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Oral Drug Therapy for Multiple Neglected Tropical Diseases: A Systematic Review

Oral Drug Therapy for Multiple Neglected Tropical Diseases: A Systematic Review Abstract Context The neglected tropical diseases include 13 conditions that occur in areas of extreme poverty and are poverty promoting. The neglected tropical diseases produce a disease burden almost as great as that associated with human immunodeficiency virus/AIDS, tuberculosis, or malaria, yet are virtually unknown by health care workers in North America, because they occur almost exclusively in the poorest regions of the world. Seven of the most prevalent diseases have existing oral drug treatments. Identifying treatments that are effective against more than 1 disease could facilitate efficient and inexpensive treatment. Objectives To systematically review the evidence for drug treatments and to increase awareness that neglected tropical diseases exist and that treatments are available. Data Sources and Study Selection Using a MEDLINE search (1966 through June 2007), randomized controlled trials (RCTs) were reviewed that examined simultaneous treatment of 2 or more of the 7 most prevalent neglected tropical diseases using oral drug therapy. Data Synthesis Twenty-nine RCTs were identified, of which 3 targeted 4 diseases simultaneously, 20 targeted 3 diseases, and 6 targeted 2 diseases. Trials were published between 1972 and 2005 and baseline prevalence of individual diseases varied among RCTs. Albendazole plus diethylcarbamazine significantly reduced prevalence of elephantiasis (16.7% to 5.3%), hookworm (10.3% to 1.9%), roundworm (34.5% to 2.3%), and whipworm (55.5% to 40.3%). Albendazole plus ivermectin significantly reduced prevalence of elephantiasis (12.6% to 4.6%), hookworm (7.8% to 0%), roundworm (33.5% to 6.1%), and whipworm (42.7% to 8.9%). Levamisole plus mebendazole significantly reduced prevalence of hookworm (94.0% to 71.8%), roundworm (62.0% to 1.4%), and whipworm (93.1% to 74.5%). Pyrantel-oxantel significantly reduced hookworm (93.4% to 85.2%), roundworm (22.8% to 1.4%), and whipworm (86.8% to 59.5%), while albendazole alone significantly reduced prevalence of hookworm (8.1% to 1.3%), roundworm (28.4% to 0.9%), and whipworm (51.9% to 31.9%). No RCT examined treatment of river blindness or trachoma as part of an intervention to target 2 or more neglected tropical diseases. Adverse events were generally inadequately reported. Conclusions At least 2 of the most prevalent neglected tropical diseases can be treated simultaneously with existing oral drug treatments, facilitating effective and efficient treatment. Increasing awareness about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases. The neglected tropical diseases are a group of 13 infections that affect more than 1 billion people worldwide1,2 who live in extreme poverty.3 Although inexpensive oral drug therapies exist to treat these conditions, they are often not accessible to the affected populations, people who live in remote areas on less than US $2 a day and without access to health care. The perpetuation of neglected tropical diseases results in part from unsafe water, poor sanitation, and substandard housing conditions.4 Infection with neglected tropical diseases can trigger life-long disabilities, disfigurement, and social stigma, and the stigma in turn makes people, particularly women, reluctant to seek care.1 Left untreated, these conditions result in severe morbidity that could be prevented. Quiz Ref IDSeven of the 13 neglected tropical diseases are caused by worms (elephantiasis, guinea worm, hookworm, river blindness, roundworm, schistosomiasis, and whipworm), 3 are protozoal (African sleeping sickness, Chagas disease, and leishmaniasis) and the rest are bacterial (Buruli ulcer, leprosy, and trachoma). Trachoma is the leading cause of preventable blindness in the world,5 elephantiasis is the second-leading cause of permanent disability in the world (by causing disfigurement of legs and genitalia),6 and hookworm causes severe anemia and is consequently one of the most important maternal-child problems.1,7 Neglected tropical diseases contribute to 500 000 deaths per year.8 Additionally, these conditions result in 57 million disability-adjusted life-years lost annually, a number almost as high as that associated with human immunodeficiency virus (HIV)/AIDS, tuberculosis, or malaria.9Quiz Ref IDInfection with a neglected tropical disease may increase susceptibility to HIV/AIDS10 and worsen outcomes in those with HIV/AIDS, tuberculosis, or malaria.11 Neglected tropical diseases primarily affect younger individuals and can result in slowed growth and poor school performance in children and decreased work productivity in adults, thereby perpetuating poverty.12 Despite the huge impact of neglected tropical diseases worldwide, the ability to treat them is largely unknown in the general medical community, and there is little public awareness of and response to this problem.9 In part, this is the result of a skewed distribution of studies published in the general medical literature in which clinical trials generally have little relevance to the 10 leading causes of the global burden of disease.13 Furthermore, less than 1% of new drug development over the last 30 years has been aimed at advancing drug treatments for tropical diseases.14,15 Quiz Ref IDThere is a substantial geographic overlap of neglected tropical diseases, with up to 6 diseases occurring in a single region.12,16 A large proportion of people are infected with more than 1.12 Additionally, neglected tropical diseases often augment the deleterious effects of one another.17 Therefore, the World Health Organization (WHO) and others have advocated the implementation of an integrated approach to neglected tropical disease management that could use drug therapies that simultaneously target 2 or more neglected tropical diseases.12,18,19 By delivering treatments using the same health sector infrastructure (eg, population-based, annual mass drug distribution), an intervention could be more effective than if each disease was targeted separately.19 Control of these diseases could lead to poverty decline.20 We systematically reviewed the evidence from randomized controlled trials (RCTs) evaluating oral medications that treat multiple neglected tropical diseases simultaneously to determine which treatments could be effective for such an integrated approach. Methods Sample Selection We searched MEDLINE (1966 through June 2007) for RCTs studying oral drug treatments for neglected tropical diseases. When the search was not limited to language, we found 4 trials that were not published in English: 2 in Chinese, each of which studied hookworm, roundworm, and whipworm (1763 participants21 and 166 participants22); 1 in French, which studied hookworm, roundworm, and whipworm (186 participants23); and 1 in Russian, which studied hookworm and roundworm (119 participants24). Because there were few non–English-language trials identified and the total number of participants in these trials was small relative to the total number in our sample, we limited our study to English-language RCTs only. We included only the most prevalent neglected tropical diseases for which the WHO has identified the existence of effective oral drug therapy. Based on 2007 WHO data,1 the 7 most prevalent neglected tropical diseases are elephantiasis, hookworm, river blindness, roundworm, schistosomiasis, trachoma, and whipworm. (While leprosy is also treatable with oral drugs, it is not as highly prevalent.9,19) We included RCTs that studied simultaneous treatment of multiple neglected tropical diseases with an oral drug therapy (ie, single drug or combination of drug therapies). We organized the RCTs by whether 4, 3, or 2 neglected tropical diseases were targeted. Outcome Measures of Neglected Tropical Disease Management We included only RCTs that used cure rates, incidence, or prevalence (eg, when interventions were at the community level) as outcome measures because these measures could be studied uniformly across all 7 neglected tropical diseases. We also recorded the population eligible or excluded from each trial. Successful treatments of neglected tropical diseases may have beneficial effects on a variety of other important morbidity measures, such as growth parameters in children (height and weight), hemoglobin levels, and school performance. We recorded morbidity measures reported in these studies. We could not include details on all these measures or on intensity of infection (ie, worm burden) as their measurement varied between individual RCTs and for different neglected tropical diseases.25 RCTs considered by all 3 authors (M.R., S.R.K., and W.W.) to have met the inclusion criteria were included. There were no disagreements regarding which RCTs met the inclusion criteria. Quality Assessment Quality assessment of RCTs is essential in conducting meaningful systematic reviews,26 but a gold standard of RCT quality assessment does not exist.26,27 The 6 items we evaluated have been identified as important measures of RCT quality: (1) adequate allocation sequence generation (ie, use of an appropriate method to generate the sequence of randomization); (2) concealed treatment allocation; (3) adequate participant blinding; (4) adequate outcome assessor blinding; (5) handling of withdrawals and dropouts; and (6) intention-to-treat analysis.28,29 Allocation concealment and double-blinding are strongly related to treatment effects.30-33 If the participants or outcome assessors are blinded, the method of blinding should be appropriate and described in the article.34 Handling of patient attrition should always be assessed when evaluating the quality of an RCT,29 and use of intention-to-treat analysis can help to minimize bias by reducing overestimation of treatment effectiveness.35,36 Three authors (M.R., S.R.K., and W.W.) independently rated RCTs on each of these items. The 2 instances of disagreement were resolved by discussion. If an RCT provided no information about a quality criterion, the item was deemed to have not been performed and therefore scored as no.29,37-39 Rather than provide an arbitrary numerical score, we present data on each of these 6 elements separately for each RCT. Additionally, we examined the trials for reporting of adverse drug events using a set of parameters described by Ioannidis and Lau.40 The same 3 authors (M.R., S.R.K., and W.W.) determined whether the number of withdrawals and discontinuations of study treatment due to toxicity was reported, whether the number was given for each specific type of adverse event leading to withdrawal, and whether the severity of the adverse events was adequately defined. There were no instances in which one of the authors considered the reporting adequate and the others inadequate. We determined the number of participants who were randomized as well as the number who completed each trial. We used the number of participants who were randomized for our calculations of total participant numbers unless an RCT provided only the number of participants who completed the trial. Results All 13 neglected tropical diseases, their clinical descriptions, geographic distributions, and worldwide prevalence are described in Table 1. The 7 neglected tropical diseases that are the most prevalent and treatable with oral drugs are listed in order of decreasing prevalence (Table 1). These conditions range from roundworm (1.2 billion people infected worldwide) to river blindness (37 million people infected worldwide).1 For the 7 most prevalent neglected tropical diseases, we identified 29 RCTs that enrolled a total of 25 749 individuals.45-73 The Figure shows the study selection process. The prevalence of individual neglected tropical diseases varied considerably among the RCTs due to different settings and patient populations. Eight RCTs45-52 studied both children and adults (aged ≥20 years) and the remaining 21 RCTs53-73 studied children only. No RCTs evaluating oral drug treatments for multiple neglected tropical diseases studied river blindness or trachoma. Adverse events were poorly reported in all the RCTs. None of the trials reported the number of withdrawals and discontinuations of study treatment due to toxicity, and none adequately described the severity of reported adverse events. Depending on the trial, individuals needed to either live in a community that was endemic for the particular neglected tropical disease studied (prevalence or incidence reported), be a part of a group (ie, schoolchildren) in a region that was endemic for the neglected tropical diseases studied (prevalence or incidence reported), or test positive for at least 1 of the neglected tropical diseases studied (in which case, prevalence or cure rates were reported). Drug Therapy Interventions Targeting 4 Neglected Tropical Diseases Three RCTs evaluated drug therapy interventions that targeted 4 neglected tropical diseases simultaneously and included 3775 individuals (Table 2).53-55 All 3 RCTs53-55 met 4 of our 6 quality criteria, including adequate description of the generation of random allocation sequences and adequate blinding of participants and outcome assessors (Table 3). None of the RCTs performed intention-to-treat analyses. Elephantiasis, Hookworm, Roundworm, and Whipworm. Fox et al53 evaluated schoolchildren in Haiti and compared 4 treatment groups: albendazole, diethylcarbamazine, combination therapy (albendazole plus diethylcarbamazine), and placebo. This trial described withdrawals and dropouts but did not conceal and describe treatment allocation. Albendazole plus diethylcarbamazine reduced the prevalence of all 4 diseases (all P < .05) (Table 2). Albendazole alone was as efficacious as combination therapy at reducing the prevalence of hookworm (8.1% to 1.3%, P < .05), roundworm (28.4% to 0.9%, P < .05), and whipworm (51.9% to 31.9%, P < .05). Adverse drug event reporting was poor; the study stated that “no severe adverse events were reported by participants,” but no definition was provided as to what specifically constituted a severe adverse event. Fever was stated to be reported more frequently in individuals who received albendazole plus diethylcarbamazine than those who received albendazole alone (P = .007), but the severity and frequency of fever was not described. Beach et al54 also studied schoolchildren in Haiti and compared 4 groups: albendazole, ivermectin, combination therapy (albendazole plus ivermectin), and placebo. This study described withdrawals and dropouts but did not describe concealed treatment allocation. Albendazole plus ivermectin reduced the prevalence of elephantiasis, hookworm, roundworm, and whipworm (all P < .05) (Table 2). Albendazole alone also reduced the prevalence of hookworm (5.5% to 0%, P < .05), roundworm (28.3% to 5.6%, P < .05), and whipworm (42.5% to 18.1%, P < .05) but was significantly less effective for whipworm than albendazole plus ivermectin (P < .05). Adverse drug event reporting was poor; systemic adverse reactions were stated in the trial to have occurred more frequently and with greater severity in children treated with albendazole plus ivermectin or ivermectin alone, but the specific definition of a systemic adverse reaction was not provided. Hookworm, Roundworm, Schistosomiasis, and Whipworm. Olds et al55 studied schoolchildren in China, the Philippines, and Kenya using 4 interventions: albendazole, praziquantel, combination treatment (albendazole plus praziquantel), and placebo. This trial described concealed treatment allocation but did not detail withdrawals or dropouts. Forty-five days after commencement of treatment, albendazole reduced the prevalence of hookworm and roundworm (P <.001), and praziquantel reduced the prevalence of schistosomiasis (P<.001) compared with placebo (Table 2). The reduction in prevalence rates was not reported by country. It was not possible to interpret whether treatment effects lasted 1 year because more people were re-treated at 6 months. In 1 site (Kajiwe, Kenya), albendazole also reduced the prevalence of whipworm, although the exact prevalence was not stated. The authors stated that the cure rates for hookworm, roundworm, and schistosomiasis resulting from the combination of albendazole and praziquantel were the same as the cure rates resulting from administration of each drug separately, but no P value was given specifically for the combination treatment. Adverse drug event reporting was poor. Adverse events were not specifically defined and their individual frequencies were not stated. Use of praziquantel, alone or in combination with albendazole, was stated to be associated with significantly higher adverse event rates (abdominal pain and headache) than either albendazole alone or placebo. Albendazole alone was not reported to produce significantly more adverse events than placebo. Drug Therapy Interventions Targeting 3 Neglected Tropical Diseases Twenty RCTs evaluated drug therapy interventions for 3 neglected tropical diseases and included 18 201 individuals (Table 4).45-52,56-67 The quality of the 20 RCTs that studied 3 neglected tropical diseases was generally suboptimal (Table 3) and none of the trials described intention-to-treat analyses. We identified 5 RCTs that met 3 or more of our 6 quality criteria. All 5 of these trials studied hookworm, roundworm, and whipworm. We describe the 4 trials that had significant findings. Albonico et al56 studied schoolchildren in Zanzibar and compared 4 treatment groups: levamisole, mebendazole, combination therapy (levamisole plus mebendazole), and placebo. This study met 5 of our 6 quality criteria (Table 3). Levamisole plus mebendazole was more efficacious than the other 2 drug regimens compared with placebo in reducing the prevalence of hookworm, roundworm, and whipworm (all P < .001) (Table 4). Levamisole alone and mebendazole alone also each resulted in a significant reduction in prevalence of all 3 diseases, but the levamisole plus mebendazole combination produced a greater reduction in hookworm prevalence compared with either drug alone (P < .001). No adverse events were reported in any drug treatment group. Another study by Albonico et al57 in Zanzibar compared mebendazole, pyrantel-oxantel, and placebo. This study met 3 of our 6 quality criteria (Table 3); it did not adequately blind participants or describe withdrawals and dropouts. When compared with placebo, pyrantel-oxantel was more efficacious than mebendazole in reducing the prevalence of hookworm, roundworm, and whipworm (all P < .001) (Table 4). Mebendazole also significantly reduced the prevalence of all 3 diseases compared with placebo, but pyrantel-oxantel had a higher reduction in prevalence in whipworm (P < .01). Individuals receiving treatment reported no adverse events for either drug. Children were weighed for dose estimation of pyrantel-oxantel. Pene et al48 studied individuals aged 3 to 40 years in France and West Africa, comparing albendazole with placebo. They found that albendazole improved the cure rates more than placebo for all 3 diseases (94.2% for hookworm, 95.9% for roundworm, and 64.1% for whipworm). This study met 3 of our 6 quality criteria and did not describe concealed treatment allocation or describe withdrawals and dropouts (Table 3). Albendazole had no more adverse events than placebo. Finally, Yangco et al49 compared flubendazole with mebendazole in US individuals aged 3 to 61 years and found that both drugs had high cure rates for hookworm and roundworm, and had similar cure rates for the treatment of whipworm (P > .05) (Table 4). This study also only met 3 of our 6 quality criteria and did not describe the generation of allocation sequences or allocation concealment (Table 3). The study stated that individuals reported “no significant adverse events” for either drug but no definition of a significant adverse event was provided. Furthermore, this RCT was not specifically designed to address the issue of equivalence.74,75 Drug Therapy Interventions Studying 2 Neglected Tropical Diseases Six RCTs evaluated interventions for 2 neglected tropical diseases simultaneously and evaluated 3773 individuals (Table 5).68-73 The quality of the trials was poor with none fulfilling more than 2 of our 6 quality criteria (Table 3). One RCT73 evaluated a drug that is no longer available and 5 RCTs68,69,71-73 provided no data on adverse events. None of the trials described withdrawals and dropouts or performed intention-to-treat analyses. The quality of the studies make it difficult to interpret the efficacy and safety of any treatment regimens studied in these trials. Comment Quiz Ref IDOur results indicate that existing oral drug therapies could be used to treat 2 or more of the most prevalent neglected tropical diseases simultaneously and that 4 of the 7 most prevalent neglected tropical diseases may be treated with a single oral drug combination, based on results from Haiti, China, the Philippines, and Kenya.53-55 Oral drug treatments are available that could potentially treat the 7 most prevalent neglected tropical diseases individually, and the first RCT showing that a single oral drug treatment could control 2 or more neglected tropical diseases was published in 1977.51 Our findings support the simultaneous treatment of multiple neglected tropical diseases; that is, an integrated approach. Our work is consistent with global initiatives that advocate an integrated strategy to control the most prevalent neglected tropical diseases using existing drug therapies.6,76-79 Neglected tropical diseases are recognized as being a significant cause of poverty.80 Health and poverty are integrally related, and controlling neglected tropical diseases may be one realistic strategy to help eliminate extreme poverty.8,81 The United Nations' Millennium Development Goals, a series of objective targets endorsed by the international community, include the goal of halving the number of people living in extreme poverty by 2015.8,81 Six of the 7 most prevalent neglected tropical diseases are caused by worms, and the Millennium Project (an initiative that focuses on implementing the Millennium Development Goals) lists regular deworming of school-aged children as a simple intervention that could make a profound difference to survival and quality of life.82 Interventions against neglected tropical diseases should be considered investments in human capital and form a fundamental part of a plan to reduce global poverty. In addition to the obvious health benefits to the individuals with these diseases, these interventions result in enormous economic benefits by improving educational outcomes and worker productivity.19 A number of measures have recently been initiated to reduce the prevalence of neglected tropical diseases and public awareness of neglected tropical diseases shows signs of increasing.83-85 The US government has committed $15 million to support neglected tropical disease control.80 In October 2006, the Clinton Global Initiative helped launch the Global Network for Neglected Tropical Diseases Control, whose mission includes promoting an integrated approach as part of neglected tropical disease control efforts.86 In December 2006, the Bill & Melinda Gates Foundation announced $46.7 million in grants toward developing evidence that an integrated approach is an effective method of eliminating neglected tropical diseases.19 Pharmaceutical companies have committed to donating all of the drug therapies required for this integrated treatment approach.3,12,87 The drug donations are valued at more than US $1 billion and constitute the largest drug donation in history.16 Other drugs that can be used to control the 7 most prevalent neglected tropical diseases are inexpensive. For example, the Global Network for Neglected Tropical Diseases Control estimates that diethylcarbamazine costs approximately US $0.01 per dose, albendazole costs approximately $0.02 per dose when used for the control of worm infections, and pharmaceutical companies donate the drug free of charge when it is used for the control of elephantiasis.88 Ivermectin, mebendazole, and praziquantel are also donated.3,88 Fenwick et al20 estimate that approximately 500 million people at risk for neglected tropical diseases in Africa could be treated with 4 effective drug therapies at an annual cost of less than US $0.40 per person, including distribution and delivery costs. Future Directions Our review has shown that currently available simple drug treatments can simultaneously target as many as 4 neglected tropical diseases. However, more operational research is needed to determine the best implementation strategies for providing these oral drug therapies at a population level. The Global Network for Neglected Tropical Diseases Control and WHO have started to explore these issues.89,90 For example, at-risk populations may be difficult to reach because they live in remote areas or do not attend school. Studies are required in the affected regions where resources are limited to identify practical methods to coordinate and execute the proposed treatment plans. This type of research has been performed for trachoma91 and is needed for other neglected tropical diseases. Additionally, drug safety is an important concern. Adverse event reporting in all of the RCTs in our analysis was poor. Ten of the 29 RCTs did not state whether adverse events were assessed,58,60,62-64,68,69,71-73 and absence of reporting of adverse events is not equivalent to the absence of such events.40 In the 14 trials in our review that reported adverse events, event frequency and severity were not specified.45,47-49,51-55,59,61,66,67,70 The poor quality of the reporting of adverse events is not unique to neglected tropical disease research—the quality and quantity of drug safety reporting have been found largely inadequate across medical fields.40 Possible drug interactions when drugs for neglected tropical diseases are used in combination also need to be considered. Neglected tropical diseases occur predominantly in vulnerable populations that can be at risk for drug toxicity, making drug safety reporting a priority.92 Experts at WHO in 2002 concluded that until further research is completed, the risks of no treatment appear to outweigh the risks of treatment in areas endemic for hookworm, roundworm, schistosomiasis, and whipworm,93-95 but further study focusing on the safety of drug treatments for neglected tropical diseases is needed, particularly for children and women. One challenge raised by the mass administration of neglected tropical disease drug treatments is that the dosing of several drugs (eg, diethylcarbamazine, ivermectin, levamisole, praziquantel, pyrantel-oxantel) requires individualization by weight or height, especially in children. Further efforts are required to determine the optimal doses, duration of treatment, and dosing schedules in different settings. Furthermore, some of these drugs should not be given to vulnerable groups, such as pregnant women, nursing mothers, or very young children.96 High-quality research is needed to address issues of optimal drug delivery.8,12,96 There are also concerns related to drug efficacy. Further research is needed to identify particular geographic regions where specific drugs are most efficacious,56,97,98 to identify areas where drug resistance (a possible consequence of mass drug administration) is emerging,99 and to identify regions with high rates of reinfection.99-101 Combination therapy may be one method of delaying the possible occurrence of drug resistance.99 Future RCTs comparing 2 or more drug treatments may need to consider design issues such as therapeutic equivalence.74,75 This issue is particularly important when evaluating whether 2 drug therapies appear to work equally well for controlling neglected tropical diseases but differ in terms of adverse event profiles, efficacy in different geographic regions (such as in areas of drug resistance), or in special populations (such as children). An example of an RCT that evaluated therapeutic equivalence demonstrated that paromomycin, which is more convenient to administer, was noninferior to amphotericin B, which often requires weeks of hospitalization, for the treatment of visceral leishmaniasis in India.102 Two of the 7 most prevalent neglected tropical diseases (river blindness and trachoma) occur in the same areas of geographic overlap as the other most prevalent neglected tropical diseases and can be treated with oral drug therapies. Future RCTs should include river blindness and trachoma as part of an integrated drug therapy strategy to treat multiple neglected tropical diseases. Finally, the concept of integrating neglected tropical disease management should go beyond drug therapy as the solution. Longer-term goals include vaccine development, under way for some of the neglected tropical diseases,12 and morbidity control and suppression of transmission of these diseases.9Quiz Ref IDDrug-based control cannot achieve a permanent reduction in neglected tropical disease incidence without ancillary measures. A truly integrated treatment plan must also include fundamental public health measures such as access to clean water and adequate sanitation. Exceptional results can even be achieved solely with nonpharmacological measures, as exemplified by the effort led by former President Carter103 to eradicate Guinea worm globally, possible primarily because people are being educated to filter water with a mesh cloth prior to use.104 Limitations To permit cross-study comparisons, we included only studies that examined incidence, prevalence, or cure rates. Although neglected tropical disease treatments may promote beneficial reductions in morbidity measures, we could not include all of them since their evaluation varied for different neglected tropical diseases and among individual RCTs.25 Only 4 of the 29 trials reported on measures of morbidity.53-55,73 These are key measures (eg, height, weight, and hemoglobin) that should be considered in any study of neglected tropical disease control. Neglected tropical diseases are often chronic and severely disabling but not immediately life-threatening. Until there are effective cures such as vaccines, morbidity reduction is a critical benefit to consider in evaluating neglected tropical disease treatments. Other studies of neglected tropical disease control have used morbidity alone as their primary outcome.105 Incidence, prevalence, and cure rates as well as morbidity are all important aspects of current neglected tropical disease control. Future studies should consider including standardized morbidity outcomes. Another measure presented inconsistently was intensity of infection; 3 of the 29 RCTs did not include any such measure.50,55,61 Future studies should consider including intensity of infection to capture the full range of effects of treatments for neglected tropical diseases. Conclusions Integration of treatment across neglected tropical diseases can be facilitated by treating 2 or more diseases simultaneously. More operational research is needed in the affected geographic regions to address issues such as the most practical means of drug delivery and to delineate specific adverse events of drug therapy interventions in vulnerable populations. Awareness by the medical community and the public about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases. Back to top Article Information Corresponding Author: Madhuri Reddy, MD, MSc, Department of Medicine, Hebrew Rehabilitation Center, 1200 Center St, Boston, MA 02131 (madhurireddy@hrca.harvard.edu). Author Contributions: Dr Reddy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Reddy, Gill, Rochon. Acquisition of data: Reddy, Kalkar, Wu. Analysis and interpretation of data: Reddy, Gill, Kalkar, Wu, Anderson, Rochon. Drafting of the manuscript: Reddy. Critical revision of the manuscript for important intellectual content: Gill, Kalkar, Wu, Anderson, Rochon. Statistical analysis: Kalkar, Wu. Obtained funding: Rochon. Administrative, technical, or material support: Kalkar, Wu, Anderson. Study supervision: Rochon. Financial Disclosures: Dr Reddy reports receiving honoraria or consulting fees from Smith and Nephew, Molynlycke, and Merck. No other authors reported financial disclosures. Funding/Support: This work was supported by a Canadian Institutes of Health Research Interdisciplinary Capacity Enhancement grant H0A-80075. Dr Gill was supported by an Ontario Ministry of Health and Long-Term Care Career Scientist Award. Role of the Sponsors: The funding organizations did not participate in the design or conduct of the study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript. Additional Contributions: Peter Hotez, MD, PhD, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, and Nilanthi de Silva, MBBS, MSc (Lond), MD, University of Kelaniya, Sri Lanka, provided their insightful comments and review of the manuscript. Dr Hotez is co-chair of the Scientific Advisory Council of the Sabin Vaccine Institute, Connecticut, and a member of the Academic Advisory Board for the Pfizer Fellowships in Infectious Diseases. 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Evaluating measures to control intestinal parasitic infections. World Health Stat Q. 1992;45(2-3):168-1791462652Google Scholar 26. Verhagen AP, de Vet HC, de Bie RA. et al. The art of quality assessment of RCTs included in systematic reviews. J Clin Epidemiol. 2001;54(7):651-65411438404Google ScholarCrossref 27. Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17(1):1-128721797Google ScholarCrossref 28. Jüni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA. 1999;282(11):1054-106010493204Google ScholarCrossref 29. Jüni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ. 2001;323(7303):42-4611440947Google ScholarCrossref 30. Jüni P, Egger M. Allocation concealment in clinical trials. JAMA. 2002;288(19):2407-240812435252Google Scholar 31. 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Soil-transmitted helminth infections: updating the global picture. Trends Parasitol. 2003;19(12):547-55114642761Google ScholarCrossref 42. Sridharan R, Lorenzo N, Ranganathan LN, Govindarajan S. Leprosy. http://www.emedicine.com/neuro/topic187.htm. Accessed April 8, 2007 43. World Health Organization. African trypanosomiasis (sleeping sickness). http://www.who.int/mediacentre/factsheets/fs259/en/index.html. Accessed April 9, 2007 44. Hopkins DR, Ruiz-Tiben E, Downs P, Withers PC Jr, Maguire JH. Dracunculiasis eradication: the final inch. Am J Trop Med Hyg. 2005;73(4):669-67516222007Google Scholar 45. Marti H, Haji HJ, Savioli L. et al. A comparative trial of a single-dose ivermectin versus three days of albendazole for treatment of Strongyloides stercoralis and other soil-transmitted helminth infections in children. Am J Trop Med Hyg. 1996;55(5):477-4818940976Google Scholar 46. Jongsuksuntigul P, Jeradit C, Pornpattanakul S, Charanasri U. 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Trop Geogr Med. 1979;31(1):111-122483364Google Scholar 51. Farahmandian I, Arfaa F, Jalali H, Reza M. Comparative studies on the evaluation of the effect of new anthelminthics on various intestinal helminthiasis in Iran: effects of anthelminthics on intestinal helminthiasis. Chemotherapy. 1977;23(2):98-105318981Google ScholarCrossref 52. Legesse M, Erko B, Medhin G. Efficacy of alebendazole and mebendazole in the treatment of Ascaris and Trichuris infections. Ethiop Med J. 2002;40(4):335-34312596653Google Scholar 53. Fox LM, Furness BW, Haser JK. et al. Tolerance and efficacy of combined diethylcarbamazine and albendazole for treatment of Wuchereria bancrofti and intestinal helminth infections in Haitian children. Am J Trop Med Hyg. 2005;73(1):115-12116014845Google Scholar 54. Beach MJ, Streit TG, Addiss DG. et al. Assessment of combined ivermectin and albendazole for treatment of intestinal helminth and Wuchereria bancrofti infections in Haitian schoolchildren. Am J Trop Med Hyg. 1999;60(3):479-48610466981Google Scholar 55. Olds GR, King C, Hewlett J. et al. Double-blind placebo-controlled study of concurrent administration of albendazole and praziquantel in schoolchildren with schistosomiasis and geohelminths. J Infect Dis. 1999;179(4):996-100310068597Google ScholarCrossref 56. Albonico M, Bickle Q, Ramsan M. et al. Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar. Bull World Health Organ. 2003;81(5):343-35212856052Google Scholar 57. Albonico M, Bickle Q, Haji HJ. et al. Evaluation of the efficacy of pyrantel-oxantel for the treatment of soil-transmitted nematode infections. Trans R Soc Trop Med Hyg. 2002;96(6):685-69012625151Google ScholarCrossref 58. Albonico M, Stoltzfus RJ, Savioli L. et al. A controlled evaluation of two school-based antihelminthic chemotherapy regimens on intensity of intestinal helminth infections. Int J Epidemiol. 1999;28(3):591-59610405869Google ScholarCrossref 59. Albonico M, Smith PG, Hall A. et al. A randomized controlled trial comparing mebendazole and albendazole against Ascaris , Trichuris and hookworm infections. Trans R Soc Trop Med Hyg. 1994;88(5):585-5897992348Google ScholarCrossref 60. Muchiri EM, Thiong'o FW, Magnussen P, Ouma JH. A comparative study of different albendazole and mebendazole regimens for the treatment of intestinal infections in school children of Usigu Division, western Kenya. J Parasitol. 2001;87(2):413-41811318574Google Scholar 61. Rahman WA. Comparative trials using albendazole and mebendazole in the treatment of soil-transmitted helminths in schoolchildren on Penang, Malaysia. Southeast Asian J Trop Med Public Health. 1996;27(4):765-7679253881Google Scholar 62. Sorensen E, Ismail M, Amarasinghe DK, Hettiarachchi I. The efficacy of three antihelminthic drugs given in a single dose. Ceylon Med J. 1996;41(2):42-458771941Google Scholar 63. Wesche D, Barnish G. A comparative study of the effectiveness of mebendazole (Janssen) and generically equivalent mebendazole (Nordia) in intestinal helminthiasis in Papua New Guinean children. P N G Med J. 1994;37(1):7-117863731Google Scholar 64. Wesche D, Lutz S, Barnish G. Comparative study of chewable pyrantel pamoate: should standards for chewable tablets be revised? P N G Med J. 1994;37(1):12-147863722Google Scholar 65. Bartoloni A, Guglielmetti P, Cancrini G. et al. Comparative efficacy of a single 400 mg dose of albendazole or mebendazole in the treatment of nematode infections in children. Trop Geogr Med. 1993;45(3):114-1168362451Google Scholar 66. Sinniah B, Sinniah D. The anthelmintic effects of pyrantel pamoate, oxantel-pyrantel pamoate, levamisole and mebendazole in the treatment of intestinal nematodes. Ann Trop Med Parasitol. 1981;75(3):315-3217305501Google Scholar 67. Lucas AO, Oduntan SO. Treatment of hookworm infection and other intestinal parasites with 1-tetramisole (Ketrax). Ann Trop Med Parasitol. 1972;66(3):391-3984634781Google Scholar 68. Charoenlarp P, Waikagul J, Muennoo C. et al. Efficacy of single-dose mebendazole, polymorphic forms A and C, in the treatment of hookworm and Trichuris infections. Southeast Asian J Trop Med Public Health. 1993;24(4):712-7167939946Google Scholar 69. Legesse M, Erko B, Medhin G. Comparative efficacy of albendazole and three brands of mebendazole in the treatment of ascariasis and trichuriasis. East Afr Med J. 2004;81(3):134-13815293971Google Scholar 70. Juan JO, Lopez Chegne N, Gargala G, Favennec L. Comparative clinical studies of nitazoxanide, albendazole and praziquantel in the treatment of ascariasis, trichuriasis and hymenolepiasis in children from Peru. Trans R Soc Trop Med Hyg. 2002;96(2):193-19612055813Google ScholarCrossref 71. Hall A, Nahar Q. Albendazole and infections with Ascaris lumbricoides and Trichuris trichiura in children in Bangladesh. Trans R Soc Trop Med Hyg. 1994;88(1):110-1128153985Google ScholarCrossref 72. Belizario VY, Amarillo ME, de Leon WU. et al. A comparison of the efficacy of single doses of albendazole, ivermectin, and diethylcarbamazine alone or in combinations against Ascaris and Trichuris spp. Bull World Health Organ. 2003;81(1):35-4212640474Google Scholar 73. Stephenson LS, Kinoti SN, Latham MC, Kurz KM, Kyobe J. Single dose metrifonate or praziquantel treatment in Kenyan children, I: effects on Schistosoma haematobium , hookworm, hemoglobin levels, splenomegaly, and hepatomegaly. Am J Trop Med Hyg. 1989;41(4):436-4442508501Google Scholar 74. Greene WL, Concato J, Feinstein AR. Claims of equivalence in medical research: are they supported by the evidence? Ann Intern Med. 2000;132(9):715-72210787365Google ScholarCrossref 75. Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med. 2006;145(1):62-6916818930Google ScholarCrossref 76. Schistosomiasis Control Initiative. Integrated mass treatment of the neglected tropical diseases in Niger. http://www.schisto.org/Niger/NigerNTDlaunch.htm. Accessed August 4, 2007 77. The Global Alliance to Eliminate Lymphatic Filariasis Web site. http://www.filariasis.org/. Accessed August 4, 2007 78. Jimmy Carter and General Dr. Yakubu Gowon encourage Nigerian officials to control schistosomiasis, other diseases [press release]. February 15, 2007. The Carter Center Web site. http://www.cartercenter.org/news/pr/nigeria_021507.html. Accessed August 4, 2007 79. Hotez PJ, Bundy DAP, Beegle K. et al. Helminth infections: soil-transmitted helminth infections and schistosomiasis. In: Jamison DT, ed. Disease Control Priorities in Developing Countries. 2nd ed. New York, NY: Oxford University Press; 2006:467-482 80. Sachs JD. The neglected tropical diseases [abstract]. Sci Am. 2007;296(1):33A17186830Google ScholarCrossref 81. Sachs JD. The End of Poverty: Economic Possibilities for Our Time. New York, NY: Penguin Press; 2005 82. Sachs JD, McArthur JW. The Millennium Project: a plan for meeting the Millennium Development Goals. Lancet. 2005;365(9456):347-35315664232Google Scholar 83. Kristof ND. Attack of the worms. New York Times. July 2, 2007 84. Global Network for Neglected Tropical Disease Control. Alyssa Milano named founding ambassador of global network for neglected tropical disease control [press release]. http://gnntdc.sabin.org/files/sabin_milano_announcement_release__06_28_07.pdf. Accessed August 4, 2007 85. Yamey G, Hotez P. Neglected tropical diseases. BMJ. 2007;335(7614):269-27017690342Google ScholarCrossref 86. Global Network for Neglected Tropical Disease Control. Global network for neglected tropical disease control chairman and founder, Dr. Peter Hotez, named ambassador in Paul G. Rogers Society for Global Health [press release]. http://gnntdc.sabin.org/files/documents/Paul%20G%20Rogers%20-%20Hotez%20Appointment.pdf. Published November 16, 2006. Accessibility verified September 20, 2007 87. Hotez P, Ottesen E, Fenwick A, Molyneux D. The neglected tropical diseases: the ancient afflictions of stigma and poverty and the prospects for their control and elimination. Adv Exp Med Biol. 2006;582:23-3316802616Google Scholar 88. Global Network for Neglected Tropical Disease Control. Control of NTDs. http://gnntdc.sabin.org/what/control.html#Drug%20Donations. Accessed July 19, 2007 89. Global Network for Neglected Tropical Diseases Web site. http://gnntdc.sabin.org/network/index.html. Accessed September 26, 2007 90. Hotez PJ, Molyneux DH, Fenwick A. et al. Control of neglected tropical diseases. N Engl J Med. 2007;357(10):1018-1027Google ScholarCrossref 91. Lietman TM, Neuwelt MD, Gandhi NG, Dalman CA, Benitah N. Trachoma research: it takes more than a village. Lancet. 2006;367(9508):39516458760Google ScholarCrossref 92. Global Network for Neglected Tropical Diseases Web site. Neglected tropical diseases, malaria and HIV/AIDS. http://gnntdc.sabin.org/what/ntds.html. Accessed September 26, 2007 93. World Health Organization. Report of the WHO informal consultation on the use of praziquantel during pregnancy and lactation and albendazole/mebendazole in children under 24 months, April 8-9, 2002. http://www.who.int/wormcontrol/documents/en/pvc_20024full.pdf. Accessibility verified September 27, 2007 94. Savioli L, Crompton DW, Neira M. Use of anthelminthic drugs during pregnancy. Am J Obstet Gynecol. 2003;188(1):5-612548188Google ScholarCrossref 95. World Health Organization. Report of the WHO informal consultation on hookworm infection and anaemia in girls and women: Geneva December 5-6, 1994. http://www.who.int/wormcontrol/documents/publications/en/96-1.pdf. Accessibility verified September 20, 2007 96. World Health Organization. Preventive chemotherapy in human helminthiasis. http://whqlibdoc.who.int/publications/2006/9241547103_eng.pdf. Accessed September 9, 2007 97. Hotez P, Bethony J, Brooker S, Albonico M. Eliminating neglected diseases in Africa. Lancet. 2005;365(9477):208915964442Google ScholarCrossref 98. Behnke JM, Pritchard DI, Wakelin D. et al. Effect of ivermectin on infection with gastro-intestinal nematodes in Sierra Leone. J Helminthol. 1994;68(3):187-1957829838Google ScholarCrossref 99. Albonico M, Engels D, Savioli L. Monitoring drug efficacy and early detection of drug resistance in human soil-transmitted nematodes. Int J Parasitol. 2004;34(11):1205-121015491582Google ScholarCrossref 100. Albonico M, Smith PG, Ercole E. et al. Rate of reinfection with intestinal nematodes after treatment of children with mebendazole or albenadazole in a highly endemic area. Trans R Soc Trop Med Hyg. 1995;89(5):538-5418560535Google ScholarCrossref 101. Leach AJ, Shelby-James TM, Mayo M. et al. 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Oral Drug Therapy for Multiple Neglected Tropical Diseases: A Systematic Review

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References (110)

Publisher
American Medical Association
Copyright
Copyright © 2007 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.298.16.1911
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Abstract

Abstract Context The neglected tropical diseases include 13 conditions that occur in areas of extreme poverty and are poverty promoting. The neglected tropical diseases produce a disease burden almost as great as that associated with human immunodeficiency virus/AIDS, tuberculosis, or malaria, yet are virtually unknown by health care workers in North America, because they occur almost exclusively in the poorest regions of the world. Seven of the most prevalent diseases have existing oral drug treatments. Identifying treatments that are effective against more than 1 disease could facilitate efficient and inexpensive treatment. Objectives To systematically review the evidence for drug treatments and to increase awareness that neglected tropical diseases exist and that treatments are available. Data Sources and Study Selection Using a MEDLINE search (1966 through June 2007), randomized controlled trials (RCTs) were reviewed that examined simultaneous treatment of 2 or more of the 7 most prevalent neglected tropical diseases using oral drug therapy. Data Synthesis Twenty-nine RCTs were identified, of which 3 targeted 4 diseases simultaneously, 20 targeted 3 diseases, and 6 targeted 2 diseases. Trials were published between 1972 and 2005 and baseline prevalence of individual diseases varied among RCTs. Albendazole plus diethylcarbamazine significantly reduced prevalence of elephantiasis (16.7% to 5.3%), hookworm (10.3% to 1.9%), roundworm (34.5% to 2.3%), and whipworm (55.5% to 40.3%). Albendazole plus ivermectin significantly reduced prevalence of elephantiasis (12.6% to 4.6%), hookworm (7.8% to 0%), roundworm (33.5% to 6.1%), and whipworm (42.7% to 8.9%). Levamisole plus mebendazole significantly reduced prevalence of hookworm (94.0% to 71.8%), roundworm (62.0% to 1.4%), and whipworm (93.1% to 74.5%). Pyrantel-oxantel significantly reduced hookworm (93.4% to 85.2%), roundworm (22.8% to 1.4%), and whipworm (86.8% to 59.5%), while albendazole alone significantly reduced prevalence of hookworm (8.1% to 1.3%), roundworm (28.4% to 0.9%), and whipworm (51.9% to 31.9%). No RCT examined treatment of river blindness or trachoma as part of an intervention to target 2 or more neglected tropical diseases. Adverse events were generally inadequately reported. Conclusions At least 2 of the most prevalent neglected tropical diseases can be treated simultaneously with existing oral drug treatments, facilitating effective and efficient treatment. Increasing awareness about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases. The neglected tropical diseases are a group of 13 infections that affect more than 1 billion people worldwide1,2 who live in extreme poverty.3 Although inexpensive oral drug therapies exist to treat these conditions, they are often not accessible to the affected populations, people who live in remote areas on less than US $2 a day and without access to health care. The perpetuation of neglected tropical diseases results in part from unsafe water, poor sanitation, and substandard housing conditions.4 Infection with neglected tropical diseases can trigger life-long disabilities, disfigurement, and social stigma, and the stigma in turn makes people, particularly women, reluctant to seek care.1 Left untreated, these conditions result in severe morbidity that could be prevented. Quiz Ref IDSeven of the 13 neglected tropical diseases are caused by worms (elephantiasis, guinea worm, hookworm, river blindness, roundworm, schistosomiasis, and whipworm), 3 are protozoal (African sleeping sickness, Chagas disease, and leishmaniasis) and the rest are bacterial (Buruli ulcer, leprosy, and trachoma). Trachoma is the leading cause of preventable blindness in the world,5 elephantiasis is the second-leading cause of permanent disability in the world (by causing disfigurement of legs and genitalia),6 and hookworm causes severe anemia and is consequently one of the most important maternal-child problems.1,7 Neglected tropical diseases contribute to 500 000 deaths per year.8 Additionally, these conditions result in 57 million disability-adjusted life-years lost annually, a number almost as high as that associated with human immunodeficiency virus (HIV)/AIDS, tuberculosis, or malaria.9Quiz Ref IDInfection with a neglected tropical disease may increase susceptibility to HIV/AIDS10 and worsen outcomes in those with HIV/AIDS, tuberculosis, or malaria.11 Neglected tropical diseases primarily affect younger individuals and can result in slowed growth and poor school performance in children and decreased work productivity in adults, thereby perpetuating poverty.12 Despite the huge impact of neglected tropical diseases worldwide, the ability to treat them is largely unknown in the general medical community, and there is little public awareness of and response to this problem.9 In part, this is the result of a skewed distribution of studies published in the general medical literature in which clinical trials generally have little relevance to the 10 leading causes of the global burden of disease.13 Furthermore, less than 1% of new drug development over the last 30 years has been aimed at advancing drug treatments for tropical diseases.14,15 Quiz Ref IDThere is a substantial geographic overlap of neglected tropical diseases, with up to 6 diseases occurring in a single region.12,16 A large proportion of people are infected with more than 1.12 Additionally, neglected tropical diseases often augment the deleterious effects of one another.17 Therefore, the World Health Organization (WHO) and others have advocated the implementation of an integrated approach to neglected tropical disease management that could use drug therapies that simultaneously target 2 or more neglected tropical diseases.12,18,19 By delivering treatments using the same health sector infrastructure (eg, population-based, annual mass drug distribution), an intervention could be more effective than if each disease was targeted separately.19 Control of these diseases could lead to poverty decline.20 We systematically reviewed the evidence from randomized controlled trials (RCTs) evaluating oral medications that treat multiple neglected tropical diseases simultaneously to determine which treatments could be effective for such an integrated approach. Methods Sample Selection We searched MEDLINE (1966 through June 2007) for RCTs studying oral drug treatments for neglected tropical diseases. When the search was not limited to language, we found 4 trials that were not published in English: 2 in Chinese, each of which studied hookworm, roundworm, and whipworm (1763 participants21 and 166 participants22); 1 in French, which studied hookworm, roundworm, and whipworm (186 participants23); and 1 in Russian, which studied hookworm and roundworm (119 participants24). Because there were few non–English-language trials identified and the total number of participants in these trials was small relative to the total number in our sample, we limited our study to English-language RCTs only. We included only the most prevalent neglected tropical diseases for which the WHO has identified the existence of effective oral drug therapy. Based on 2007 WHO data,1 the 7 most prevalent neglected tropical diseases are elephantiasis, hookworm, river blindness, roundworm, schistosomiasis, trachoma, and whipworm. (While leprosy is also treatable with oral drugs, it is not as highly prevalent.9,19) We included RCTs that studied simultaneous treatment of multiple neglected tropical diseases with an oral drug therapy (ie, single drug or combination of drug therapies). We organized the RCTs by whether 4, 3, or 2 neglected tropical diseases were targeted. Outcome Measures of Neglected Tropical Disease Management We included only RCTs that used cure rates, incidence, or prevalence (eg, when interventions were at the community level) as outcome measures because these measures could be studied uniformly across all 7 neglected tropical diseases. We also recorded the population eligible or excluded from each trial. Successful treatments of neglected tropical diseases may have beneficial effects on a variety of other important morbidity measures, such as growth parameters in children (height and weight), hemoglobin levels, and school performance. We recorded morbidity measures reported in these studies. We could not include details on all these measures or on intensity of infection (ie, worm burden) as their measurement varied between individual RCTs and for different neglected tropical diseases.25 RCTs considered by all 3 authors (M.R., S.R.K., and W.W.) to have met the inclusion criteria were included. There were no disagreements regarding which RCTs met the inclusion criteria. Quality Assessment Quality assessment of RCTs is essential in conducting meaningful systematic reviews,26 but a gold standard of RCT quality assessment does not exist.26,27 The 6 items we evaluated have been identified as important measures of RCT quality: (1) adequate allocation sequence generation (ie, use of an appropriate method to generate the sequence of randomization); (2) concealed treatment allocation; (3) adequate participant blinding; (4) adequate outcome assessor blinding; (5) handling of withdrawals and dropouts; and (6) intention-to-treat analysis.28,29 Allocation concealment and double-blinding are strongly related to treatment effects.30-33 If the participants or outcome assessors are blinded, the method of blinding should be appropriate and described in the article.34 Handling of patient attrition should always be assessed when evaluating the quality of an RCT,29 and use of intention-to-treat analysis can help to minimize bias by reducing overestimation of treatment effectiveness.35,36 Three authors (M.R., S.R.K., and W.W.) independently rated RCTs on each of these items. The 2 instances of disagreement were resolved by discussion. If an RCT provided no information about a quality criterion, the item was deemed to have not been performed and therefore scored as no.29,37-39 Rather than provide an arbitrary numerical score, we present data on each of these 6 elements separately for each RCT. Additionally, we examined the trials for reporting of adverse drug events using a set of parameters described by Ioannidis and Lau.40 The same 3 authors (M.R., S.R.K., and W.W.) determined whether the number of withdrawals and discontinuations of study treatment due to toxicity was reported, whether the number was given for each specific type of adverse event leading to withdrawal, and whether the severity of the adverse events was adequately defined. There were no instances in which one of the authors considered the reporting adequate and the others inadequate. We determined the number of participants who were randomized as well as the number who completed each trial. We used the number of participants who were randomized for our calculations of total participant numbers unless an RCT provided only the number of participants who completed the trial. Results All 13 neglected tropical diseases, their clinical descriptions, geographic distributions, and worldwide prevalence are described in Table 1. The 7 neglected tropical diseases that are the most prevalent and treatable with oral drugs are listed in order of decreasing prevalence (Table 1). These conditions range from roundworm (1.2 billion people infected worldwide) to river blindness (37 million people infected worldwide).1 For the 7 most prevalent neglected tropical diseases, we identified 29 RCTs that enrolled a total of 25 749 individuals.45-73 The Figure shows the study selection process. The prevalence of individual neglected tropical diseases varied considerably among the RCTs due to different settings and patient populations. Eight RCTs45-52 studied both children and adults (aged ≥20 years) and the remaining 21 RCTs53-73 studied children only. No RCTs evaluating oral drug treatments for multiple neglected tropical diseases studied river blindness or trachoma. Adverse events were poorly reported in all the RCTs. None of the trials reported the number of withdrawals and discontinuations of study treatment due to toxicity, and none adequately described the severity of reported adverse events. Depending on the trial, individuals needed to either live in a community that was endemic for the particular neglected tropical disease studied (prevalence or incidence reported), be a part of a group (ie, schoolchildren) in a region that was endemic for the neglected tropical diseases studied (prevalence or incidence reported), or test positive for at least 1 of the neglected tropical diseases studied (in which case, prevalence or cure rates were reported). Drug Therapy Interventions Targeting 4 Neglected Tropical Diseases Three RCTs evaluated drug therapy interventions that targeted 4 neglected tropical diseases simultaneously and included 3775 individuals (Table 2).53-55 All 3 RCTs53-55 met 4 of our 6 quality criteria, including adequate description of the generation of random allocation sequences and adequate blinding of participants and outcome assessors (Table 3). None of the RCTs performed intention-to-treat analyses. Elephantiasis, Hookworm, Roundworm, and Whipworm. Fox et al53 evaluated schoolchildren in Haiti and compared 4 treatment groups: albendazole, diethylcarbamazine, combination therapy (albendazole plus diethylcarbamazine), and placebo. This trial described withdrawals and dropouts but did not conceal and describe treatment allocation. Albendazole plus diethylcarbamazine reduced the prevalence of all 4 diseases (all P < .05) (Table 2). Albendazole alone was as efficacious as combination therapy at reducing the prevalence of hookworm (8.1% to 1.3%, P < .05), roundworm (28.4% to 0.9%, P < .05), and whipworm (51.9% to 31.9%, P < .05). Adverse drug event reporting was poor; the study stated that “no severe adverse events were reported by participants,” but no definition was provided as to what specifically constituted a severe adverse event. Fever was stated to be reported more frequently in individuals who received albendazole plus diethylcarbamazine than those who received albendazole alone (P = .007), but the severity and frequency of fever was not described. Beach et al54 also studied schoolchildren in Haiti and compared 4 groups: albendazole, ivermectin, combination therapy (albendazole plus ivermectin), and placebo. This study described withdrawals and dropouts but did not describe concealed treatment allocation. Albendazole plus ivermectin reduced the prevalence of elephantiasis, hookworm, roundworm, and whipworm (all P < .05) (Table 2). Albendazole alone also reduced the prevalence of hookworm (5.5% to 0%, P < .05), roundworm (28.3% to 5.6%, P < .05), and whipworm (42.5% to 18.1%, P < .05) but was significantly less effective for whipworm than albendazole plus ivermectin (P < .05). Adverse drug event reporting was poor; systemic adverse reactions were stated in the trial to have occurred more frequently and with greater severity in children treated with albendazole plus ivermectin or ivermectin alone, but the specific definition of a systemic adverse reaction was not provided. Hookworm, Roundworm, Schistosomiasis, and Whipworm. Olds et al55 studied schoolchildren in China, the Philippines, and Kenya using 4 interventions: albendazole, praziquantel, combination treatment (albendazole plus praziquantel), and placebo. This trial described concealed treatment allocation but did not detail withdrawals or dropouts. Forty-five days after commencement of treatment, albendazole reduced the prevalence of hookworm and roundworm (P <.001), and praziquantel reduced the prevalence of schistosomiasis (P<.001) compared with placebo (Table 2). The reduction in prevalence rates was not reported by country. It was not possible to interpret whether treatment effects lasted 1 year because more people were re-treated at 6 months. In 1 site (Kajiwe, Kenya), albendazole also reduced the prevalence of whipworm, although the exact prevalence was not stated. The authors stated that the cure rates for hookworm, roundworm, and schistosomiasis resulting from the combination of albendazole and praziquantel were the same as the cure rates resulting from administration of each drug separately, but no P value was given specifically for the combination treatment. Adverse drug event reporting was poor. Adverse events were not specifically defined and their individual frequencies were not stated. Use of praziquantel, alone or in combination with albendazole, was stated to be associated with significantly higher adverse event rates (abdominal pain and headache) than either albendazole alone or placebo. Albendazole alone was not reported to produce significantly more adverse events than placebo. Drug Therapy Interventions Targeting 3 Neglected Tropical Diseases Twenty RCTs evaluated drug therapy interventions for 3 neglected tropical diseases and included 18 201 individuals (Table 4).45-52,56-67 The quality of the 20 RCTs that studied 3 neglected tropical diseases was generally suboptimal (Table 3) and none of the trials described intention-to-treat analyses. We identified 5 RCTs that met 3 or more of our 6 quality criteria. All 5 of these trials studied hookworm, roundworm, and whipworm. We describe the 4 trials that had significant findings. Albonico et al56 studied schoolchildren in Zanzibar and compared 4 treatment groups: levamisole, mebendazole, combination therapy (levamisole plus mebendazole), and placebo. This study met 5 of our 6 quality criteria (Table 3). Levamisole plus mebendazole was more efficacious than the other 2 drug regimens compared with placebo in reducing the prevalence of hookworm, roundworm, and whipworm (all P < .001) (Table 4). Levamisole alone and mebendazole alone also each resulted in a significant reduction in prevalence of all 3 diseases, but the levamisole plus mebendazole combination produced a greater reduction in hookworm prevalence compared with either drug alone (P < .001). No adverse events were reported in any drug treatment group. Another study by Albonico et al57 in Zanzibar compared mebendazole, pyrantel-oxantel, and placebo. This study met 3 of our 6 quality criteria (Table 3); it did not adequately blind participants or describe withdrawals and dropouts. When compared with placebo, pyrantel-oxantel was more efficacious than mebendazole in reducing the prevalence of hookworm, roundworm, and whipworm (all P < .001) (Table 4). Mebendazole also significantly reduced the prevalence of all 3 diseases compared with placebo, but pyrantel-oxantel had a higher reduction in prevalence in whipworm (P < .01). Individuals receiving treatment reported no adverse events for either drug. Children were weighed for dose estimation of pyrantel-oxantel. Pene et al48 studied individuals aged 3 to 40 years in France and West Africa, comparing albendazole with placebo. They found that albendazole improved the cure rates more than placebo for all 3 diseases (94.2% for hookworm, 95.9% for roundworm, and 64.1% for whipworm). This study met 3 of our 6 quality criteria and did not describe concealed treatment allocation or describe withdrawals and dropouts (Table 3). Albendazole had no more adverse events than placebo. Finally, Yangco et al49 compared flubendazole with mebendazole in US individuals aged 3 to 61 years and found that both drugs had high cure rates for hookworm and roundworm, and had similar cure rates for the treatment of whipworm (P > .05) (Table 4). This study also only met 3 of our 6 quality criteria and did not describe the generation of allocation sequences or allocation concealment (Table 3). The study stated that individuals reported “no significant adverse events” for either drug but no definition of a significant adverse event was provided. Furthermore, this RCT was not specifically designed to address the issue of equivalence.74,75 Drug Therapy Interventions Studying 2 Neglected Tropical Diseases Six RCTs evaluated interventions for 2 neglected tropical diseases simultaneously and evaluated 3773 individuals (Table 5).68-73 The quality of the trials was poor with none fulfilling more than 2 of our 6 quality criteria (Table 3). One RCT73 evaluated a drug that is no longer available and 5 RCTs68,69,71-73 provided no data on adverse events. None of the trials described withdrawals and dropouts or performed intention-to-treat analyses. The quality of the studies make it difficult to interpret the efficacy and safety of any treatment regimens studied in these trials. Comment Quiz Ref IDOur results indicate that existing oral drug therapies could be used to treat 2 or more of the most prevalent neglected tropical diseases simultaneously and that 4 of the 7 most prevalent neglected tropical diseases may be treated with a single oral drug combination, based on results from Haiti, China, the Philippines, and Kenya.53-55 Oral drug treatments are available that could potentially treat the 7 most prevalent neglected tropical diseases individually, and the first RCT showing that a single oral drug treatment could control 2 or more neglected tropical diseases was published in 1977.51 Our findings support the simultaneous treatment of multiple neglected tropical diseases; that is, an integrated approach. Our work is consistent with global initiatives that advocate an integrated strategy to control the most prevalent neglected tropical diseases using existing drug therapies.6,76-79 Neglected tropical diseases are recognized as being a significant cause of poverty.80 Health and poverty are integrally related, and controlling neglected tropical diseases may be one realistic strategy to help eliminate extreme poverty.8,81 The United Nations' Millennium Development Goals, a series of objective targets endorsed by the international community, include the goal of halving the number of people living in extreme poverty by 2015.8,81 Six of the 7 most prevalent neglected tropical diseases are caused by worms, and the Millennium Project (an initiative that focuses on implementing the Millennium Development Goals) lists regular deworming of school-aged children as a simple intervention that could make a profound difference to survival and quality of life.82 Interventions against neglected tropical diseases should be considered investments in human capital and form a fundamental part of a plan to reduce global poverty. In addition to the obvious health benefits to the individuals with these diseases, these interventions result in enormous economic benefits by improving educational outcomes and worker productivity.19 A number of measures have recently been initiated to reduce the prevalence of neglected tropical diseases and public awareness of neglected tropical diseases shows signs of increasing.83-85 The US government has committed $15 million to support neglected tropical disease control.80 In October 2006, the Clinton Global Initiative helped launch the Global Network for Neglected Tropical Diseases Control, whose mission includes promoting an integrated approach as part of neglected tropical disease control efforts.86 In December 2006, the Bill & Melinda Gates Foundation announced $46.7 million in grants toward developing evidence that an integrated approach is an effective method of eliminating neglected tropical diseases.19 Pharmaceutical companies have committed to donating all of the drug therapies required for this integrated treatment approach.3,12,87 The drug donations are valued at more than US $1 billion and constitute the largest drug donation in history.16 Other drugs that can be used to control the 7 most prevalent neglected tropical diseases are inexpensive. For example, the Global Network for Neglected Tropical Diseases Control estimates that diethylcarbamazine costs approximately US $0.01 per dose, albendazole costs approximately $0.02 per dose when used for the control of worm infections, and pharmaceutical companies donate the drug free of charge when it is used for the control of elephantiasis.88 Ivermectin, mebendazole, and praziquantel are also donated.3,88 Fenwick et al20 estimate that approximately 500 million people at risk for neglected tropical diseases in Africa could be treated with 4 effective drug therapies at an annual cost of less than US $0.40 per person, including distribution and delivery costs. Future Directions Our review has shown that currently available simple drug treatments can simultaneously target as many as 4 neglected tropical diseases. However, more operational research is needed to determine the best implementation strategies for providing these oral drug therapies at a population level. The Global Network for Neglected Tropical Diseases Control and WHO have started to explore these issues.89,90 For example, at-risk populations may be difficult to reach because they live in remote areas or do not attend school. Studies are required in the affected regions where resources are limited to identify practical methods to coordinate and execute the proposed treatment plans. This type of research has been performed for trachoma91 and is needed for other neglected tropical diseases. Additionally, drug safety is an important concern. Adverse event reporting in all of the RCTs in our analysis was poor. Ten of the 29 RCTs did not state whether adverse events were assessed,58,60,62-64,68,69,71-73 and absence of reporting of adverse events is not equivalent to the absence of such events.40 In the 14 trials in our review that reported adverse events, event frequency and severity were not specified.45,47-49,51-55,59,61,66,67,70 The poor quality of the reporting of adverse events is not unique to neglected tropical disease research—the quality and quantity of drug safety reporting have been found largely inadequate across medical fields.40 Possible drug interactions when drugs for neglected tropical diseases are used in combination also need to be considered. Neglected tropical diseases occur predominantly in vulnerable populations that can be at risk for drug toxicity, making drug safety reporting a priority.92 Experts at WHO in 2002 concluded that until further research is completed, the risks of no treatment appear to outweigh the risks of treatment in areas endemic for hookworm, roundworm, schistosomiasis, and whipworm,93-95 but further study focusing on the safety of drug treatments for neglected tropical diseases is needed, particularly for children and women. One challenge raised by the mass administration of neglected tropical disease drug treatments is that the dosing of several drugs (eg, diethylcarbamazine, ivermectin, levamisole, praziquantel, pyrantel-oxantel) requires individualization by weight or height, especially in children. Further efforts are required to determine the optimal doses, duration of treatment, and dosing schedules in different settings. Furthermore, some of these drugs should not be given to vulnerable groups, such as pregnant women, nursing mothers, or very young children.96 High-quality research is needed to address issues of optimal drug delivery.8,12,96 There are also concerns related to drug efficacy. Further research is needed to identify particular geographic regions where specific drugs are most efficacious,56,97,98 to identify areas where drug resistance (a possible consequence of mass drug administration) is emerging,99 and to identify regions with high rates of reinfection.99-101 Combination therapy may be one method of delaying the possible occurrence of drug resistance.99 Future RCTs comparing 2 or more drug treatments may need to consider design issues such as therapeutic equivalence.74,75 This issue is particularly important when evaluating whether 2 drug therapies appear to work equally well for controlling neglected tropical diseases but differ in terms of adverse event profiles, efficacy in different geographic regions (such as in areas of drug resistance), or in special populations (such as children). An example of an RCT that evaluated therapeutic equivalence demonstrated that paromomycin, which is more convenient to administer, was noninferior to amphotericin B, which often requires weeks of hospitalization, for the treatment of visceral leishmaniasis in India.102 Two of the 7 most prevalent neglected tropical diseases (river blindness and trachoma) occur in the same areas of geographic overlap as the other most prevalent neglected tropical diseases and can be treated with oral drug therapies. Future RCTs should include river blindness and trachoma as part of an integrated drug therapy strategy to treat multiple neglected tropical diseases. Finally, the concept of integrating neglected tropical disease management should go beyond drug therapy as the solution. Longer-term goals include vaccine development, under way for some of the neglected tropical diseases,12 and morbidity control and suppression of transmission of these diseases.9Quiz Ref IDDrug-based control cannot achieve a permanent reduction in neglected tropical disease incidence without ancillary measures. A truly integrated treatment plan must also include fundamental public health measures such as access to clean water and adequate sanitation. Exceptional results can even be achieved solely with nonpharmacological measures, as exemplified by the effort led by former President Carter103 to eradicate Guinea worm globally, possible primarily because people are being educated to filter water with a mesh cloth prior to use.104 Limitations To permit cross-study comparisons, we included only studies that examined incidence, prevalence, or cure rates. Although neglected tropical disease treatments may promote beneficial reductions in morbidity measures, we could not include all of them since their evaluation varied for different neglected tropical diseases and among individual RCTs.25 Only 4 of the 29 trials reported on measures of morbidity.53-55,73 These are key measures (eg, height, weight, and hemoglobin) that should be considered in any study of neglected tropical disease control. Neglected tropical diseases are often chronic and severely disabling but not immediately life-threatening. Until there are effective cures such as vaccines, morbidity reduction is a critical benefit to consider in evaluating neglected tropical disease treatments. Other studies of neglected tropical disease control have used morbidity alone as their primary outcome.105 Incidence, prevalence, and cure rates as well as morbidity are all important aspects of current neglected tropical disease control. Future studies should consider including standardized morbidity outcomes. Another measure presented inconsistently was intensity of infection; 3 of the 29 RCTs did not include any such measure.50,55,61 Future studies should consider including intensity of infection to capture the full range of effects of treatments for neglected tropical diseases. Conclusions Integration of treatment across neglected tropical diseases can be facilitated by treating 2 or more diseases simultaneously. More operational research is needed in the affected geographic regions to address issues such as the most practical means of drug delivery and to delineate specific adverse events of drug therapy interventions in vulnerable populations. Awareness by the medical community and the public about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases. Back to top Article Information Corresponding Author: Madhuri Reddy, MD, MSc, Department of Medicine, Hebrew Rehabilitation Center, 1200 Center St, Boston, MA 02131 (madhurireddy@hrca.harvard.edu). Author Contributions: Dr Reddy had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Reddy, Gill, Rochon. Acquisition of data: Reddy, Kalkar, Wu. Analysis and interpretation of data: Reddy, Gill, Kalkar, Wu, Anderson, Rochon. Drafting of the manuscript: Reddy. Critical revision of the manuscript for important intellectual content: Gill, Kalkar, Wu, Anderson, Rochon. Statistical analysis: Kalkar, Wu. Obtained funding: Rochon. Administrative, technical, or material support: Kalkar, Wu, Anderson. Study supervision: Rochon. Financial Disclosures: Dr Reddy reports receiving honoraria or consulting fees from Smith and Nephew, Molynlycke, and Merck. No other authors reported financial disclosures. Funding/Support: This work was supported by a Canadian Institutes of Health Research Interdisciplinary Capacity Enhancement grant H0A-80075. Dr Gill was supported by an Ontario Ministry of Health and Long-Term Care Career Scientist Award. Role of the Sponsors: The funding organizations did not participate in the design or conduct of the study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the manuscript. Additional Contributions: Peter Hotez, MD, PhD, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, and Nilanthi de Silva, MBBS, MSc (Lond), MD, University of Kelaniya, Sri Lanka, provided their insightful comments and review of the manuscript. Dr Hotez is co-chair of the Scientific Advisory Council of the Sabin Vaccine Institute, Connecticut, and a member of the Academic Advisory Board for the Pfizer Fellowships in Infectious Diseases. 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Journal

JAMA – American Medical Association

Published: Oct 24, 2007

Keywords: pharmacotherapy,tropical disease,nematode infections,trichuriasis,adverse event

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