Evidence Against Rapid Emergence of Praziquantel Resistance in Schistosoma haematobium, Kenya

Charles H. King, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA; Eric M. Muchiri, John H. Ouma, Ministry of Health, Nairobi, Kenya

Disclosures

Emerging Infectious Diseases. 2000;6(6) 

In This Article

Results

During 1984 to 1992, we observed substantial year-to-year variations in cure rates (conversion from egg-positive to egg-negative status on urine Nuclepore filtration examination) for both praziquantel and metrifonate (Table 1). The response to metrifonate treatment declined each year, from 79% in 1984 to 47% in 1987 (p <0.001, Figure 1); in contrast, we observed no consistent downward trend in response to praziquantel treatment, despite repeated use of the drug in many patients (Figures 1 and 2). However, the response to praziquantel varied significantly from year to year (p <0.001), from a cure rate of 96% in 1990 (year 7 of the project) to a cure rate of 65% in 1986 (year 3, p <0.001). This level of efficacy was within the previous range of S. haematobium cure rates, both in Coast Province and elsewhere in Africa (Table 2). In suppression of infection intensity, the praziquantel-mediated reduction of mean S. haematobium egg counts was consistently >=83% for all years of observation.

Figure 1. Yearly efficacy of drug therapy. Results of praziquantel treatment (solid bars) or metrifonate treatment (shaded bars) for Schistosoma haematobium infection in the Msambweni area during 1984 to 1992. Cure rates (conversion from egg-positive to egg-negative urine in annual follow-up testing) are shown for all egg-positive cases, by year of treatment. Only metrifonate therapy was given in 1987, and no treatment was given in 1988.

In both the study periods during which repeated, annual praziquantel treatment was used (1984-1987 and 1989-1993), the observed cure rate for egg-positive children increased in year 2 of treatment, then decreased in year 3 (Figure 1). The number of egg-positive children remaining to be treated in successive years was small, and this sample did not have sufficient statistical power to determine whether the year 3 decrease in praziquantel response was due to fluctuations in transmission[30], progressive selection of patients at high risk for exposure to S. haematobium[27,31], or gradual selection of praziquantel-resistant parasites.

Given the incomplete efficacy of praziquantel in eradicating infection[6] and the single annual follow-up, our study design could not distinguish reinfection from possible drug failure. Therefore, we used several indirect variables to estimate ongoing praziquantel efficacy: the level of persistent egg-positivity at 1 year after praziquantel treatment, compared with rates of new infection (egg-negative to egg-positive conversion) each year; the efficacy of the drug in children receiving a second, third, or fourth dose, compared with efficacy in children receiving a first dose; and the efficacy of the drug in children who remained egg-positive after their first dose compared with efficacy in children whose infections cleared but who subsequently became reinfected.

The yearly efficacy of praziquantel treatment and infection or reinfection rates (egg-negative to egg-positive conversion) were compiled for the study population (Table 1). Yearly infection or reinfection rates varied from 15% in 1984 to 1985 to a low of 9% in 1985 to 1986 and a high of 21% in 1991 to 1992 (average 13%). Infection rates for children initially treated with praziquantel who subsequently missed 1 year or more of treatment were 22% to 34% in subsequent surveys 2 to 4 years later. These rates suggested a time-dependent average accumulation of reinfection at an annual rate of 9% to 15%. The high transmission levels in 1991 to 1992 (21% new infection or reinfection) may explain the apparent decrease in praziquantel efficacy during this 12-month period. However, estimated transmission did not explain the decreased efficacy seen in 1986 to 1987, when the population egg-negative to -positive conversion rate was only 11%.

To examine whether an increasing core of resistant infection might account for the higher post-treatment prevalence after year 2 of treatment, we compared the relative annual efficacy in egg-positive patients who received praziquantel for the first time with efficacy in patients receiving their second, third, or fourth treatments. We found that after the first cycle of treatment, i.e., from 1985 on, praziquantel-mediated cure rates did not differ for patients with first-time treatment and those with a history of praziquantel treatment (Figure 2). We further examined the response to second, third, and fourth treatments in patients who did not become egg-negative after their first dose (i.e., initial nonresponse, possibly resistant) (Figure 3). We compared these results with those of patients who tested negative after the first praziquantel dose, then became egg-positive in later years (those reinfected after cure, Figure 3). Children from these two groups, who were at greatest risk for infection with resistant parasites, eventually reverted to egg-negative status after treatment with one to three supplemental praziquantel doses. The two groups did not differ significantly in their response rates to the second, third, or fourth doses.

Figure 2. Efficacy of praziquantel therapy for Schistosoma haematobium according to prior treatment status. Solid bars indicate yearly cure rates for patients receiving their first praziquantel treatment. Hatched bars indicate cure rates for children with a history of prior praziquantel treatment. No significant differences in efficacy were noted in any of the years studied (1985-1991).

Figure 3. Extra doses needed to cure Schistosoma haematobium infection in 1984-entry cohort children who were not cured with a first dose of praziquantel (initial nonresponse, N=123, top bar) compared with doses needed to cure children reinfected after successful praziquantel treatment (reinfected post-cure, N= 36, bottom bar). The filled areas in each bar indicate the percentage of each group requiring one (solid), two (hatched), or three (shaded) more doses of praziquantel to become egg negative. No significant differences were observed between the two groups in age, sex, or cure rates.

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