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Impact Of Mass Drug Administration On Aedes-Transmitted Filariasis In The Pacific

21 Jan 2008

Source: WHO/TDR

TR Burkot ¹ , WD Melrose ² , DN Durrheim ^2, ³ , R Speare ² , K Ichimori ⁴

¹Centers for Disease Prevention and Control, Atlanta, Georgia, USA
²WHO Lymphatic Filariasis Collaborating Center, James Cook University, Townsville, Australia
³Hunter New England Population Health, Newcastle, New South Wales, Australia
⁴PacELF, Suva, Fiji

Working paper for the Scientific Working Group meeting on Lymphatic Filariasis Research, convened by the Special Programme for Research and Training in Tropical Diseases, Geneva, 10–12 May 2005

Full text source: Scientific Working Group, Report on Lymphatic Filariasis, 10–12 May 2005, Geneva, Swizterland, Copyright © World Health Organization on behalf of the Special Programme for Research and Training in Tropical Diseases, 2005, http://www.who.int/tdr/publications/publications/swg_lymph_fil.htm

Overview of lymphatic filariasis control / elimination in the region

Vector control was the primary tool for controlling filariasis in the Pacific when effective antifilarial drugs were unknown and, even after effective antifilarials became available, was preferred because mass drug administration (MDA) campaigns were considered too labour intensive [3]. Beginning in the 1950s, various diethylcarbamazine (DEC)-based population treatment strategies were undertaken to control lymphatic filariasis (details below). These campaigns often succeeded in achieving significant reductions in microfilariae (mf) rates and densities. However, mf rates frequently rebounded due to: (1) poor compliance; (2) inadequate duration of campaigns; and (3) failure of DEC to completely kill or sterilize adult Wuchereria bancrofti in all people treated, despite repeated administration [8].

The present Pacific Programme for the Elimination of Lymphatic Filariasis (PacELF) relies on repeated annual mass drug administration (MDA) of diethylcarbamazine (DEC) and albendazole, with nearly universal coverage of affected populations. Evidence that the present DEC/albendazole combination will be more successful than monotherapy with DEC against adult worms is supported by falling adult worm antigen levels and clinical reactions in infected humans receiving the drug combination [23]. A number of the PacELF countries have now completed five annual rounds of MDA but their impact has not yet been fully evaluated. There is, however, evidence from Samoa and French Polynesia where Aedes polynesiensis is an important vector that, despite high coverage with MDA campaigns, transmission was not interrupted by the DEC-based campaigns as there were increases in microfilaria (mf) prevalence after the campaigns. There may well be a need for adjunct control measures, including vector control, to accomplish disease elimination where mf levels are not adequately suppressed by MDA alone.

Vector control as an adjunct to MDA for lymphatic filariasis elimination

Success in the control and elimination of filariasis based only on anti-vector activities has been demonstrated in the Pacific. In Papua New Guinea and the Solomon Islands, where species of Anopheles are the vectors of malaria and filariasis, filariasis was eliminated from areas where DDT spraying campaigns to control malaria were undertaken [1,27,28]. Similarly, W. bancrofti was eliminated from Australia, primarily by sanitation campaigns against C. quinquefasciatus [2]. Comparable vector control based successes in the areas where Ae. polynesiensis is the vector do not exist. Ae. polynesiensis is a notoriously efficient vector due to ‘limitation’, a characteristic whereby the efficiency of transmission increases with decreasing densities of mf [24].

In areas where W. bancrofti is subperiodic, lymphatic filariasis (LF) transmission can be complex due to the presence of multiple vectors; in the region from Fiji to French Polynesia, there are 14 reported Aedes vectors (six LF vectors are found in Fiji) (table 1). With the exception of Ae. polynesiensis and Ae. vigilax, little is known about the ecology of these mosquitoes and there is almost no documentation of attempts to control them. Ae. polynesiensis is believed to pose the greatest challenge to LF elimination and is the most important Aedes LF vector in the Pacific, and is thus the focus of this manuscript.

Table 1

Reported Aedes vectors of lymphatic filariasis in the Pacific

Vector	Countries where found
Aedes cooki	Niue
Aedes fijiensis	Fiji
Aedes horrensces	Fiji
Aedes kochi	Papua New Guinea
Aedes marshallensis	Kiribati
Aedes oceanicus	Tonga
Aedes polynesiensis (Burnett GF,	American Samoa, Samoa, Cook Islands, Tokelau,
1960[a])	Tuvalu, French Polynesia, Wallis and Futuna, Fiji
Aedes pseudoscutellaris	Fiji
Aedes rotumae	Rotuma Island in Fiji
Aedes samoanus	Samoa
Aedes tabu	Tonga
Aedes tutuilae	Samoa
Aedes upolenis	Samoa
Aedes vigilax	New Caledonia, Fiji

Vector Control Strategies for Aedes

Mosquito surveillance and control is an integral part of filariasis elimination plans in many Pacific islands. Among these island countries, larval surveys for filariasis vectors are often advocated with environmental sanitation to reduce mosquito breeding sites, as are bednets and ultra-low-volume (ULV) spraying against adult mosquitoes. Unfortunately, the effectiveness of these interventions at the population level has rarely been evaluated. For example, many studies on controlling Ae. aegypti for dengue have shown that treating rainwater drums with larvicides dramatically reduces the numbers of mosquitoes breeding in these drums, but there are only a few studies showing the impact that elimination of drums has on the number of adult mosquitoes.

There have not been any studies on controlling Ae. vigilax in the Pacific. The long flight range of this vector means that focal larviciding is unlikely to be feasible or cost-effective. However, as Ae. vigilax breeds in salt marshes, runnels (ditches designed to allow flushing of salt marshes by tides) had some impact on larval numbers in Australia [9]. Unfortunately, the impact on biting rates was not measured in this study.

More operational research for control of Ae. polynesiensis at population level has been conducted in the Pacific (table 2). Mesocyclops aspericornis reduced by 98% the number of Ae. polynesiensis larvae in treated crab holes. However, despite treating more than 14 000 crab holes on one French Polynesian island, no measurable impact on the number of biting Ae. polynesiensis was demonstrated [20]. Insecticide fogging and spraying campaigns have had minimal impacts on Ae. polynesiensis biting rates, with reductions of less than 64% in three trials [8,26,29].

Table 2

Summary of field trials for controlling Aedes in the Pacific

Vector^*	Breeding site	Country	Control method	% Reduction in		Reference
Vector^*	Breeding site	Country	Control method	Breeding sites	Mosquitoes	Reference
Ae. polynesiensis	Tree holes	Fiji	Destroying tree holes	87%	?	Burnett GF, 1960[a]
Ae. polynesiensis	Crab holes	Fiji	1% Lindane and plugging of crab holes	?	0% on biting	Burnett GF, 1960[a]
Ae. polynesiensis	All types	French Polynesia	Breeding site elimination within 100 yd. of village	?	80% to 90%	Kessel JF, 1965
Ae. polynesiensis	All types	French Polynesia	Breeding site elimination within 100 yd. of village	?	90% of larvae	Laigret J, 1958
Ae. polynesiensis	All types	French Polynesia	Breeding site elimination; vegetation control	?	81% biting	Byrd EE, St Amant LS, 1959
Ae. polynesiensis and Ae. samoanus	All types	Samoa	DDT spray of breeding site and fogging of houses/bush	?	64% biting	Suzuki T, Stone F, 1976
Ae. polynesiensis and Ae. samoanus	Not known	Samoa	Abate larvicide and malathion fog	?	60%	Chow CY, 1974
Ae. polynesiensis	Not available	American Samoa	DDT house spraying; aerial spraying every 14 days	Not available	0% at 14 days	Wharton and Jachowski, 1980
Ae. aegypti and Ae. polynesiensis	Cisterns, wells, drums	French Polynesia	Integrated control (Abate, sealing drums, polystyrene beads, Poecillia reticulata)	94%	84%	Lardeux F et al, 2002(a)
Ae. polynesiensis	Crab holes	French Polynesia	Mesocyclops aspericornis		98% of larvae 0% of adults	Lardeux F et al, 1992
Ae. polynesiensis	Crab holes	French Polynesia	Insecticide impregnated crab bait		86%	Lardeux F et al, 2002(b)

* References in the literature to Ae. pseudoscutellaris prior to 1960 are believed to be Ae. polynesiensis and are listed as Ae. polynesiensis. Ae. polynesiensis was described by Marks as a separate species in 1955.

The effectiveness of larval source-reduction campaigns against Ae. polynesiensis has been repeatedly demonstrated in French Polynesia [15,18], particularly when integrated with other measures [21] including removal of vegetation to facilitate discovery of breeding sites [7]. However, the sustainability of source reduction is unproven. A Fijian study documented the rapidity with which breeding sites reappear after clean-up campaigns. Within 4.5 months, 3906 destroyed containers were replaced with 2040 new breeding sites and 2544 destroyed tree holes were replaced with 388 new tree holes demonstrating breeding [6]. These efforts are labour-intensive. Hairston (1973) [13] estimated that one man-month of work was needed to eliminate breeding sites around each village, and that only 77% of breeding sites were amenable to destruction.

Targeted source reduction of Ae. polynesiensis will only be possible if we have more complete knowledge on the importance of different breeding sites. Although studies show that Ae. polynesiensis will breed in a large variety of man-made (storage drums, tyres, rain gutters) and natural (crab holes, tree holes, leaf axils, rat-damaged coconuts) containers, their relative importance in different areas is not known. Specific local studies are required to guide control efforts. In American Samoa, for example, Lambdin (Masters in Public Health [MPH] thesis, Emory University, unpublished) found that almost 70% of Ae. polynesiensis pupae were present during the wet season in five container categories (drums, tyres, buckets, ice cream containers, folded plastic sheets). Similar results were obtained during the dry season, with 66% of Ae. polynesiensis pupae produced in buckets and plastic containers (Burkot, unpublished) although buckets and plastic containers were only 27% of all containers surveyed.

Anti-dengue campaigns worldwide are now primarily based on larval source reduction and, while important behavioural differences exist between Aedes aegypti and Ae. polynesiensis, there are sufficient similarities between the two species (both bite in the daytime and breed in containers) to allow us to draw some lessons from the anti-Ae. aegypti campaigns for Ae. polynesiensis control. Of particular importance is the need for local information on breeding sites and community practices prior to the implementation of health education campaigns aimed at encouraging the community to reduce the number of breeding sites.

There are very few data on control strategies targeting adult Ae. polynesiensis mosquitoes. A trial is being conducted in Fiji to evaluate the impact of insecticide-treated curtains and bednets on transmission by Ae. polynesiensis (Koroivueta, Ichimori and Burkot, personal communication). There is clearly a need to investigate the potential of additional personal protection measures, including naturally occurring botanical extracts, as components of an integrated Ae. polynesiensis control strategy. University of Kentucky researchers are conducting trials using Wolbachia-induced cytoplasmic incompatibility for Ae. polynesiensis elimination (Dobson, personal communication).

From the above review, it is clear that much of our understanding of Aedes behaviour and transmission of W. bancrofti is based on studies conducted many decades ago, and that there has been limited investment in recent years in operational research to guide an integrated approach to LF control and elimination.

Impact of mass drug administration on transmission

Prior to the 1950s, LF control in the Pacific relied almost exclusively on vector control. With the discovery of the anti-microfilaricidal activity of DEC, emphasis shifted to MDA campaign-based control. These campaigns, particularly in Samoa and French Polynesia, achieved significant reductions in mf rates and densities [11,14,19]. In Samoa, five extensive campaigns using DEC, including 12–18 month treatments in 1966 and 1971, and single annual doses in 1982, 1983 and 1986, reduced the mf rate from 21% in 1964 to 2.3% in 1987. Mf rates declined to 0.14% in 1974, following the second DEC campaign, but rebounded to 2.1% within two years [14].

In French Polynesia, since 1955 but excluding the years 1960–67 and 1970–74, twice yearly DEC chemotherapy (6 mg/kg) was administered to an average of 85% of the population on Maupiti island [11]. In addition, mosquito control using DDT (1955–1957) and larval breeding source destruction (1955–1970) were implemented. Despite these efforts, a comprehensive survey in 2000 found that 0.4% of residents had mf and 4.6% had antigenaemia [11].

After cessation of the MDA campaigns in Samoa and French Polynesia, mf rates increased [14,16]. While the extensive campaigns succeeded in minimizing filariasis as a public health problem by significantly reducing the number of clinical cases of the disease, elimination of the parasite was not achieved. A subsequent analysis of LF positives on Maupiti suggests that residual positives may have persistently not complied with the MDA programme (Nguyen, personal communication).

Under the PacELF MDA programme, annual administration of DEC and albendazole has been undertaken in the following countries where Aedes species are important vectors: American Samoa, Cook Islands, Fiji, French Polynesia, Niue, Samoa, Tokelau, Tonga, Tuvalu, and Wallis and Futuna. By the end of 2005, five rounds of MDA will have been completed in the Cook Islands, French Polynesia, Niue, Samoa and Tonga. Samoa is the only country to have completed its prevalence assessment after five rounds of MDA, with annual coverage ranging from 57% to 90%, but the results of this assessment are not yet available.

Feasibility of terminating transmission by MDA or other interventions, and risk of recrudescence

Despite phenomenal progress in the Pacific towards elimination of LF, several major challenges remain. Firstly, we do not know the exact level of suppression of mf that needs to be achieved in order for elimination to be realized. This obstacle is even more vexing where Aedes is the vector. The implications of Pichon's (2002) [24] ‘limitation’ models have been verified by observations on mf rates following MDA campaigns with DEC in Samoa. Despite reducing mf rates to less than 0.33% between 1972 and 1974, LF rates rose afterwards. It is likely that ‘pockets of infection’ capable of initiating resurgence of LF will remain and that relatively low levels of microfilaraemia may permit resurgence and pose a formidable challenge to traditional survey techniques. New surveillance tools will certainly be necessary where Aedes mosquitoes are the vectors if MDA is used alone for elimination of LF.

A second significant challenge is the mobility of Pacific islanders; migration is particularly common in many of the Pacific islands where Aedes is an important LF vector. More Cook Islanders live in New Zealand than on the main island of Rarotonga, and thus may have missed annual MDA treatment. Frequent travel back to the Cook Islands carries with it the possibility of reintroduction of LF. Similarly, Samoans frequently travel between Samoa and American Samoa for economic opportunities and to visit relatives and friends living in the neighbouring country. Thus, the PacELF regional approach to LF in the Pacific is appropriate but migration between the various Pacific countries, including Australia and New Zealand, must be taken into consideration.

A third challenge is the presence of individuals whose behaviour places them at risk of infection or who do not regularly participate in MDA, placing their communities at risk of ongoing transmission [12]. Merely increasing the number of years of MDA campaigns will not reach these individuals, but a better understanding of their perceptions and priorities will allow tailoring of messages and interventions so that they are locally appropriate and acceptable [10].

A fourth challenge is the potential for W. bancrofti to develop resistance to either DEC or albendazole. Albendazole resistance is already common amongst helminths of veterinary importance. Although there is currently no evidence of resistance to DEC or albendazole in areas where LF elimination programmes are under way, no reliable assay system is currently available to allow assessment of resistance. Resistance is more likely to appear late in an MDA programme when success appears feasible.

These challenges can be reduced by integrating vector control with MDA for LF elimination [3]. A country-wide vector control programme can: suppress LF transmission without the need for identifying all individual ‘pockets of infection’; minimize the risk from imported mf positives; and reduce the spread of any DEC or albendazole resistant W. bancrofti. Furthermore, control measures targeting Aedes vectors may also decrease the risk of dengue transmission. Vector control strategies as adjuncts to the MDA campaigns are certainly needed in the next five years to ensure success of the elimination efforts.

Impact of MDA on disease, and elimination of LF as a public health problem

Clinical presentations, now known to be consistent with LF infection, were first reported in Polynesia by early European explorers, including Captain Cook. In recent years there have been relatively few cross-sectional surveys on prevalence of LF disease; however, overt pathology was seen to diminish concurrently with previous widespread DEC-based MDA. The most recent data available from Pacific countries in Aedes transmission areas include:

In Samoa in 1954, an elephantiasis rate of 3.6% and a lymphadenitis rate of 15%–20% were reported [25].
In Tonga in 1977, a 0.39% prevalence of elephantiasis and a 2.4% prevalence of hydrocele were found.
In Tuvalu in 1928, 23% of men surveyed had hydroceles and there was an 8.1% elephantiasis rate [25].
In Tokelau during a 1994 survey, a single case of elephantiasis was found (Tokelau country report to the PacELF annual meeting, Apia, Somoa, 1994).
In Niue in 1960, a clinical survey found 5.5% of the population with symptoms of LF (Ichimori, unpublished).
In French Polynesia, the most recent data report a 1.3% prevalence of elephantiasis [25].
In Fiji between 1991 and 1995, a countrywide clinical survey of 18 253 people found 16% of people had lymph node enlargement, 0.9 % had hydrocele, and 0.2% had elephantiasis (Fiji MOH, unpublished).
In the Cook Islands during 1965, a survey found that 3.8% of 498 people examined had elephantiasis [25].

Summary of the major remaining uncertainties, research questions and suggestions for specific studies

The ability of Ae. polynesiensis to sustain LF transmission at low mf levels demands an integrated approach to control that is sensitive to local vector and human characteristics and behaviour. The following conclusions may be drawn from the limited number of population-based studies of Aedes control strategies:

The contribution of human behaviour and perceptions to achieving and sustaining adequate MDA coverage, and to placing individuals at risk of infection, needs to be better understood and probably poses the biggest threat to achieving elimination of LF.
As well as benefits in eliminating LF transmission, Ae. polynesiensis control strategies offer potential in preventing and controlling dengue through their concurrent impact on Ae. aegypti.
Source reduction of Ae. polynesiensis breeding sites has demonstrated the most consistent success in reducing Ae. polynesiensis numbers.
When source reduction is integrated with other control measures, for example use of insecticide-treated crab baits where crab holes are the major breeding sites, then the impact on biting rates and possibly transmission is enhanced.
While insecticide-treated bednets have been shown to effectively control filariasis where it is transmitted by anophelines, their impact on the day-time biting Aedes vectors in the Pacific is unknown. It may be that insecticide-treated materials, including curtains, could have a significant impact in either killing vectors or repelling vectors from houses.
Insecticides have not been effective in reducing adult Ae. polynesiensis populations when used alone.
The demonstrated ability of LF to rebound in Ae. polynesiensis transmission areas, even at very low mf rates, and the high mobility of Pacific island peoples makes recrudescence a real threat:
- surveillance systems are needed to promptly detect mf positive individuals
- vector control can reduce the risk of LF resurgence.
Little in known about the impact of the PacELF MDAs on the prevalence of LF disease.

Recommendations for specific studies

As a large number of countries with Aedes vectors of LF have completed five rounds of MDA, there is an urgent need for population-based trials of Aedes control strategies for implementation as adjunct measures to MDA. Strategies that deserve further evaluation include:

novel biological, chemical and mechanical source reduction measures, including the use of crab baits impregnated with insecticides use of insecticide-treated materials, including clothing and curtains personal protection measures.

Control strategies that integrate a combination of approaches consistent with the ecology of local vectors should be encouraged.

Simple survey methods for trapping adult Aedes that can be implemented at local level need to be evaluated, as standard traps are not effective.

Pupal surveys need to be undertaken to identify the most productive containers for producing adult Aedes.

Qualitative studies are required to provide a better understanding of human behavioural and perceptual contributions to ongoing transmission.

Surveys of remaining LF pathology are needed to determine the impact of the MDA strategy where Aedes species are the vectors.

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