Effect of transmission reduction by ITNs on the prevalence of mutations associated with resistance to sulfadoxine-pyrimethamine and chloroquine in western Kenya Open Access

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…………………………………………

1

2. Chapter II: Manuscript……………………………………………………………..

7

a. Introduction……………………………………………………………

8

b. Methods………………………………………………………………..

9

c. Results………………………………………………………………….

16

d. Discussion………………………………………………………………

19

e. References……………………………………………………………...

25

f. Tables…………………………………………………………………...

30

i. 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………………………………………………...

33

i. 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……..

38

4. Appendices

a. Appendix A: Study questionnaires…………………………………………

40

b. Appendix B: Laboratory procedures……………………………………….

44

c. Appendix C: Variable and outcome descriptions and coding……………...

45

d. Appendix D: Univariable analysis for all study variables for genes associated with SP resistance………………………………………………..............

47

e. Appendix E: Univariable analysis for all study variables for genes associated with CQ resistance……………………………………………................

49

f. Appendix F: Assessment of interaction……………………………………........

50

g. Appendix G: Collinearity Information Matrices…………………………......

52

h. Appendix H: Assessment of confounding………………………………….......

61

i. Appendix I: Assessment of assumption that continuous variables are linear on log scale……………………………………………………………..….........

66

j. Appendix J: Emory IRB determination letter……………………………….....

75

About this Master's Thesis

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Global Epidemiology - MPH & MSPH
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Biology, Parasitology Health Sciences, Epidemiology
Keyword	ITN malaria drug resistance
Committee Chair / Thesis Advisor	Sullivan, Kevin M, Emory University
Committee Members	Shi, Ya Ping, CDC
Partnering Agencies	CDC

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