Seasonal Malaria Chemoprevention: Emerging issues from on-going evaluations 1 Dr E.S.Baba Africa Technical Director Malaria Consortium

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 Protective efficacy against uncomplicated clinical malaria = 83% (95% CI: 78%, 87%) No protection Source : Diadier Diallo et al, Oral presentation TEG symposium, Seasonal Malaria CHhemoprevention (SMC) For Malaria Control In Sub-Saharan Africa: From research to policy, 29 th March 2012

Impact of SMC on severe malaria, anaemia and all-cause mortality Protective effect EndpointsPE (95%CI) Severe malaria76 % (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, 29 th March 2012

LLIN + PlaceboLLIN + SMC No. of cases Incidence rate (95% CI) No. of cases Incidence rate (95% CI) PE (95%CI) P value Malaria (parasitaemia > 5000) ( ) ( ) 75 (72-77) <0.001 Severe malaria (0.001 – 0.003) ( – ) 82 (48–94)0.002 All-cause hospital admissions (0.042– 0.075) (0.023 – 0.049) 41 (5–63) 0.03 Efficacy of SMC in context of high ITN coverage 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 findings- provisional results

BMGF Katsina SMC project… highlights of findings- Provisional results

Administrative vs. Actual Coverage 11 SMC 2014 Administrative Coverage End Line Survey Coverage First Cycle Second Cycle Third Cycle Forth Cycle Child received at least one dose of SMC (During last cycle of SMC before the survey) Child received at least 3 doses of SMC LGAs Dutsi86%106%118%106% Maiadua92%93%94%93% Total89%99%104%99% 83.9% [ ] 61.8% [ ]

BMGF Katsina SMC project… highlights of findings- Provisional 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 findings- Provisional 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: /AAC , 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 64 th Annual meeting of the American society of tropical medicine & hygiene ; October 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