We enrolled 1377 patients into the study. Characteristics on enrolment were similar over the five years of study (), although parasite density on presentation apparently increased in 2001 and 2002. One thousand and eighteen (73.9%) of the enrolled participants completed 14 days of follow up; 246 (17.9%) were lost to follow up before day 14, 30 (2.2%) withdrew consent to continue in the study, 40 (2.9%) were withdrawn owing to protocol violations, and 43 (3.1%) had incomplete follow up for unspecified reasons. Most protocol violations were receipt of curative treatment for malaria from sources other than study investigators. We could not determine therapeutic efficacy for 95 (9%) of 1054 participants for whom parasitological outcomes could be determined. This was because of clinical judgments made to treat persistent or recurrent malaria infections that did not meet criteria for treatment failures—that is, treatment of symptomatic but afebrile parasitaemias between day 4 and day 14. No trends towards increasing rates of withdrawal or loss to follow up occurred throughout the course of the study.
Characteristics at time of treatment for uncomplicated falciparum malaria
As shown in the and , the 14 day efficacy remained stable over the five year study period, with adequate clinical response rates remaining above 80% (top left of figure: P = 0.44, odds ratio 0.95, 95% confidence interval 0.82 to 1.09). Among participants followed for 28 days, the rate of adequate clinical response decreased from 73% in 1998 to 60% in 2002 (bottom left: P = 0.02, odds ratio 0.86, 0.75 to 0.98). Rates of sensitive or RI parasitological responses at both 14 and 28 days also decreased significantly over the five year study period (top right: P = 0.015, odds ratio 0.84, 0.73 to 0.97; bottom right: P = 0.004, odds ratio 0.81, 0.71 to 0.94). Neither parasitological resistance nor therapeutic failure was associated with age in this population with a median age of 2.4 years.
Figure 1 Sulfadoxine-pyrimethamine treatment outcomes, 1998-2002. Top left: therapeutic efficacy at 14 days; bottom left: therapeutic efficacy at 28 days; top right: parasitological resistance at 14 days; bottom right: parasitological resistance at 28 days. ACR=adequate (more ...)
Sulfadoxine-pyrimethamine treatment outcomes, 1998-2002. Values are numbers (percentages)
Haematological recovery rates between days 0 and 14 did not differ between cases of adequate clinical response and those with treatment failure or between sensitive cases and those with RI-RIII resistance (data not shown). In univariate analyses, anaemia (haemoglobin < 10 g/dl) at day 14 was associated with both treatment failure (odds ratio 2.05, 1.15 to 3.65, P = 0.009) and RI-RIII resistance (odds ratio 1.46, 1.01 to 2.10, P = 0.034). However, when we included treatment failure and parasitological resistance separately in a logistic regression model with parasite density at day 0 and age as covariates, only the association between age and anaemia at day 14 remained significant (P < 0.001). Anaemia was more common at day 28 among children with adequate clinical response and asymptomatic parasitaemia than in children with adequate clinical response and no parasites (42.4% v 26.7%; relative risk 1.59, 1.23 to 2.05, P < 0.001). This association remained significant after we controlled for age and initial parasitaemia in a regression model (P = 0.009).
We found excellent agreement between measures of therapeutic efficacy and parasitological resistance. With adequate clinical response corresponding to sensitivity or RI resistance, late treatment failure corresponding to RI or RII resistance, and early treatment failure corresponding to RIII resistance, we found only 10/959 (1%) cases of discordance among cases for which both efficacy and resistance could be determined. One sensitive case and two RI cases met non-parasitological criteria for early treatment failure, and seven cases met criteria for RII resistance but had adequate clinical responses (one case) or were late treatment failures (six cases) because fever did not always accompany persistent parasitaemia.