- Record: found
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How Effective Is School-Based Deworming for the Community-Wide Control of Soil-Transmitted Helminths?
research-article
Author(s):
Roy M. Anderson
1
,
* ,
James E. Truscott
2 ,
Rachel L. Pullan
3 ,
Simon J. Brooker
3
,
4 ,
T. Deirdre Hollingsworth
5
,
*
Publication date (Electronic):
28 February 2013
Journal:
PLoS Neglected Tropical Diseases
Publisher:
Public Library of Science
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Abstract
Background
The London Declaration on neglected tropical diseases was based in part on a new World Health Organization roadmap to “sustain, expand and extend drug access programmes to ensure the necessary supply of drugs and other interventions to help control by 2020”. Large drug donations from the pharmaceutical industry form the backbone to this aim, especially for soil-transmitted helminths (STHs) raising the question of how best to use these resources. Deworming for STHs is often targeted at school children because they are at greatest risk of morbidity and because it is remarkably cost-effective. However, the impact of school-based deworming on transmission in the wider community remains unclear.
Methods
We first estimate the proportion of parasites targeted by school-based deworming using demography, school enrolment, and data from a small number of example settings where age-specific intensity of infection (either worms or eggs) has been measured for all ages. We also use transmission models to investigate the potential impact of this coverage on transmission for different mixing scenarios.
Principal Findings
In the example settings <30% of the population are 5 to <15 years old. Combining this demography with the infection age-intensity profile we estimate that in one setting school children output as little as 15% of hookworm eggs, whereas in another setting they harbour up to 50% of Ascaris lumbricoides worms (the highest proportion of parasites for our examples). In addition, it is estimated that from 40–70% of these children are enrolled at school.
Conclusions
These estimates suggest that, whilst school-based programmes have many important benefits, the proportion of infective stages targeted by school-based deworming may be limited, particularly where hookworm predominates. We discuss the consequences for transmission for a range of scenarios, including when infective stages deposited by children are more likely to contribute to transmission than those from adults.
Author Summary
Large donations of drugs to treat soil-transmitted helminths (STHs, intestinal worms) means that many more school-aged children will be treated, improving their well-being and development. These children will have to be repeatedly treated since reinfection will occur due to contaminated environments in the absence of improvements in hygiene and sanitation. Repeated treatment of school-aged children may have the added benefit of reductions in levels of infection for the whole community. This will in part be determined by the proportion of the total worms harboured or eggs output by school-aged children, a product of how heavily infected school-aged children are and how many school-aged children there are in the community. In one setting school-aged children output as little as 15% of hookworm eggs whereas in another setting they harbour up to 50% of roundworms. Thus, whilst school-based programmes may have important health benefits, the community-level impact on transmission could be limited unless school-aged children over-contribute to infection. We use mathematical models to show that if children contribute more infective stages to the environment which adults are exposed to than adults do, the reductions in transmission resulting from treating children will be larger, but may still be limited.
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Most cited references40
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The Global Programme to Eliminate Lymphatic Filariasis: Health Impact after 8 Years
Eric A. Ottesen, Pamela Hooper, Mark Bradley … (2008)
Introduction In 1997, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was created in response to a specific resolution by the World Health Assembly [1]. At that time the World health Organization (WHO), having recently devised a strategy aimed at achieving LF elimination through ‘mass drug administration’ (MDA) [2], received extraordinary pledges from two pharmaceutical companies (GlaxoSmithKline and Merck & Co., Inc.) for long-term drug donations of unprecedented size to jumpstart this nascent program. The impressive programmatic progress made by the GPELF has been documented in a number of valuable reviews and updates [1], [3]–[7]; however, what is most needed now – for donors who are supporting this effort, for the Ministries of Health and health workers who are laboring on its behalf and for endemic communities who continue to invest their energies and resources towards its success – is to understand not just the technical achievements, but especially what difference it all has made to the health and welfare of the at-risk populations. What impact has 10 years of focus on LF – long recognized as one of the most debilitating and economically-draining of the neglected tropical diseases – really had? To answer this question requires not just a tabulation of the GPELF's programmatic achievements in providing necessary drugs to the targeted at-risk populations, but also, importantly, a projection of the public health gain from this effort, using estimates based on the most accurate data and most reasonable assumptions available. Methods Data sources Specific sources for the data are identified as they are presented; in general, however: Numbers related to LF endemicity, populations at-risk (Table 1) and treatments delivered were derived from publications by WHO in the Weekly Epidemiological Record (WER) and WHO Annual Reports between 2000 and 2008 [4]–[10]; this information is also recorded at www.who.int/lymphatic_filariasis. Information on the quantities of albendazole, ivermectin (Mectizan) and diethylcarbamazine (DEC) used in the GPELF came from these same WER reports [4]–[7], from WHO's Annual Reports (available at www.who.int/lymphatic_filariasis) and from records of GlaxoSmithKline and the Mectizan Donation Program. Population demographic figures used to calculate age or gender subpopulations of the total at-risk populations were taken from the Population Reference Bureau [11] and the World Bank Health, Nutrition and Population Statistics [12]. Disability weights and formulas for calculating Disability Adjusted Life Years (DALYs) were derived from the Global Burden of Disease [13]. Information on the clinical profiles and the effectiveness of treatment for both LF and soil transmitted helminth (STH) infections has been taken from scientific publications [3], [14]–[16]. Estimates of the epidemiology of STH infections (number and distribution of affected individuals worldwide) came from published information [17]. 10.1371/journal.pntd.0000317.t001 Table 1 Population at Risk [5] Region # of Endemic Countries At-Risk Population (millions) Children at Risk (millions) Africa (AFRO) 39 394 176 Americas (AMRO) 7 8.87 3.39 Eastern Mediterranean (EMRO) 3 14.9 6.50 South-east Asia (SEARO) 9 851 297 Western Pacific (WPRO) 25 31.6 11.1 TOTAL: 83 1,300 494 Impact Projections The assumptions made and the rationale behind the projections are outlined below and summarized in Tables 2 and 3. 10.1371/journal.pntd.0000317.t002 Table 2 Projected Health Impact – LF Related. Impact #1 Individuals Protected Disease Prevented DALYs Averted 6.6 million newborns 1.4 million cases of hydrocele 3.2 million DALYs 800,000 cases of lymphedema 2.8 million DALYs 4.4 million cases of subclinical disease ? Assumptions and Reasoning 1) 66 million babies born into at-risk areas under MDA 2000–2007 (discounted for infant mortality) [11] 2) LF infections occur in 10% of at-risk population [3] 3) 12.5% of LF infections result in lymphedema, 20.8% in hydrocele, 66.7% in subclinical damage [3] 4) Disability weights (based on Global Burden of Disease methods): 0.105 for lymphedema, 0.073 for hydrocele; onset at age 20; life span is Region-specific 5) LF transmission (estimated by mosquito infection rates) falls progressively to 50%, 25%, 12%, 6%, and 0% pre-MDA levels after each of the first 5 MDAs, respectively Impact #2 Individuals Protected Disease Prevented DALYs Averted 9.5 million people 6.0 million cases of hydrocele 14 million DALYs 3.5 million cases of lymphedema 12 million DALYs Assumptions and Reasoning 1) 570 million individuals (at minimum) treated under MDAs 2000–2007. The maximal number of individuals treated in any single MDA was determined for each country. The sum of these numbers indicates the minimum total number of individuals treated. 2) LF infections occur in 10% of at-risk (i.e., treated) population [3] (here 57 million) with 1/3 having clinical manifestations and 2/3 having subclinical disease [3] (here 38 million) 3) To maintain this 1/3∶2/3 ratio 50% of those with subclinical disease must progress to overt disease (62.5% manifesting hydrocele [11.9 million] and 37.5%, lymphedema [7.1 million]) [3] 4) If treatment halts progression in only 50% of the subclinical cases (a conservative estimate [19]), 9.5 million people would have been protected from developing overt disease (6 million hydrocele; 3.5 million lymphedema) 5) Disability weights**: 0.105 for lymphedema, 0.073 for hydrocele; onset at age 20; life span, Region-specific 6) Treated individuals will not become re-infected in context of diminished LF transmission in MDA-covered areas 10.1371/journal.pntd.0000317.t003 Table 3 Projected Health Impact – Beyond LF. Impact #3 Individuals Reached Target Health Benefits 56.6 million children -minimal estimate- Soil-transmitted helminthes (intestinal parasites: hookworm, roundworm, whipworm) Weight/height gain, learning ability, cognitive testing, school attendance, fitness, activity [14], [26]–[28] Assumptions and Reasoning 1) 172 million treatments of albendazole given to children (age 2–15 in countries treated with DEC+albendazole; 5–15 in countries using ivermectin+albendazole) in 48 countries during MDAs 2000–2007 [4]–[7]. 2) The maximal number of children treated in any single MDA was determined for each country. The sum of these numbers indicates the minimum total number of children treated (56.6 million) [4]–[7]. 3) Uncertainty of STH prevalence estimates limits the specific quantification of health benefits despite their description in published studies [14], [26]–[28]. Impact #4 Individuals Reached Target Health Benefits 44.5 million women of childbearing age (not pregnant) -minimal estimate- Soil-transmitted helminthes (intestinal parasites: hookworm, roundworm, whipworm) Decreased anemia [16], maternal mortality, infant mortality; increased infant birth-weight [29] Assumptions and Reasoning 1) 140 million treatments of albendazole given to non-pregnant women-of-childbearing-age (15–49 years old) in 48 countries during MDAs 2000–2007 [4]–[7],[12]. 2) The maximal number of such women treated in any single MDA was determined for each country [4]–[7]. The sum of these numbers indicates the minimum total number of women-of-childbearing-age treated (44.5 million). 3) Uncertainty of STH prevalence estimates limits the specific quantification of health benefits despite their description in published studies [16],[27],[30]. Impact #5 Individuals Reached Target Health Benefits 45 million people in Africa -minimal estimate- Onchocerciasis, scabies, lice Decreased physical, mental discomfort (severe itching) [32]; prevention of renal complications of streptococcal superinfections [35] Assumptions and Reasoning 1) 149 million treatments of ivermectin given to communities in 12 African countries during MDAs 2000–2007 [4]–[7]. 2) The maximal number of individuals treated in any single MDA was determined for each country. The sum of these numbers indicates the minimum total number of individuals treated (45 million) [4]–[7]. 3) Uncertainty of prevalence estimates for each of these conditions limits the specific calculation of health benefits despite the descriptions reported in published studies [32]–[34]. Impact estimates: LF-related Babies protected from infection. To estimate the number of babies born into LF treatment areas between 2000 and 2007, demographic data from each country (births per 1,000 population discounted by infant mortality rates [18] were applied to those populations living in areas targeted for LF treatments. Since LF transmission might not stop immediately after MDAs begin, changes observed in mosquito infection rates post MDA were used to estimate changes in LF transmission as progressively decreasing to 50%, 25%, 12%, 6%, and 0% of pre-MDA levels after each of the first 5 MDAs. These multipliers were used on a country-by-country and MDA-by-MDA basis to discount the number of surviving babies born into MDA areas, thereby allowing an estimate of the number of newborns protected from potential LF infection (66 million). Since LF infections are estimated to occur in approximately 10% of the at-risk population [3], 6.6 million newborn babies are therefore considered protected from contracting LF. Cases of morbidity prevented in newborns. Globally, 12.5% of LF infections are estimated to result in lymphedema, 20.8% in hydrocele and the remainder, 66.7%, in subclinical disease [3]. Cases of disease averted (hydrocele, lymphedema and subclinical) were calculated by multiplying these proportions by the number of LF infections averted in babies. DALYs averted in newborns. The number of DALYs averted in newborns was calculated using methods outlined in Global Burden of Disease, utilizing disability weights, the number of cases of clinical disease averted (hydrocele and lymphedema), an estimated onset of disease at age 20 and region-specific life spans [13]. Since disability weights are not available for subclinical LF disease, DALYs associated with this manifestation were not estimated. For all of the calculations associated with the prevention of LF disease, it was assumed, based on available information, that treated individuals will not become re-infected in the context of diminished LF transmission in MDA-covered areas. Infected individuals protected from progression of subclinical disease to clinical disease. For each country the number of individuals treated in each MDA is known, but since it is not known how many unique individuals have received treatment in a program with multiple MDAs, the conservative approach to identifying this number of unique individuals treated in any one country is to identify the maximal numbers of individuals treated in any single MDA for each country. These numbers were then summed for all countries and used as the minimum total number of individuals already treated (570 million). Since LF infections are estimated to occur in approximately 10% of the at-risk population [3], 57 million would be expected to be infected with LF. Approximately two-thirds of infected individuals have subclinical disease [3] (38 million), with 50% of those expected to progress to overt disease (19 million). Approximately 62.5% of individuals with overt disease manifest hydrocele (11.9 million) and 37.5% manifest lymphedema (7.1 million). If it is assumed that treatment halts disease progression in only 50% of subclinical cases (a conservative estimate [19]), 9.5 million people would have been protected from developing overt disease (i.e., 6 million cases of hydrocele and 3.5 million cases of lymphedema averted). DALYs averted through halting progression of disease. The number of DALYs averted through progression of disease was calculated using methods outlined in Global Burden of Disease, utilizing disability weights, the number of cases of clinical disease averted (hydrocele and lymphedema; calculated as described above), an estimated onset of disease at age 20 and region-specific life spans [13]. Impact estimates: ‘Beyond-LF’ benefits Because individual country estimates of the prevalence and distribution of soil transmitted helminthiases are generally not available, it was not possible to estimate directly the number of STH infections, either in children or women of child bearing age, that have been treated as a consequence of LF MDA activities. However, since it is widely accepted that the common STH infections are distributed throughout the pan-tropical belt where lymphatic filariasis is endemic [17], we recognize that a proportion of the albendazole and ivermectin treatments delivered for LF will have had a beneficial impact for children and women of child bearing age who harbor intestinal helminth infections. The number of individual children less than 15 years of age treated with albendazole was estimated by multiplying demographic data (children under the age of 15 years, for each country [11] by that country's total treatment figures, then summing the maximal number of children treated in any single MDA for each country between 2000 and 2007 (the conservative estimate of the number of unique individuals treated; see above). Since age is an exclusion criterion for LF treatment, the annual estimates thus derived were discounted depending on the therapeutic regimen applied as follows: in ivermectin and albendazole areas of Africa and the Yemen, data for children 5 to 15 years of age only are included, whereas for the rest of the world where DEC and albendazole are utilized, data for children 3 to 15 years of age are included. Women between 15 and 49 years were considered to be of childbearing age, and the number of individuals treated in this age class was calculated by multiplying demographic data [11] for each country by that country's total treatment figures, then summing the maximal number treated in any single MDA for each country between 2000 and 2007 (the conservative estimate of the number of unique individuals treated; see above). Since pregnancy is an exclusion criterion for LF treatment, the annual estimates thus derived were discounted by subtracting the estimated percent of the female population that is pregnant at any given time: the total fertility rate for each region was multiplied by a nine month gestational period and divided by 408 months (representing the estimated average number of reproductive months in a woman's lifetime). Whilst the beneficial outcomes of treating STH infections in these population groups are listed, we do not attempt to quantify the accumulated health impact because of the uncertainty surrounding the prevalence estimates. The same rationale and argument adopted for soil transmitted helminth infections were applied when we considered the impact of ivermectin treatments on skin diseases of various etiology in Africa. Results Programmatic achievements of the GPELF 2000–2007 1. The Global Programme One hundred twenty million people are affected with LF – 40 million with limb or genital damage recognized as either lymphedema/elephantiasis (15 million) or hydrocele (25 million), and twice that number with subclinical disease principally of the lymphatics or kidneys [3]. These 120 million people live in 83 endemic countries of the tropics and subtropics where 1.3 billion people (1/5 of the world's population) comprise the total population considered ‘at risk’ for infection through their exposure to LF's mosquito-borne infective larvae (Table 1) [5]. More than a third of these are children [11]. Little more than a decade ago it was established that single doses of a 2-drug regimen (either albendazole+ivermectin or albendazole+DEC) can effectively eliminate microfilariae from the blood of infected individuals for periods often in excess of a year [20]. Once understood, this drug effectiveness permitted development of a strategy for LF elimination based on treating entire at-risk populations yearly with one of these two safe, effective 2-drug regimens in order to reduce microfilaremia (MF) below a ‘transmission threshold’ where future recrudescence would be unlikely even after population treatment was halted. From estimates of the life span of the adult parasites (Wuchereria bancrofti or Brugia malayi), from projections of the levels of ‘drug coverage’ that must be achieved in the targeted populations and from earlier experiences in countries targeting LF elimination, the average number of rounds of effectively conducted, yearly ‘mass drug administrations’ (MDAs) necessary to achieve success for national programs was estimated to be 4–6 [2]. Recent experience from both program observations and specific research studies is consistent with this notion that in most instances between 2 and 6 rounds of effective MDA are able to clear microfilaremia (see below for sentinel site data). There are, however, specific situations where more than 6 rounds might be required, since the number of MDAs necessary appears to depend principally on the pre-treatment microfilaremia levels, programmatic drug ‘coverage’ and local vector parasite complex [21]. 2. Treatments delivered Since its official inauguration in 2000 the GPELF has seen the most rapid expansion of any drug delivery program in public health history; by the end of 2007 more than 1.9 billion treatments for LF had been delivered [7], almost ¾ by the program in India (initially a program based on DEC alone; more recently, on albendazole+DEC) with the remainder distributed in the 47 other countries with active MDA programs (Fig 1). The amount of drug donated to support this Programme has been extraordinary: more than 740 million tablets of albendazole and more than 590 million tablets of ivermectin were provided between 2000–2007 by the Global Programme's partners in the pharmaceutical industry. The amount of the non-donated drug (DEC) that had to be purchased during this same period by countries that utilize DEC instead of ivermectin (which is used for LF only in Africa [3]) was more than 4.7 billion tablets (Fig 2A & B). 10.1371/journal.pntd.0000317.g001 Figure 1 Cumulative treatments in GPELF. Progressive increase in number of treatments given through 2007; distribution by WHO region is depicted in pie-chart. 10.1371/journal.pntd.0000317.g002 Figure 2 Cumulative totals of donated drugs (Panel A), albendazole and ivermectin (Mectizan), and purchased drug (Panel B) DEC, used in GPELF between 2000 and 2007. 3. Programme effectiveness in decreasing LF prevalence The effectiveness of GPELF's strategy to reduce the prevalence of microfilaremia in an endemic population to levels below that believed necessary to sustain the parasite's life cycle has been substantiated by research teams in well-controlled, large-scale initiatives (e.g. in Egypt [22] and Papua New Guinea [23]). In addition, assessment of programmatically collected data available to WHO from another 20 countries shows similar progressive declines in mf prevalence in treated communities (Fig. 3), with greater than 10-fold reduction in mf-prevalence levels seen in sentinel-site communities that have received 6 rounds of MDA and total clearance of mf (by inference, interruption of LF transmission) recorded in almost 2/3 of the communities after 5 MDA rounds (Fig. 4). 10.1371/journal.pntd.0000317.g003 Figure 3 Effect of MDA on microfilaremia prevalence. Individuals in all of the sentinel sites (approximately 500 persons per site) reporting to the Global Programme were evaluated for microfilaremia. Progressive decline in prevalence among these individuals was recorded during yearly assessments (n = 131 sentinel sites for year 1; n = 124 for year 2; n = 139 for year 3; n = 148 for year 4; n = 68 for year 5; and n = 12 for year 6). 10.1371/journal.pntd.0000317.g004 Figure 4 Clearance of microfilaremia from each sentinel site (approximately 500 persons per site) reporting to the Global Programme after 5 rounds of MDA treatment (n = 68). Health impact of the GPELF 2000–2007 As impressive as the record is for the number of treatments given, the number of albendazole and ivermectin tablets donated, the amount of DEC purchased, and the number of communities cleared of microfilaremia during the first 8 years of this Global Programme, still the most important Programme outcome is the overall health benefit that the GPELF has brought to populations at-risk for LF. This benefit must derive from projections based on the best data and most reasonable assumptions available (see below and Tables 2 & 3 for the assumptions and implications). There are two principal sources of this health benefit: LF-related benefits – i.e., those coming directly from the effects of the MDAs in preventing the acquisition of lymphatic filarial disease or in arresting its progression ‘Beyond-LF’ benefits – i.e., those coming from ancillary benefits of the highly effective, broad-spectrum anti-parasitic drugs, albendazole and ivermectin, used in the Programme. 1. Projected health impact that is LF-related Protecting newborns from LF infection and disease. Since MDAs, by decreasing and then stopping LF transmission, will prevent uninfected individuals from becoming infected, the clearest measure of the Programme's long-term health impact is the amount of disease prevented over the lifetime of babies born into areas where their likelihood of acquiring infection has become much diminished or nil. To determine this impact requires an understanding of the number of babies born (and surviving) in areas covered by LF MDAs, the number who would have acquired infection (and disease) in the absence of GPELF, the ‘disability weights’ for different manifestations of LF disease and the rate at which exposure to LF infection declines in treated populations. When these variables were assessed [see Discussion and Table 2 for fuller description], the following conclusions could be made: Impact #1 - Prevention of LF infection (and disease): Between 2000–2007, 6.6 million newborns (the fraction of all newborns who would have been expected to acquire LF) were protected by GPELF – thereby averting in their lifetimes nearly 1.4 million cases of hydrocele, more than 800,000 cases of lymphedema and 4.4 million cases of subclinical disease ( Table 2 ). Because of this disease prevention, 6.0 million Disability Adjusted Life Years (DALYs) have been averted (3.2 million from prevention of hydrocele and 2.8 million from prevention of lymphedema [Table 2]). Preventing the progression to overt disease in LF-endemic populations. With evidence now available that the MDA treatment regimens for LF can halt, or even reverse, the progression of subclinical to overt disease [19],[24],[25], it is clear that those already infected but having no overt disease also benefit directly from the yearly MDAs. To quantify this benefit requires understanding the number of individuals treated during the MDAs, the proportion of these individuals with subclinical LF disease, the number who would have progressed to each of the manifestations of LF disease and the ‘disability weights’ for each of these manifestations. When all of these were considered (see Discussion and Table 2), the following could be recognized: Impact #2 - Prevention of LF disease: Between 2000–2007, 9.5 million individuals – previously infected but without overt manifestations of disease – were protected by GPELF from developing hydrocele (6.0 million) or lymphedema 3.5 million). This disease prevention translates into 26 million DALYs averted (14 million from hydrocele prevention and 12 million from lymphedema prevention). 2. Projected health impact from ‘Beyond-LF’ benefits Preventing the consequences of intestinal parasite infections. The best drugs to control intestinal parasites (i.e., ‘soil-transmitted helminths’ [STH]: hookworm, roundworm and whipworm) are the same drugs (albendazole and ivermectin) used to eliminate LF [3],[20]. Though Mectizan (ivermectin) has formal regulatory approval only for lymphatic filariasis and onchocerciasis and is donated by Merck & Co., Inc. only for those indications, each year millions of children and women-of-childbearing-age are concomitantly treated for debilitating intestinal parasite infections (without additional cost or effort) while participating in their national programs to eliminate LF. To identify the impact of such treatment requires estimation of the number of children and the number of women-of-childbearing-age who received albendazole (with or without ivermectin) in all GPELF countries. Thus, Impact #3 - ‘Beyond-LF’ benefit for children with intestinal parasites: Between 2000–2007, more than 172 million treatments for intestinal parasite infections were given to 56.6 million children by GPELF ( Table 3 ) Based on earlier research studies, each infected child receiving treatment would be expected to develop increased appetite [26] (leading, in some settings, to 1 kg of extra weight gain and 0.6 cm extra growth in the first 5 months) [27] ; greater eye-hand coordination, learning ability and concentration [14] ; better school attendance, cognitive testing (20% improvement) [28], fitness scores and spontaneous play activity (43% increase) [26],[27]. Impact #4 - ‘Beyond-LF’ benefit for women-of-childbearing-age with intestinal parasites: Between 2000–2007 more than 140 million treatments for STH were given to 44.5 million women-of-childbearing age by GPELF ( Table 3 ). Repeated treatment of hookworm and other intestinal parasites improves both nutritional status and, most importantly, iron stores in women during their reproductive years [16],[29] . Prior studies predict that such treatment can lead to an increase in infant birth-weights by more than 50 grams and a drop in infant mortality by as much as 40% [29] . Maternal mortality should also decrease significantly in women receiving GPELF treatments, since iron deficiency anemia is a prominent cause of maternal mortality [30] . Prevention of debilitating skin diseases. Onchocerciasis, scabies, and pediculosis (lice) are all diseases of the skin caused by parasites common in resource poor communities and associated with appreciable mental and physical disability in affected populations. Ivermectin, one of the two drugs co-administered by the GPELF in Africa, is the best oral treatment for all of these debilitating skin diseases [31]–[33]; it is also the mainstay drug for onchocerciasis control programs in Africa [34]. To gauge the GPELF impact on skin diseases it is necessary first to understand the number of individuals receiving ivermectin through GPELF activities in Africa. Thus, Impact #5 - ‘Beyond-LF’ benefit for people with skin diseases in Africa: Between 2000–2007, over 149 million treatments with ivermectin were administered by GPELF or APOC (African Programme for Onchocerciasis Control) to more than 45 million people in African communities ( Table 3 ) where the prevalence of scabies skin infection may exceed 30% and the prevalence of onchocerciasis even more. Ivermectin's long lasting impact on scabies can cause community prevalence to fall dramatically after 1 cycle of treatment and to disappear almost completely after 2 or more treatments [31] . Cured individuals show improvements in sleep patterns and overall wellbeing, but also importantly, treatment of scabies in childhood can prevent the post-streptococcal renal disease induced by group B streptococcus skin infections that often complicate chronic scabies infection [35] . Because of its broad geographic range, the GPELF has brought ivermectin treatment to additional millions of people living in onchocerciasis-endemic areas not previously targeted by onchocerciasis control programs (as these programs focus only on communities where the prevalence of onchocerciasis exceeds 40%) [34] . Discussion Since WHO's Global Programme to Eliminate Lymphatic Filariasis was officially launched in 2000, its programmatic achievements [recorded here through 2007] are unparalleled (Box 1): 1.9 billion treatments delivered through yearly MDAs to over 570 million people in 48 endemic countries. These accomplishments were made possible by the enormous drug donations of albendazole (over 740 million tablets from GlaxoSmithKline through 2007) and ivermectin (over 590 million tablets of Mectizan from Merck & Co., Inc.), by the willingness of National Programs to procure 4.7 billion tablets of DEC, and by the early support from numerous other organizations – most significantly the Bill and Melinda Gates Foundation, the Arab Fund for Economic and Social Development, the international development agencies of Japan and the United Kingdom and the Ministries of Health of endemic countries. Box 1. The Global Programme to Eliminate LF – Its First 8 Years. Reach Nearly 2 billion treatments delivered to more than 560 million people in 48 countries. Dissemination More than 50% of endemic countries actively involved in annual MDA programmes. Child Protection Nearly 176 million children already treated for LF, and over 66 million babies born into areas now protected by MDA. Public Health Impact on LF More than 6 million cases of hydrocele and 4 million cases of lymphoedema prevented, translating into more than 32 million DALYs averted. Additional Health Benefits More than 310 million treatments of albendazole delivered to women of child-bearing age and school-age children, providing sustained relief from the negative consequences of soil-transmitted helminth (STH) infections that include maternal anemia, low birth weight newborns, excess infant mortality, inhibited growth and development, diminished intellectual performance. Almost 150 million treatments of ivermectin delivered to African communities, providing sustained relief from onchocercal skin disease, scabies, lice and important STH infections. Though it is without question that this Programme has had a very great impact on global health, quantifying this impact still poses difficult challenges. Principally this is because all projections must be made not just from the numbers of people treated but also from the more-difficult-to-quantify effects of such treatment. Assumptions derived from current best understanding must be linked with the available data to formulate the health impact projections, and while making such assumptions is never entirely satisfactory, the present analysis does endeavor to identify clearly both the assumptions themselves and the sources of the data used to generate the projections; it also has chosen to err on the conservative side in most estimations. For the GPELF, health benefits lie in two domains: one related to the Programme's effects on lymphatic filarial disease and its consequences, and the other related to the outcome of treating LF-endemic populations with one or both of the very safe, broad-spectrum anti-parasitic drugs used by the Programme, albendazole and ivermectin. LF-related impact To gauge the LF-related impact, this analysis has considered quantitatively only what has been accomplished by: 1) preventing infection in those born into areas where GPELF is active and 2) stopping the progression to clinical disease in previously infected individuals whose disease has not yet expressed itself overtly. 1) To identify the amount of infection prevented, the number of babies born in areas under LF MDAs between 2000–2007 who survived infancy was first determined, by country [11],[12]. Estimation of how many of these newborns would have acquired LF during their lives and what manifestations they would have developed was based on the global prevalence figures available for LF and its clinical manifestations (Table 2) [3]. Calculation of the DALYs attributable to that amount of disease during the lifetimes of those newborns assumed that clinical expression of disease (hydrocele and lymphedema) had its onset at an average age of 20 years and persisted throughout the life of the individual. Since the risk of exposure of these infants to LF depends on the level of local transmission, it is necessary to estimate the rate of decline of transmission (here using vector infection in mosquitoes as a surrogate for transmission) as MDA programs progress. While programmatic evidence exists that effective transmission of LF might cease very soon after the initiation of MDA activities [22],[23],[36], entomologic studies linked with anti-filarial single-dose treatment regimens indicate that the decline in vector infection may be more gradual [22], [23], [37]–[41]. Since the availability of such data is too limited (with respect to vector species, collection techniques, parasite assessments, LF prevalence, treatment regimens, and other variables) to give precise estimates of post-MDA changes in vector infection, data from available studies [22], [23], [37]–[41] were pooled, yielding a relationship that describes an ‘average’ rate-of-decline of vector infection; namely, declines to 50%, 25%, 12%, 6% and 0% of pre-treatment levels following each of the first 5 MDAs, respectively. (As these numbers were empirically defined, they already incorporate the influence of population ‘coverage’ on MDA effectiveness.) This information was then used to estimate the effect that each MDA had for each treated population in each country in order to approximate the exposure to LF in infants born after initiation of GPELF activities. 2) Stopping the progression of subclinical to clinical disease in those already infected contributes appreciably to the calculations of LF-related health benefits from GPELF (Table 2). Evidence for such effectiveness of MDA regimens in halting disease progression is relatively recent and has focused particularly on children with subclinical or early-stage lymphatic disease [19],[25]. Because these effects are just now being studied comprehensively, and in order to be conservative in estimating GPELF's health impact, the present calculations are based on the conservative assumption [19] that the MDA programs would arrest subclinical disease progression in only 50% of the affected individuals (Table 2). Though one cannot be completely certain of all of the calculations in Table 2, it is still hard to escape the conclusion that these values for GPELF's LF-related health impact are almost certainly gross underestimates – for at least 2 reasons. First, not considered at all in the assessments of GPELF's LF-prevention benefits are those related to any of the manifestations of LF disease other than hydrocele and lymphedema. Among those omitted, quantitatively most important would be the Programme's impact on subclinical LF disease [24],[25],[42] – especially microfilaremia, hematuria, lymphatic dilatation and lymphatic dysfunction – which affect a very large percentage of those with LF infection [3] but for which there are no ‘disability weights’ available for calculating DALYs or DALYs averted. Also overlooked are other extremely important, often debilitating overt clinical manifestations of infection – especially, the very common, recurrent acute adenolymphangitis episodes (ADL) and the progressive, crippling pulmonary disease, tropical pulmonary eosinophilia (TPE) [3]. Excluding all of these important consequences of LF infection from the calculations of GPELF's health impact from preventing LF ensures that these calculations will significantly underestimate the Programme's impact. Second, none of these quantitative calculations of GPELF's LF-related health impact has taken into consideration the direct effect that this Programme has had on arresting progression or ameliorating clinical disease of affected individuals. In addition to its delivery of essential anti-filarial drugs, the GPELF is also a program that advocates and initiates ‘morbidity management’ activities based on vigorous personal hygiene management of lymphedema or elephantiasis [43]. Dramatic improvement in both physical state and mental attitude occurs in patients following the hygiene guidelines [43],[44], but none of the health impact of this component of the GPELF has been quantified or captured in the calculations of Table 2. Similarly uncaptured is the potential direct improvement in both lymphedema and hydrocele now being reported by patients following MDA treatment alone (i.e., even in the absence of hygiene management) [23]. ‘Beyond-LF’ Health Impact If the LF-related health impact of GPELF seems difficult to quantify, the ‘beyond-LF’ impact presents an even greater challenge. A major reason is that many of the ‘beyond LF’ benefits come from the impact that the GPELF drugs have on soil transmitted helminth (STH) infections in the treated populations. The quantitative epidemiology of these infections remains poorly characterized, albeit for good reasons: not only are STH infections caused by three distinct parasites (hookworm, roundworm and whipworm), but these three infections also occur in unequal proportions in different endemic regions and cause different diseases with varying severity and health consequences. Further, while the geographic overlap of STH infections with the LF at-risk areas is felt to be almost universal [45], it is rarely known which STH infections occur or with what abundance in which areas. Thus, while general estimates of overall STH prevalence can be approximated for areas where GPELF is active, the data itself is not certain enough to be used quantitatively to project GPELF's health impact from treating STH infections. Despite such limitations, a number of very important studies have been carried out to document and measure the health consequences of STH infections – usually by monitoring changes in outcome indicators following treatment with albendazole or other drugs. These have shown, for example, that Soil transmitted helminth infections exact a severe toll on the nutritional status and growth of infected children, but intervention with albendazole and ivermectin can make an extraordinary difference in their physical development, with spectacular gains in growth parameters quantified in a number of important studies [14]–[16],[46],[47]. Lethargy and lack of physical stamina often characterize children infected with intestinal worms, but within weeks of treatment significant increases can be found in physical activity and spontaneous play. Resting heart rates, physical fitness on the Harvard step test, and measurements of spontaneous play behavior all improved in children from Kenya and Indonesia after being treated for intestinal worms [14],[26],[27],[47]. Children infected with intestinal worms are frequently seen to miss many more school days than their uninfected peers, as documented in Jamaica where children with intense Trichuris infections missed twice as many school days as their infection-free peers [48]. Treatment leads to significant reduction in school absenteeism; a 25% reduction was recorded in Kenya following school-based treatment for STH [49]. Children infected with intestinal worms perform poorly in learning ability tests, cognitive function and educational achievement, but treating school age children increases their ability to learn, as documented by improvement in children's short and long term memory, executive function language, problem solving and attention [50],[51]. These STH infections that are treated by the GPELF MDAs are not just important for children. While their effect on the health and productivity of men remains poorly defined, in women-of-childbearing-age hookworm infection is recognized as a major cause of anemia, and this anemia significantly affects both maternal and newborn morbidity and mortality. Indeed, WHO estimates that women in developing countries may be pregnant for half their reproductive lives and are at an increased risk of anemia during this time [30]. Anemia in pregnancy has been clearly associated with poor birth outcome, including low birth-weight [52]–[55] and increased maternal morbidity and mortality [30],[56],[57]. Hookworm-attributable anemia, induced by deficiencies in iron, protein and total energy, is a significant cause of intrauterine growth retardation and low birth weight [58]. It might even exacerbate the sometimes fatal effects of malaria infection in infants and young children. Treating STH infections in women-of-child-bearing-age improves both maternal health status and the status of infants born to infection-free mothers; therefore, WHO recommends that anthelminthic treatment be included in strategies to improve maternal nutrition wherever hookworm infection and anemia are prevalent [30]. (GPELF, however, currently restricts its treatment to women who are not pregnant.) In addition to its effect on certain of the STH infections, ivermectin – as GPELF's second drug with broad-spectrum anti-parasite activity – is unsurpassed for the oral treatment of both onchocerciasis [34] and ectoparasites (scabies and lice) [31]. While ivermectin has been the mainstay of onchocerciasis control programs for the past 2 decades, the control programs in Africa (where 99% of the onchocerciasis is found) have as their principal target only communities designated hyper- or meso-endemic (i.e., prevalence ≥40%), so that many communities endemic for onchocerciasis were left untreated until GPELF was initiated [34]. Since LF is distributed very much more widely than onchocerciasis, and since almost all regions of Africa where onchocerciasis is endemic are also ‘at risk’ for LF, GPELF activity in those areas has resulted in the treatment of millions of additional individuals in these onchocerciasis-endemic areas who were not covered under the older control programs. These individuals are generally not those with blinding onchocerciasis but with severe onchocercal skin disease (OSD) and “troublesome itching”; the burden of illness from this OSD, quantified in DALYS lost, is recognized as essentially equivalent to that estimated for onchocercal ocular disease and blindness [33]. GPELF's impact on improving OSD is not yet quantified, but it can be defined once the number of individuals with onchocerciasis who live in the expanded treatment areas is more well understood [34]. On the other hand, for the very important skin diseases caused by scabies and lice, the significant health benefits that GPELF brings through its use of ivermectin in affected populations will be much more difficult to quantify, since so much less is known about the epidemiology of these widespread ectoparasite diseases, and no burden-of-illness estimates have yet been established [32]. The Global Programme to Eliminate LF is not a static program; indeed, its reach continues to expand each year. In 2008 it is projected that >500 million people will be treated in that year alone. The effect on the calculated health benefits of the Programme that these progressively increasing numbers will have each year is enormous, since the number of protected children and cases of disease prevented will increase rapidly as new cohorts of treated individuals are added each year; in addition, of course, all of those benefits not currently quantified (both LF-related and beyond-LF effects) will continue to multiply as well. Already the GPELF has been described as a ‘best buy’ in global health, and the present tally of health benefits only strengthens this contention. Even during its first 8 years, almost 2 billion MDA treatments have been given and 32 million DALYs-averted have been identified by considering (conservatively) just 2 of the 5 specific impacts attributable to the Programme (Tables 2 & 3). Considering only these DALYs and estimating treatment costs at $0.10/person (a ‘high’ estimate given the fact that the preponderance of treatments were in countries where costs have been identified as being much lower [59]) suggests that, excluding the donated drug costs, $190 million will have been spent to effect the 1.9 billion treatments. If the 32 million averted DALYs were the only benefits achieved, each DALY averted by the Programme would have cost $5.90. This cost is extremely low compared to DALY averted costs of other programs [60], but even it is a gross overestimate of the true cost of DALYs-averted by GPELF activities, since so much of the Programme's benefit (Tables 2 & 3) remain unquantified and not included in this calculation. As this LF Elimination Programme continues to expand, its benefits will continue to accrue; as our ability to quantify these benefits improves, the Programme's true value will become progressively still more impressive. Supporting Information Alternative Language Abstract S1 Translation of the Abstract into French by P. J. Hooper (0.06 MB PDF) Click here for additional data file.
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The global limits and population at risk of soil-transmitted helminth infections in 2010
Rachel L. Pullan, Simon J. Brooker (2012)
Background Understanding the global limits of transmission of soil-transmitted helminth (STH) species is essential for quantifying the population at-risk and the burden of disease. This paper aims to define these limits on the basis of environmental and socioeconomic factors, and additionally seeks to investigate the effects of urbanisation and economic development on STH transmission, and estimate numbers at-risk of infection with Ascaris lumbricoides, Trichuris trichiura and hookworm in 2010. Methods A total of 4,840 geo-referenced estimates of infection prevalence were abstracted from the Global Atlas of Helminth Infection and related to a range of environmental factors to delineate the biological limits of transmission. The relationship between STH transmission and urbanisation and economic development was investigated using high resolution population surfaces and country-level socioeconomic indicators, respectively. Based on the identified limits, the global population at risk of STH transmission in 2010 was estimated. Results High and low land surface temperature and extremely arid environments were found to limit STH transmission, with differential limits identified for each species. There was evidence that the prevalence of A. lumbricoides and of T. trichiura infection was statistically greater in peri-urban areas compared to urban and rural areas, whilst the prevalence of hookworm was highest in rural areas. At national levels, no clear socioeconomic correlates of transmission were identified, with the exception that little or no infection was observed for countries with a per capita gross domestic product greater than US$ 20,000. Globally in 2010, an estimated 5.3 billion people, including 1.0 billion school-aged children, lived in areas stable for transmission of at least one STH species, with 69% of these individuals living in Asia. A further 143 million (31.1 million school-aged children) lived in areas of unstable transmission for at least one STH species. Conclusions These limits provide the most contemporary, plausible representation of the extent of STH risk globally, and provide an essential basis for estimating the global disease burden due to STH infection.
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Assessment of the Anthelmintic Efficacy of Albendazole in School Children in Seven Countries Where Soil-Transmitted Helminths Are Endemic
Jozef Vercruysse, Jerzy Behnke, Marco Albonico … (2011)
Introduction The three major Soil-Transmitted Helminths (STH), Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm) and Necator americanus/Ancylostoma duodenale (the hookworms) are amongst the most widespread parasites worldwide. An estimated 4.5 billion individuals are at risk of STH infection and more than one billion individuals are thought to be infected, of whom 450 million suffer morbidity from their infection, the majority of who are children. An additional 44 million infected pregnant women suffer significant morbidity and mortality due to hookworm-associated anemia. Approximately 135,000 deaths occur per year, mainly due to infections with hookworms or A. lumbricoides [1]. The most widely implemented method of controlling STH infections is through periodic administration of anthelmintics. Rather than aiming to achieve eradication, current control programs are focused on reducing infection intensity and transmission potential, primarily to reduce morbidity and avoid mortality associated with the disease [2]. The benzimidazole (BZ) drugs, i.e. albendazole (ALB) and mebendazole, are the most widely used drugs for the control of STH. While both show broad-spectrum anthelmintic activity, for hookworms a single dose of ALB is more effective than mebendazole [3]. The scale up of chemotherapy programs that is underway in various parts of Africa, Asia and South America, particularly targeting school children, is likely to exert increasing drug pressure on parasite populations, a circumstance that is likely to favor parasite genotypes that can resist anthelmintic drugs. Given the paucity of suitable alternative anthelmintics it is imperative that monitoring programs are introduced, both to assess progress and to detect any changes in therapeutic efficacy that may arise from the selection of worms carrying genes responsible for drug resistance. The well documented occurrence of resistance to anthelmintics in nematode populations of livestock [4], highlights the potential for frequent treatments used in chemotherapy programs to select drug resistant worms. Such an eventuality threatens the success of treatment programs in humans, both at individual and community levels [5]. Although some small scale studies [6], [7], have suggested emerging drug resistance in human STH, these studies should be interpreted with some caution, since suboptimal efficacy could have been due to factors other than drug resistance. Moreover, although for the BZ drugs there are many published studies reporting the Cure Rate (CR) and the Fecal Egg Count Reduction (FECR), the two most widely used indicators for assessing the efficacy of an anthelmintic in human medicine, comparison of such studies is difficult, largely because there is no widely accepted standard operating procedure for undertaking such trials [8]. Published studies are confounded by methodological variations including treatment regimens, poor quality of drugs, differing statistical analyses used to calculate therapeutic efficacy, as well as a range of other problems in study design, such as small sample size, diagnostic methods, variation in pre-intervention infection intensities and confounding factors related to geographical locations. Such variation among studies greatly complicates direct comparison [3]. A World Health Organization-World Bank (WHO-WB) meeting on “Monitoring of Drug Efficacy in Large Scale Treatment Programs for Human Helminthiasis”, held in Washington DC at the end of 2007, highlighted the need to closely monitor anthelmintic drug efficacy and to develop standard operating procedures for this purpose. In a systematic meta-analysis of published single-dose studies, Keiser and Utzinger [8], confirmed that there was a paucity of high quality trials, and that the majority of trials were carried out more than 20 years ago. They recommended that well-designed, adequately powered, and rigorously implemented trials should be undertaken to provide current data regarding the efficacy of anthelmintics against the main species of STH. These should be designed to establish benchmarks (including standard operating procedures) for subsequent monitoring of drug resistance. The objective of the present work was to validate a standard protocol that has been developed for monitoring efficacy of anthelmintics against STH. To give the study wide relevance, we conducted the trial in seven populations in different geographic locations in Brazil, Cameroon, Cambodia, Ethiopia, India, Tanzania and Vietnam. In each of the study sites, different epidemiologic patterns of infection prevail, including different combinations of STH. We assessed the efficacy of a single dose (400 mg) of ALB in terms of the CR and the FECR in school children between 14 and 30 days following treatment. The McMaster egg counting technique was used in a standardized fashion, with rigorous quality control. Levecke et al. [9] reported that the McMaster holds promise as a standardized method on account of its applicability for quantitative screening of large numbers of subjects. This method is the recommended method for measuring fecal egg counts (FEC) when performing FECR for the detection of anthelmintic resistance in veterinary medicine [10], [11]. Methods Study sites This study was carried out in seven different countries covering Africa (Cameroon, Ethiopia and Tanzania), Asia (Cambodia, India and Vietnam) and South-America (Brazil). However, it is important to note, that while we refer to individual countries to identify results from particular trials, we do not make any conclusions about any country as such. Here, names of countries are used only to distinguish between 7 separate trials that were conducted in 7 geographically disparate regions of the world. In total ten study sites with varying STH and treatment history were included. These seven STH endemic countries were selected because of the presence of investigator groups with previous extensive experience in the diagnosis and control of STH. Table 1 provides their specific locations (district/province/state) and treatment history. Both species of hookworms (N. americanus and A. duodenale) were present in all study sites in varying degree with the exception of Brazil where only N. americanus was present. 10.1371/journal.pntd.0000948.t001 Table 1 The location and treatment history of the ten study sites. Country District/Province/State Treatment history Brazil Minas Gerais LSAT since 2007 (ALB) Cambodia Kratie LSAT since 1997, last in 2007 (MBD) Cameroon Loum LSAT (MBD/ALB) since 1999, last in 2008 (MBD) Yoyo No LSAT Ethiopia Jimma No LSAT India Vellore LSAT, since 2001, last in 2008 (ALB) Thiruvanamalai No LSAT Tanzania (Zanzibar) Pemba Island LSAT since 1994, last in 2006 (PZQ, IVM, ALB) Vietnam Thái Nguyên LSAT since 2005 Tuyên Quang No LSAT LSAT: large scale anthelmintic treatment, MBD: mebendazole, PZQ: praziquantel, IVM: ivermectine, ALB: albendazole. Trial design During the pre-intervention survey, school children aged 4 to 18 years at the different study sites were asked to provide a stool sample. For the initial sampling the aim was to enroll at least 250 infected children with a minimum of 150 eggs per gram of feces (EPG) for at least one of the STH. This sample size was selected based on statistical analysis of study power, using random simulations of correlated over-dispersed FEC data reflecting the variance-covariance structure in a selection of real FEC data sets. This analysis suggested that a sample size of up to 200 individuals (α = 0.05, power = 80%) was required to detect a 10 percentage point drop from a null efficacy of ∼ 80% (mean percentage FEC Δ per individual) over a wide range of infection scenarios. Standard power analyses for proportions also indicated that the detection of a ∼10 percentage point drop from a null cure rate required sample sizes up to 200 (the largest samples being required to detect departures from null efficacies of around 50%). Given an anticipated non-compliance rate of 25%, a sample of 250 individuals with >150 EPG pre-treatment was therefore considered necessary at each study site. Fecal samples were processed using the McMaster technique (analytic sensitivity of 50 EPG) for the detection and the enumeration of infections with A. lumbricoides, T. trichiura and hookworms [9]. None of the samples were preserved. Samples which could not be processed within 24 hours were kept at 4°C. A single dose of 400 mg ALB (Zentel) from the same manufacturer (GlaxoSmithKline Pharmaceuticals Limited, India) and same lot (batch number: B.N°: L298) was used at all trial sites. No placebo control subjects were included in the trial for ethical and operational reasons. Between 14 to 30 days after the pre-intervention survey, stool samples were collected from the treated subjects and processed by the McMaster technique. All of the trials were carried out in a single calendar year (2009). Subjects who were unable to provide a stool sample at follow-up, or who were experiencing a severe concurrent medical condition or had diarrhea at time of the first sampling, were excluded from the study. The participation, the occurrence of STH and sample submission compliance for pre- and post-intervention surveys are summarized in Figure 1. 10.1371/journal.pntd.0000948.g001 Figure 1 The participation, occurrence of STH and sample submission compliance for pre- and post-intervention surveys. Subjects who were not able to provide a sample for the follow-up, or who were experiencing a severe current medical condition or had diarrhea at the time of the first sampling were excluded from the trial. The McMaster counting technique The McMaster counting technique (McMaster) was based on the modified McMaster described by the Ministry of Agriculture, Fisheries and Food (UK; 1986) [12]. Two grams of fresh stool samples were suspended in 30 ml of saturated salt solution (density = 1.2). The suspension was poured three times through a wire mesh to remove large debris. Then 0.15 ml aliquots were added to each of the 2 chambers of a McMaster slide. Both chambers were examined under a light microscope using a 100x magnification and the FEC for each helminth species was obtained by multiplying the total number of eggs by 50. Statistical analysis The efficacy of the treatment for each of the three STH was evaluated qualitatively based on the reduction in infected children (CR) and quantitatively based on the reduction in fecal egg counts (FECR). The outcome of the FECR was calculated using three formulae. The first two formulae were based on the mean (arithmetic/geometric) of the pre- and post-intervention fecal egg count (FEC) ignoring the individual variability, whereas the third formula represented the mean of the reduction in the FEC per subject. The latter is the only quantitative indicator of efficacy for which the importance of confounding factors can be assessed by statistical analysis. The CR and the FECR (1-3) outputs were calculated for the different trials, both sexes, age classes (A: 4–8 years; B: 9–13 years and C: 14–18 years) and for the level of egg excretion intensity at the pre-intervention survey. These levels corresponded to the low, moderate and high intensities of infection as described Montresor et al. [13] For A. lumbricoides these were 1–4,999 EPG, 5,000–49,999 EPG and >49,999 EPG; for T. trichiura these levels were 1–999 EPG, 1000–9,999 EPG and >9,999 EPG; and for hookworms these were 1–1,999 EPG, 2,000–3,999 EPG and >3,999 EPG, respectively. In addition, the robustness of the three FECR formulae was explored by comparing the FEC reduction rate obtained from all samples containing STH and those obtained from samples containing more than 150 EPG as recommended in the anthelmintic resistance guidelines of the World Association for the Advancement of Veterinary Parasitology [9]. Finally, putative factors affecting the CR and the FECR (3) were evaluated. For the CR, generalized linear models (binomial error) were built with the test result (infected /uninfected) as the outcome, ‘trial’ (7 levels: trials in Brazil, Cambodia, Cameroon, Ethiopia, India, Tanzania and Vietnam) and ‘sex’ (2 levels: female and male) as factors, and ‘age’ and the log transformed pre-intervention FEC as covariates. Full factorial models were evaluated by the backward selection procedure using the likelihood ratio test of χ2. Finally, the CR for each of the observed values of the covariate and factor was calculated based on these models (The R Foundation for Statistical Computing, version 2.10.0 [14]). For analysis of the data from FECR (3), non-parametric methods were used, because models based on parametric statistics, even with negative binomial error structures, or based on transformed data would not converge satisfactorily as a consequence of the high proportion of FEC with zero EPG. Hence, the impact of the factors ‘trial’ and ‘sex’ were assessed by the Kruskal-Wallis test (for more than 2 group comparisons) and the Mann-Whitney U test, respectively. The correlation between the outputs of FECR (3) and the covariates (age and pre-intervention FEC) was estimated by the Spearman rank order correlation coefficient (SAS 9.1.3, SAS Institute Inc.; Cary, NC, USA). Ethics statement The overall protocol of the study was approved by the Ethics committee of the Faculty of Medicine, Ghent University (Nr B67020084254) and was followed by a separate local ethical approval for each study site. For Brazil, approval was obtained from the Institutional Review Board from Centro de Pesquisas René Rachou (Nr 21/2008), for Cambodia from the National Ethic Commitee for Health Research, for Cameroon from the National Ethics Committee (Nr 072/CNE/DNM08), for Ethiopia from the Ethical Review Board of Jimma University, for India from the Institutional Review Board of the Christian Medical College (Nr 6541), for Tanzania (Nr 20) from the Zanzibar Health Research Council and the Ministry of Health and Social Welfare, for Vietnam by the Ministry of Health of Vietnam. An informed consent form was signed by the parents of all subjects included in the study. This clinical trial was registered under the ClinicalTrials.gov Identifier NCT01087099. Results The cure rate (CR) Overall, the highest CRs were observed for A. lumbricoides (98.2%), followed by hookworm (87.8%) and T. trichiura (46.6%). However, as shown in Table 2, the CRs varied across the different trials, age classes and pre-intervention FEC levels. The differences in CRs between trials were most pronounced for T. trichiura, ranging from 21.0 (Tanzania) to 88.9% (India). The T. trichiura CRs of 100% for the trials in Brazil and Cambodia are not considered here as they were based on only 1 and 2 individuals, respectively. For hookworms and A. lumbricoides, the CRs varied from 74.7 (India) to 100% (Vietnam) and from 96.4 (Tanzania) to 99.3% (Ethiopia and Cameroon), respectively. The CRs for A. lumbricoides in Cambodia (100%) and India (95.2%) are not considered here as they were based on fewer than 50 individuals. The CRs increased over the three age classes (A. lumbricoides: 95.8 to 100%; T. trichiura: 44.7 to 54.1%), except for hookworms where the CRs ranged from 86.1 to 88.3, and then to 87.5%. For each of the three STH, there was a decline in the CR with increasing levels of infection intensities at the pre-intervention survey. The largest drop was observed for T. trichiura, which decreased from 53.9 to 12.5%. For the two other STH, the drop in the CR was less pronounced, ranging from 88.6 to 76.9% for hookworms and only from 98.3 to 95% for A. lumbricoides. The observed differences between sexes were negligible for all three STH. 10.1371/journal.pntd.0000948.t002 Table 2 The cure rate (CR) for treatment with a single dose of albendazole against soil-transmitted helminths. A. lumbricoides T. trichiura Hookworms n CR (%) N CR (%) n CR (%) Country Brazil 50 98.0 1* 100 52 88.5 Cambodia 5* 100 2* 100 127 87.4 Cameroon 298 99.3 386 47.4 140 87.1 Ethiopia 151 99.3 105 85.7 91 98.9 India 21* 95.2 18* 88.9 95 74.7 Tanzania 279 96.4 396 21.0 349 86.8 Vietnam 148 98.6 138 81.2 58 100 Age class A (4–8) 215 95.8 219 44.7 173 86.1 B (9–13) 669 98.8 753 46.3 643 88.3 C (14–18) 68 100 74 54.1 96 87.5 Sex Female 462 98.1 503 48.5 393 89.1 Male 490 98.4 543 44.8 519 86.9 Pre-intervention infection intensity Low 662 98.3 823 53.9 859 88.6 Moderate 270 98.1 215 19.5 40 75.0 High 20 95.0 8 12.5 13 76.9 Total 952 98.2 1046 46.6 912 87.8 *Due to the low number of infected subjects ( 75%). The pre-intervention FEC was probably the most important as it had a considerable effect on the CR of A. lumbricoides (χ2 1 = 4.14, p 99.3%). The results of FECR (3) mostly yielded comparable or lower values than those from FECR (1). The low values (sometimes negative) can be explained by subjects for whom the post-intervention FEC exceeded the pre-intervention FEC. These subjects contributed to a negative FEC reduction rate which had a significant impact on the final FEC reduction rate calculated with FECR (3). This became apparent in the FEC reduction rate for A. lumbricoides, where a Cameroonian male subject of 7 years with a pre-intervention FEC of 100 and a post-intervention FEC of 22,050 EPG, contributed markedly to lowering the overall values for the data-set from the trial in Cameroon (FECR (1): 99.2%; FECR (3): 26.0%). This lowering of FECR (3) compared to FECR (1) for A. lumbricoides also occurred with age class A (FECR (1): 98.9%; FECR (3): −2.7%) and the low pre-intervention infection intensity level (FECR (1): 97.8%; FECR (3): 66.6%), but not for the remaining variables. The number of negative individual FEC reduction rates, and the magnitude of the difference between pre- and post-intervention FEC, both contributed to the discrepancies found for T. trichiura (176 subjects) and hookworms (10 subjects). Robustness of FECR formulae Table 5 summarizes the FEC reduction rates restricted to samples of more than 150 EPG indicating that the results of FECR (1) and FECR (2) remained roughly unchanged. The values from FECR (3) increased and were mostly comparable with those obtained by FECR (1). This change in the results of FECR (3) is due to the exclusion of negative individual FEC reduction rates which mostly occurred among the subjects with low pre-intervention FEC (see also Table 4). Differences of more than 5% between the results of FECR (3) and FECR (1) were limited to T. trichiura (country: Cameroon, India, Tanzania and Vietnam; age class: A and C). 10.1371/journal.pntd.0000948.t005 Table 5 Fecal egg count reduction for samples with a pre-intervention FEC of more than 150 EPG. A. lumbricoides T. trichiura Hookworms n FECR(1)(%) FECR(2)(%) FECR(3)(%) n FECR(1)(%) FECR(2)(%) FECR(3)(%) n FECR(1)(%) FECR(2)(%) FECR(3)(%) Country Brazil 47* 100.0 100.0 100.0 0* _ _ _ 46* 97.5 99.6 97.5 Cambodia 1* 100.0 100.0 100.0 1* 100.0 99.7 100.0 100 97.7 99.6 96.7 Cameroon 266 99.8 100.0 100.0 233 39.9 93.4 50.4 71 93.6 99.5 95.1 Ethiopia 145 100.0 99.9 100.0 72 92.3 99.2 92.6 66 99.6 99.7 99.8 India 17* 98.9 99.9 99.6 11* 72.0 99.1 87.0 83 87.8 99.3 84.2 Tanzania 266 100.0 100.0 99.9 325 58.3 86.6 36.4 281 95.4 99.7 93.1 Vietnam 130 100.0 99.9 99.9 71 93.1 99.2 88.0 19* 100.0 99.7 100.0 Age class A (4–8) 196 99.9 100.0 99.8 153 65.1 94.8 57.2 130 94.7 99.6 94.4 B (9–12) 613 99.8 100.0 99.9 515 48.4 94.1 51.8 460 94.9 99.6 93.2 C (13–18) 63 100.0 100.0 100.0 45 60.2 94.4 46.4 76 96.4 99.6 97.1 Sex Female 428 100.0 100.0 99.9 343 54.0 94.7 57.7 286 95.2 99.6 93.8 Male 444 99.7 100.0 99.9 370 53.0 93.8 48.0 380 94.8 99.6 94.0 Pre-intervention infection intensity Low 582 99.9 99.9 99.9 490 49.0 95.1 50.2 613 94.1 99.6 93.6 Moderate 270 100.0 100.0 100.0 215 58.7 92.2 58.7 40 97.6 99.9 97.1 High 20 99.5 100.0 99.6 8 40.0 88.6 40.1 13 95.9 99.9 96.4 Total 872 99.9 100.0 99.9 713 53.5 94.3 52.7 666 95.0 99.6 93.9 FECR(1): group based and arithmetic mean; FECR(2): group based and geometric mean; FECR(3): individual based and arithmetic. *Due to the low number of infected subjects ( 95% for A. lumbricoides and >90% for hookworms are appropriate thresholds, and that efficacy levels below this should raise concern. The great variability of the FECR for T. trichiura and the relatively low efficacy of ALB, confirmed in this present study, indicate that it is not possible to propose an efficacy threshold for this parasite based on our data. In conclusion, the present study is the first to evaluate drug efficacy of a single-oral dose of ALB on such a scale and across three continents. The results confirm the therapeutic efficacy of this treatment against A. lumbricoides and hookworms, and the low efficacy against T. trichiura. Efficacy varied widely across the seven different trials, particularly in the case of T. trichiura and it remains unclear which factors were principally responsible for this variation, although pre-intervention FEC and age played clear roles in this respect. The FEC reduction rate based on arithmetic means is the best available indicator of drug efficacy, and should be adopted in future monitoring and evaluation studies of large scale anthelmintic treatment programs. Finally, our findings emphasize the need to revise the WHO recommended efficacy threshold for single dose ALB treatments. Supporting Information Checklist S1 CONSORT Checklist (0.22 MB DOC) Click here for additional data file. Protocol S1 Trial Protocol (1.17 MB PDF) Click here for additional data file.
Author and article information
Contributors
Patrick J. Lammie: Role: Editor
Journal
Journal ID (nlm-ta): PLoS Negl Trop Dis
Journal ID (iso-abbrev): PLoS Negl Trop Dis
Journal ID (publisher-id): plos
Journal ID (pmc): plosntds
Title:
PLoS Neglected Tropical Diseases
Publisher:
Public Library of Science
(San Francisco, USA
)
ISSN
(Print):
1935-2727
ISSN
(Electronic):
1935-2735
Publication date Collection:
February
2013
Publication date
(Electronic):
28
February
2013
Volume: 7
Issue: 2
Electronic Location Identifier: e2027
Affiliations
[1
]London Centre for Neglected Tropical Diseases, Department of Infectious Disease Epidemiology,
School of Public Health, Imperial College London, London, United Kingdom
[2
]Partnership for Child Development, Department of Infectious Disease Epidemiology,
School of Public Health, Imperial College London, London, United Kingdom
[3
]Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical
Medicine, London, United Kingdom
Author notes
* E-mail:
roy.anderson@
123456imperial.ac.uk
(RMA);
d.hollingsworth@
123456imperial.ac.uk
(TDH)
Article
Publisher ID: PNTD-D-12-00742DOI: 10.1371/journal.pntd.0002027
PMC ID: 3585037
PubMed ID: 23469293
SO-VID: e6a672e1-c1fb-4daa-8bfb-1d0336200e8a
Copyright statement:
Copyright @
2013
License:
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 1
June
2012
Date
accepted
: 7
December
2012
Related
Epidemiologic Models, Key Logs, and Realizing the Promise of WHA 54.19
Page count
Pages: 15
Funding
The authors gratefully acknowledge grant support for this research from the Bill and
Melinda Gates Foundation and the Partnership for Child Development. SJB is supported
by a Senior Fellowship in Basic Biomedical Science from the Wellcome Trust (098045),
which also funds RLP. RMA thanks GSK for Centre Funding. TDH gratefully acknowledges
Imperial College London for funding of her Junior Research Fellowship, the Vaccine
Modelling Initiative, funded by the Bill and Melinda Gates Foundation, and the Medical
Research Council for Centre Funding. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Categories
Subject:
Research Article
Subject:
Biology
Subject:
Computational Biology
Subject:
Population Modeling
Subject:
Infectious Disease Modeling
Subject:
Population Biology
Subject:
Epidemiology
Subject:
Infectious Disease Epidemiology
Subject:
Medicine
Subject:
Epidemiology
Subject:
Infectious Disease Epidemiology
Subject:
Infectious Diseases
Subject:
Neglected Tropical Diseases
Subject:
Soil-Transmitted Helminths
Subject:
Parasitic Diseases
Subject:
Soil-Transmitted Helminths
ScienceOpen disciplines: Infectious disease & Microbiology
Data availability:
ScienceOpen disciplines: Infectious disease & Microbiology