Date Published: June 24, 2019
Publisher: Public Library of Science
Author(s): Gary J. Weil, Joshua Bogus, Michael Christian, Christine Dubray, Yenny Djuardi, Peter U. Fischer, Charles W. Goss, Myra Hardy, Purushothaman Jambulingam, Christopher L. King, Vijesh Sridhar Kuttiat, Kaliannagounder Krishnamoorthy, Moses Laman, Jean Frantz Lemoine, Katiuscia K. O’Brian, Leanne J. Robinson, Josaia Samuela, Kenneth B. Schechtman, Anita Sircar, Adinarayanan Srividya, Andrew C. Steer, Taniawati Supali, Swaminathan Subramanian, Paul Garner
Abstract: 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 < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites.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
Partial Text: Lymphatic filariasis (LF) is a disabling and deforming neglected tropical disease caused by filarial nematode parasites (Wuchereria bancrofti, Brugia malayi, and B. timori) that are transmitted by mosquitoes. Adult filarial worms reside in lymphatic vessels; the adult worms (and host inflammatory responses to them) lead to lymphedema, elephantiasis, and hydroceles. The Global Programme to Eliminate Lymphatic Filariasis (GPELF, coordinated by the World Health Organization [WHO]) was launched in the year 2000 with the goal of eliminating LF as a public health problem by 2020 [1,2]. At that time, some 80 countries were considered to be endemic for LF, and the target population at risk for infection was more than 1.3 billion. GPELF’s elimination strategy is largely based on repeated rounds of mass administration of antifilarial drugs (MDA) to populations at risk for infection. These drugs temporarily clear microfilariae (Mf) from the blood (preventing uptake by mosquitoes), and they have partial macrofilaricidal activity (the ability to kill adult filarial worms). Drug donations from pharmaceutical companies allowed GPELF to quickly expand, and progress has been very significant [3–5]. Between 2000 and 2016, some 6.7 billion treatments were delivered to more than 850 million people. In addition, the number of countries that required additional MDA was reduced to 52, and the population at risk for infection was reduced by approximately 40% . GPELF is arguably the largest control or elimination program for an infectious disease to date based on MDA.
This open-label, cluster-randomized study was conducted to assess the safety of a new triple-drug treatment regimen for use in LF elimination programs. When we designed this study, we had preliminary results from three small clinical trials that showed that IDA was much more effective than the widely used two-drug DA or IA regimens for achieving sustained clearance of Mf from the blood [7,8,9]. For example, a study in Papua New Guinea documented complete clearance of Mf from the blood in 96% of subjects 12 months after a single dose of IDA versus 25% with Mf clearance after DA . A second study performed in Cote d’Ivoire documented complete Mf clearance in 76% of participants 1 year after IDA versus 26% with complete Mf clearance after IA . Many subjects experienced AEs in these trials (59% after IDA versus 41% after DA in Papua New Guinea and 38% after IDA versus 39% after IA in Cote d’Ivoire). Moderate (grade 2) AEs were more common after IDA than after DA (27% versus 5%) or IA (19% versus 2%) in these studies, but no serious posttreatment AEs were observed in either study. Thus, results from these small studies suggested that the improved efficacy of IDA was accompanied by more frequent mild or moderate AEs. More safety data were needed before IDA could be recommended for widespread use in community settings.