Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from \u3e26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the gold standard for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing

Safety and efficacy of co-administered diethylcarbamazine, albendazole and ivermectin during mass drug administration for lymphatic filariasis in Haiti: Results from a two-armed, open-label, cluster-randomized, community study

In Haiti, 22 communes still require mass drug administration (MDA) to eliminate lymphatic filariasis (LF) as a public health problem. Several clinical trials have shown that a single oral dose of ivermectin (IVM), diethylcarbamazine (DEC) and albendazole (ALB) (IDA) is more effective than DEC plus ALB (DA) for clearing Wuchereria bancrofti microfilariae (Mf). We performed a cluster-randomized community study to compare the safety and efficacy of IDA and DA in an LF-endemic area in northern Haiti. Ten localities were randomized to receive either DA or IDA. Participants were monitored for adverse events (AE), parasite antigenemia, and microfilaremia. Antigen-positive participants were retested one year after MDA to assess treatment efficacy. Fewer participants (11.0%, 321/2917) experienced at least one AE after IDA compared to DA (17.3%, 491/2844, P<0.001). Most AEs were mild, and the three most common AEs reported were headaches, dizziness and abdominal pain. Serious AEs developed in three participants who received DA. Baseline prevalence for filarial antigenemia was 8.0% (239/3004) in IDA localities and 11.5% (344/2994) in DA localities (<0.001). Of those with positive antigenemia, 17.6% (42/239) in IDA localities and 20.9% (72/344, P = 0.25) in DA localities were microfilaremic. One year after treatment, 84% percent of persons with positive filarial antigen tests at baseline could be retested. Clearance rates for filarial antigenemia were 20.5% (41/200) after IDA versus 25.4% (74/289) after DA (P = 0.3). However, 94.4% (34/36) of IDA recipients and 75.9% (44/58) of DA recipients with baseline microfilaremia were Mf negative at the time of retest (P = 0.02). Thus, MDA with IDA was at least as well tolerated and significantly more effective for clearing Mf compared to the standard DA regimen in this study. Effective MDA coverage with IDA could accelerate the elimination of LF as a public health problem in the 22 communes that still require MDA in Haiti

Polisy Kont Moustik: A Culturally Competent Approach to Larval Source Reduction in the Context of Lymphatic Filariasis and Malaria Elimination in Haiti

Community engagement has become an increasingly important focus of global health programs. Arbovirus emergence in the Americas (Zika and chikungunya virues), and global goals for malaria and lymphatic filariasis elimination, mean that community-based mosquito control has taken on a new salience. But how should mosquito control initiatives be designed and implemented in ways that best engage local people? What are the challenges and trade-offs of different strategies, not only for effectiveness but also for scale-up? In this paper, we describe the social and political dynamics of a pilot study in a small town in northern Haiti. With the aim of developing a culturally-competent approach to larval source management (LSM), our pilot project combined larval surveillance with environmental management, social engagement, community education, and larvicide application. Orientated around a network of ‘Mosquito Police’ (Polisye Kont Moustik, in Haitian Creole), our approach integrated elements of formative research, social learning, and community participation. Here, we reflect on the challenges we encountered in the field, from larval mapping, staff management, education and behavior change, engagement with formal and informal leaders, and community-based environmental cleanup. We discuss how these programmatic efforts were influenced and shaped by a complex range of social, cultural, political, and economic realities, and conclude by discussing the implications of our community-based approach for the elimination of lymphatic filariasis and malaria, and other vector-borne diseases, in Haiti

Models of effectiveness of interventions against malaria transmitted by Anopheles albimanus

Most impact prediction of malaria vector control interventions has been based on African vectors. Anopheles albimanus, the main vector in Central America and the Caribbean, has higher intrinsic mortality, is more zoophilic and less likely to rest indoors. Therefore, relative impact among interventions may be different. Prioritizing interventions, in particular for eliminating Plasmodium falciparum from Haiti, should consider local vector characteristics.; Field bionomics data of An. albimanus from Hispaniola and intervention effect data from southern Mexico were used to parameterize mathematical malaria models. Indoor residual spraying (IRS), insecticide-treated nets (ITNs), and house-screening were analysed by inferring their impact on the vectorial capacity in a difference-equation model. Impact of larval source management (LSM) was assumed linear with coverage. Case management, mass drug administration and vaccination were evaluated by estimating their effects on transmission in a susceptible-infected-susceptible model. Analogous analyses were done for Anopheles gambiae parameterized with data from Tanzania, Benin and Nigeria.; While LSM was equally effective against both vectors, impact of ITNs on transmission by An. albimanus was much lower than for An. gambiae. Assuming that people are outside until bedtime, this was similar for the impact of IRS with dichlorodiphenyltrichloroethane (DDT) or bendiocarb, and impact of IRS was less than that of ITNs. However, assuming people go inside when biting starts, IRS had more impact on An. albimanus than ITNs. While house-screening had less impact than ITNs or IRS on An. gambiae, it had more impact on An. albimanus than ITNs or IRS. The impacts of chemoprevention and chemotherapy were comparable in magnitude to those of strategies against An. albimanus. Chemo-prevention impact increased steeply as coverage approached 100%, whilst clinical-case management impact saturated because of remaining asymptomatic infections.; House-screening and repellent IRS are potentially highly effective against An. albimanus if people are indoors during the evening. This is consistent with historical impacts of IRS with DDT, which can be largely attributed to excito-repellency. It also supports the idea that housing improvements have played a critical role in malaria control in North America. For elimination planning, impact estimates need to be combined with feasibility and cost-analysis

Effectiveness of insecticide-treated bednets in malaria prevention in Haiti: a case-control study

Background Insecticide-treated bednets (ITNs) are eff ective in preventing malaria where vectors primarily bite indoors and late at night, but their eff ectiveness is uncertain where vectors bite outdoors and earlier in the evening. We studied the eff ectiveness of ITNs following a mass distribution in Haiti from May to September, 2012, where the Anopheles albimanus vector bites primarily outdoors and often when people are awake. Methods In this case-control study, we enrolled febrile patients presenting to outpatient departments at 17 health facilities throughout Haiti from Sept 4, 2012, to Feb 27, 2014, who were tested with malaria rapid diagnostic tests (RDTs), and administered questionnaires on ITN use and other risk factors. Cases were defi ned by positive RDT and controls were febrile patients from the same clinic with a negative RDT. Our primary analysis retrospectively matched cases and controls by age, sex, location, and date, and used conditional logistic regression on the matched sample. A sensitivity analysis used propensity scores to match patients on ITN use propensity and analyse malaria among ITN users and non-users. Additional ITN bioeffi cacy and entomological data were collected. Findings We enrolled 9317 patients, including 378 (4%) RDT-positive cases. 1202 (13%) patients reported ITN use. Post-hoc matching of cases and controls yielded 362 cases and 1201 matched controls, 19% (333) of whom reported consistent campaign net use. After using propensity scores to match on consistent campaign ITN use, 2298 patients, including 138 (7%) RDT-positive cases, were included: 1149 consistent campaign ITN users and 1149 non-consistent campaign ITN users. Both analyses revealed that ITNs did not signifi cantly protect against clinical malaria (odds ratio [OR]=0·95, 95% CI 0·68–1·32, p=0·745 for case-control analysis; OR=0·95, 95% CI 0·45–1·97, p=0·884 for propensity score analysis). ITN and entomological data indicated good ITN physical integrity and bioeffi cacy, and no permethrin resistance among local mosquitoes. Interpretation We found no evidence that mass ITN campaigns reduce clinical malaria in this observational study in Haiti; alternative malaria control strategies should be prioritised

Risk Factors for Malaria Infection and Seropositivity in the Elimination Area of Grand'Anse, Haiti: A Case-Control Study among Febrile Individuals Seeking Treatment at Public Health Facilities.

The island of Hispaniola aims to eliminate malaria by 2025; however, there are limited data to describe epidemiologic risk factors for malaria in this setting. A prospective case-control study was conducted at four health facilities in southwest Haiti, aiming to describe factors influencing the risk of current and past malaria infection. Cases were defined as individuals attending facilities with current or recent fever and positive malaria rapid diagnostic test (RDT), while controls were those with current or recent fever and RDT negative. Serological markers of recent and cumulative exposure to Plasmodium were assessed using the multiplex bead assay from dried blood spots and used for alternate case definitions. Kuldorff's spatial scan statistic was used to identify local clusters of infection or exposure. Logistic regression models were used to assess potential risk factors for RDT positivity and recent exposure markers, including age-group, gender, and recruiting health facility as group-matching variables. A total of 192 cases (RDT positive) and 915 controls (RDT negative) were recruited. Consistent spatial clusters were identified for all three infection and exposure metrics, indicating temporal stability of malaria transmission at these sites. Risk factors included remoteness from health facilities and household construction, furthermore, insecticide-treated net ownership or use was associated with reduced odds of RDT positivity. These findings indicate the malaria risk in Grand'Anse is driven primarily by location. Travel, occupation, and other behavioral factors were not associated with malaria. These data can support the National Malaria Program to refine and target their intervention approaches, and to move toward elimination

A multi-center, open-labeled, cluster-randomized study of the safety of double and triple drug community mass drug administration for lymphatic filariasis

BackgroundThe Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings.Methods and findingsLarge community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P ConclusionsIn this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA.Trial registrationClinicaltrials.gov registration number: NCT02899936

Community end user perceptions of hessian fabric transfluthrin vapour emanators for protecting against mosquitoes under conditions of routine use in Port-au-Prince, Haiti

Background: A treated fabric device for emanating the volatile pyrethroid transfluthrin was recently developed in Tanzania that protected against night-biting Anopheles and Culex mosquitoes for several months. Here perceptions of community end users provided with such transfluthrin emanators, primarily intended to protect them against day-active Aedes vectors of human arboviruses that often attack people outdoors, were assessed in Port-au-Prince, Haiti. Methods: Following the distribution of transfluthrin emanators to participating households in poor-to-middle class urban neighbourhoods, questionnaire surveys and in-depth interviews of end-user households were supplemented with conventional and Photovoice-based focus group discussions. Observations were assessed synthetically to evaluate user perceptions of protection and acceptability, and to solicit advice for improving and promoting them in the future. Results: Many participants viewed emanators positively and several outlined various advantages over current alternatives, although some expressed concerns about smell, health hazards, bulkiness, unattractiveness and future cost. Most participants expressed moderate to high satisfaction with protection against mosquitoes, especially indoors. Protection against other arthropod pests was also commonly reported, although satisfaction levels were highly variable. Diverse use practices were reported, some of which probably targeted nocturnal Culex resting indoors, rather than Aedes attacking them outdoors during daylight hours. Perceived durability of protection varied: While many participants noted some slow loss over months, others noted rapid decline within days. A few participants specifically attributed efficacy loss to outdoor use and exposure to wind or moisture. Many expressed stringent expectations of satisfactory protection levels, with even a single mosquito bite considered unsatisfactory. Some participants considered emanators superior to fans, bedsheets, sprays and coils, but it is concerning that several preferred them to bed nets and consequently stopped using the latter. Conclusions: The perspectives shared by Haitian end-users are consistent with those from similar studies in Brazil and recent epidemiological evidence from Peru that other transfluthrin emanator products can protect against arbovirus infection. While these encouraging sociological observations contrast starkly with evidence of essentially negligible effects upon Aedes landing rates from parallel entomological assessments across Haiti, Tanzania, Brazil and Peru, no other reason to doubt the generally encouraging views expressed herein by Haitian end users could be identified

A multicenter, community-based, mixed methods assessment of the acceptability of a triple drug regimen for elimination of lymphatic filariasis

BackgroundMany countries will not reach elimination targets for lymphatic filariasis in 2020 using the two-drug treatment regimen (diethylcarbamazine citrate [DEC] and albendazole [DA]). A cluster-randomized, community-based safety study performed in Fiji, Haiti, India, Indonesia and Papua New Guinea tested the safety and efficacy of a new regimen of ivermectin, DEC and albendazole (IDA).Methodology/principal findingsTo assess acceptability of IDA and DA, a mixed methods study was embedded within this community-based safety study. The study objective was to assess the acceptability of IDA versus DA. Community surveys were performed in each country with randomly selected participants (>14 years) from the safety study participant list in both DA and IDA arms. In depth interviews (IDI) and focus group discussions (FGD) assessed acceptability-related themes. In 1919 individuals, distribution of sex, microfilariae (Mf) presence and circulating filarial antigenemia (CFA), adverse events (AE) and age were similar across arms. A composite acceptability score summed the values from nine indicators (range 9-36). The median (22.5) score indicated threshold of acceptability. There was no difference in scores for IDA and DA regimens. Mean acceptability scores across both treatment arms were: Fiji 33.7 (95% CI: 33.1-34.3); Papua New Guinea 32.9 (95% CI: 31.9-33.8); Indonesia 30.6 (95% CI: 29.8-31.3); Haiti 28.6 (95% CI: 27.8-29.4); India 26.8 (95% CI: 25.6-28) (PConclusions/significanceIDA and DA regimens for LF elimination were highly and equally acceptable in individuals participating in the community-based safety study in Fiji, Haiti, India, Indonesia, and Papua New Guinea. Country variation in acceptability was significant. Acceptability of the professionalism of the treatment delivery was highlighted

The Immediate Effects of a Combined Mass Drug Administration and Indoor Residual Spraying Campaign to Accelerate Progress Toward Malaria Elimination in Grande-Anse, Haiti.

BACKGROUND: Haiti is planning targeted interventions to accelerate progress toward malaria elimination. In the most affected department (Grande-Anse), a combined mass drug administration (MDA) and indoor residual spraying (IRS) campaign was launched in October 2018. This study assessed the intervention's effectiveness in reducing Plasmodium falciparum prevalence. METHODS: An ecological quasi-experimental study was designed, using a pretest and posttest with a nonrandomized control group. Surveys were conducted in November 2017 in a panel of easy access groups (25 schools and 16 clinics) and were repeated 2-6 weeks after the campaign, in November 2018. Single-dose sulfadoxine-pyrimethamine and primaquine was used for MDA, and pirimiphos-methyl as insecticide for IRS. RESULTS: A total of 10 006 participants were recruited. Fifty-two percent of the population in the intervention area reported having received MDA. Prevalence diminished between 2017 and 2018 in both areas, but the reduction was significantly larger in the intervention area (ratio of adjusted risk ratios, 0.32 [95% confidence interval, .104-.998]). CONCLUSIONS: Despite a moderate coverage, the campaign was effective in reducing P. falciparum prevalence immediately after 1 round. Targeted MDA plus IRS is useful in preelimination settings to rapidly decrease the parasite reservoir, an encouraging step to accelerate progress toward malaria elimination