dot represents a new focus of infection Luzon.
increased dosage of 10 and 15 injections that resulted in cure rates of 61.2% and 86.7%, respectively, after one month. But the proportion of cured patients dropped to 38.3% among those given 10 injections and 48.6% in patients with 15 doses six months after treatment. Almost half of those who participated in the trial dropped out due to pain at the site of injection or to drug reactions. Reactions to the drug, such as dizziness, vomiting, body weakness, nausea, anorexia, and joint and muscular pains, were observed in 83.9% of the patients [24]. In middle of the 1960s use of another anti-schistosome drug, parasoniline pamoate, a complex azo dye from gentian violet which comes in oral preparation as gelatine capsules, was started in the Philippines. A clinical trial on this drug was conducted in San Lazaro Hospital and the Bureau of Research Laboratories in Manila, while the field study was done in the municipalities of Palo and Tanauan in Leyte. Results of these trials proved parasoniline pamoate to be safe and effective, but the course of treatment was long, 52 treatment days spread
over 203 days, and the number of capsules to be taken was numerous (3e4 capsules 3 per day) [26]. Another antimonial, sodium antimony dimethylcysteine tatrate, was introduced later in 1960s. In a preliminary trial, a dose of 400 mg per day for 5 days was administered intramuscularly and resulted in negative stool results for six months in all trial subjects. However, patients suffered from severe adverse reactions. Aside from common drug reactions like anorexia, malaise, vomiting, pain at the site of injection, fine vesicular eruptions, fever and nausea, patients were also hospitalized with signs of myocardial injury. In a further trial wherein patients were given a lower dosage, 48.5% of patients showed myocardial toxicity [24]. In 1979, PZQ was introduced in the country and a preliminary clinical trial on the tolerance and efficacy of the drug was conducted in Palo, Leyte (Table 1). The cure rate among patients given a single dose of 50 mg/kg PZQ was 71% on the sixth month after treatment, which was reduced to 54% one
Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Author
Study type Year of publication
Site
Santos AT et al.
Clinical trial
Palo, Leyte 1975
Nosenas JS et al.
Santos AT
Clinical trial
Clinical trial
1979
1984
1984
Year of study
Q7
No. Baseline No. Treated PZQ dose Enrolled prevalence cases
Leyte
Oriental Mindoro, Sorsogon, Leyte, Davao del Norte Misamis Occidental, Leyte, Davao del Norte Irosin, Sorsogon
42.7
Cohort study
1996
PHDP Report
1997 Case finding and treatment survey
Leyte
1981
Regions 4, 1989 5, 7, 8, 9, 11, 12 and ARMM
5122
25.0e44.0
7.5
Cure rate Egg Proportion Post-treatment Other findings Duration from prevalence reduction with treatment rate adverse to post-treatment events assessment
56
3 20 mg/kg
2 aliquots of each of the 3 stool samples
6 months
84.0
96.5
53.3
30
1 50 mg/kg
2 aliquots of each of the 3 stool samples
6 months
65.5
93.0
70.0
26
3 20 mg/kg
6 months
72.0
89.7
61.5
12
1 50 mg/kg
2 aliquots of each of the 3 stool samples 2 aliquots of each of the 3 stool samples
6 months
83.3
97.1
58.3
75
1 40 mg/kg
6 months
76.5
95.9
52.0
75 74 6751
2 35 mg/kg 3 25 mg/kg 2 30 mg/kg
6 months 6 months 6 months
80.0 80.0 88.5
98.9 99.5 95.4
64.0 35.5 67.9
933
2 20 mg/kg
6 months
91.6
99.0
782
50e60 mg/kg
1 year
667 488 Olveda RM et al.
No. of slides and stool samples
50e60 mg/kg 50 mg/kg in 2 divided doses
2 years 3 years 2 slides per stool; 1 3e4 years stool sample
3 years
Subjects without advanced disease Subjects without advanced disease Subjects with hepatosplenic involvement Subjects with hepatosplenic involvement
16.8 13.7 15.2 4.0e13.0
3.9
Prevalence and incidence did not increase despite deferment of treatment in years 6 and 7 The target of reducing the prevalence to 1% was not attained nor the expected 10% decrease in prevalence per year.
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Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
Table 1 Summary of praziqantel treatment campaigns since 1979 in the Philippines.
66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Mass treatment campaign Coutinho HM et al. Cohort study
2007
Caraga
1999
18.0
3 years
3.0
2006
Leyte
2000
982
61.6
477
60 mg/kg
2 slides per sample; 4 weeks 3 stool samples
94.1
Subjects were 7e20 years old; 41.6% had higher egg counts at follow-up on 6th month as compared to the third month indicating a high rate of reinfection Subjects were 7e30 years old Subjects were 7e30 years old; 82.7% were reinfected after 12 months,; 89.3% after 18 months
Kurtis JD et al.
Cohort study
2006
Leyte
2000
1262
60.0
616
60 mg/kg
2 slides per sample; 4 weeks 3 stool samples
83.1
Leenstra T et al.
Cohort study
2006
Leyte
2000
1262
60.0
550
60 mg/kg
2 slides per sample; 4 weeks 3 stool samples
93.2
Olliaro PL et al.
Clinical trial
2011
Agusan del 2005e2006 1848 Sur
32.0
101
40 mg/kg
92.2
90.1
99
60 mg/kg
2 slides per sample; 3 weeks 2 stool samples 2 slides per sample; 3 weeks 2 stool samples
97.0
90.8
Note: Blanks spaces indicate no data was available.
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DOH AO-20070015
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M.T. Inobaya et al. / Microbes and Infection xx (2014) 1e10
year after treatment. PZQ given at a dosage of 3 20 mg/kg resulted in cure rates of 80% and 76% after six and 12 months, respectively. This dosage also resulted in a large decrease in egg counts, with egg reduction rates reported at 96% at six months and 95% at 12 months. Unfortunately, there was a high incidence of adverse reactions to PZQ such as: abdominal discomfort, recurrent diarrhea, fever, drowsiness, syncope, headache, malaise, sweating, and urticarial. It is noteworthy that the same symptoms were noted prior to drug intake in a subset of patients and this may have been a manifestation of Schistosome infection [27] (Fig. 3). Subsequent clinical trials for PZQ were conducted in the Philippines (Table 1). A Phase II trial of different doses of PZQ was conducted in Leyte and resulted in cure rates of 70.7e80.0% and egg reduction rates of >95.0% six months after treatment [28]. In a Phase III trial undertaken in Oriental Mindoro, Sorsogon, Leyte and Davao del Norte, a dosage of 2 30 mg/kg PZQ was used and cure rates were high, ranging from 84.3% to 97.4% [28]. However, episodes of severe adverse reactions in 1.3% of the cases caused concern in using this dosage in selective mass treatments, especially in rural areas where access to medical services was a challenge. Hence, further trials were performed using 2 20 mg/kg PZQ which resulted in a cure rate of 91.6% (range 85.3e92.2%) which was comparable to that obtained using the higher dose of 3 20 mg/kg [28]. A study by the Schistosomiasis Control and Research Services (SCRS) of the Philippines Ministry of Health in 1979 influenced a shift from snail control to morbidity reduction using PZQ [29]. This was done in Irosin, Sorsogon in order to determine the effect of chemotherapy on the transmission of schistosomiasis. Stool examinations were done in two villages and positive cases in one village were treated with 60 mg/kg PZQ divided in two doses and with a single dose of 50 mg/kg PZQ in the other village. Follow-up stool examinations of the general population were conducted annually for three years and all positive cases were treated. This case finding resulted in a significant decrease in prevalence from 42.71% at baseline to 16.79%, 13.73% and 15.17% after one, two and three years of treatment, respectively. The decrease in infection led to subsequent egg output reduction which ultimately lowered snail infection rates. More specifically, infection rates in
Oncomelania hupensis quadrasae snails dropped from 5.54% at baseline to 0.97% in year two and to 0.21% in year three. Infection in sentinel snails also decreased from 2.67% to 0.20% after two years of treatment. Morbidity involving liver (95.7%), spleen (12.9%) and liver-spleen (12.9%) also significantly changed over the course of treatments to 69.8%, 7.8% and 7.8%, respectively. In sum, the repeated selective mass treatment had a significant impact on the disease prevalence, morbidity and transmission [30]. Additional studies were carried out to assess the impact of case finding and treatment with PZQ on S. japonicum prevalence, intensity of infection and associated morbidity. A combination of case finding and treatment with environmental sanitation, health education and mollusciciding was also conducted [23]. A study on the long-term impact of case finding and treatment with PZQ on the prevalence, intensity and morbidity of S. japonicum infection was carried out from 1981 to 1989. Annual screening and treatment of positive cases with praziquantel were performed in three rural villages in Leyte with low, moderate and high prevalence of infection. Compliance rates for both case finding and treatment were >85%. Although the prevalence and incidence of infection in the study areas dropped dramatically after 3 years of intensive case finding and treatment, the levels of infection remained at around 50% compared with the baseline for the rest of the study period suggesting that community-based chemotherapy alone with PZQ was unable to eliminate schistosomiasis in the Philippines. The authors also concluded that relaxation in the chemotherapy-based approach would result in rebound of prevalence, intensity and morbidity of S. japonicum infection [31]. In 1990, under the Philippine Health Development Plan, the Philippine National Schistosomiasis Control Program received a loan from the World Bank that allowed the authorities to increase the target to 95% case finding and 100% treatment. This move resulted in a decrease in the prevalence from greater than 10% before the implementation of the program to less than 5% in 1995 [32]. The subsequent decrease in funding that followed resulted in inadequate manpower to sustain active case finding and treatment. The Department of Health (DOH) modified the strategy in 1996 from case finding to mass drug administration (MDA). In all endemic areas, school
Fig. 3. Delivering ‘preventive chemotherapy’ on foot to a remote endemic village in Northern Samar, The Philippines. Please cite this article in press as: Inobaya MT, et al., Schistosomiasis mass drug administration in the Philippines: Lessons learnt and the global implications, Microbes and Infection (2014), http://dx.doi.org/10.1016/j.micinf.2014.10.006
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children were tested, and the prevalence rates used to determine intervention. If the prevalence rate was less than 10%, passive case finding and treatment of positive cases would be implemented in the area whereas with prevalence rates of 10% and higher, mass treatment of all those 6 years and older was indicated [33]. Floods in the schistosome-endemic region of Caragain the latter part of the 1990s brought about the concern that there may be an increase in the number of cases of schistosomiasis. Hence, an administrative order (AO) was issued by the DOH to implement mass treatment among the population of individuals 5 years and older in the region for three consecutive years [34]. The mass treatment successfully reduced the prevalence from 18% to 3%. Hence, this strategy was implemented for all endemic areas nationwide through the issuance of AO 55 s. 2000 [35]. This was ordered by DOH in order to attain the target of disease elimination or a disease prevalence of less than 1% [36]. After the issuance of AO 55 s. 2000, a PZQ treatment study was undertaken in Leyte in 2002e2003 whereby Coutinho and colleagues [37] enrolled children and adolescent participants from three rural villages to assess the magnitude of improvement in nutritional status after treatment with a split dose of 60 mg/kg. The split dose treatment resulted in a 94.1% cure rate and a significant improvement in nutritional status. The negative effect of reinfection on hemoglobin level improvement and reduction in absolute growth due to high intensity of infection at 18 month followup indicated the need for annual treatment to prevent nutritional morbidities [37]. Another study was performed in the same region involving individuals aged 7e30 years [38]. This study aimed to evaluate the impact of host pubertal development on the prevalence and intensity of infection of S. japonicum in a crosssectional sample and the intensity of reinfection following PZQ treatment. The cure rate observed at four weeks posttreatment was 83.1%, while an additional 9.4% and 0.97% were negative on stool examination after three and six months, respectively. Leenstra et al. [39] assessed the effect of reinfection after PZQ treatment on hemoglobin levels, and the occurrence of iron deficiency anemia and non-iron deficiency anemia among residents of three villages. PZQ treatment resulted in a cure rate of 93.2%, but a remarkable 89.3% were reinfected 18 months post-treatment. The median time from treatment to reinfection was 13.5 months [39]. A further study on 7e19 year olds in Leyte revealed that control of schistosome infection using PZQ and simultaneous deworming against soil-transmitted helminths had a significant impact on cognitive performance [40]. In 2007, DOH released revised guidelines for the management and prevention of schistosomiasis whereby mass treatment would only be implemented in endemic areas where prevalence exceeded 10%. Without stool examination, all residents aged 5e65 years would be given a single dose of 40 mg/kg PZQ. For selective mass treatment or treatment of cases seen during active or passive surveillance, cases would be identified by stool examination. Confirmed cases would be
7
treated with PZQ at a dosage of 60 mg/kg given at two divided doses 4e6 h apart. A repeat of treatment would be done 2e3 weeks after the first to ensure that all the worms had been killed by the PZQ [35]. Aside from the goal of eliminating schistosomiasis as a public health problem as stated in the National Objectives for Health Year 2005e2010, the DOH has also recognized the need to protect the exposed population from the consequent development of chronic infection by providing them with ‘preventive chemotherapy’. Through issuance AO 2009-0013, the DOH declared the month of July as mass treatment and awareness month for schistosomiasis. Mass treatment of the population aged 5e65 years old is conducted in 24 endemic provinces, targeting at least 85% coverage for at least three years or until elimination (prevalence
