The content we created in 2009 appears below. This content is likely to be no longer fully accurate, both with respect to the research it presents and with respect to what it implies about our views and positions.

Published: 2009

# In a nutshell

• The Problem: Lymphatic filariasis can cause severe debilitation (including disfiguration of limbs through elephantiasis) that can lead to an inability to work and societal discrimination.
• The Program: Mass drug administration (MDA) of ivermectin and albendazole for all members of the population, aiming to eliminate lymphatic filariasis from endemic areas.
• Track record: Mass drug administration has been rigorously shown to reduce lymphatic filariasis infection rates, though evidence for its effect on symptoms is thinner. The program has led to repeated larger-scale, country-level successes which significantly reduced prevalence of lymphatic filariasis.
• Cost-effectiveness: We have not done thorough cost-effectiveness analysis of this program, since we haven't found what we consider a strong opportunity for individuals' donations to result in more of it. An independently available cost-effectiveness estimate implies that this program costs roughly $0.40-$2.50 per year of symptomatic lymphatic filariasis (generally involving swollen limbs and/or scrotum) averted. We believe this figure should be used with great caution as it comes from a source that we have found substantial problems with in the past; it is also substantially out of date, and may be making contextual assumptions that don't match real-world giving opportunities.
• Bottom line: This program is a relatively well-supported and potentially cost-effective way to improve lives.

## Basics of the program

### What is the program? What problem does it target?

The World Health Organization recommends annual treatment with a single combination dose of albendazole and either diethylcarbamazine (DEC) or ivermectin to everyone in the target region in order to control and ultimately eliminate lymphatic filariasis. Ivermectin replaces DEC in regions where onchocerciasis may also be endemic.1

Lymphatic filariasis is caused by parasitic worms that are transmitted by mosquitoes;2 it can ultimately lead to severe debilitation through extreme enlargement of limbs or the genitals.3 (More information on lymphatic filariasis.)

### What are the components required to implement this program - how does it work?

This program requires drugs (albendazole and ivermectin) and a means of distributing them as efficiently as possible. Both GlaxoSmithKline (manufacturer of albendazole) and Merck (manufacturer of ivermectin) have committed to donate their drugs as long as they are necessary to eliminate lymphatic filariasis as a global health problem.4

## Program track record

### Micro evidence: Has this program been rigorously evaluated and shown to work?

Ivermectin, alone: A recent review finds 15 high-quality evaluations of ivermectin's effects on microfilariae (parasites) in the blood, considered the primary indicator of lymphatic filariasis infection. 8 of these evaluations compare a dose to no dose, while the other 7 compare doses of different sizes. A meta-analysis of all 15 (748 total patients) finds that "administered as a single dose, ivermectin induced nearly complete clearance of microfilariae from the blood from the first day to 30 days post-treatment, followed by gradual recurrence of microfilaraemia and increase in its intensity. Higher doses of ivermectin showed greater clearance effects and maintained lower microfilaraemia levels for a longer time.... Ivermectin given at a single annual dose of 200 ug/kg body weight or higher, whether or not in combination with DEC [diethylcarbamazine], has great potential for therapeutic strategies to control bancroftian filariasis."5

Albendazole in addition to ivermectin: A recent review of the benefit of adding albendazole to an existing regimen of ivermectin found "insufficient evidence to say whether a single dose of the drug albendazole kills the worms, or whether, if given in combination with diethylcarbamazine or ivermectin, it enhances the killing of these worms or the larvae they produce."6

Drug's effect on more advanced stages of the disease: Despite ivermectin's efficacy in killing parasites in the blood, it may not kill adult worms,7 and the Disease Control Priorities in Developing Countries report notes that "The effect...on hydrocele and lymphedema [symptoms] is not yet well established."8

More on our interpretation of "micro evidence" and evaluation quality.

### Macro evidence: Has this program played a role in large-scale success stories?

Lymphatic filariasis prevalence has fallen significantly - from 10-20% to 0-5% - in several countries that have completed several rounds of mass administration of ivermectin and albendazole.9

A report on the Global Program to Eliminate Lymphatic Filariasis reports large declines in prevalence across large numbers (over 100) of sample sites.10 This program has involved the use of ivermectin in some places and DEC in others.11

## Recommendations and concerns

### What are the potential downsides of the intervention?

• Drug resistance could emerge.12
• Ivermectin causes some adverse reactions, but they are normally mild.13

## Cost-effectiveness

### What is the cost-effectiveness of this intervention?

We have not done thorough cost-effectiveness analysis of this program. Because such analysis is highly time-consuming - and because the results can vary significantly depending on details of the context - we generally do not provide cost-effectiveness analysis for an intervention unless we find what we consider to be a strong associated giving opportunity.

We provide some preliminary figures based on the Disease Control Priorities in Developing Countries report, which we previously used for cost-effectiveness estimates until we vetted its work in 2011, finding major errors that raised general concerns.

The report estimates costs at $0.35-2.22 per person treated and$4.40-$29 per disability-adjusted life-year (DALY) averted for this program type, though this estimate is highly dependent on assumptions regarding disease prevalence and effectiveness of treatment against hydrocele and lymphedema.14 This figure would place it among the most cost-effective programs.15 (More on the DALY metric.) A simple conversion calculation implies, from the figure above, that$100 prevents 15-85 total years of lymphedema (swollen limbs) and 25-165 total years of hydrocele (swollen scrotum). Note that benefits may be much higher if a program is continued to the point of eliminating the disease permanently from an area; they may also be much more questionable if a program is poorly carried out, or abandoned, allowing the disease to spread again.

## Sources

• 1.

"To interrupt transmission, districts in which lymphatic filariasis is endemic must be identified, and then community-wide ("mass treatment") programmes implemented to treat the entire at-risk population. In most countries, the programme will be based on once-yearly administration of single doses of two drugs given together: albendazole plus either diethylcarbamazine (DEC) or ivermectin, the latter in areas where either onchocerciasis or loiasis may also be endemic; this yearly, single-dose treatment must be carried out for 4-6 years. An alternative community-wide regimen with equal effectiveness is the use of common table/ cooking salt fortified with DEC in the endemic region for a period of one year." World Health Organization, "Lymphatic Filariasis."

• 2.

"The thread-like, parasitic filarial worms Wuchereria bancrofti and Brugia malayi that cause lymphatic filariasis live almost exclusively in humans. These worms lodge in the lymphatic system, the network of nodes and vessels that maintain the delicate fluid balance between the tissues and blood and are an essential component for the body's immune defence system. They live for 4-6 years, producing millions of immature microfilariae (minute larvae) that circulate in the blood.... The disease is transmitted by mosquitoes that bite infected humans and pick up the microfilariae that develop, inside the mosquito, into the infective stage in a process that usually takes 7-21 days. The larvae then migrate to the mosquitoes' biting mouth-parts, ready to enter the punctured skin following the mosquito bite, thus completing the cycle." World Health Organization, "Lymphatic Filariasis."

• 3.

"In its most obvious manifestations, lymphatic filariasis causes enlargement of the entire leg or arm, the genitals, vulva and breasts. In endemic communities, 10-50% of men and up to 10% of women can be affected. The psychological and social stigma associated with these aspects of the disease are immense. In addition, even more common than the overt abnormalities is hidden, internal damage to the kidneys and lymphatic system caused by the filariae." World Health Organization, "Lymphatic Filariasis."

• 4.
• "In 1998, GSK formed a partnership with the World Health Organization (WHO) to eliminate LF, and committed to donate its antiparasitic medicine, albendazole, to all countries at risk for as long as necessary to eliminate the disease as a public health problem." GlaxoSmithKline, "Eliminating Lymphatic Filariasis."
• "Merck has made a long-term commitment to donate as much MECTIZAN as necessary to treat river blindness and to prevent lymphatic filariasis. The goal is to eliminate both diseases as public health problems." Merck, "Mectizan® Donation Program."
• 5.

Full conclusion: "The efficacy and safety of ivermectin in the treatment of filariasis due to Wuchereria bancrofti was assessed by a meta-analysis of the results from 15 published clinical trials. Seven hundred and forty-eight microfilaraemic patients were enrolled in 7 dose-finding and 8 comparative studies. Administered as a single dose, ivermectin induced nearly complete clearance of microfilariae from the blood from the first day to 30 days post-treatment, followed by gradual recurrence of microfilaraemia and increase in its intensity. Higher doses of ivermectin showed greater clearance effects and maintained lower microfilaraemia levels for a longer time. The adverse reactions caused by the drug were flu-like, transient, generally mild and well tolerated by patients. The frequency and intensity of adverse reactions were strongly associated with pretreatment microfilaria counts in the blood, but independent of dose. The findings of the meta-analysis suggest that ivermectin given at a single annual dose of 200 micrograms/kg body weight or higher, whether or not in combination with DEC, has great potential for therapeutic strategies to control bancroftian filariasis." Cao et al. 1997, Pg 393.

• 6.

Full summary of results: "Seven trials including 6997 participants (995 with detectable microfilariae) met the criteria. A comparison of albendazole and placebo detected no effect on microfilariae prevalence (920 participants; 3 trials); one trial (499 participants) reported significantly lower microfilariae density at six months. Albendazole performed slightly worse than ivermectin in two trials (436 participants). Compared with diethylcarbamazine (DEC), two small trials (56 participants) found little difference in microfilariae prevalence over an extended follow up. One larger trial (502 participants) found a statistically significant effect for DEC at six months, but none at three months. Microfilariae prevalence and density were statistically significantly lower with the combination of albendazole and ivermectin compared with ivermectin alone in two of three trials (649 participants). Two trials compared albendazole plus DEC with DEC alone and found no statistically significant difference in microfilariae prevalence, though one trial favoured the combination at six months (risk ratio 0.62, 95% confidence interval 0.32 to 1.21; 491 participants). This trial also found a statistically significant reduction in microfilariae density. There is insufficient evidence to confirm or refute that albendazole co-administered with DEC or ivermectin is more effective than DEC or ivermectin alone in clearing microfilariae or killing adult worms. Albendazole combined with ivermectin appears to have a small effect on microfilaraemia, but this was not consistently demonstrated. The effect of albendazole against adult and larval filarial parasites, alone and in combination with other antifilarial drugs, deserves further rigorous research." Addiss et al. 2005, Pg 1-2.

• 7.

"Recent ultrasound studies suggest that adult worms are not killed by ivermectin, even at high doses over a period of six months." Addiss 2005, Pg 4.

• 8.

Jamison et al. 2006, Pg 443.

• 9.

World Health Organization, "Elimination of Lymphatic Filariasis: Hope for Future Generations, Highlights of Achievements of the Programme in the Africa Region (2000-2006)," Pgs 15-18, Sheet 11.

• 10.

"Individuals in all of the sentinel sites (approximately 500 persons per site) reporting to the Global Programme were evaluated for microfilaremia. Progressive decline in prevalence among these individuals was recorded during yearly assessments (n=131 sentinel sites for year 1; n=124 for year 2; n=139 for year 3; n=148 for year 4; n=68 for year 5; and n=12 for year 6)." Ottesen et al. 2008, Pg 7, Figure 3.

• 11.

"In ivermectin and albendazole areas of Africa and the Yemen, data for children 5 to 15 years of age only are included, whereas for the rest of the world where DEC and albendazole are utilized, data for children 3 to 15 years of age are included." Ottesen et al. 2008, Pg 3.

• 12.

"Another risk is drug resistance. The control programs rely on just a few drugs, and even though drug resistance is not currently apparent, if it were to emerge, the essential tools for control would be lost. Hence, although elimination is in sight, the battle has not yet been won, and research to develop new and improved interventions and strategies for these tropical diseases remains important." Jamison et al. 2006, Pg 442.

• 13.

"Higher doses of ivermectin showed greater clearance effects and maintained lower microfilaraemia levels for a longer time. The adverse reactions caused by the drug were flu-like, transient, generally mild and well tolerated by patients." Cao 1997, Pg 393.

• 14.

Jamison et al. 2006, Pg 443, Table 22.2.

• 15.

Jamison et al. 2006, Pgs 41-42, Figures 2.2 and 2.3.