Pharmacovigilance in mass drug administration for the control and elimination of lymphatic filariasis in Kenya

The World Health Organization (WHO) recommends periodic mass drug administration (MDA) of anti-filarial drugs as preventive chemotherapy to control and eliminate Lymphatic Filariasis (LF)as a public health problem. Since 2002, Kenya has been implementing dual therapy with Diethylcarbamazine and Albendazole combination (DA). In 2018, Kenya introduced triple-drug therapy with Ivermectin, Diethylcarbamazine, and Albendazole (IDA). We conducted a comparative safety surveillance of the newly introduced triple therapy against the standard dual therapy and the effectiveness of IDA in reducing the prevalence of LF in the community and clearance of circulating filarial antigens (CFA) among LF-infected (CFA positive) patients in Kenya's coastal region.

Firstly, an active safety surveillance study was conducted (Paper I) to determine the safety and tolerability of dual therapy (DA) in the general population (n=10,010). The cumulative incidence of MDA-associated adverse events (AEs) was 16.2% (95% confidence interval [CI], 15.5-16.9%). Most of the AEs were mild to moderate and transient in nature. The five most common AEs were dizziness, headache, loss of appetite, fever, and drowsiness. Older age, taking concurrent medications, ingesting three or more tablets of DEC, and type of meal taken before MDA were significant predictors of AEs.

Secondly, comparative safety surveillance of the newly introduced triple therapy (IDA, n=10,411) versus the standard dual therapy (DA, n=10,010) was conducted (Paper II). The findings revealed a significantly higher incidence of AEs in the IDA group 27.3%; 95% CI 26.4-28.2) compared to the DA group (16.2%; 95% CI 15.5-16.9). Female sex, obesity, taking three or more DEC or IVM tablets, and having pre- existing clinical symptoms were significant predictors of adverse events following IDA treatment.

At last, the safety, tolerability, and effectiveness of triple therapy in reducing the prevalence of LF antigenemia in the community and clearance rate of CFA after 2 and 4 months of post-MDA among LF-infected (CFA Positive) participants were conducted (Paper III). In the community, the prevalence of LF-antigenemia after two rounds of annual MDA assessed in 2021 (0.66%, 36/5464) was significantly lower than the baseline prevalence rate in 2018 (1.39%, 48/3464) (p < 0.001, 95% CI for proportions' difference = 0.003 to 0.012). Among LF-positive individuals, the clearance rates of CFA at two and four months of post-MDA were 63.2% (95% CI = 41.0% - 80.1%) and 68.4% (95% CI = 46.0% - 86.6%) respectively. The cumulative incidence of AE over a 7-day follow-up was 37.7% (95% CI: 25.6%-51.7%). The most common AEs were nausea, diarrhoea, stomach pain, and headache.

In conclusion, preventive chemotherapy with IDA is as safe and tolerable as standard DA therapy in the general population. However, the high incidence of AEs, particularly among LF-infected (CFA Positive) individuals, highlights the need for integrating pharmacovigilance into MDA campaigns. The effectiveness of IDA in reducing LF prevalence in the community and achieving high CFA clearance rates among the LF-positive individuals underscores its role as a critical intervention to halt transmission and eliminate LF. Strengthening collaborations between National Pharmacovigilance Centers and the NTD Programs is recommended to enhance future safety surveillance activities.

List of scientific papers

I. Khaemba C, Barry A, Omondi WP, Bota K, Matendechero S, Wandera C, Siyoi F, Kirui E, Oluka M, Nambwa P, Gurumurthy P, Njenga SM, Guantai A, Aklillu E. Safety and Tolerabilty of Mass Diethylcarbamzine and Albendazole Administration for Elimination of Lymphatic Filariasis in Kenya: An Active Surveillance Study. Pharmaceuticals (Basel). 2021 Mar 15;14(3):264. https://doi.org/10.3390/ph14030264

II. Khaemba C, Barry A, Omondi WP, Kirui E, Oluka M, Parthasarathi G, Njenga SM, Guantai A, Aklillu. Comparative Safety Surveillance of Triple (IDA) Versus Dual Therapy (DA) in Mass Drug Administration for Elimination of Lymphatic Filariasis in Kenya: A Cohort Event Monitoring Study. Drug Saf. 2023 Oct;46(10):961-974. doi: 10.1007/s40264-023-01338-9. Epub 2023 Aug 8. https://doi.org/10.1007/s40264-023-01338-9

III. Khaemba C, Njenga SM, Omondi WP, Kirui E, Oluka M, Guantai A, Aklillu E. Safety, Tolerability, and Effectiveness of triple-drug therapy with Ivermectin, Diethylcarbamazine, and Albendazole in Individuals with Circulating Filarial Antigens in Coastal Kenya: A Prospective Cohort Study. [Submitted]