Effect of transmission reduction by ITNs on the prevalence of mutations associated with resistance to sulfadoxine-pyrimethamine and chloroquine in western Kenya Público
Shah, Monica (2011)
Published
Abstract
Background: Malaria is a devastating disease affecting
people living in tropical areas,
particularly in sub-Saharan Africa. Despite the clear benefit of
insecticide-treated bednets
(ITNs) in preventing malaria infection, the impact of malaria
transmission-reduction by
vector control on the spread of drug resistance is not well
understood. We investigated
the effect of sustained transmission reduction by ITNs on the
prevalence of Plasmodium
falciparum drug resistant gene mutations in an ITN trial
carried out between 1996 and
2001 in western Kenya during a national drug policy shift from
chloroquine (CQ) to
sulfadoxine-pyrimethamine (SP).
Methods: We compared the prevalence of mutations at
dhfr-51,59,108,164 and dhps-
437, 540 (SP resistance) and pfcrt-76 and pfmdr1-86
(CQ resistance) in P. falciparum
smear-positive
samples collected from children under the age of five years during
cross-
sectional surveys prior to ITN introduction (baseline, n=250) and
five years post-ITN
intervention (year 5 survey, n=242). Multivariable logistic
regression models were used
to explore the association between two primary exposures of
interest, survey year and
antimalarial drug use (antifolate class, SP, or CQ), and drug
resistance genotypes.
Results: We observed significant increases in the prevalence
of dhps mutations and the
SP quintuple mutant (p<0.0001), and a significant reduction in
the proportion of mixed
infections detected at dhfr-51,59 and dhps-437,540
SNPs (p<0.004) from baseline to the
year 5 survey. There was no change in the high prevalence of CQ
mutations (82% and
75% at baseline to 82% and 73% at year 5 survey, for
pfcrt-76 and pfmdr1-86,
respectively). Multivariable regression results showed that
antifolate drug use ( dhps
mutations aOR, 2.4 [95% CI,
1.2-5.1]) and year of survey ( dhps mutations aOR,
10.3
[95% CI, 6.2-17.2]; dhfr/dhps mutations aOR, 8.8 [95% CI,
5.5-14.3]) were significantly
associated with more SP drug resistant mutations.
Conclusions: Our results suggest that increased antifolate
use likely led to the high
prevalence of SP drug resistant mutations 5 years post-ITN
intervention and reduced
transmission had no apparent effect on the existing high prevalence
of CQ drug resistant
mutations. There is no evidence from the current study that
sustained transmission
reduction by ITNs reduces the prevalence of genes associated with
antimalarial drug
resistance.
Table of Contents
1. Chapter I: Background/Literature Review…………………………………………
12. Chapter II: Manuscript……………………………………………………………..
7a. Introduction……………………………………………………………
8b. Methods………………………………………………………………..
9c. Results………………………………………………………………….
16d. Discussion………………………………………………………………
19e. References……………………………………………………………...
25f. Tables…………………………………………………………………...
30i. Table 1: Characteristics of study participants at baseline (1996) and year 5 survey (2001)
ii. Table 2: Univariable and multivariable analyses of the association between specific predictors and mutations in dhfr, dhps, and dhfr/dhps combined
iii. Table 3: Univariable and multivariable analyses of the association between specific predictors and mutations in CQ-linked drug resistance genes
g. Figures/Figure Legends………………………………………………...
33i. Figure 1: Conceptual framework for relationship between transmission intensity and anti-malarial drug resistance
ii. Figure 2: Flow Diagram of ITN trial and drug resistance study samples
iii. Figure 3: Comparison of mutation prevalence by SNP between baseline (1996) and year 5 survey (2001)
iv. Figure 4: Prevalence of SP genotypes at baseline (1996) and year 5 survey (2001)
3. Chapter III: Summary, public health implications, possible future directions……..
384. Appendices
a. Appendix A: Study questionnaires…………………………………………
40b. Appendix B: Laboratory procedures……………………………………….
44c. Appendix C: Variable and outcome descriptions and coding……………...
45d. Appendix D: Univariable analysis for all study variables for genes associated with SP resistance………………………………………………..............
47e. Appendix E: Univariable analysis for all study variables for genes associated with CQ resistance……………………………………………................
49f. Appendix F: Assessment of interaction……………………………………........
50g. Appendix G: Collinearity Information Matrices…………………………......
52h. Appendix H: Assessment of confounding………………………………….......
61i. Appendix I: Assessment of assumption that continuous variables are linear on log scale……………………………………………………………..….........
66j. Appendix J: Emory IRB determination letter……………………………….....
75About this Master's Thesis
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