Adverse events following single dose treatment of lymphatic filariasis: Observations from a review of the literature

Abstract

Background: WHO's Global Programme to Eliminate Lymphatic Filariasis (LF) uses mass drug administration (MDA) of anthelmintic medications to interrupt LF transmission in endemic areas. Recently, a single dose combination of ivermectin (IVM), diethylcarbamazine (DEC), and albendazole (ALB) was shown to be markedly more effective than the standard two-drug regimens (DEC or IVM, plus ALB) for achieving long-term clearance of microfilaremia.

Objective and methods: To provide context for the results of a large-scale, international safety trial of MDA using triple drug therapy, we searched Ovid Medline for studies published from 1985-2017 that reported adverse events (AEs) following treatment of LF with IVM, DEC, ALB, or any combination of these medications. Studies that reported AE rates by treatment group were included.

Findings: We reviewed 162 published manuscripts, 55 of which met inclusion criteria. Among these, 34 were clinic or hospital-based clinical trials, and 21 were community-based studies. Reported AE rates varied widely. The median AE rate following DEC or IVM treatment was greater than 60% among microfilaremic participants and less than 10% in persons without microfilaremia. The most common AEs reported were fever, headache, myalgia or arthralgia, fatigue, and malaise.

Interpretation: Mild to moderate systemic AEs related to death of microfilariae are common following LF treatment. Post-treatment AEs are transient and rarely severe or serious. Comparison of AE rates from different community studies is difficult due to inconsistent AE reporting, varied infection rates, and varied intensity of follow-up. A more uniform approach for assessing and reporting AEs in LF community treatment studies would be helpful.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. PRISMA flow diagram for inclusion of articles in the quantitative synthesis.

Fig 2. Box plot of reported percentage of participants experiencing at least one AE among individual treatment groups (study arms), comparing active (dark boxes) and passive (light boxes) surveillance methods, excluding placebos.

Groups where no participants (0%) or all participants (100%) were Mf positive were from hospital or clinic-based clinical trials; those with “varied” Mf status were from community studies. A) Results when each study group was considered to have equal weight. B) Results when results were adjusted to consider the number of participants in each study group. Boxes indicate the interquartile range (IQR) and dashed line the median. Whiskers indicate the upper and lower adjacent values: upper = the greatest value less than (75th percentile + (1.5 x IQR)); lower = the lowest value greater than (25th percentile–(1.5 x IQR)).

Fig 3. Percentage of participants experiencing at least one AE in studies with active surveillance, according to the microfilaremia (Mf) status of participants.

Groups where no participants (0%) or all participants (100%) were Mf positive were from hospital or clinic-based clinical trials; those with “varied” Mf status were from community studies. The top panels show equal weighting for each study, regardless of participant number; results in the bottom panels are weighted by participant number. Boxes indicate the interquartile range (IQR) and dashed line the median. Whiskers indicate the upper and lower adjacent values: upper = the greatest value less than (75th percentile + (1.5 x IQR)); lower = the lowest value greater than (25th percentile–(1.5 x IQR). Abbreviations: ALB = Albendazole, DA = DEC + Albendazole, DI = DEC + Ivermectin, IA = Ivermectin + Albendazole, IDA = Ivermectin + DEC + Albendazole, IVM = Ivermectin.

Fig 4. Reported percentages of specific AEs in treatment arms with 100% microfilaremia rates (shaded bars) or no microfilaremia (open bars).

Only studies with active AE reporting are included and each study arm is given equal weight (not weighted by participant number). Boxes indicate the interquartile range (IQR) and dashed line the median. Whiskers indicate the upper and lower adjacent values: upper = the greatest value less than (75th percentile + (1.5 x IQR)); lower = the lowest value greater than (25th percentile–(1.5 x IQR)).

Fig 5. Percentage of participants experiencing common systemic AEs by treatment group, according to the microfilaremia status of participants.

DEC and IVM data include all study arms where the indicated drug was given alone or in combination (with or without ALB). For clarity, the ALB panel shows only study arms in which ALB alone was given. The upper panels assign each study are equal weight; the lower panels are weighted according to number of participants per study arm. Boxes indicate the interquartile range (IQR) and horizontal line the median. Whiskers indicate the upper and lower adjacent values: upper = the greatest value less than (75th percentile + (1.5 x IQR)); lower = the lowest value greater than (25th percentile–(1.5 x IQR)).