The Impact of Mass Drug Administration on Lymphatic Filariasis

Mass drug administration (MDA) has made a signifcant impact on the control of lymphatic flariasis (LF) since the establishment of the Global Programme to Eliminate Lymphatic Filariasis. However, its implementation is associated with several challenges, hampering interruption of parasite transmission and LF elimination in endemic areas. Tis study assessed the impact of MDA by comparing baseline microflaria and antigen prevalence with those after three years (mid-term) and ≥ 5years of MDA implementation and their respective prevalence reductions and identifed specifc challenges that may hinder its efective implementation. Tree years of MDA implementation were observed to have microflaria prevalence reductions (88.54% to 98.66%) comparable to those of studies that implemented MDA for fve to 10 years ( ≥ 5 years, 79.23% to 98.26%). Inadequate community understanding of and participation in the LF MDA programme are major drawbacks to its efective implementation. Te implementation of MDA that incorporates community participation, incentivisation, education, and training strategies has the potential of increasing MDA coverage and compliance, thereby interrupting parasite transmission and reducing microflarial prevalence to levels that warrant LF elimination.


Introduction
Lymphatic flariasis (LF) is a debilitating, neglected tropical disease caused by three species of parasitic worms: Wuchereria bancrofti, Brugia malayi, and B. timori. Tese arthropod-borne nematodes are transmitted to humans by the bite of infected mosquitoes in the genera Culex, Anopheles, Mansonia, and Aedes. Globally, 51.4 million people are estimated to be infected with LF [1], and the disease can compromise the health of victims and have an enormous socioeconomic burden [2,3].
In 1997, following major advances in diagnosing and testing for LF infection and improved understanding of the epidemiology and treatment of chronic LF-related disease, the 50th World Health Assembly resolved to eliminate LF as a public health problem [4]. Subsequently, the World Health Organization (WHO) in the year 2000 established the Global Programme to Eliminate Lymphatic Filariasis (GPELF) to assist member states in achieving this goal by 2020 through morbidity management and preventive annual mass drug administration (MDA) [5].
Mass drug administration involving the two principal regimens of albendazole plus either ivermectin or diethylcarbamazine [DEC] for 4-6 years [6] or the exclusive use of table salt or cooking salt fortifed with DEC for 1-2 years [7] has been implemented in various settings with varying degrees of successes and challenges. Tis study assessed the impact of MDA implementation on the control of LF in endemic areas and identifes specifc challenges that may hinder efective implementation of MDA and reduction in microflarial prevalence to levels below target thresholds [8] to warrant LF elimination.
can be accessed (osf.io/ct6rb). Tis review and the selection of relevant literature were undertaken using the PRISMA (Preferred Reporting Items for Systematic Reviews and Metaanalysis) guidelines [9].

Eligibility Criteria.
Te review employed stringent eligibility criteria. Based on the recommendation of WHO's Technical Advisory Group on the Global Elimination of LF on the assessment of the impact of MDA [10], studies from the baseline that have carried out a series of mass drug administration (MDA) using the two principal regimens [6,7] but not reported on transmission assessment surveys (TASs) and verifcation of LF elimination were included in the review. Studies which reported on prevalence of LF, an indicator in the operational defnition of LF elimination [11], and the primary outcome of interest in this review were included. Studies which did not meet these criteria, including those reporting on LF prevalence without MDA, missed rounds of MDA, mono-and triple-therapies against LF, control of LF using mosquito nets and MDA, LF mapping, systematic reviews, and coinfections were excluded from the review.

Method of Study Selection, Data Collection, and Analysis.
Te studies for the review were selected using a similar relevant article identifcation approach described previously [12]. Te articles were screened independently by reading the titles to exclude nonlymphatic flariasis studies. Te abstracts of lymphatic flariasis studies were read to assess their relevance based on the inclusion criteria. Full text articles deemed to be relevant were downloaded and used for the review.
Each relevant full text article was read to document its characteristics: country, setting, population, drugs administered in MDA programme, MDA coverage, and compliance. Data on microflaria (Mf ) and Mf antigenic cases reported at baseline, three years (mid-term), and ≥5 years (pretransmission assessment survey, pre-TAS) of MDA implementation were extracted and used to calculate their respective prevalence using the following equation: where P � prevalence, nc � number of cases, and N � sample size. Te percentage reductions for mid-term and pre-TAS microflaria and Mf antigen prevalence compared to baseline prevalence were calculated using the following equations: where MPR � mid-term prevalence reduction, BP � baseline prevalence, MP � mid-term prevalence, PPR � pre-TAS prevalence reduction, and PP � pre-TAS prevalence.

Defnition of Variables.
Prevalence in this review is the proportion of persons diagnosed as having microflaria (Mf ) of any of the LF parasites or Mf antigen in their blood and was calculated before (baseline), three years (mid-term), and ≥5 years (pre-TAS) of MDA implementation. MDA coverage is the percentage of the population at risk of LF covered by MDA, and compliance with MDA is the percentage of persons who ingested the prescribed drugs during MDA implementation in an LF endemic area.

Risk of Study Bias Assessment. Te risk of bias in in-
dividual studies was assessed independently by reviewers using the quality assessment tool developed for prevalence studies [13]. It was based on the assignment of numbers to a yes (0, low risk) and no (1, high risk) answers for ten parameters (Supplemental Table S1) on the external and internal validity of the studies. Te overall study quality assessment was determined by summing up the assigned numbers based on the levels of risk of bias categorized as low (≤2), moderate (3)(4) or high (≥5).

Study Selection and Risk of Bias Assessment.
A total of 1,678 results were obtained from the PubMed Central literature search out of which 14 were deemed to be relevant to the research question. Figure 1 shows the study selection process.
Based on the risk of bias assessment of the 14 studies included, 9 (64.3%) and fve (35.7%) were observed to have low and moderate risks of publication bias, respectively (Supplemental Table S1).

Data Extraction.
Characteristics of the relevant lymphatic flariasis studies extracted are presented in Table 1. Based on the assessment of the impact of mass drug administration (MDA) on lymphatic flariasis (LF) control, data on microflaria (Mf ) and Mf antigenic cases reported at baseline, three years (mid-term), and ≥5 years (pretransmission assessment survey, pre-TAS) of MDA  implementation were extracted and presented in Table 2.
Baseline, mid-term and pre-TAS microflaria (Table 3) and Mf antigen (Table 4) prevalence were calculated. Te percentage reductions for mid-term and pre-TAS microflaria ( Table 3) and Mf antigen (Table 4) prevalence compared to baseline prevalence were also calculated.  [29]. Albendazole and ivermectin are administered in areas where LF is co-endemic with onchocerciasis, as observed in sub-Saharan Africa [30]. However, treatment with DEC is contraindicated in areas where onchocerciasis or loiasis might coexist [29], accounting for its use in onchocerciasis-free regions. Tis is due to the potential for severe adverse events such as the induction of strong local infammation in patients with ocular microflariae attributable to microflariae death [31]. Tese regimens, at adequate levels of coverage, safely and efectively reduce the number of microflariae circulating in the blood and, therefore, the prevalence of infection in the entire LF endemic community [11]. Tis review assessed the impact of MDA implementation by comparing baseline microflaria and antigen prevalence with those of three years (mid-term) and ≥5 years (pre-TAS) and their respective percentage reductions. Although the stringent eligibility criteria limited the number of articles, this review provides useful information for stakeholders in the control of LF. In this review, 11 (78.57%) and three (21.43%) studies reported variable MDA coverage (19% to 100%) and compliance (70.10% to 80%), respectively (Table 1), highlighting the challenge of attaining and maintaining high treatment coverage. To achieve interruption of parasite transmission, MDA coverage of at least 80% [32] and compliance exceeding 65-75% [33] are required.

Discussion
Te percentage microflaria (Mf ) prevalence reduction three years after MDA implementation was high, ranging from 88.54% to 98.66% in the majority of the mid-term studies (4 [80%], Table 3), with one reporting a low prevalence reduction of 58.74%. Interestingly, these reductions are comparable to those of studies that implemented MDA for fve to 10 years (≥5 years) with a majority of them (5, 83.33%) having prevalence reductions ranging from 79.23% to 98.26% (Table 3) with one unusually increasing in Mf prevalence by 36.15% attributable to very low MDA coverage of 46-56% [25]. Te percentage antigen prevalence reductions at three years and fve to 10 years of MDA implementation compared to baseline antigen prevalence appeared to be comparable (Table 4). Various studies have reported that two [16,34] or three [18] years of MDA implementation with high coverage (≥80%) have a similar impact on the reduction of LF prevalence compared with ≥5 years of MDA recommended for interruption of parasite transmission [32]. Tey suggest that efectively addressing the challenges of MDA implementation has the potential to cause an early interruption of parasite transmission, thereby reducing the years of MDA implementation. Tese fndings highlight the importance of efective implementation of MDA in LF control.   Journal of Tropical Medicine

Challenges of MDA Implementation.
Te implementation of MDA in LF control is associated with several challenges such as low compliance [35] and the difculty attaining and maintaining of high treatment coverage [36,37]. Widespread noncompliance may increase the number of individuals serving as reservoirs of infection in the population, thereby increasing the chance of LF transmission [16,32]. Inadequate community understanding of and participation in LF MDA programme is, therefore, a major drawback to its efective implementation. Moreover, the difculty in retaining community health volunteers, involved in training and drug distribution, on account of low fnancial incentives [38], inaccurate [39,40], and late data reporting on LF treatment coverage [41] has also been documented. Tese challenges create the opportunity for LF parasites to remain in circulation in endemic areas, making interruption of their transmission difcult.

Implications for Lymphatic Filariasis Elimination.
Mass drug administration (MDA) for LF control is aimed at reducing the density of parasites circulating in the blood of LF victims and the prevalence of infection in communities to levels where transmission is no longer sustainable by the mosquito vector [6]. In this regard, community participation in MDA programmes is highly recommended. Te involvement of opinion, traditional, and religious leaders in MDA implementation campaigns will generate interest in and acceptance of the programme and, thus, enhance cooperation and programme participation. Educating community members on the importance of the programme, the safety of the drug, and its side efects will allay their fears and should be an integral part of MDA programmes. Provision of incentives in the form of bed nets to community members [42] and adequate allowances to community health volunteers for training and drug distribution [43,44] has the desired efects of increasing drug uptake and community participation. Te use of convenient period for drug distribution may also increase drug uptake, as absence from home during drug distribution is an important reason for not taking the drugs [36]. Tese strategies are likely to increase compliance with MDA and MDA coverage to the required levels [32,33] to interrupt parasite transmission and reduce microflarial prevalence to levels that warrant LF elimination.

Conclusion
Tis study revealed high microflaria (Mf ) prevalence reductions for studies that implemented MDA for LF control  for three years, comparable to those of studies that implemented MDA for fve to 10 years. However, variable MDA coverage ranging from 19% to 100% was reported, highlighting the challenge of attaining and maintaining the high LF treatment coverage (≥80%) required to achieve interruption of parasite transmission. Mass drug administration (MDA) for LF control should aim at drawing attention to the importance of the programme and improving its understanding as well as community participation. Tis approach is fundamental to increasing compliance with MDA and MDA coverage, thereby interrupting parasite transmission.

Data Availability
No primary data were used to support this study. Information presented in this review is based on published papers which have been duly cited.

Conflicts of Interest
Te authors declare that there are no conficts of interest.