New advances in the treatment and control of malaria in pregnancy
- Impact Case Studies
4 December 2020
The Dangers of Malaria
Malaria in pregnancy is one of the leading causes of adverse pregnancy outcomes. Current control strategies are under threat due to increasing drug resistance and suboptimal coverage with existing tools. LSTM has been the coordinating centre of the Gates-EU-funded ‘Malaria in Pregnancy Consortium’, a network of 40 research institutions, that aimed to improve the control of malaria in pregnancy. Research led by LSTM, consisting of meta-analyses, observational studies, and multicentre trials, has contributed directly to WHO and endemic country policies on the treatment and prevention of malaria in pregnancy in different transmission and drug resistance strata in sub-Saharan Africa and Asia-Pacific.
Treatment and control of malaria in pregnancy: improved policy guidelines and practice
Research led by LSTM and partners has contributed directly to improved WHO and endemic country policies and practices for the treatment and prevention of malaria in pregnancy in different transmission and drug resistance strata in sub-Saharan Africa and Asia-Pacific.
Specifically, ministries of health in 36 African nations are now implementing a more effective malaria prevention strategy improving the outcome of an estimated 32 million pregnancies at risk annually and thereby the lives of mothers and their infants. The research has also resulted in label changes for the use of artemisinin combination therapies, the most effective antimalarials to date, for treatment of malaria in pregnancy.
Dr Feiko ter Kuile is Professor of Tropical Epidemiology, heading the malaria epidemiology section in the department of Clinical Sciences and LSTM’s malaria research collaboration with KEMRI’s Centre for Global Health Research and CDC’s malaria branch in western Kenya. His main research interest is the epidemiology of malaria and the evaluation of new interventions for the for the control of malaria in children and pregnant women. He headed the Malaria in Pregnancy Consortium, a network of 47 research institutions worldwide conducting research on the treatment and prevention of malaria in pregnancy.
so welcome everybody it’s my pleasure to introduce an lstn professor fico tequila
to give today’s um impact seminar so fico’s been with lstm for the past 17
years he heads the malaria epidemiology group in the department of clinical sciences
he’s normally based in he’s calling from the netherlands today he’s joining us from from there but he’s normally
uh most of the time in kenya where he works closely with with clemory and with cdc
on various different um malaria control projects and trials he
heads the malaria in pregnancy consortium so that which has been running since uh 2007 and works with
47 different partners across the globe to address key um gaps in research and implementation
for the control of malaria and pregnancy and today he’s going to present his work on work from the this
consortium on improving the treatment and prevention of malaria pregnancy so
fico welcome and thank you thank you very much uh hillary and thank you all for joining
today as i’m sure there are more important things that you could do and i can’t blame you if you’re also keeping an eye on
cnn or bbc to track the vote cuts uh across the pond what what i wanted to do is um
in the next 45 minutes is presents probably over 10 years of work from many different individuals and i
would like to stress this and partnerships and what you see here in this slide are the
investigators from lstm from the malaria practice consortium are listed on the left
and the core group from the malaria epidemiology section involved with these vanarium pregnancy
studies are listed in bold and you can see their pictures including jenny hill who holds the dual
role of program manager of all the malaria practice related research and public health scientists responsible
for the social science and the implementation research within the consortium
and on the mig flag sort of the the top left with that yellow background is a medical epidemiologist who is
currently in atlanta georgia probably holding her breath what georgia’s going to do
and she conducted many of the meta-analysis involved and then we have stephanie delicour a
pharmacoepidemiologist as well as cheryl pace who were involved in the drug safety studies and carole kyrella
who an epidemiologist based in bordeaux france who helped with a lot of the data analysis
and then roxanna ahmet is a pediatrician from the maldives trained in australia who led these
studies in indonesia and there were many other investigators
involved from lstm over the years with the different aspects of these studies including the
statistical team led by professor duardo wang from the global health trial unit
and paul garner who supported some of the influential meta-analysis that were conducted
and then more recently emily adams group with the diagnostics research in
indonesia and in kenya and in the beginning steve ward’s group who let some of the pharmacokinetic work
within the mip consortium and i i also want to acknowledge in advance
the fabulous support we received over the years from alison reynolds from helen wong tracy saturn and cheryl
giddings which are the photos at the top right who helped run the malaria epic group in the malaria
practical torture and kept us all sane and
on schedule now and there of course there are many other people in the school who have helped and
i probably want to specifically mention the pre and post award teams including
katie davis and and helen mccormick and the work that i will present here
are also part of phd training of six students five of whom have now
graduated and one is still active as a postdoc in the field
the sixth one started more recently he’s conducted the ongoing research in in kenya
and the working government was supported by these four major donors and included
approximately 30 million us dollars from the gates foundation for the malaria pregnancy
consortium which at that time was worth only 15 million british pounds
and it also includes three grand from the joint global health trial scheme which as you probably know
is co-funded by the uk mrc david the welcome trust and
nihr as well as significant funding from edctp and more recently from
the medicines for malaria venture to that study specifically to continue our
safety work with anti-malarials in pregnancy now mind you this is a lot of money
especially the ground from the bill manila gates foundation but it was a consortium and
we were the hosts but uh 75 to 80 of that funding was for our partners so
it wasn’t all necessarily for lsdm and lsdm led research
and what i will be presenting today is specifically the lstm led or coordinated research
and just as a brief background um i will start with sort of um explaining why we’re interested or
worried about malaria and pregnancy and what we were aiming to achieve with our research
strategy and for clarity i’ll i’ll split the discussion in a treatment component
and a prevention component and then the prevention is split by region as the prevention policies in
these regions are very different between africa and asia for example and
at the end i’ll show you one or two slides with some of our other outputs
firstly malaria practicing is one of the most common causes of pregnancy loss and
adverse pregnancy outcomes in resource poor countries and we estimate that approximately
60 of all birth worldwide are potentially at risk of some degree
of malaria exposure during the nine months pregnancies and pregnancy is a particularly
vulnerable period as pregnant women for a range of reasons are more susceptible to
acquiring malaria infections than their age-matched non-pregnant peers and when they do get
infected the infections tend to be more severe resulting in
for example severe maternal anemia or severe acute feeble illness multi-organ
failure and even maternal death in some women however
one of the main challenges for malaria controls that a
very large proportion of the malaria infections during pregnancy can remain asymptomatic and this often
depends on the degree of of background immunity the mother has acquired prior to the
pregnancy or during previous pregnancies and the the more our diagnostic tests
improve the more we realize how big that proportion is of infections that are not
associated with symptoms yet we do know that these silent
infections if you will which can which are harvard in the placenta and cause placental
insufficiency can result in the loss of pregnancy or otherwise pre-term delivery or
intrauterine growth presentation resulting in turn in a child being born too small for the gestational age
giving these children a disenfronted start in life and placing them as a
consequence at risk of further morbidity or developmental delays in in early
childhood
and as i mentioned malaria is one of the most common causes of
pregnancy laws and as well as pregnancy outcomes and sorry
one of the main challenges for malaria control in pregnancy is the much more limited
choice of drugs available to treat infections during pregnancy because of safety concerns for
the for the growing fetus and since the thalidomide disaster new medicines often carry
prescribing caveats that they should not be used in pregnancy because of insufficient safety data even
if if no safety signals are detected in pre-clinical studies but the dilemma is that for new drugs
there never is sufficient safety data and this was aptly described by
nick white as a catch-22 situation in an opinion piece they published in
the in the journal plosmet as you can imagine so new drugs are not
recommended because of lack of safety data therefore not prescribed thus no new
safety data becomes available therefore they are not recommended etc
and as a result pregnant women with potentially fatal diseases such as malaria are often
prescribed old and inferior drugs in this case um queenie this was very true
for the treatment of malaria and pregnancy in 2005 which was the year when we started to discuss the potential
of creating a malaria pregnancy consortium and we realized that we needed dedicated
research for pregnant women with a better coordination of the research agenda to
avoid duplications and probably research at your much larger scale than done and funded before
and to address this we start to talk to several donors around 2005 and created the malaria pregnancy
consortium formerly in 2007 to look at new strategies
as well as new drugs for both the treatment and prevention in pregnant women and
the malaria practice consortium which ran from 2007 to 217
was a consortium consisting as hillary mentioned of 41 different partners based in 29
different countries and the secretariat was based with us here at lstm with jenny hill as the manager and
myself as the director and supported by the team that i showed you earlier in the in the first set of
slides we were very fortunate to receive
two startup grants from the gates foundation and from edctp which allowed us to bring together
different partners with a range of expertise with the main aim to develop a five and
perhaps ten year research strategy for the control of malaria pregnancy and
at that time we decided to exclude malaria vaccine work because other consortia were already focusing on this
and because it required a longer time frame and significantly more funding if you
were to include malaria effects and studies and as you can imagine developing a
research strategy with so many different partners was a challenge as each partner would bring their own
research wishes and priorities to the table and there were many different
gaps that needed to be addressed because this was a neglected field of research for for quite a few
years and also although the gates foundation did hang a large fruity apple above our heads promising
potential funding if we managed to work together and come up with a sensible research strategy
we were also told that the funding would be limited to 30 million us dollars at that time
so and as you can imagine um clinical trials treatment prevention trials are
expensive to do so we had to restrict the agenda eventually to what we call the
priorities of priorities and we ended up organizing a
dedicated donor meeting to discuss the research agenda in the hope that these different
donors would be interested in different aspects of of the of the wide range of research agenda
and this was a luxury to to do to have that startup ground and it was very successful and for
example edctp came out with a dedicated call for malaria pregnancy
for about 12 million euro and although the call was open for
anyone to apply the three winning awards were all went to members of the consortium
and all had a great upfront to do this under the umbrella of the consortium which meant clear coordination and
sharing of tools and data early on in the process and the
the final research agenda was broadly divided in these five themes that you can see here
in the slides including a treatment study so this is case management of women that are sick
with malaria and prevention studies in split again in africa versus asia and latin america and
then public health impact research including anthropologic studies health economics
and implementation research there at the top right and in addition there were other
components that were cross-cutting across the treatment and prevention themes including pharmacokinetic studies
from vigilance and drug safety and studies of the pathogenesis and an immunity and of course it also
provided a great opportunity for capacity developing including the training of several phd
and postdoc students from epidemic or endemic countries
now it appeared early on that one of jenny’s hill’s
hidden talents are her negotiation skills with the lands of infectious diseases
and somehow she managed to convince the editors that they should publish our systematic reviews that were conducted as part of the
development process of the research strategy and this resulted in a dedicated issue
in the london city factory diseases in 2007 with eight articles written by the core members of the consortium
and i don’t know if you can read it but you can spot some other names listed here including eve warl from the liverpool
school and steve ward who led the pharmacokinetic and drug safety review
so overall this was a very encouraging start for the for this new partnership and
jenny’s negotiating skills were probably not a chance finding because she managed to convince the same editors again to publish 10 years
later the results of the consortium activities this time in three dedicated articles
split by burden and economic impact then treatment and prevention
and the lsdm authors were senior authors on two of them and the second author on the third
so what was the research about and it’s important to
appreciate that the current control strategies from mip vary by region and by malaria
transmission intensity in in sub-saharan africa which falls under the
derby afro region there is a so-called strategic framework for malaria
pregnancy which consists of case management of women who have acute malaria
and the two other components are specific to prevention which includes insecticide treated bed
nets or itns as well as ipt and i’ll come back to
the term ipt a bit later but i just wanted to stress here that the insecticide treated
bettness per se are very effective and we know from a cochrane review that we jointly
conducted with paul garner’s group very early on the bet nets reduce the
risk of low birth weight by 23 and pregnancy loss
by 33 so this is including spontaneous miscarriages and
stillbirths and these are very impressive reductions
in risk by a single intervention probably also illustrating the huge
burden that malaria causes during pregnancy in africa and there are not that many interventions that have such a large
impact on pregnancy loss and low birth rate and the
third component ipt which stands for intermittent preventive treatment which is a term that is probably familiar to
many of you is provided to hiv uninfected women
and pregnant women living with hiv already getting daily cultural microsoft
for opportunistic infections um and as you probably know cotrimoxazole also has
anti-malarial properties and as such it acts as a daily prophylaxis against malaria in this group so hiv
infected women are not getting ipt i will be talking um about malaria
control and hiv infected women in the in the next slides but i’ll focus on
ipt in hiv uninfected women
but i wanted to start by describing ldcm’s role in the treatment studies so
this focuses on the safety of the new generation of anti-malarials in pregnancy
and as i mentioned before in 2005 we were in a catch-22 situation
with regards to the use of these acts and acts are to measuring
base combination therapy are the most effective anti-malarials we have today
and first-line treatment in the entire population with the exception of women in the first trimester and this is
where the catch-22 situation comes in so acts were not recommended because there was
insufficient safety data in humans available and during this vulnerable period in
pregnancy there were preclinical data suggesting that the artemisinins were embryo toxic
in several animal models and some of the pre-clinical work was conducted here at lstm
by steve ward’s group so the concerns about the use of these art emissions in the
first trimester were certainly justified at the time however we we don’t live in a perfect
world and in real life women are much more likely to be treated with acts than with queening in the first
trimester for example western kenya where we work studies conducted by stephanie daly
cooper and colleagues from cdc suggested that over 80 percent of first
trimester malarias are actually treated with artemisimoventrin instead of greening despite queenie
being the first line treatment in the national guidelines and there are several reasons for this perhaps the
most important one is that the lack of queening in many of these facilities and the perception
among the staff that acts are much more effective than even seven days of grinning now acting
acts are known and have been documented to be very effective in the second and third trimester
probably resulting in 80 percent less treatment first and with unsupervised cleaning plus
they can be given over three days instead of seven days and queening like many of the
anti-malarials is also extremely bitter a queen in in much smaller
amounts is an ingredient of for example tonic drinks acting as a bittering agent if you
drink about eight liters of gin and tonic three times a day you might be protected from malaria
but queening is badly tolerated although the side effects are usually melt and transient they include ringing
of the ears flushing headaches dizziness it’s it’s a complex called
kinchenism which is not something you would enjoy for a whole week and especially when
you’re pregnant and so it’s it’s one of the main reasons why many women don’t complete a seven day
regimen with greening resulting in incomplete treatment of malaria
and of course the associated risk of subsequent treatment failure
with the risk of malaria coming back furthermore queening resistance is
well described in southeast asia although in africa there’s no evidence yet of of green
resistance so in 2005 to 2007 many
policy makers in africa were wondering why they had to continue treating one of
the highest risk groups with these old and failing regimens
like queenie yet the majority of women were actually
being treated by with the artemisian derivatives and it was clear that a more
comprehensive risk benefits assessment was needed of the acts compared to queening
and that this was urgently needed which is the reason why we embarked on a
series of prospective studies to compare the pregnancy outcomes of women who were inadvertently exposed to acts in the
first trimester for example because they didn’t know they were pregnant or they did not
want to report they were pregnant and compared those outcomes with women that were treated
with queening also in the first semester this was part of stephanie delicour’s
phd well based in liverpool and then later in kenya and she coordinated a series of
studies in africa founded by the malaria practicing consortium and other partners
and eventually we combined all the available safety data from these studies with 25
years of data collected by the group of francois nosten and rose mcgreedy from the tiger miss
border which they had published previously in the lands of effective diseases and all this data was combined in a
in a meta-analysis and the combined results were important
because they they did not only suggest that the artemisians were not associated
with an increased risk of congenital anomalies at birth relative to queening but they also
suggested that the risk of pregnancy loss or miscarriage and stillbirth was about 42 lower
among women who had received acts compared to women who had received queening
and by then we had also conducted a meta-analysis
of all the efficacy studies which is that screenshots at the bottom right
comparing the efficacy of acts versus queening for the treatment of non-severe malaria in the second
and third trimester and this showed that malaria treatment failures were much
lower 80 percent lower with the att’s than with queening so we concluded
that compared to queening the act antiminerals were much better tolerated much easier to administer so
three instead of seven days and much more effective at treating malaria
and likely to be at least as safe as screening
and because malaria practicing requires prompt safe and effective treatment we
concluded that the risk benefit balance favors acts in all three trimesters
and that the act should either replace queening or as a minimum be offered as an
alternative to queening in the first trimester
and these results were presented to derbyshire who initially agreed and a series of three
to four meetings were held over two years including the committee that determined
the malaria treatment guidelines and all agreed that act should be considered in the first semester
however as you can see the policy making process at double joe is complicated and if
anyone especially the lawyers want to put a spanner in the wheel they will find plenty of
opportunity to do so and those for various reasons this has still not been included
in the malaria dream guidelines and in fact the process came to a complete hold in november last year resulting in
heated debates within who itself where some felt very strongly that this
should be moving forwards and also resulting in letters to medical journals questioning why
derbyshire was still delaying the implementation of these findings into policy
and fortunately we learned last week that derbyshire decided to re-open the
policy-making process again with the goal of now finalizing this by
mid-2021 so next year and we were asked last week to provide an update to
ensure all the safety data collected since 215 can now also be included
and this will include some of the safety work that roxanna i met from our team has recently completed in
indonesia so hopefully the policy brief
that was developed by jenny hill last year will still be put to good news as this took a long
time to develop that received input from many different parts including from who itself and from the
rollback malaria program from the gates foundation from mmv from the welcome trust unit in thailand and
from unit 8.
so one of the reasons why we think or hope that double cho is
now able to reopen the discussions is because of the label changes that have occurred
since 215 based on the evidence presented in in the meta-analysis by stephanie delicourt
and both the us fda and the european regulator and the ema have taken this evidence on board as well as
the whole pre-qualification team which is a completely different team and department within who from the
global malaria programme and this is important we’re really encouraged by this because this meant
that probably for the first time our academically sponsored data so academic
research is now being considered by stringent regulators such as the fda
normally they use data from generated by manufacturers themselves
and it was the regulators that are encouraging the manufacturers to update their labels including the
usfda which requests the label chains by novartis and the novartis is the manufacturer of
artemithelium fentrin under the brand name of kortem and this
this is important because automethylmercentin is the most commonly used act
worldwide also interesting in some countries in
indonesia was the first did not want to wait for the change in double choice policy and
they changed their guidelines in september 2019 to allow the use of acts in the first
trimester and according to our colleagues at derby afro several countries in africa have also
recently updated their guidelines but they are waiting for a formal derby show communication
before implementing the change
now lastly before we move on to prevention so we are going to continue to collect more safety
data and the main reason here is that eighty percent of the existing data is based on
art methodology now there’s a far less data available for the newer
anti-malarial such as dha preparation dihydroartemisian preparation
and power narrative taginate and for this we recently received a new
grant of 3.9 million pounds from mmv which also meant that
stephanie delacour is now back with us at lstm on loan from the uk regulator from the
mhra in london to coordinate this new pregnancy regis initiative
and the field work will hopefully start this month or next month in kenya
i’m going to switch gears now and move from treatment to prevention and we’ll discuss our studies
with ipt in particular and ipt now i’m sure this is familiar
to many of you but to those who are not familiar with the term it’s it’s a it’s the main drug based
prevention strategy used in africa for malaria pregnancy and ipt as i mentioned stands for
intermittent preventive treatment and the concept was developed in the early 1990s with the first studies
conducted in malawi and consists of provision of full treatment courses of a long-acting
anti-monero that is given presumptively so without screening for symptoms or malaria
parasites in the blood at regular intervals during pregnancy
and the only anti-malarial currently recommended for ipt is sulfatoxin paramethamine or
sb for short better known perhaps as francida which is one of the brand names
and sp has excellent properties for ipt because it’s it can clear existing infections so if the parasite
at least are sensitive and it’s slowly eliminated from the body so it hangs around for several weeks
providing so-called post-treatment prophylaxis for at least four weeks in sensitive infections and
that’s that’s illustrated here by these in the next slide by the hedge bars but
it’s importantly it’s it’s it’s well tolerated it’s widely available and opposed to a cts that require
three-day regiments sp can be given as a single dose of three tablets
and this as directly observed therapy in the antenatal clinics
this this shows sort of the concept graphically and the initial regimen
recommended by derby cho until 2012 consisted of approximately two doses
during pregnancy once at the beginning of the second trimester and another dose at the beginning of the
third trimester hence the term intermittently
these two courses can clear existing infections and then provide four to six
weeks of prophylaxis illustrated here by these hedge bars and but as you can see they do not
provide complete protection as women are
unprotected before the first dose in between the two courses and after
drug levels have waned following the last course but they do provide protection during a
critical period of fetal growth and despite these imperfections it is
known to be very effective even in women protected by bad nets resulting in a
29 reduction in low birth weight for example
but these gaps in protection led us to believe that more frequent regimens could be even more protective
and kasum cayenne tower was our phd student from mali and he had just completed a large trial
in maori showing that women who had received three or more doses of sb
were much better protected than women receiving the standard two-dose regimen
and he combined the data from his trial with six other trials in a meta-analysis
again in collaboration with paul garner’s group and each of the individual trials both
relatively modest in size and designed to detect the impact on malaria infection as the primary outcome
but not power to detect the impact on adverse pregnancy outcomes such as pregnancy loss and
and low birth rate and this is the real value of a meta-analysis that combines all these
existing studies and these full data showed
overwhelmingly that providing more doses and providing monthly doses
instead of just two courses is first of all safe and results in much greater public health gains where you
can see here in that box on the left that the additional reduction in low birth weight
by giving monthly doses was there was 20 more reduction in low birth weight then you could achieve with the standard
two-dose regimen these results were published in jama
and a subsequent cost-effective analysis also showed this was one of the most cost-effective
interventions to reduce the risk of low birth weight because the price of sb is very low and
the delivery mechanism is already there now you can give sp as directly observed therapy
in the antenatal clinic when women come to you it’s not something where you have to deliver an intervention to the
to the population and the study was presented to who and
led to a revision of the derby joe ipt guidelines about a year later
and which is now being implemented in 36 different countries in in sub-saharan
africa the main challenge however today is
resistance to sp and i mentioned this being the only anti-malarial recommended so far by
derby cho which is illustrated here in in this map
showing that east and southern africa are mostly affected by resistance and parasites in west africa remain
fully sensitive to sp and what we did with the malaria
consortium malaria pregnancy uh studies in um in a series of observational studies in
six countries across a range of resistance severity is to get a better understanding of the
impact of of different degrees of sp resistance all the ability of speed to clear existing infections and
prevent prevent new infections from occurring i.e the the treatment effect and the
prophylactic effect and this showed clearly the massive problem
some of the high resistant countries were facing in the early 2000s
in areas with full sensitivity of the malaria parasite usb depicted here by the yellow and the red
lines at the bottom representing data from mali in burkina faso in west africa
sp was able to clear existing all existing infections plus provide at least 28 days of
post-treatment prophylaxis where the y-axis here shows the risk of
recurrent malaria and the x-axis shows the time since the dose was given so this suggests that
monthly regimens with sbe would be able to provide complete prophylaxis during the second
and third trimester if women were indeed taking it on a on a monthly basis but by contrast
as you can see from the blue and purple gray survival curves here at the top
in areas with high speed resistance and these were in malawi and kenya
approximately 30 of the women have malaria again by the time they were due for their next
monthly course and this was as high as 50 percent by day 42
so clearly as an anti-malarial sp was failing to clear existing
infections and prevent new infections from occurring in these high transmission areas
so much of its anti-malarial effect was was compromised
and we then continued with a large meta-analysis which was conducted by by
anna mig von egg and published in the the last in fact diseases in
last year 219 and this confirmed not surprisingly perhaps that the trends
towards decreased effectiveness with increasing levels of speed resistance in the parasite
population was was evident with clear sustained efficacy in west
africa and reduced benefits in east and southern africa
and so this this meta-analysis showed i think for the first time a clear
correlation between the clinical impact and the presence of resistance in the parasite population
based on the prevalence of certain molecular markers of resistance
and these results were shared with w joe who used the data to make two different recommendations one was
that molecular markers surveillance could be used to track the impact of sp
for ipt and this was important because as this provides a much more
pragmatic tool to track the impact of sp resistance than doing these labor intensive in vivo studies
that we did earlier with the mib consortium and the second recommendation um
was because we showed even in areas with high resistance
ipt with sp was still associated with some beneficial effect on birth rate albeit
um less than areas with no resistance so domicio recommended that countries could
continue or should continue using ipt with sp in these high resistance areas
and that also was important to know um for many of the countries because they were asking questions to derby show and
seeking guidance from derby whether they should stop using ipt with sb completely
as at that moment in time there were no alternative drugs available yet that could replace sp and as you can
imagine it would be much easier to replace a drug with another drug than completely stop a strategy like ipt
and then having to reintroduce it to five years later once an alternative drug has been identified
and these um david cho recommendations also use the public health impact reviews
that jenny hill published in the
however it was also clear from this meta-analysis that alternative solutions to usb
were needed um soon and this led to a series of
approximately i’ve never really counted it but probably 17 trials to determine the
alternative drugs that could potentially replace sp or
alternative strategies that could completely replace the entire concept of ipt
and we first looked at intermittent screening and treatment or ist as an alternative to ipt with sb
with ist women where they are screened at regular
intervals during pregnancy using a rapid diagnostic test which is then used to determine whether
a woman should be treated with anti-malarials and these rapid diagnostic tests can be used at a point
of contact in the antenatal clinic by midwives and nurses and doesn’t
require any much more labor-intensive microscopy for example
now before moving on to discuss our drag trials on the left i first want to
briefly discuss the findings from the screen and treat studies
and to be honest they were disappointing there have been
four different trials conducted in in six different countries in the last 10 years the good news is that
the results across those trials were consistent but they were unfortunately consistently
bad [Music]
and we found that to our surprise that women
in the ist arm so in the screening arm tended to have more placental malaria
than in the sbr and that the mean birth weights were statistically significantly higher
in the sp arm so the arm that was supposedly failing and this was surprising because
it was also seen in the areas with high sp resistance
also surprising because at the time that we were designing these studies we had
debates within the malaria pregnancy consortium and and some of the members questioned
whether it was even ethical to do such a study in high resistance areas because it was going to be obvious that
the screening arm was going to be better than the failing regimen with a sp
and i’m really glad we did this because um together with the findings from the
resistance analysis in the previous methods conducted by anamik it started to give us an inkling of the of the importance
of sp and that sp was actually doing much better than we had anticipated in these
in these high resistance areas and and we will see more of that in in the next chemo prevention trials
this was also presented to to w joe and nwo recommended that further trials with
a new generation of more sensitive rdts should now be considered and
these are at the moment ongoing so there are new generations of highly sensitive rdts
and find is coordinating this set of trials
so as i mentioned um four years and and um six million dollars later fading the ist
trials the the the quest was really going to be to find alternative drugs to replace sp as ibt
and was this going to be more successful and the answer probably is
maybe because over the last 10 years there have been
probably 10 trials looking at alternative drugs to sp and these included chloroquine
either alone or combined with the citromycin ammo diagram again alone or combined
with sp which is the main regiment used for a siege little malaria key intervention in cell countries
and methocrine at a dose slightly lower than the standard treatment dose or a dose of 15 milligram
per kilogram per month as well as dihydroactivation in preparation so dhip or peregrine
and the first three zercon and amordiac and america were conducted by other groups and the main challenge
with drug-based regimens for prevention is that they don’t only need to be safe
at least in the second and third trimester but they also need to be long-acting and provide approximately four weeks of prophylaxis
after each dose and importantly they they need to be
really well tolerated now the risk benefit ratio is different for drugs that are used for
case management as you can appreciate but in women that are getting drugs for prevention
now they walk in happy and healthy into the clinic and you don’t want them to go home
feeling nauseated having headache and even vomit um if they get a drug for
prevention especially if this is a three-day regimen and they’re supposed to take the second and the third day at home
and this is unfortunately exactly what happened with um chloroquine ammo diagram african
these these drugs were found not to be tolerated well enough to be used for prevention
and in some of these trials for example in the chloroquine azithromycin trial and in the immediate
trials these arms were stopped early the studies were stopped early for fertility
as it was very clear early on that this is not a potential replacement of sp and the only
combination that did look promising is dha preparation which is better
tolerated than the other anti-malarials
and to date eight trials comparing the age of american versus sp for ipt are either completed or ongoing
and we conducted the first trial as part of our long-term collaboration with cdc in western kenya
where we compared ipt with sb as the control arm against ipt with dhf
apparaquin this study was published in the lancet showing for the first time that the age
of apparently was much more effective than sp at preventing malaria and pregnancy
and at the time unbeknownst to us a similar trial a much smaller and 200
women were started just across the border in uganda as part of collaboration with the grant dorset
group from ucsf and their study was published a year later in the new england journal
and came to similar conclusions and three years later they confirmed their findings in a much larger trial
which was also published in the lancet and and this effect is illustrated here this
graph which i borrowed from their publication in the new england journal which shows the risk of malaria during
the second and third trimester in women randomized to the ipt regimen
with sp which is the black line and we’re randomized to either three doses of the age of a paragon the the blue line
or monster gate hyperbaric than the red line
and what it shows the first of all the very high burden of malaria in this area with two-thirds of the women showing evidence
of malaria by the time they entered the study nsp appeared to be able to halve
this risk to about 30 percent but as you can see the monthly dp regimented deadline
that the red line was able to provide almost complete prophylaxis with no evidence of malaria
at the time of delivery so a very effective regimen if it is given on a monthly basis
and we combined the results of these three first trials and compared to the
standard ipt regimen there’s a 90 reduction in clinical malaria
the 65 reduction in malaria infection an impressive 41 reduction in
severe maternal anemia and importantly an almost halfing of the
risk of of pregnancy loss so 46 reduction and we also looked at the composite of
adverse pregnancy outcomes which is essentially an outcome that that everything that you want to
prevent in pregnancies included so fetal loss low birth very small percussion
age preacher and delivery and neonatal deaths and there is some hint that the aha
preparation is also able to reduce that but the effect is
small 16 and it certainly wasn’t statistically significant in these first three studies
and some of these findings that of the first two trials were discussed with derby cho and
darwicho agreed that the use of ipt with the ancient preparation held promise
but because the studies did not have enough power to provide definitive evidence of its ability to
improve adverse pregnancy outcomes so with clinical outcomes they recommended that more trials
were needed and they also indicated that they would like to see further studies of the acceptability and
feasibility and and cost effectiveness of the preparation so we
had our homework cut out for us and this resulted in us successfully applying for two
grants to both the joint global health trials which and edctp and these two
trials called improve trials are designed
with larger sample sizes and budgets to allow us to provide a more definitive answer on these
clinical outcomes [Music] in the meantime while these studies are
ongoing we we looked again at the pulled data from the three trials to see
what potentially the outcome could be of these much larger improved trials and the
results could be interesting and potentially surprising and
i’m saying this because if we look at birth weight again what we’re finding is
despite these massive reductions in the dhea preparation arm the women
born to um or the the the newborns brought to women in the women randomized to sb had
higher rather than lower mean birth rates so they the birth rates were higher despite the
facts that they were born to women that had much more malaria during pregnancy than those in the dnc
preparation arm and this is not a chance finding because we’re seeing this in all three trials so
it’s very consistent and we’ve just been told that there’s a much smaller fourth trial completed in malawi where they’re seeing
the same phenomenon and so one of the questions is now what
what is the resilient effect of sb on birth weight despite dp being a much more effective
anti-malarial and one option is that sb doesn’t necessarily have to clear these
parasites perhaps suppression of parasites is enough to
prevent some of the harmful effects and the placental insufficiency that you may see with malaria but other
hypotheses include the normal area effect of sp which would be very interesting and as you appreciate sp is not just an
anti-malarial it’s also a broad spectrum antibiotic it may also possibly have
anti-inflammatory immune modulating effects similar to those that have been described for
cooper moxazole but we haven’t looked at yet that yet with sp and lastly sp
may have a modulating effect on birthday through perhaps modifying effects on the vagina or intestinal microbiome
so we’re not yet sure um why sp is able to provide to birth
weights and but these data have potential
policy implications as they suggest that rather than replacing sp with the agent paraquin it
may be better to combine these two drugs as they could achieve greater reductions
and all cause adverse pregnancy outcomes than either therapy alone nowhere where dhea preparation could help reduce
clinical malaria maternal anemia and pregnancy loss nsp would help further reduce low birth
rate due to preterm delivery or intrauterine growth resultation and
we’re we’re hoping to to get funding for this kind of trial which we would then probably call
improve three and we will see if we are successful in the coming year
so i’m almost at the end but in the last few minutes i just wanted to briefly mention our portfolio of
research in in southeast asia and as i mentioned earlier there is dark differences
in the prevention strategies between africa and asia and most countries in southeast asia
issue bad nets to pregnant women and use so-called single screen and treat strategies where
all women are screened for malaria at the first antenatal visit and then treated if they found to be positive but then during the rest of the
pregnancy no specific prophylaxis is giving or screening tests are conducted unless the women are
symptomatic so so passives are veins and very little research has been done
on the prevention of malaria and pregnancy in this region and that’s partly because malaria
transmission is low in most of southeast asia making doing trials difficult and potentially
very expensive and partly because sb which as i mentioned is the only drug currently
recommended for ipt is no longer working in most of southeast asia because of parasite
resistance and further challenges include the
existing of 5x malaria which has the added challenge that this is that has dormant liver stages resulting
in frequent elapses from old infections that can hide the liver for months
and these liver stages are not susceptible to standard antimicrobials that can treat the blood stage parasites
and the drugs used to kill these liver stages are contraindicated in pregnancy which are the
eight amino acrylenes primocrine and tofanoquin which are known to be associated with
potentially fatal hemolysis in in patients with g6pd deficiency
so we thought women could potentially benefit from chemoprophylactic during pregnancy with for example dha perperon
which is why we conducted a trial which was published in the lancet infections in
two sites in indonesia in southwest zuma beautiful islands but unfortunately with very very little
malaria transmission and in papua indonesia which has a moderate year-round transmission so
very different from the rest of indonesia and we compared uh monkey dha
preparation against this single treat and single screen and trade strategy that was
national policy in indonesia with the goal of reducing both for separate and
via effects malaria and we found very similar findings to
what we’ve seen earlier in africa with sp is the control arm with very clear reductions in malaria
but the effects were only seen in papua and the paparazzi the higher transmission side northern zumba
whereas i mentioned unfortunately it’s remission so low that during the study that would have been required
tens of thousands of women to show any impact um so this was one of the studies where
we’re really fortunate to be funded by the joint global health trials which is an excellent funding agent and this study
also suffered from an unexpected delay in the recruitment due to tribal wars that broke out in
papua in the first half of the study and with the extra support from from the
joint global health trials we would be we were able to extend the study for an extra year and record more women
in papua after the war had been settled
as a result of this trial the indonesian moh is now planning to pilot the implementation of ipt in papa which
is very exciting and they’ve asked jenny’s team to help and jenny was fortunate enough to receive a new ground
from the mrc to help the moh for implementation research which we
hope to start early next year proven permitting of course and the study also results in a
long-term collaboration with professor rick rick prank’s great crisis group at
menses school of public health in darwin australia and we hope to set up a
malaria and pregnancy vivex research hub in the region in the coming years as part of this
collaboration now this is one of the last slides as a
researcher of course the greatest reward is to see that our efforts are translated into
policy hopefully benefiting many newborns with a better start in life however a
ref case control the case studies would not be complete without showing you some of the other
outputs and this slide provides a summary of the publications since the mid consortium started these
are the publications with lstm authors and almost all of these publications
were from the last 10 years and we are fortunate to work i guess on a topic that appeals to
journals and have published over 100 articles and these included two influential
papers in general about ipt with sb and one in the lancets about the as i mentioned the first trial
with dhl the peregrine and another 20 or so in the lancet family of journals
and plosmets have also been kind to us especially to jenny hill and stephanie daddy cooper
who managed to publish some big chunks of their phds in in plosmet
and then just one other output that i want to mention is um is jenny and anamix
to the rollback malaria progress and impact series 10 which they essentially authored
which is a beautiful illustrated book summarizing the challenges and the progress
made in malaria controlled pregnancy in the last decade and we’ve also maintained a malaria
pregnancy library since 2007 which is real monk’s work or perhaps i
should say nuns work because it’s maintained by on the meek the library is updated
every four months and contains all the relevant published and perhaps more importantly unpublished
gray literature on the topic including for example phds and master thesis or who reports
and for the last four years we’ve also been the lead of the malaria pregnancy science group at
warren the worldwide entrepreneurial resistance network for which we continue to receive gates
funding and discussions are ongoing with the gates foundation and it’s promising that they will
receive a renew round of funding before the end of this year
and then lastly a big thank you to our partners which we’ve built a very
large network of collaborators over the last few years and these are the logos of our primary partners today with our
privacy we’re concentrated currently in kenya malawi tanzania and mali in africa
and powerpoint indonesia and asia these are the partners for the malaria
pregnancy research we of course also have other partners for non-malaria practice related studies
so that brings me to the end of this talk if you’re still there many thanks for
listening especially on a day like today where we should all be glued to our television screens
thank you also hilary for inviting us to give this overview which was a real honor obviously the work
continues and we are about to embark on a new set of studies if you’re interested to learn more
please don’t hesitate to contact jenny or me thank you very much
thank you so much psycho for that really interesting comprehensive talk that i think
really nicely highlights how the consortium over a 15-year period has gone from identifying the key
key research questions to conducting the high quality research but then importantly as you say following it through
to policy implementation and monitoring and evaluation and i think this tells a really uh
really great story and as always many many more questions to be answered i’m fascinated by the
the effects of the continued effect of sp despite the the resistance i’d like to talk
more about and um but we are running a bit over time so
i think what we’ll have to do now and is is to close it to questions and ask people to get in in touch with you
uh directly or with jenny as you say if you do have any questions but thank you once again for
um for the excellent presentation
pleasure thank you
The Malaria in Pregnancy (MiP) Consortium
Led by the Liverpool School of Tropical Medicine, the consortium was established in 2007 with an initial grant of $30 million from the Bill & Melinda Gates Foundation and is also supported by the European Union and EDCTP.  The research programme directly benefits the 50 million women globally who face exposure to malaria whilst pregnant every year.
The IMPROVE Consortium was established to evaluate whether intermittent preventive therapy (IPTp) with dihydroartemisinin-piperaquine (DP), with or without azithromycin (AZ), is a viable alternative to current policy for the prevention of malaria and sexually transmitted and reproductive tract infections (STIs/RTIs) in pregnancy in high SP resistance areas in Kenya, Malawi, and Tanzania.
The Consortium comprises two multicentre trials, one conducted among HIV-uninfected women (IMPROVE) and one among HIV-infected women taking co-trimoxazole (IMPROVE-2).
Research Outputs
Hill J, D’Mello-Guyett L, Hoyt J, van Eijk AM, ter Kuile FO, Webster J. Women’s access and provider practices for the case management of malaria during pregnancy: a systematic review and meta-analysis.(link is external)(opens in a new tab) PLoS medicine. 2014;11(8):e1001688. doi: 10.1371/journal.pmed.1001688.
Dellicour S, Sevene E, McGready R, Tinto H, Mosha D, Manyando C, et al. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: A meta-analysis of observational studies. (link is external)(opens in a new tab)PLoS medicine. 2017;14(5):e1002290. Epub 2017/05/04. doi: 10.1371/journal.pmed.1002290. PubMed PMID: 28463996; PubMed Central PMCID: PMCPMC5412992.
Kayentao K, Garner P, van Eijk AM, Naidoo I, Roper C, Mulokozi A, MacArthur JR, Luntamo M, Ashorn P, Doumbo OK, ter Kuile FO. Intermittent preventive therapy for malaria during pregnancy using 2 vs 3 or more doses of sulfadoxine-pyrimethamine and risk of low birth weight in Africa: systematic review and meta-analysis. (link is external)(opens in a new tab)(2013). JAMA 309: 594-604.
van Eijk AM, Larsen DA, Kayentao K, Koshy G, Slaughter DEC, Roper C, et al. Impact of Plasmodium falciparum Sulphadoxine-Pyrimethamine Resistance on the Effectiveness of Intermittent Preventive Therapy for Malaria in Pregnancy in Africa: A Systematic Review and Meta-Analysis.(link is external)(opens in a new tab) Lancet Infect Dis (2019). 19; 5:546-556.
Desai M, Gutman J, L’Lanziva A, Otieno K, Juma E, Kariuki S, et al. Intermittent screening and treatment or intermittent preventive treatment with dihydroartemisinin-piperaquine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for the control of malaria during pregnancy in western Kenya: an open-label, three-group, randomised controlled superiority trial.(link is external)(opens in a new tab) Lancet. 2015. doi: 10.1016/S0140-6736(15)00310-4.
Ahmed R, Poespoprodjo JR, Syafruddin D, Khairallah C, Pace C, Lukito T, Maratina SS, Asih PBS, Santana-Morales MA, Adams ER, Unwin VT, Williams CT, Chen T, Smedley J, Wang D, Faragher B, Price RN, Ter Kuile FO, 2019. Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin-piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial.(link is external)(opens in a new tab) Lancet Infect Dis 19: 973-987. Doi: 10.1016/S1473-3099(19)30156-2