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 96% (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://ichgcp.net/clinical-trials-registry/NCT02899936.

Conflict of interest statement

The authors have declared that no competing interests exist. Author Steven Kumai was unable to confirm their authorship contributions. On their behalf, the corresponding author has reported their contributions to the best of their knowledge.

Figures

Fig 1. Study communities of Bogia District, Madang, Papua New Guinea.

A) Map of Bogia District, where each dot represents a village, with communities that received IDA shown in red and those that received DA shown in black. B) Map of Papua New Guinea showing the location of Bogia District. Sources: Esri, HERE, Garmin, FAO, NOAA, USGS, OpenStreetMap contributors, and the GIS User Community; https://www.arcgis.com/home/webmap/viewer.html?layers=7dc6cea0b1764a1f9af2e679f642f0f5.

Fig 2. CONSORT flow diagram detailing participants included in safety and efficacy analysis.

Fig 3. Proportion of participants CFA positive (A) and Mf positive (B) by age-group and sex before receiving mass drug administration (baseline).

CFA, circulating filarial antigenemia; Mf, microfilariae.

Fig 4. Forest plot showing adjusted odds ratios and 95% confidence intervals (estimates from multivariable logistic regression model) for factors associated with adverse events following treatment for lymphatic filariasis.

Unadjusted odd ratio and 95% confidence intervals also provided. Odds ratios were assessed relative to the listed reference groups. P-values for comparisons to references group: *

Fig 5. Frequencies of the most commonly observed adverse events by treatment arm.

Frequencies are expressed as percentages of participants who were assessed for AEs after treatment. AE: adverse event; DA: diethylcarbamazine and albendazole; IDA: ivermectin, diethylcarbamazine and albendazole.

Fig 6. Reduction in microfilaremia 12 months after treatment by drug regimen.

Data included only from participants who were microfilaremic at baseline (N = 67 in DA arm, N = 54 in IDA arm). DA: diethylcarbamazine and albendazole; IDA: ivermectin, diethylcarbamazine and albendazole; Mf: microfilaremia.

Fig 7. FTS score distribution at baseline and 1-year after mass drug administration by treatment arm.

DA: diethylcarbamazine and albendazole; IDA: ivermectin, diethylcarbamazine and albendazole; FTS: Filarial Test Strip (Alere).