Parasite clearance following treatment with sulphadoxine-pyrimethamine for intermittent preventive treatment in Burkina-Faso and Mali: 42-day in vivo follow-up study

Abstract

Background: Intermittent Preventive Treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is widely used for the control of malaria in pregnancy in Africa. The emergence of resistance to SP is a concern requiring monitoring the effectiveness of SP for IPTp.

Methods: This was an in-vivo efficacy study to determine the parasitological treatment response and the duration of post-treatment prophylaxis among asymptomatic pregnant women receiving SP as part of IPTp in Mali and Burkina-Faso. The primary outcome was the PCR-unadjusted % of patients with parasites recurrence by day 42 defined as a positive diagnostic test by malaria smear at any visit between days 4 and 42. Treatment failure was based on the standard World Health Organization criteria. The therapeutic response was estimated using the Kaplan-Meier curve.

Results: A total of 580 women were enrolled in Mali (N=268) and Burkina-Faso (N=312) and followed weekly for 42 days. Among these, 94.3% completed the follow-up. The PCR-unadjusted cumulative risk of recurrence by day 42 was 4.9% overall, and 3.2% and 6.5% in Mali and Burkina Faso respectively (Hazard Ratio [HR] =2.14, 95%, CI [0.93-4.90]; P=0.070), and higher among the primi- and secundigravida (6.4%) than multigravida (2.2%, HR=3.01 [1.04-8.69]; P=0.042). The PCR-adjusted failure risk was 1.1% overall (Mali 0.8%, Burkina-Faso 1.4%). The frequencies (95% CI) of the dhfr double and triple mutant and dhps 437 and 540 alleles mutant genotype at enrolment were 24.2% (23.7-25.0), 4.7% (4.4-5.0), and 21.4% (20.8-22.0) and 0.37% (0.29-0.44) in Mali, and 7.1% (6.5-7.7), 44.9% (43.8-46.0) and 75.3% (74.5-76.2) and 0% in Burkina-Faso, respectively. There were no dhfr 164L or dhps 581G mutations.

Conclusion: SP remains effective at clearing existing infections when provided as IPTp to asymptomatic pregnant women in Mali and Burkina. Continued monitoring of IPTp-SP effectiveness, including of the impact on birth parameters in this region is essential.

Figure 1

Study sites in Mali (Kita and San) and Burkina Faso (Ziniaré).

Figure 2

Study flow chart.

Figure 3

Probability of parasitological failure by microscopy in Burkina-Faso and Mali. Notes: This graph shows the crude and PCR adjusted risk of parasitological failure in Mali and Burkina-Faso. Treatment failure was defined according to the standard WHO criteria and the cumulative risk of recurrence was determined using Kaplan-Meier survival analysis. Blue lines represent Mali and red lines Burkina-Faso. Panel A and panel B represent survival analysis for crude and PCR adjusted analysis, respectively.

Figure 4

Probability of parasitological failure by microscopy by gravida group. Notes: (Gravidae 1&2, primi-secundigravida; Gravidae>=3, multigravida): PCR unadjusted (Panel A) and PCR adjusted (Panel B). This graph shows the crude and PCR adjusted risk of parasitological failure in both primi-secundigravida and multigravida using Kaplan-Meier survival analysis. Blue lines represents multigravida (gravidae>=3) and the red lines represent primi-secundigravida (gravidae 1&2), respectively.

Figure 5

Increase in haemoglobin concentrations by country in all gravida. Notes: (top panel) and by gravidae group (bottom panel). Analysis was done with repeated measures Generalized Estimating Equation (GEE), adjusted for the baseline hemoglobin levels on Day-0. Black squares or diamonds represent the point estimates and vertical lines the corresponding 95% confidence intervals.

Figure 6

Prevalence of SP resistance molecular makers in Burkina-Faso and Mali among parasitaemic women at their antenatal booking visit (pre-SP). Notes: dhfr /dhps alleles (Top panel) and dhfr haplotypes (Bottom panel). Mutant allele frequencies are represented in the top panel graph by horizontal bars. Lines depict the 95% confidence intervals. The presence of “0” represents the absence of point mutations for a designed codon. The bottom panel represents the frequency of dhfr haplotypes (N51I, C59R, and S108N) per country.