Peter Onyango Sangoro Thesis submitted in accordance with the requirements for the d

439 Pages·2017·8.11 MB·English

LSHTM Research Online
Sangoro,P;(2015)CanrepellentspreventmalariainTanzania? PhDthesis,LondonSchoolofHygiene
& Tropical Medicine. DOI: https://doi.org/10.17037/PUBS.02374474
Downloaded from: https://researchonline.lshtm.ac.uk/id/eprint/2374474/
DOI: https://doi.org/10.17037/PUBS.02374474
Usage Guidelines:
Please refer to usage guidelines at https://researchonline.lshtm.ac.uk/policies.html or alternatively
contact [email protected].
Available under license. To note, 3rd party material is not necessarily covered under this li-
cense: http://creativecommons.org/licenses/by-nc-nd/3.0/
honline.lshtm.ac.ukhttps://researc
Can repellents prevent malaria in Tanzania?

Peter Onyango Sangoro

Thesis submitted in accordance with the requirements for the
degree of Doctor of Philosophy

University of London
August 2015

Department of Disease Control
Faculty of Infectious and Tropical Diseases

Funding: This work was funded by Maude Christian Meier,
PhD, of SC Johnson who also donated the topical repellents
used in this study
Declaration
This work was supervised by:
Dr. Mary Cameron, PhD,
Senior Lecturer
Department of Disease Control, Faculty of Infectious and Tropical
Diseases, London School of Hygiene and Tropical Medicine

I, Sangoro Peter Onyango, confirm that the work presented in this
thesis is my own and has not been submitted for another degree or
diploma at any university or institution of tertiary education. Where
information has been derived from other sources, I confirm that this
has been indicated in the thesis. The contributions made by other
authors in this work have also been acknowledged.
th
Signature: Date: 10 August 2015
1

Abstract
Background: Current malaria control tools, long lasting insecticidal nets and indoor
residual spraying have had a significant impact on malaria transmission in sub-Saharan
Africa. However these tools will not be able to eradicate malaria and there is need for
complementary tools if this goal is to be attained. This work focused on evaluating and
recommending tools that can be used to complement current control tools with emphasis on
outdoor and early evening transmission. The main tool evaluated in this thesis was a topical
repellent to be used in the early evening. Other tools recommended were spatial repellents
and permethrin-impregnated clothing.

Methods: A repellent efficacy trial was conducted in the semi-field and field setting to
evaluate the protection from early evening biting given by a topical repellent lotion
containing 15% N.N-diethyl-m-toluamide (DEET). A cluster randomized, placebo controlled
clinical trial, designed to assess the effect of 15% DEET against malaria transmitted in the
early evening was then conducted in a village in rural Tanzania. A total of 940 households
were recruited and randomized, with 462 households randomized to the intervention arm and
462 households randomized to the control arm. The feasibility of lotion repellent use was
assessed using entry and exit questionnaires. Focus group discussions were conducted 3 years
after a clinical trial to assess the community knowledge, attitude and practice towards a
different set of repellents to those used during the clinical trial. A systematic review was then
conducted to put the results of this trial in context with other repellent trials. An attempt was
made to design a clinical trial taking into account the shortcomings of the current and other
repellent trials reviewed.
2
Findings: Topical repellents containing 15% DEET provided >80% protection against
early evening biting over four hours. According to protocol analysis of the cluster
randomized trial found no difference between the intervention and control arms after
accounting for socio-economic status, education of household head and household
construction materials (Wilcoxon rank sum z = 0.529, p = 0.596). The most important
predictor of malaria in this study was age, with younger age categories significantly
associated with greater malaria risk. Socio-economic status was not associated with malaria.
Compliance to repellent use was reported to be 80% during the study. From the FGDs, it
emerged that community knowledge was the major barrier to repellent use, followed closely
with availability. The community preferred using long lasting insecticidal nets (LLINs)
because of their cost effectiveness. However, the community preferred using repellents in the
early evening before employing LLINs.
Interpretation: This study demonstrates that topical repellents have no effect against
early evening malaria transmission in this community. However, shortcomings in the design
and implementation might have masked the treatment effect and better-designed studies are
required to establish repellents effect in this setting. Topical repellents provided protection
against early evening biting and were readily accepted and used in this community, indicating
the potential of using repellents complimentary to LLINs in this setting. The short-term
duration of effect of this repellent, required frequent reapplication and therefore impacted
compliance, emphasizing that future studies should consider using longer lasting tools such
as spatial repellents.
3
Acknowledgements
First and foremost, I would like to thank the Almighty God for seeing me
through this long journey. Secondly, I thank my Supervisor Dr. Sarah J Moore,
for giving me the opportunity to pursue my doctorate degree. Thank you for you
great mentorship and immense patience throughout, even when it seemed I did
not want to learn. Thank you for always being there when needed most and for a
sympathetic ear and encouraging words when I was about to give up. It has not
always been smooth sailing, all through, but we made it. I am profoundly
grateful.

I would also like to thank Prof. Steve Lindsay, Dr. Joanna Schellenberg and Dr.
Mary Cameron, all of the London School of Hygiene and Tropical Medicine,
for their literary critic all through this work. Thank you for looking after me
while at the School. I would also like to thank Dr. Elizabeth Turner, for teaching
me my statistics. I would be remised if I did not remember to mention Dr. Nigel
Hill. Thank you for you humor and words of inspiration “Not to worry, the sun
will rise tomorrow” when things were looking down.
To the technicians, Hassan Ngoyani, Emmanuel Simfukwe, Edgar Mbeyela and
Antone Mseka who sat with me during those agonizing nights sampling
mosquitoes. Thank you for your selflessness. To the field workers, Yakila
Mpumu, Elson Yusuf, Sarah Mtali, Fanuel Ndaga and Dennis Ngoike. Thank
you for your relentless follow-up of participants. A big thank you also to
4
Mohammed Dangaya for reading and recording all those blood slides in Mbingu
village. And to the people of Mbingu thank you for allowing me to conduct this
work in your homes.

To Fredros Oketch Okumu (Wuod Oketch), thank you for your inspiration and
making me believe that anything is possible. To Dr. Marta Maia, thank you for
your scientific contribution to this work and for being a friend. To Dickson,
Sam and Maganga, nothing lasts forever. To Sheila Ogoma and Maggy Sikulu,
thank you for being there when needed.

I am most grateful to Dr. Maude Christian Meier, and the whole SC Johnsons &
Sons fraternity for funding my PhD and donating the repellent for this study. I
would also like to thank Janee E. Miller and Population Services International
for funding this study. A note of thank you also goes to Dr. Gerry Killeen, for
all the constructive criticism.

A more personal mention goes to the love of my life, Jacinta Nzinga, for taking
care of the girls and Kwelz while I was away. I could not have asked for a better
partner along for this journey. You have my eternal gratitude.
To my family, Ma, Do and Dad, thank you for your immense support and
encouragement throughout.
And to Ba, I hope you are smiling down old man.
5

Dedication

For Imani, Neema and Kweli.

You can achieve anything by simply applying yourself.
6
Table of Contents
Abstract ....................................................................................................................................1
Acknowledgements................................................................................................................3
Dedication................................................................................................................................5
List of Tables ........................................................................................................................ 10
List of figures........................................................................................................................ 11
Contribution made by others.......................................................................................... 342
Acronyms .............................................................................................................................. 12
Chapter 1: General Introduction ...................................................................................... 16
1.1 Malaria epidemiology in Africa ............................................................................................................... 16
1.2 Change in Malaria epidemiology in sub Saharan Africa ........................................................... 19
1.3 Statement of the problem ........................................................................................................................... 23
1.4 Safety and toxicity of DEET ........................................................................................................................ 25
1.5 Hypothesis ........................................................................................................................................................... 31
1.6 Objectives ............................................................................................................................................................. 32
1.7 References ........................................................................................................................................................... 33
Chapter 2: Use of a semi-field system to evaluate the efficacy of topical repellents
under user conditions provides a disease exposure free technique comparable
with field data ...................................................................................................................... 49
2.1 Abstract ................................................................................................................................................................. 50
2.2 Background ......................................................................................................................................................... 51
2.3 Methods ................................................................................................................................................................. 53
2.3.1 Study area.......................................................................................................................................................53
2.3.2 Semi-field evaluations of topically applied repellents ...............................................................53
2.3.3 Mosquitoes.....................................................................................................................................................53
2.3.4 Volunteers ......................................................................................................................................................54
2.3.5 Repellents.......................................................................................................................................................54
2.3.6 Repellent application ................................................................................................................................55
2.4 Study design........................................................................................................................................................ 56
2.4.1 Field evaluation of topically applied repellents ............................................................................57
2.5 Statistical analysis........................................................................................................................................... 58
2.5.1 Calculation of percentage protection .................................................................................................58
2.5.2 Poisson regression analysis ...................................................................................................................59
2.6 Ethical considerations .................................................................................................................................. 60
2.7 Results.................................................................................................................................................................... 61
2.7.1 Semi-field experiments ............................................................................................................................61
Field trial experiments.........................................................................................................................................62
2.8 Discussion ............................................................................................................................................................ 72
2.9 Conclusion............................................................................................................................................................ 77
2.10 References ........................................................................................................................................................ 78
Chapter 3: A cluster-randomized controlled trial to assess the effectiveness of
using 15% DEET topical repellent with long-lasting insecticidal nets (LLINs)
compared to a placebo lotion on malaria transmission ............................................. 83
3.1 Abstract ................................................................................................................................................................. 84
3.2 Background ......................................................................................................................................................... 86
3.3 Methods ................................................................................................................................................................. 89
7
3.3.1 Study area.......................................................................................................................................................89
3.3.2 Sample size rationale ................................................................................................................................89
3.3.3. Household recruitment ...........................................................................................................................90
3.3.4 Enrolment of households into the study ..........................................................................................90
3.3.5 Second phase of household recruitment, household enrolment and cluster generation
........................................................................................................................................................................................91
3.3.6 Eligibility criteria ........................................................................................................................................93
3.3.7 Randomization of clusters to treatments.........................................................................................94
3.3.8 Blinding ...........................................................................................................................................................94
3.3.9 Repellent issuance, application and compliance ..........................................................................95
3.3.10 Clinical data collection ...........................................................................................................................97
3.4 Data management ........................................................................................................................................... 98
3.5 Statistical analysis........................................................................................................................................... 99
3.5.1 Socio-economic status (SES)..................................................................................................................99
3.5.2 Clinical data ................................................................................................................................................ 100
3.5.3 Person-time at risk estimation for according-to-protocol analysis................................... 100
3.5.4 Malaria incidence rates and regression analysis of the intervention effect .................. 101
3.5.5 Knowledge attitude and practice (KAP) of community members in relation to malaria
and repellent ......................................................................................................................................................... 102
3.6 Ethical and safety considerations ....................................................................................................... 102
3.7 Results................................................................................................................................................................. 103
3.7.1 Trial profile and baseline data ........................................................................................................... 103
3.7.2 Clinical outcomes ..................................................................................................................................... 108
3.8 Discussion ......................................................................................................................................................... 110
3.8.1 Power ............................................................................................................................................................ 111
3.8.2 Compliance ................................................................................................................................................. 112
3.8.3 Active versus passive case detection .............................................................................................. 112
3.8.4 Sources of bias........................................................................................................................................... 113
3.9 Recommendations ....................................................................................................................................... 116
3.10 Conclusion...................................................................................................................................................... 117
3.11 References ..................................................................................................................................................... 118
Chapter 4: Feasibility of repellent use in a context of increasing outdoor
transmission: a qualitative study in rural Tanzania.................................................. 126
4.1 Abstract .............................................................................................................................................................. 127
4.1 Background ...................................................................................................................................................... 129
4.2 Methods .............................................................................................................................................................. 132
4.2.1 Study area and population................................................................................................................... 132
4.2.2 Outline of study......................................................................................................................................... 132
4.2.3 Baseline survey ......................................................................................................................................... 133
4.2.4 Follow-up survey ..................................................................................................................................... 134
4.2.5 Post-study survey .................................................................................................................................... 134
4.2.6 Focus group discussions ....................................................................................................................... 135
4.2.7 Procedures .................................................................................................................................................. 138
4.3 Data management ........................................................................................................................................ 139
4.4 Data analysis ................................................................................................................................................... 139
4.5 Ethical consideration ................................................................................................................................. 141
4.6 Results................................................................................................................................................................. 141
4.6.1 Baseline survey ......................................................................................................................................... 141
4.6.2 Follow-up survey ..................................................................................................................................... 145
4.6.3 Post-study survey .................................................................................................................................... 147
4.6.4 Focus group discussions ....................................................................................................................... 149
4.8 Discussion ......................................................................................................................................................... 155
4.9 Conclusion......................................................................................................................................................... 163