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Ivermectin as a complementary strategy to kill

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L
e r
mosquitoes and stop malaria transmission?

I D ho
t
Guido Bastiaens MD, PhD

CM
Dept. of Medical Microbiology, Radboud University Medical Center

u
guido.bastiaens@radboudumc.nl

S y a
E
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Malaria 2000
ib r
L
e r
I D ho
CM u t
S y a
E
Cumulative probability of dying from
malaria (in absence of other causes
from 0-80 years) Murray Lancet 2012
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Malaria 2010
ib r
L
e r
I D ho
2015:

CM
• 438 000 deaths
u t
• 214 million cases worldwide

S
2000 – 2015:

y a
• Malaria incidence
Cumulativerates  37%
probability dying from malariaPlasmodium
of globally, in

E
Cumulative
 42% in
•malaria
Malaria
probability
Africa
the absence
(in absence
of of
dying
of other
age 80 years
mortality
from 0-80 years)
 66% in Africa
rates
from causes from birth tofalciparum
all other
causes
 60% globally
in 2010 88% morbidity
90% mortality Murray Lancet 2012, WHO 2015
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Disease progression of P.falciparum malaria
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L
• Very rapid and life-threatening disease

e r
• Parasite densities increase
exponentially

I D ho
M t
• Yet… not always

u
• Asymptomatic parasite carriage in

S C
Apac, northern Uganda

a
E y Baird Clin Microbiol Rev 2013; Proietti Am J Trop Med Hyg 2011
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Detecting infections
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L
e r Symptoms

D ho
No symptoms

M I MASS DRUG ADMINISTRATION

t
Below threshold
for detection

C a u (up to 80%)

E S
In all malaria-endemic settings,

y
asymptomatic carriers represent
a large fraction of malaria-
infected individuals
Responsible
for most
transmission

Okell Nature Comm. 2012

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ib r
Artemisinin combination therapy (ACT)

L
e r
ACT-MDA alone will
not prevent spread
of malaria from

D ho
parasite carriers in

M I t
elimination settings

X
>11 days

C a u Clinical
symptoms

E S y
Transmission of
parasites Cowman J Cell Biol 2012; Bousema JID 2006;
Sawa JID 2013; Poirot Cochrane 2013
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Spread of artemisinin resistant malaria
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L
e r
I D ho
CM u t
S y a
 No safe, effective drug that prevents malaria transmission after ACT-MDA

E • In elimination settings
• In artemisinin resistance settings (containment strategies) Dondorp NEJM 2009
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Single-dose primaquine
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L
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Clinical
cure

I D ho
CM u t
S y a
E Eziefula Lancet ID 2014
Sawa J Infect Dis 2013
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Single-dose primaquine
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L
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Clinical
cure

I D ho Primaquine primaquine

Single-dose of 0.25 mg/kg primaquine, given alongside ACT was safe and efficacious

CM u t
for the prevention of P falciparum malaria transmission in G6PD normal participants

Hemolysis after a single

S y a dose of primaquine
(G6PD-deficiency)

E Eziefula Lancet ID 2014

Sawa J Infect Dis 2013
Dicko Lancet ID 2016
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Impact of MDA improved with vector control

L
e r
I D ho
CM u t
S y a
E WHO 2015
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Alternative to prevent malaria transmission

L
e r
I D ho
CM u t
S y a
E
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Ivermectin-mass drug administration (MDA)
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•

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Ivermectin-MDA treatment for

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onchocerciasis and lymphatic filariasis
in villages in southeastern Senegal

•
I D ho
3 replicate collections of mosquitoes

t
in treated and pair-matched

CM
untreated, control villages

u
•

S a
Ivermectin-MDA reduced the

y
proportion of Plasmodium falciparum

E infectious Anopheles gambiae

mosquitoes
Filled (●) = IVM treated villages
Open (○) = untreated control villages

Kobylinski Am J Trop Med Hyg 2011

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Ivermectin-MDA, why is it relevant now?
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•

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Novel interventions required to maintain

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the current achievements and further
reduce the burden of malaria until

D ho
elimination.

I t
•

M
Containment strategies for artemisinin

u
resistance and malaria elimination require

S C
approaches beyond the treatment of

a
clinical cases, since treatment of

E y
symptomatic cases would have limited
impact on community-wide transmission.
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Ivermectin: the wonder drug?
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•
•
L
Used in veterinary medicine against animal parasites

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Administered to > 80 million adults and children in mass treatment campaigns
against onchocerciasis (river blindness)

I D ho
 Interferes with neuromuscular physiology

t
of invertebrates

CM
 Reduces the life-span of mosquitoes that

u
feed on an IVM-treated individual

S y a
E
• Animal studies
Foy et al. Trends Parasitol 2011
Chaccour et al. J Infect Dis 2010
Bastiaens et al. Malar W J 2012
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A double-blind, randomized trial with ACT-IVM
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1.
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Study questions:

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Can ACTs be safely given together with
IVM?
Population:
•
•
Balonghin, Burkina Faso
120 asymptomatically infected

D ho
o Side effects individuals

M I
o Drug interactions
2. Are repeated doses of IVM needed?

t
3. Active against An. gambiae and
•
•
•
15 to 25 years
Haemoglobin ≥11 g/dl
No Loa loa or other filariasis infection

C u
An. funestus?

a
E S y
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Trial profile
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L
418 Screened

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Enrollment
214 excluded:
• 159 no parasites
• 14 too low BMI
• 12 Hb <11 g/L

I D ho
120 Randomized
• 1 pregnant
• 28 microfilariae in blood

CM u t
Allocation

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40 AL 40 AL-IVM1 40 AL-IVM2
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Treatment groups
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Group:

AL
Day 0
Morning
L
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Afternoon
Day 1
Morning Afternoon
Day 2
Morning Afternoon
Day 3
Morning
Day 7
Morning

D ho
n=40

AL-IVM1
n=40

M I t
AL-IVM2

C a u
S
n=40

E y = AL, artemether-lumefantrine (=ACT)

= IVM, ivermectin
= placebo
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Enrolment characteristics
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Age, median (IQR)
L
e r
AL (n=40)

18.5 (16.0 – 21.3)

AL-IVM1 (n=40)

16.0 (15.0 – 20.0)

AL-IVM2 (n=40)

17.0 (16.0 – 18.5)

I D ho
Parasitaemia by
microscopy,

M t
parasites/μL, median
(IQR)

C u
109.5 (38.3 – 222.0) 87.0 (28.0 – 203.5) 134.0 (45.0 – 406.0)

S y a
Gametocyte prevalence
20.0 (8/40) 12.5 (5/40) 12.5 (5/40)

E
by microscopy, % (n/N)
Gametocyte prevalence
97.2 (35/36) 86.8 (33/38) 91.9 (34/37)
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Results
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•

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All 120 participants had asexual parasites (range 8-7063 par/µL) on day 0; all

e r
cleared their asexual parasites by day 3
No significant differences in lumefantrine (AL) concentration among treatment

D ho
arms

M I  Efficacy of AL not affected by IVM

t
Gametocyte prevalence declined from 91.5% (day 0) to 52.5.% (day 3) and 36.8%

C u
(day 7) with no significant difference between treatment arms (p≥0.91)

a
 ACT does not sufficiently kill malaria transmission stages

E
• S y
22 mild/moderate adverse events
Full blood count and biochemistry on days 0 & 7: no abnormalities
 ACT-IVM combination is safe
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Safety of ACT-IVM
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Few adverse events (n=22)

L
Adverse events of any severity (n)

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Abdominal pain
Abscess on hand
Abscess on leg
AL (n=38) AL-IVM1 (n=39)
2
AL-IVM2 (n=40)

1
1

I D ho
Bronchitis
Conjunctivitis
Cough
1
1
1 1

M
Dental pain
Diarrhoea

C
Fever

u t 1
1
1

Headache

S
Orchitis

y a 1 1
2
4

E
Painful swelling of leg 1
Pharyngitis 1
Urinary infection 1
Subjects with severe adverse events - - -
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Determining mosquito mortality
ib r
L
e r
I D ho
CM u t
S y a
E Mosquito survival until day 10 after feeding
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ib r
L
e r
I D ho
CM u t
S y a
E
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Mosquito survival rate after feeding

L
e r
I D ho
CM u t
S y a
E
(ns)

(similar findings for An. funestus)

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Mosquito killing effect
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L 1.0 r=0.75, p<0.0001 … is strongly associated
Cumulative mosquito mortality on d10

e r 0.8
with ivermectin plasma
concentrations

I D ho 0.6

CM u t 0.4

a
0.2

E S y 0.0
0 2 4 6 8 10 12 14
Ivermectin concentration (ng/mL)
male participant
16

female participant
18
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Ivermectin plasma concentrations
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L
… are significantly higher in female

e r
compared to male participants
… are strongly associated with BMI
r=0.57, p<0.0001

I D ho
CM u t
S y a
E
Female participants  significantly ↑ mean BMI  ↑ plasma [ ]  mosquitocidal effect ↑
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ib
Estimated impact on transmission r
L
e r Compared to AL we estimate that:
• Individuals in the AL-IVM1 group

I D ho had a 27.2% reduction in their

contribution to transmission in

CM u t first week after start treatment

• Individuals in the AL-IVM2 group

a
35.4% reduction

E S
IVM
y
IVM
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Conclusions from our trial
ib r
•
•
•
L
AL-IVM is well tolerated

e r
IVM affects both An. gambiae and funestus mosquito survival
The effect is incomplete, even 24h after a single IVM-dose
•

D ho
Doubling the IVM-dose may increase mosquitocidal activity until 7 days after

I
initiation of ACT treatment
•

•
CM u t
The mosquitocidal effect is larger in female participants due to higher plasma
concentrations of IVM

a
Single and repeated IVM-doses may lead to significant reductions in post-

E S treatment malaria transmission from individual patients in the first week after
ACT

y
 a r
Modelling results
ib r
•
L
MDA is more effective

e r
than MSAT at reducing
prevalence

•
I D ho
Adding IVM results in a

M u t
greater reduction of
malaria than MSAT or

C a
MDA alone

E S y
4 treatment rounds
preferable to a single
round Slater JID 2014
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Acknowledgements
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•
•
•
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CNRFP Ouagadougou, Burkina Faso

e r
André Lin Ouédraogo
Alfred Tiono & clinical team
Moussa Guelbeogo
LSHTM, UK
•
•
Chris Drakeley
Harparkash Kaur
MRC, The Gambia
• Umberto d’Alessandro

Institut de Recherche
•

D ho
Sodiomon Sirima

I
Radboudumc, the Netherlands
Walter Reed, US
• Kevin Kobylinski
Sciences de la Santé, Burkina
Faso
•

t
Halidou Tinto
•
•
• M
Teun Bousema

u
Kjerstin Lanke

C
Will Stone
IRD, France
• Karine Mouline University of Iowa, US

a
• Lawrence Fleckenstein
• Robert Sauerwein

•
•
E S y
Imperial college, UK
Hannah Slater
Thomas Churcher