Evidence Against Rapid Emergence of Praziquantel Resistance in Schistosoma haematobium, Kenya - Statistical Data Included

Emerging Infectious Diseases, Nov, 2000 by Charles H. King, Eric M. Muchiri, John H. Ouma

We examined the long-term efficacy of praziquantel against Schistosoma haematobium, the causative agent of urinary schistosomiasis, during a school-based treatment program in the Msambweni area of Coast Province, Kenya, where the disease is highly endemic. Our results, derived from treating 4,031 of 7,641 children from 1984 to 1993, indicate substantial year-to-year variation in drug efficacy. However, the pattern of this variation was not consistent with primary or progressive emergence of praziquantel resistance. Mathematical modeling indicated that, at current treatment rates, praziquantel resistance will likely take 10 or more years to emerge.

Schistosomiasis remains a public health problem in many regions, including Africa, the Middle East, Asia, and South America (1). For many of the Schistosoma species that infect humans, isoquinolin-4-one, praziquantel, is the only effective drug (2,3). Its minimal side effects and high degree of efficacy against both trematodes and cestodes have made it the drug of choice for many human and veterinary parasitic infections (2,4). However, praziquantel has been in use for more than 20 years (5), and concern is increasing that resistance has emerged, or will soon emerge, in human parasites (6,7).

Loss of praziquantel efficacy would set back helminth control efforts. Many community-based programs depend on praziquantel for treating patients with schistosomiasis, cysticercosis, echinococcosis, and tapeworm and other fluke infections (5,8-13). Concern over possible loss of efficacy prompted the European Commission to establish an International Initiative on Praziquantel Use, which met in February 1998 (14) and again in February 1999 (15). The group reviewed reports of low efficacy in clinical trials in Senegal and Egypt (16-19) and of laboratory isolation of schistosome strains resistant to standard and high doses of the drug (20-23). Although there was no definitive laboratory evidence of genetically transmissible and drug-selectable resistance (as had been demonstrated for the antischistosome drug hycanthone [24]), concern was raised over possible low-level resistance. The need was expressed for continued monitoring for resistant strains under the pressure of widespread praziquantel use (14).

We examined drug efficacy in the community and among schoolchildren given repeated praziquantel treatment for S. haematobium in Coast Province, Kenya. Year-to-year variation in treatment response was assessed, and the likely time-to-emergence of resistance was evaluated through the use of mathematical modeling of resistance-gene transmission in this obligately diecious parasite.

Materials and Methods

Study Design

The overall goal of the community study was to treat urinary schistosomiasis in schoolchildren (initial N - 3,196) in a nine-village area in Kwale District, Coast Province, Kenya. After oral informed consent was obtained under a human investigations protocol approved by the institutional review boards of University Hospitals of Cleveland and the Ministry of Health, Kenya, case-finding was performed by school-based and follow-up village surveys. Details of the protocols have been published (25-27). In 1984, the initial treatment year, S. haematobium-infected children were randomly assigned to groups for treatment with either praziquantel (Biltricide, Bayer, Leverkusen, Germany), 40 mg/kg once a year, or metrifonate (Bilarcil, Bayer), 10 mg/kg three times a year. In years 2 and 3, the initial treatment was repeated, independent of parasitologic findings. New entrants to the study were assigned randomly to either the praziquantel or metrifonate treatment groups, according to the original 1984 protocol. In 1987, half the 1984 cohort, treated either with praziquantel or with metrifonate, was randomized to receive a single dose of metrifonate, 10 mg/kg, as a "consolidation" treatment. After a 2-year hiatus, annual treatment was resumed in 1989 to 1991; during this period, only children in whose urine samples eggs were identified (egg-positive children) were treated with praziquantel alone.

Infection status was determined by Nuclepore (Whatman, Kent, UK) filtration of two 10-mL samples from stirred midday urine specimens. Infection-associated disease was determined by physical examination, dipstick urine examination for hematuria and proteinuria, and ultrasound examination of the kidneys and bladder (25). Clinical and parasitologic testing was performed each year. Results were coded and entered for analysis in databases at Case Western Reserve University and the Kenyan Ministry of Health.

Data Analysis

Results of annual treatments were scored as "cure" for patients whose status changed from egg-positive to egg-negative, "noncure" for those whose status remained egg-positive, and "infected or reinfected" for those whose status changed from egg-negative to egg-positive between yearly examinations. Because of the skewed distribution of egg counts in the infected population, the effects of treatment on average intensity of infection were assessed by determining the change in geometric mean egg count between examinations. Differences between outcome rates were assessed by the chi-square test with Yates' correction or Fisher's exact test.