High resistance of Plasmodium falciparum to sulphadoxine/pyrimethamine in northern Tanzania and the emergence of dhps resistance mutation at Codon 581

Samwel Gesase, Roly D Gosling, Ramadhan Hashim, Rosalynn Ord, Inbarani Naidoo, Rashid Madebe, Jacklin F Mosha, Angel Joho, Victor Mandia, Hedwiga Mrema, Ephraim Mapunda, Zacharia Savael, Martha Lemnge, Frank W Mosha, Brian Greenwood, Cally Roper, Daniel Chandramohan, Samwel Gesase, Roly D Gosling, Ramadhan Hashim, Rosalynn Ord, Inbarani Naidoo, Rashid Madebe, Jacklin F Mosha, Angel Joho, Victor Mandia, Hedwiga Mrema, Ephraim Mapunda, Zacharia Savael, Martha Lemnge, Frank W Mosha, Brian Greenwood, Cally Roper, Daniel Chandramohan

Abstract

Background: Sulphadoxine-pyrimethamine (SP) a widely used treatment for uncomplicated malaria and recommended for intermittent preventive treatment of malaria in pregnancy, is being investigated for intermittent preventive treatment of malaria in infants (IPTi). High levels of drug resistance to SP have been reported from north-eastern Tanzania associated with mutations in parasite genes. This study compared the in vivo efficacy of SP in symptomatic 6-59 month children with uncomplicated malaria and in asymptomatic 2-10 month old infants.

Methodology and principal findings: An open label single arm (SP) standard 28 day in vivo WHO antimalarial efficacy protocol was used in 6 to 59 months old symptomatic children and a modified protocol used in 2 to 10 months old asymptomatic infants. Enrolment was stopped early (87 in the symptomatic and 25 in the asymptomatic studies) due to the high failure rate. Molecular markers were examined for recrudescence, re-infection and markers of drug resistance and a review of literature of studies looking for the 581G dhps mutation was carried out. In symptomatic children PCR-corrected early treatment failure was 38.8% (95% CI 26.8-50.8) and total failures by day 28 were 82.2% (95% CI 72.5-92.0). There was no significant difference in treatment failures between asymptomatic and symptomatic children. 96% of samples carried parasites with mutations at codons 51, 59 and 108 in the dhfr gene and 63% carried a double mutation at codons 437 and 540. 55% carried a third mutation with the addition of a mutation at codon 581 in the dhps gene. This triple: triple haplotype maybe associated with earlier treatment failure.

Conclusion: In northern Tanzania SP is a failed drug for treatment and its utility for prophylaxis is doubtful. The study found a new combination of parasite mutations that maybe associated with increased and earlier failure.

Trial registration: ClinicalTrials.gov NCT00361114.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Trial profiles.
Figure 1. Trial profiles.
*Incomplete follow up on Day 14 (2 in symptomatic study, 1 asymptomatic study missed visit and were followed up at later times).
Figure 2. Cumulative proportion of treatment failures…
Figure 2. Cumulative proportion of treatment failures of Sulphadoxine-Pyrimethamine in symptomatic 6–59 month and asymptomatic 2–10 month old children with malaria.
Figure 3. Comparison of Multiplicity of Infection…
Figure 3. Comparison of Multiplicity of Infection (MoI) at enrolment and at day of failure and the mean MoI in cases of recrudescence by week of failure.
LEGEND: 67 symptomatic treatment failures cases were successfully analysed by both MSP2 and pfPK2 and were sorted according to week of failure post treatment. White bars show the mean multiplicity of infection (MoI) at enrolment. Grey bars show the MoI on the day of treatment failure. Black bars show the mean number of matching alleles in the pre and post treatment sample of each patient (N = 49 after exclusion of those defined as new infections).
Figure 4. Cumulative proportions of treatment failure…
Figure 4. Cumulative proportions of treatment failure of Sulphadoxine-Pyrimethamine in symptomatic 6–59 month old children with malaria parasites carrying or not-carrying the A581G mutation in the dhps gene at enrolment.
Unadjusted effect dhps gene mutation at 581, p-value = 0.012.
Figure 5. Distribution of 581G mutation in…
Figure 5. Distribution of 581G mutation in Tanzania.
Figure 6. Distribution of 581G mutation in…
Figure 6. Distribution of 581G mutation in Africa.

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Source: PubMed

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