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://clinicaltrials.gov/ct2/show/NCT02899936.

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: *<0.05, **<0.01, *** < 0.001. CI; Confidence Interval; DA: diethylcarbamazine and albendazole; IDA: ivermectin, diethylcarbamazine and albendazole; CFA: circulating filarial antigen; MF, microfilaremia; (-), Negative results; (+), Positive results. Note that both unadjusted and adjusted models contain a random effect to account for correlation among subjects within a locality.

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).