Lymphatic filariasis (LF) is a vector-borne neglected tropical disease caused by infection with the filariae Wuchereria bancrofti, Brugia malayi and Brugia timori (Brugia spp.). The adult worms live in the lymphatic system of humans. After mating, the female worms produce several thousand larvae (microfilariae), which circulate in the peripheral blood at times that coincide with the biting activity of the mosquito vectors. The microfilariae are ingested by the mosquitoes during blood-feeding, develop inside the insects and are transmitted when the infected mosquito bites other human hosts (1). Filarial infection may be clinically asymptomatic or present as one or more acute manifestations, including fever, local swelling, tropical pulmonary eosinophilia syndrome and lymphangitis. Chronic complications include lymphoedema (elephantiasis) of the limbs, damage to the scrotum in men (hydrocele), damage to the kidney (including chyluria) and damage to the lymphatic system (1, 2).
An estimated 1 billion people in 72 countries live in areas where the disease is endemic, including at least 36 million people who are affected by the associated morbidity (3, 4). Reduced productivity experienced by patients results in hundreds of millions of dollars in economic losses each year (3, 5, 6). The disease is not fatal. However, WHO has ranked it as one of the world’s leading causes of permanent and long-term disability (7, 8).
In 1997, the Fiftieth World Health Assembly resolved to eliminate LF as a public health problem, with resolution WHA50.29 urging WHO Member States “… to take advantage of recent advances in the understanding of lymphatic filariasis and the new opportunities for its elimination by developing national plans…” and “… to improve clinical, epidemiological and operational activities directed towards eliminating lymphatic filariasis as a public health problem” (9). In response, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched by WHO in 2000 with a comprehensive two-pronged strategy to achieve the elimination target by 2020: (i) interrupt transmission through annual mass drug administration (MDA) targeting the eligible population; and (ii) implement morbidity management and disability prevention to prevent and alleviate the suffering of affected individuals (8, 10–12).
Elimination of LF as a public health problem is operationally defined as reducing infection to levels at which transmission is no longer sustainable and ensuring the availability of a WHO-recommended basic package of care to manage lymphoedema and hydrocele. The following measurable elimination thresholds must be demonstrated before stopping MDA: (i) microfilaraemia prevalence of less than 1% or antigenaemia prevalence of less than 2% in sentinel and spot-check surveys; and (ii) incident infection below 1% or 2%1 measured during the transmission assessment survey (TAS) (8). Documentation that these infection thresholds have been met for at least 4 consecutive years after MDA has been discontinued is required to validate the claim of elimination (13). Follow-up surveys in sentinel and spot-check sites, also known as pre-TAS, are recommended after five MDA rounds and the results used to determine eligibility for implementing TAS.
The regimens recommended by WHO for MDA to eliminate LF (LF MDA) using the antifilarial medicines listed below (Box 1) are administered annually for the duration of the reproductive lifespan of adult worms. Microfilaricides display destructive properties against the microfilariae, but some have a limited effect on the adult parasite (14–16). All are designated antifilarials in the WHO model list of essential medicines (17). MDA plays a role in primary prevention by decreasing and reducing transmission rates in populations at risk. Additionally, MDA can prevent progression from subclinical to clinical disease and worsening morbidity, thereby yielding economic savings at the community level and enhanced productivity from healthier individuals (2, 18). The effectiveness of the MDA strategy depends on epidemiological coverage, which is defined as the proportion of the total population ingesting the medicines during MDA. WHO considers at least 65% epidemiological coverage to be an effective MDA round. In programmes where drug coverage is poor or where transmission is particularly intense, more than five MDA rounds are needed to lower levels of infection below elimination thresholds (8).
Existing WHO recommendations for MDA to eliminate lymphatic filariasis.
Since the launch of GPELF in 2000, MDA has expanded globally, with 6.7 billion treatments delivered to more than 850 million people at least once. This achievement is the result of strong political will at the country level, unprecedented levels of donor support and coordinated partnership among stakeholders. Annual coverage of MDA using the existing regimens recommended by WHO has expanded from 3 million people in 12 countries to just under 700 million people in 63 countries, representing a greater than 200-fold increase in people treated and a more than 5-fold increase in countries treated in 15 years (3, 8). Of the 72 endemic countries, 20 (28%) have successfully implemented the recommended strategies, discontinued MDA and are under surveillance to demonstrate that elimination has been achieved (3). Programme interventions through 2015 are estimated to have prevented or cured more than 97 million cases of the disease and to have averted more than US$ 100 billion in economic losses over the lifetime of those who have benefitted (4, 25).
Despite the dramatic expansion of LF MDA in endemic countries and the progress made under GPELF, 22 of 52 (42%) countries remain endemic and require MDA but have not started MDA in all of their endemic implementation units [IUs] (3). Because at least five effective MDA rounds are needed, achieving the elimination target in these countries by 2020 is unlikely. Additionally, countries with IUs that have already achieved five effective MDA rounds are grappling with assessment results that reveal suboptimal responses to current MDA regimens (3). Given the current status of GPELF countries, achieving global elimination of LF by 2020 is no longer technically feasible using the existing regimens. Countries have therefore requested guidance from WHO on how to realign their national programmes towards achieving the 2020 target. In response, WHO has evaluated the available evidence on alternative regimens and employed a rigorous guideline development process (Chapter 2) for recommending alternative LF MDA regimens to eliminate the disease (Chapters 3 and 4). With the global 2020 target on the horizon, this guideline is part of the intensified efforts required to realign countries endemic for LF on the path towards elimination.
1.1. Objective of the guideline
The consideration of alternative LF MDA regimens focused on a three-drug regimen of antifilarials comprising ivermectin, diethylcarbamazine and albendazole (IDA) compared to the current DA and IA regimens; and biannual MDA with DA, IA and albendazole compared to annual MDA with the same regimens. This document provides endemic countries with the option of using recommended alternative MDA regimens where warranted. summarizes existing and alternative recommendations for national programmes that take into account specific epidemiological situations of co-endemicity with onchocerciasis and loiasis at both the country and IU levels.
Recommended MDA regimen changes from existing WHO recommendations, by co-endemicity setting.
While this guideline was written to be applicable in all LF epidemiological situations, it is specific in that it focuses only on LF MDA. It does not cover any of the other important public health interventions targeted for LF, including morbidity management and disability prevention, vector control, health education, and details on comprehensive monitoring and evaluation for the various LF interventions. Guidance qualifying these aspects of implementation for LF elimination has already been published by WHO.1
1.2. Guiding principles
The goal of WHO is to ensure the highest attainable level of health for all people globally, while promoting the utmost level of respect for their dignity, worth, equality and diversity (26). This guideline has been developed with this principle in mind, as well as that of the United Nations Universal Declaration of Human Rights (27). Many people suffering from LF are socially marginalized and have inadequate access to health care. Those with visible hydrocele and lymphoedema (elephantiasis) in particular are often the victims of discrimination and stigmatization in their communities (28). Decision-makers in countries where the disease is endemic are therefore urged to ensure that this guideline and the policies derived from it incorporate basic human rights, and that the rights of individuals and patients to confidentiality of information and informed decision-making are upheld in accordance with prescribed national ethical guidelines (2).
1.3. Target audience
This guideline presents the summary of evidence that formed the basis of the WHO recommendations contained herein. It is intended to help key decision-makers in countries where LF is endemic determine if, when and how to use alternative MDA regimens. The guideline will be used to inform policy on MDA for LF endemic countries. The target audience includes coordinators of national programmes to control and eliminate neglected tropical diseases, managers of national programmes to eliminate LF, and national committees or technical groups that help programmes make critical programmatic decisions about policy. It is intended for use as a reference document for all stakeholders supporting GPELF, including but not limited to health ministries, WHO, the regional programme review groups, and other technical review bodies, pharmaceutical manufacturers of MDA medicines, bilateral donor organizations, nongovernmental organizations and academic institutions.
1.4. Guideline questions
The WHO steering committee tabled the provisional guideline questions and determined the scope of the guideline. The guideline development group confirmed the scope and further refined the questions. The guideline questions ( and ) were formulated as per the recommended approach with pre-specified PICO (population, intervention, comparator and outcomes) questions. These questions formed the basis for the protocol of the systematic review of the literature and the strategies for the literature searches.
PICO questions used in the comparison of alternative versus existing MDA regimens in countries using DA to eliminate lymphatic filariasis.
PICO questions used in the comparison of alternative versus existing MDA regimens in countries co-endemic for onchocerciasis using IA to eliminate lymphatic filariasis.
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Incident infection of < 1% antigenaemia in areas where Wuchereria bancrofti is transmitted by Aedes spp.; < 2% antigenaemia for W. bancrofti and other vectors; and < 2% antibody prevalence for filariasis due to Brugia spp. (8).
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This guideline on alternative MDA regimens to eliminate LF was designed to complement the following published WHO guidelines and materials on (i) preparing and implementing a national plan to eliminate LF where onchocerciasis is and is not co-endemic (WHO, 2000), (ii) preparing and implementing a programme for integrated MDA for neglected tropical diseases (WHO, 2006), (iii) provisional guidance on LF treatment in implementation units co-endemic for loa loa from eighth meeting the Strategic Technical and Advisory Group for Neglected Tropical Diseases (WHO, 2015), (iv) monitoring and evaluation of LF across the lifespan of a programme (WHO, 2011), (v) management of serious adverse events in control of neglected tropical diseases (WHO, 2011), (vi) morbidity management and disability prevention strategies for LF (WHO, 2013), (vii) drug coverage evaluation surveys for MDA (WHO, 2016) and (viii) validation of the elimination of LF as a public health problem (WHO, 2017). These documents in their entirety are available at www.who.int.
