Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole + diethylcarbamazine + ivermectin for lymphatic filariasis in Papua New Guinea: An open-label, cluster-randomised trial

Abstract

Background Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. Methodology All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. Principal findings Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 97% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007). Conclusion IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. Trial registration Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.

Safety and Tolerability of Ivermectin and Albendazole Mass Drug Administration in Lymphatic Filariasis Endemic Communities of Tanzania: A Cohort Event Monitoring Study

“…Safety studies conducted elsewhere using diverse study designs, target populations, and treatment indications reported varying incidence rates of mild-to-moderate AEs in the first two days of treatment [ 25 , 26 , 27 , 28 ]. A higher incidence (>15%) of mild-to-moderate AEs following MDA with diethylcarbamazine containing triple therapy (diethylcarbamazine + ivermectin + albendazole) or dual therapy (diethylcarbamazine + albendazole) is reported [ 19 , 29 , 30 , 31 ]. The relatively lower incidence of AEs in our study indicates a better safety profile of IA combination chemotherapy than diethylcarbamazine containing dual or triple chemotherapy for the elimination of LF.…”

“…This is in line with previous studies reporting a higher incidence of treatment-associated systemic AEs related to the death of microfilariae in LF-infected individuals than those without the disease [ 7 ]. Circulating filarial antigens (CFA) and microfilaremia (mf) positivity and high mf density were significantly associated with higher rates of AEs following MDA with albendazole + diethylcarbamazine + Ivermectin [ 29 ]. The increase in cytokine, filarial DNA, and CFA levels were related to the development of AEs following treatment of LF [ 37 ].…”

Mass drug administration of ivermectin, diethylcarbamazine, plus albendazole compared with diethylcarbamazine plus albendazole for reduction of lymphatic filariasis endemicity in Papua New Guinea: a cluster-randomised trial

“…A large multicentre cluster-randomised trial has shown that the triple-drug regimen has an acceptable safety profile compared with the two-drug regimen, 13 and 1-year follow-up studies of microfilaraemia-positive individuals from these safety studies showed the superior efficacy of the triple-drug regimen over the two-drug regimen in multiple countries. 14 , 15 , 16 , 17 As a result, WHO now recommends the triple-drug regimen for areas outside of Africa with no previous mass drug administration and in areas where transmission has not been interrupted despite multiple rounds of the two-drug regimen. 18 The current WHO recommendation is for two annual rounds of mass drug administration with the triple-drug regimen to interrupt transmission, 18 although the actual number of rounds required is not yet established and the effectiveness of the triple-drug regimen has not been assessed in populations.…”

Environmental impacts of mass drug administration programs: exposures, risks, and mitigation of antimicrobial resistance

“…While the success of MDA programs might contribute to reducing childhood morbidity and mortality related to NTDs at the population level [ 2 – 5 ]. Potentially adverse environmental effects of those programs must be carefully weighed alongside expected benefits and adverse events of MDA in humans [ 6 , 7 ]. A hallmark of MDA programs is to eliminate the need for individual diagnosis and to administer treatment to all members in a given community at the same time, regardless of clinical presentation.…”