Oral Drug Therapy for Multiple Neglected Tropical Diseases: Title and subTitle BreakA Systematic Review FREE

The neglected tropical diseases are a group of 13 infections that affect more than 1 billion people worldwide^{1 - 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.

Seven 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.⁹ Infection 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}

There 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.

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.

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 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.

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 RCTs^{45 - 52} studied both children and adults (aged ≥20 years) and the remaining 21 RCTs^{53 - 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).

Three RCTs evaluated drug therapy interventions that targeted 4 neglected tropical diseases simultaneously and included 3775 individuals (Table 2).^{53 - 55} All 3 RCTs^{53 - 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.

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}

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 RCTs^{68 - 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.

Our 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.

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.⁹ Drug-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

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.

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.