Transcript Document

Ivermectin mass drug administration to humans
as a potential tool for malaria elimination
Kevin Kobylinski1,2, Alongkot Ponlawat2, Ratawan Ubalee2, Brian Foy3,
Joel Tarning4, Thanaporn Wattanakul4, MAJ Wes McCardle2,
CDR Dan Szumlas1, and LTC Jason Richardson1,2,5
[email protected]
1 Walter
Reed Army Institute of Research (WRAIR): Entomology Branch
2 Armed Forces Research Institute of Medical Sciences (AFRIMS): Department of Entomology
3 Colorado State University: Department of Microbiology, Immunology and Pathology
4 Mahidol-Oxford Tropical Medicine Research Unit
5 Armed Forces Pest Management Board
Effect of ivermectin in an African context
Ivermectin MDA reduces the proportion of
wild P. falciparum-infectious An. gambiae
(www.mectizan.org)
Mean percent P. falciparum
infectious An. gambiae
(Kobylinski)
Background
• Ivermectin is an extremely safe oral drug, with over 300 million treatments distributed
annually by mass drug administration (MDA) for onchocerciasis and lymphatic
filariasis elimination in Africa and Latin America
• Ivermectin can reduce the survivorship of African Anopheles including:
An. gambiae (Chaccour et al. 2010, Sylla et al. 2010, Ouédraogo et al. 2014),
An. arabiensis (Fritz et al. 2012), and An. funestus (Ouédraogo et al. 2014),
suppresses P. falciparum transmission (Kobylinski et al. 2011, Alout et al. 2014) and
effects four out of five variables in the vectorial capacity equation (see right figures)
• A recent clinical trial showed that ivermectin is safe and well tolerated when administered
with artemther-lumefantrine (Ouédraogo et al. 2014), and modelling efforts predict
that ivermectin MDA coupled with artemisinin combination therapy (ACT) MDA in
Africa would accelerate elimination efforts (Slater et al. 2014)
• Ivermectin can reduce the survivorship of Greater Mekong Subregion (GMS) Anopheles
including: An. dirus, An. minimus, An. campestris, and An. sawadwongporni
(see below)
• Ivermectin MDA fulfills many of the demands for novel vector control interventions put
forth by the Malaria Eradication Research Agenda Consultative Group on Vector
Control (Alonso et al. 2011) including: a different mode of action from currently
used insecticides, it targets both indoor- and outdoor-feeding Anopheles, an
avoidance of behavioral resistance mechanisms, an integration with current vector
control tools, and it alters the mosquito population age structure (Alout et al. 2014)
• Ivermectin MDA directly targets exophagic and endophagic human-feeding
Anopheles regardless of feeding time, thus it could be a powerful new tool to
aid the current artemisinin-resistance containment in the GMS and malaria elimination
efforts worldwide
m a2 p n b
V=
-lnp
Time relative to MDA (days)
Ivermectin ingestion delays the
time to re-feed in An. gambiae
*Treatment x time was significant (χ2 = 25.89, P < 0.0001). Mean sporozoite rate in control villages
did not differ significantly (P=1, while the sporozoite rate significantly reduced the first (P = 0.0074)
and second (P=0.0018) weeks after MDA
(Alout et al. 2014)
Ivermectin (LC25) inhibits the sporogony
of P. falciparum in An. gambiae
*
Vectorial Capacity
V – average number of potentially infective bites that
will be delivered by all vectors feeding on a
single host in one day
p – daily probability of adult mosquito survivorship
a – daily probability an Anopheles feeds on a human
(human bloodmeal index x feeding frequency)
n – duration of the extrinsic incubation period
b – vector competence
(ie. proportion of Anopheles that ingest
Plasmodium and successfully become infectious)
m – vector density in relation to the host
*
*
(χ2 = 23.83, P < 0.0001, Hazard ratio = 7.656 [3.487, 18.63])
(Kobylinski et al. 2010)
7
Oocyst
DDPI
Stage
χ2= 15.48, P = 0.0002
12
Sporozoite
χ2= 13.47, P = 0.0003
14
Sporozoite
χ2= 19.96, P < 0.0001
(Kobylinski et al. 2012)
Effect of ivermectin in a Greater Mekong Subregion context
GMS Anopheles LC50 ( ) and LC25 ( ) values plotted on model estimates
60
= LC5
Model estimates for 200, 400, 800 μg/kg doses
180
40
30
20
10
160
140
120
100
80
60
40
20
0
0
dirus
n=5029, r=6
sawadwongporni campestris
n=1431, r=4
n=2786, r=4
minimus
n=2376, r=6
0
gambiae
n=2013, r=8
(reference)
• Various concentrations of ivermectin were blood fed to An. dirus,
An. sawadwongporni, An. campestris and An. minimus via membrane feeders
• Mosquito survivorship was monitored for seven days
• A non-linear mixed model (Kobylinski et al. 2010) was used to estimate the lethal
concentration that killed 50, 25, and 5 (LC50, LC25, LC5) percent of mosquitoes
Number of oocysts per An. dirus
Sporontocidal impact of ivermectin on P. vivax in An. dirus
1
2
1180
80
200
D oμg/kg
se=200
1160
60
400
D oμg/kg
se=400
1140
40
800
D oμg/kg
se=800
1120
20
1100
00
8800
6600
4400
2200
00 3
4
0
1
T im0 e ( d a1y s )
5
6
7
22
33
44
55
66
77
Ivermectin concentration (ng/ml)
50
= LC25
Iv e r m e c tin C o n c . ( n g /m l)
Ivermectin concentration (ng/ml)
= LC50
Iv e rm e c tin C o n c . (n g /m l)
Ivermectin concentration (ng/ml)
Lethal concentration of ivermectin that kills GMS Anopheles
D ose=200
D ose=400
D ose=800
Time
T im e(days)
(d a y s )
• Ivermectin PK data from 23 adult Thai (12 F: 11M) (Na-Bangchang
et al. 2006) raw data kindly provided by Dr. Kesara Na-Bangchang
• Data re-fitted using nonlinear mixed-effects modelling (NONMEM)
• Standard dosing of 200 ug/kg was assumed (no individual dose data)
• Simulations (n=500) were performed for a standard person weighing 56 kg
pharmacokinetic models kindly created by Dr. Joel Tarning and
Thanaporn Wattanakul
Time (hours)
dirus
Ivermectin concentration (ng/ml)
• Escalating concentratins of ivermectin reduce number of P. vivax oocysts per An. dirus
• Ongoing work indicates that ivermectin also reduces proportion of vectors that
develop P. vivax oocysts
campestris
minimus
gambiae
• The 400 μg/kg concentration appears to be ideal as it reaches the LC50 of An. dirus
• Ivermectin (400 μg/kg ) is extremely safe and well tolerated
Future directions
• Clinical trials to investigate combination of ivermectin and dihydroartemisinin
plus piperaquine will commence soon
• Modelling efforts will be used to determine frequency of ivermectin MDAs
to maximize impact on transmission
• Perform repeated ivermectin MDAs with or without ACTs in Africa and the GMS
and monitor impacts on entomological (eg. vector density, population age
structure, and sporozoite rate) and parasitological (eg. symptomatic and
asymptomatic Plasmodium prevalence, and molecular Force of Infection)
indices of transmission
P=0.0129 P=0.0007 P=0.0010 P=0.0003 P=0.0032 P=0.0002 P<0.0001
sawadwongporni
Funding Sources
The Military Infectious Disease Research Program, US Armed Forces Health
Surveillance Center: Global Emerging Infections Surveillance Network,
Colorado State University CRC 1686174 , the Bill & Melinda Gates Foundation
OPP1095931 and Grand Challenges Explorations grant 51995, and the National
Institute of Allergy and Infectious Diseases grants R21-A1079528 and R01A1094349-01A1. This research was performed while the author held a National
Research Council Research Associateship Award at the Walter Reed Institute
of Research – Armed Forces Research Institute of Medical Sciences.
Disclaimer
Material has been reviewed by the Walter Reed Army Institute of Research –
Armed Forces Research Institute of Medical Sciences. There is no objection to
its publication. The opinions or assertions contained herein are the private
views of the authors, and are not to be construed as official, or as reflecting
true views of the Department of the Army or the Department of Defense.