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Seasonal Malaria Chemoprevention: Emerging
issues from on-going evaluations
Dr E.S.Baba
Africa Technical Director
Malaria Consortium
1
Public Health Impact
Impact of SMC as an intervention on morbidity & mortality quite well known.
 Intermittent preventive treatment for malaria in children living in areas with seasonal
transmission (Review) (2012) The Cochrane Collaboration. John Wiley & Sons, Ltd.
 Dicko A. et al. Intermittent Preventive Treatment of Malaria Provides Substantial Protection of
Malaria in Children Already Protected by an Insecticide-Treated Bednet in Mali – A Randomised,
Double-Blind, Placebo-Controlled Trial (2011) PLoS Medicine. Vol. 8 Issue 2.
 Konate A. et al. Intermittent Preventive Treatment of Malaria Provides Substantial Protection of
Malaria in Children Already Protected by an Insecticide-Treated Bednet in Burkina Faso – A
Randomised, Double-Blind, Placebo-Controlled Trial (2011). PLoS Medicine. Vol. 8 Issue 2.
 Bojang K et al. Two strategies for the delivery of IPTc in an area of seasonal malaria transmission
in The Gambia: a randomized controlled trial (2011). PLoS Medicine. Vol 8, Issue 2.
 Greenwood B. Review: Intermittent preventive treatment – a new approach to the prevention of
malaria in children in areas with seasonal malaria transmission (2006) Tropical Medicine and
International Health.Vol. 11, No. 7.
 Bojang K et al. Two strategies for the delivery of IPTc in an area of seasonal malaria transmission
in The Gambia: a randomized controlled trial (2011) PLoS Medicine. Vol 8, Issue 2.
Impact of monthly SMC (any drug regimen) on clinical
malaria during the intervention period
No protection
%
Study
Rate
Weight
ID
Ratio (95% CI)
(D+L)
Kweku, 2008, AS+AQ
0.25 (0.18, 0.35)
12.32
Cisse, 2006, SP+AS
0.17 (0.14, 0.21)
13.58
Bojang, 2010, DHA+PQ
0.13 (0.06, 0.29)
6.72
Bojang, 2010, SP+PQ
0.07 (0.03, 0.20)
4.98
Bojang, 2010, SP+AQ
0.07 (0.03, 0.21)
4.98
Dicko, 2011, SP+AQ
0.17 (0.14, 0.20)
14.03
Konate, 2011, SP+AQ
0.29 (0.26, 0.33)
14.49
Sesay, 2011, SP+AQ
0.51 (0.05, 5.59)
1.25
Zongo, unpub SPAQ
0.13 (0.10, 0.15)
13.76
Zongo, unpub DHAPQ
0.15 (0.13, 0.18)
13.88
D+L Overall (I-squared = 89.9%, p = 0.000)
0.17 (0.13, 0.22)
100.00
I-V Overall
0.20 (0.19, 0.22)
NOTE: Weights are from random effects analysis
.02
.2
.5
Rate Ratio
1
1.5
6
Protective efficacy against uncomplicated clinical malaria
= 83% (95% CI: 78% , 87%)
Source : Diadier Diallo et al, Oral presentation TEG symposium, Seasonal Malaria CHhemoprevention (SMC) For Malaria Control In
Sub-Saharan Africa: From research to policy , 29th March 2012
Impact of SMC on severe malaria,
anaemia and all-cause mortality
Protective effect
Endpoints
PE (95%CI)
Severe malaria
76 % (46% to 89%)
Anaemia Hb,8g/dl or PCV < 25%
20% (- 5% to 38%)
All-cause mortality (all regimens)
18% (-69% to 61%)
All-cause mortality (SP+AQ only)
34% (- 73% to 75%)
Source : Diadier Diallo et al, Oral presentation TEG symposium, Seasonal Malaria CHhemoprevention (SMC) For Malaria Control In
Sub-Saharan Africa: From research to policy , 29th March 2012
Efficacy of SMC in context of high ITN
coverage
LLIN + Placebo
No. of Incidence rate
cases
(95% CI)
Malaria
1656
(parasitaemia
> 5000)
Severe
malaria
All-cause
hospital
admissions
2.38 (2.27-2.50)
22
0.002
(0.001 – 0.003)
45
0.056
(0.042– 0.075)
LLIN + SMC
No. of Incidence rate
cases
(95% CI)
PE
(95%CI)
P value
<0.001
458
0.61 (0.56-0.67)
75
(72-77)
4
0.0004
(0.0001 – 0.0011)
82
(48–94)
0.002
27
0.033
(0.023 – 0.049)
41
(5–63)
0.03
Source: Konaté et al, 2011 and Dicko et al, 2011
Public Health Impact
This evidence , the basis for policy guidance on SMC
 WHO Policy Recommendation: Seasonal Malaria Chemoprevention (SMC) for Plasmodium falciparum
malaria control in highly seasonal transmission areas of the Sahel sub-region in Africa (2012). Global
Malaria Programme, World Health Organization
However, several unanswered questions on:
 The determinants of intervention uptake,
 Potential unintended benefits,
 Emerging limitation and
 Challenges arising from SMC delivery at scale.
Progress in evaluating SMC impact
• MSF
 Three year comprehensive evaluation of SMC underway
 Multiple locations and quite broad based
 Preliminary findings shared at ASTMH primarily focused on coverage and delivery strategies
 Review meeting planned in March 2016, to explore emerging research questions among
others
•PMI
 Evaluation of SMC implementation in 10 districts in Mali (preliminary findings shared at
ASTMH
•ACCESS SMC
 In progress
 Most comprehensive in scope
•BMGF Katsina SMC project
 Implementing SMC in 4 LGA over 2013, 2014 transmission seasons
 Preliminary reports developed and shared with donor
BMGF Katsina SMC project… highlights of findingsprovisional results
Summary of key indicators
Indicator
Baseline
2013
n,[95% CI
Endline 2014
n,[95% CI]
Household characteristics
Household ownership of a mobile phone
Proportion of household heads with no education
Proportion
of
households
insecticide treated net (ITN)
with
at
least
one
Proportion of households with at least two ITN
Proportion of children who slept inside a net the
previous night
55.3
53.3
[51.4-59.0]
[49.7-45.9]
68.4
69.8
[64.8-71.8]
[66.3-73]
83.7
74.6
[80.7-86.3]
[71.3-77.6]
76.2
66
[72.9-79.2]
[62.5-69.4]
80.7
73.1
[77.7-83.5]
[70.8-75.3]
BMGF Katsina SMC project… highlights of findingsprovisional results
Summary of key indicators
Indicator
Baseline
2013
n,[95% CI
Caregiver
experiences
chemoprevention
with
seasonal
Endline 2014
n,[95% CI]
malaria
Caregiver’s knowledge of
91
n/a
Caregiver took child for SMC
[88.6-92.9]
87.7
n/a
[85-89.9]
Caregiver took child for SMC at fixed point only
8.8
n/a
[6.7-11.3]
Caregiver’s children received SMC from home only
n/a
82.1 [78.9-85]
BMGF Katsina SMC project… highlights of findingsProvisional results
Summary of key indicators…contd.
Indicator
Baseline
2013
n,[95% CI
Endline 2014
n,[95% CI]
SMC coverage
Child received at least one dose of SMC (During last
cycle of SMC before the survey)
83.9
n/a
[82-85.7]
Child received at least 3 doses of SMC
61.8
n/a
[59.4-64.2]
Morbidity in children
Proportion of children with measured fever at time
of visit
Percentage
mRDT
Proportion
g/dl)
of
children
who
tested
positive
21.7
4
[18.6-25.3]
[2.6-5.9]
with
43.8
76.9
[39.8-47.8]
of
children
with
severe
anaemia
(<8.0
24.6
18.5
[21.3-28.3]
[15.6-21.8]
Consumer satisfaction
Among those who took their child for SMC,
percentage of caregivers who were satisfied with
services provided through:
Door to door mechanisms
Fixed post mechanisms
72.8%
37.7%
Average waiting time during:
Door to door distribution
-Fixed Post
21.9 Min
47.1 Min
Administrative vs. Actual Coverage
SMC 2014 Administrative Coverage
Second
First Cycle Cycle
Third
Cycle
Forth
Cycle
118%
94%
106%
93%
End Line Survey Coverage
Child received
at least one
dose of SMC
(During last
Child
cycle of SMC received at
before the least 3 doses
survey)
of SMC
LGAs
Dutsi
Maiadua
Total
86%
92%
89%
106%
93%
99%
104%
99%
83.9%
[82-85.7]
61.8%
[59.4-64.2]
11
BMGF Katsina SMC project… highlights of findingsProvisional results
FIGURE HIGHLIGHTING TRENDS OF REPORTED MALARIA CASES FROM 6 SENTINEL FACILITIES IN INTERVENTION AND ADJACENT NONE INTERVENTION LGAS
SOURCE: KATSINA MINISTRY OF HEALTH, KATSINA STATE PRIMARY HEALTH CARE, AND DEVELOPMENT AGENCY, BGMF KATSINA SMC PROJECT
BMGF Katsina SMC project… highlights of findingsProvisional results.
BMGF Katsina SMC project… highlights of findingsProvisional results.
BMGF Katsina SMC project… highlights of
findings…contd.
Lessons & limitations
Challenges in the case control study due to poor record keeping at household levels
and week follow up beyond the health facility
Resource limitations resulting in missed opportunities for more data collection and
analysis on resistance markers
Need to continue to support data collection in sentinel facilities
There may need to collect additional information on underlying determinants and
associated factors e.g. climatic information , nutritional status , immunization
coverage
Additional data points needed on trends in reported cases of severe malaria
Missed opportunity to implement a more robust analytic framework in order to go
beyond macro estimation of cost, to cost per delivery approach
Objective measurement of reported ADRs and Serious ADRs within the context of
existing reporting systems present a challenge for objective inference
Loss of data due to loss of household records and recall
Emerging issues from on-going evaluations
1. Evaluation methods
 Methodological issues associated in estimating public health impact
 Sampling methods
 Standardizing instruments across studies
 Design & Inferential challenges e.g related to interpretation of results of preventive
efficacy
 Standardization of SMC indicators
 Roles of MERG & WHO Surveillance TEG and modalities for engagement
 Defining paths of influence for channelling evidence based policy development




Role of WWARN, WHO Expert Review panel
Potential Donors
National Programmes
Research Community
Emerging issues from on-going evaluations
2. Responding to emerging research questions
 Potential alternative drug formulations for SMC
Randomized non-inferiority trial of dihydroartemisinin-piperaquine (DHP) compared with
sulfadoxine- pyrimethamine plus amodiaquine for SMC in Burkina Faso; Issaka Zongo et al ,
AAC Accepted Manuscript Posted Online 27 April 2015 Antimicrob. Agents Chemother.
doi:10.1128/AAC.04923-14 2015, American Society for Microbiology
 1499 children aged 3-59 months were randomized to receive SMC with SPAQ or
DHAPQ over three months.
 The primary outcome measure was the risk of clinical malaria (fever or a history of
fever with a parasite density of at least 3000/μL).
 A cohort of 250 children outside the trial was followed up as a control group.
Molecular markers of drug resistance were assessed.
Emerging issues from on-going evaluations
 Potential alternative drug formulations for SMC contd.
Results:
 The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds
ratio of 1.33 (95%CI 1.02,1.72).
Efficacy of SMC compared to the control group was 77% (67%, 32 84%) for DHAPQ and 83%
(74%,89%) for SPAQ.
pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in
parasites from children who received SPAQ than in children who received DHAPQ.
Both regimens were efficacious and well tolerated , although SPAQ higher levels of efficacy
(Cumulative hazard at 3 Months was 0.16 (SPAQ) and 0.21 (DHAPQ) , hazard ratio 1.29 (95% CI
0.97,1.71)
Potential implication
Implications for DHA & P reserve status for case management?
DHA very short acting & an Artemisinin derivative , implication Artemisinin resistance?
What other alternative preparation are in development?
Emerging issues from on-going evaluations.
2. Responding to emerging research questions…contd.
Modelling potential impact of extending age range to children 5-10yrs
Potential impact of extending age range to children 5-10yrs, Matthew Cairns et al. Oral
presentation at the 64th Annual meeting of the American society of tropical medicine &
hygiene ; October 2015.
Results:




SMC may be cost effective in a wider range of settings
Large number of additional children could potentially be protected
Indirect effect of SMC likely to be modest on overall burden but have the potential to effect
transmission in some settings
Extension cost effective in a wide range of settings. However may be different in areas of high and
areas with moderate to high transmission
Potential implications




What would be the potential effect on drug resistance?
Prioritization needed in light of continued limited resources, such as commodity availability?
Wider range of doses needed?
At what level of transmission would SMC in its present form (targeting U5s) fail to be cost effective
in impacting morbidity ?
Emerging issues from on-going
evaluations…contd.
2. Emerging Research questions…contd.
Potential rebound effect on withdrawal of SMC use
 Questions raised about potential effect on non continuance of SMC administration after long term
use .
 Does an increase case reporting to commensurate incidence levels appropriate for specific
transmission settings equate to rebound?

Though some relatively dated literature establishing the occurrence of rebound effect within the
context of IPTc, no documented literature on the presence or absence of rebound effect within the
context of SMC.
 Available data unclear and difficult to interpret.
 Several potential confounders to be considered in the available data e.g. compliance to
treatment advise , changes in or extension in transmission season, very limited evidence on
change in severity of occurrence of illness after period of SMC administration.
 What is the role of other underlying predisposing factors for severe malaria e.g. underlying moderate
to severe anaemia in confounding inference?
 Measurement of market impact of ACCESS SMC project
 Though there is no doubt the market impact of the ACCESS project , what modalities would be most
appropriate to objectively quantify the market impact of the project?
 How do we quantify in economic terms are the potential cost benefits of the the public health
impact of SMC?
Emerging issues from on-going
evaluations…contd.
2. Emerging Research questions…contd.
 Impact of SMC on parasite resistance profiles of existing molecules, and effect of preventive
efficacy
 Though significant work has been done in mapping resistance marker to SP more
generally and within the context of IPTp, very little is known on potential effect of
resistance markers and protective efficacy of SP/AQ within the context of SMC
 Study design for answering the question above taking due consideration for any ethical
limitations?
 Determinants and distribution patterns of serious ADRs
 Very few cases reported during the intervention, which Is a plus
As scale of implementation increases , do we have a sufficiently robust mechanism for
reporting and confirmation of reported serious ADR?
Does existing framework allow the profiling to establish the distribution of the
confirmed serious ADRs?
Acknowledgements
UNITAID
BMGF
MC Global technical & AFRO Programmes team
Malaria Consortium Nigeria team
Katsina state ministry of health
LSHTM
Other SMC Partner organizations ( MSH, CRS , SUA)
Thank you