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Randomized Controlled Trial
. 2010 Sep 7;5(9):e12618.
doi: 10.1371/journal.pone.0012618.

Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi) using sulfadoxine-pyrimethamine and parasite resistance

Jamie T Griffin  1 , Matthew Cairns, Azra C Ghani, Cally Roper, David Schellenberg, Ilona Carneiro, Robert D Newman, Martin P Grobusch, Brian Greenwood, Daniel Chandramohan, Roly D Gosling
Affiliations
Randomized Controlled Trial

Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi) using sulfadoxine-pyrimethamine and parasite resistance

Jamie T Griffin et al. PLoS One. .

Abstract

Background: Intermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi) is recommended by WHO for implementation in settings where resistance to SP is not high. Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance.

Methods and results: We analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50 km of the trial sites. We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi. This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times. However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively.

Conclusions: A significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose. An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias. It was not possible to define a more definite relationship based on the data available from these trials.

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Conflict of interest statement

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

Figures

Figure 1
Figure 1. Relationship between protective efficacies of IPTi for the seven trial sites plotted against markers of resistance.
(a) the 14 day ACPR (rank correlation = 0.03 (p = 0.96) for the 3 month dose, 0.09 (p = 0.87) for the 9 month dose and 0.26 (p = 0.62) over 12 months); (b) the frequency of the dhfr triple mutation (rank correlation = −0.54 (p = 0.22) for the 3 month dose, −0.61 (p = 0.15) for the 9 month dose and −0.75 (p = 0.05) over 12 months); (c) the frequency of dhps double mutation (rank correlation = −0.46 (p = 0.29) for the 3 month dose, −0.32 (p = 0.48) for the 9 month dose and −0.61 (p = 0.15) over 12 months); (d) the frequency of the dhfr/dhps quintuple (rank correlation = −0.66 (p = 0.16) for the 3 month dose, −0.26 (p = 0.62) for the 9 month dose and −0.71 (p = 0.11) over 12 months).
Figure 2
Figure 2. Observed and fitted protective efficacies of IPTi for the seven trial sites.
a) during 35 days after a dose at 3 months; b) during 35 days aftera dose at 9 months; and c) up to 12 months of age. Model predictions are based only on the frequency of the dhfr triple mutation, dhps double mutation and combined dhfr and dhps quintuple mutation and do not adjust for any other differences between the trials or the trial sites.
Figure 3
Figure 3. Expected protective efficacy of SP- IPTi of the 3 month dose at different frequencies of the dhfr triple mutation in settings of different frequencies of the dhps double mutation.
(a) 0%, (b) 10%, (c) 50%, (d) 90% and (e) 100% frequency of the dhps double mutation.
Figure 4
Figure 4. Expected protective efficacy of SP- IPTi after the 9 month dose at different frequencies of the dhfr triple mutation in settings of different frequencies of the dhps double mutation.
(a) 0%, (b) 10%, (c) 50%, (d) 90% and (e) 100% frequency of the dhps double mutation.
Figure 5
Figure 5. Expected protective efficacy of SP- IPTi up to 12 months of age at different frequencies of the dhfr triple mutation in settings of different frequencies of the dhps double mutation.
(a) 0%, (b) 10%, (c) 50%, (d) 90% and (e) 100% frequency of the dhps double mutation.
Figure 6
Figure 6. Length of protection of SP- IPTi in 2 settings.
a) low resistance to SP and b) high resistance.
See this image and copyright information in PMC

References

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