MALARIA ELIMINATION AND ERADICATION: HOPES, CHALLENGES, BARRIERS

Transcription

1 MALARIA ELIMINATION AND ERADICATION: HOPES, CHALLENGES, BARRIERS 14 th Conference of the International Society of Travel Medicine 28 May 2015 Quebec, Canada Alan Magill MD Director, Malaria Bill & Melinda Gates Foundation

2 CONFLICT OF INTEREST DECLARATION The opinions presented in this lecture are those of the author and do not reflect the official views of the Bill & Melinda Gates Foundation. Dr. Magill has no financial conflicts of interests to declare. Bill & Melinda Gates Foundation 2

3 MALARIA ELIMINATION AND ERADICATION Hopes The past 15 years: Half way there with current tools, current strategies The next 15 years to End Malaria with Current tools, new strategies Challenges Barriers Bill & Melinda Gates Foundation 3

4 Bill & Melinda Gates Foundation 4

5 WHAT A DIFFERENCE 15 YEARS MAKES million acute malaria cases 2 million deaths No Long Lasting Insecticide treated Nets (LLINs). No Indoor Residual Spray (IRS) Widespread chloroquine and sulfadoxine-pyrimethamine (SP) resistance and no ACTs. Limited diagnostic testing available. No IPTp or SMC Limited new product pipeline. No Global Fund and PMI. Limited political will and financial resources million acute cases 627,000 deaths 136 million new LLINs distributed 135 million people protected by IRS. 331 million ACT courses were procured by the public and private sectors in endemic countries. mrdts and Test, Treat, and Track (T3) policy. Targeted interventions for highest risk populations: IPTp, SMC Promising pipeline of diagnostics, drugs, vaccines, delivery strategies and innovative vector control tools. The Global Fund and the President s Malaria Initiative disburse > $1 Billion/Year Mortality rates decreased by 45% globally: 3.3M lives saved, 90% in under 5 in Africa Today s Malaria Eradication Goals and Planning was enabled by the Success of the Past Decade Bill & Melinda Gates Foundation 5

6 Bill & Melinda Gates Foundation 6

7 Bill & Melinda Gates Foundation 7

8 THE CURRENT MALARIA CONTROL TOOLBOX CURRENT TOOLS Pyrethroid only LLINs Insecticides CURRENT STRATEGIES Universal distribution 4 classes available used in limited indoor residual spray (IRS) 1 st generation mrdts Increased use enabling test, treat, and track (T3) Artemisinin combination treatments (ACTs) Sulfadoxine + pyrimethamine (SP) Amodiaquine-+ SP Treat symptomatic people seeking care Targeted to pregnant women for IPTp Seasonal Malaria Chemoprophylaxis Bill & Melinda Gates Foundation 8

9 THE CURRENT CONTROL PARADIGM Focus is disease burden reduction A limited set of Interventions must be continuously applied at high coverage and maintained indefinitely. Bill & Melinda Gates Foundation 9

10 P. FALCIPARUM CONTROL PARADIGM Not infected Asymptomatic LLINs IRS Mosquitoes infected Infected Asymptomatic Infected Symptomatic Three types of people in malaria endemic areas Ignored Transmission reservoir remains untouched RDT + ACT No effect on gametocytes Goal: Prevent death and severe disease Interventions Outcomes: Infected Asymptomatic reservoir Bill & Melinda Gates Foundation 10

11 THREE POTENTIAL FUTURE TRAJECTORIES FOR MALARIA Global annual malaria parasite incidence Resurgence Current Tools New strategies New Tools New strategies Bend the Curve Sustain progress Accelerate to zero 2040 and beyond Bill & Melinda Gates Foundation 11

12 RESURGENCE OF MALARIA IS THE ONLY ASSURED FUTURE WHY ERADICATION IS THE ONLY SUSTAINABLE FUTURE Resurgence of malaria predictability occurs when current control efforts fail Cohen, J., et. al., Malaria Resurgence. Malar J Apr 24;11:122 Bill & Melinda Gates Foundation 12

13 MALARIA ERADICATION: AN AUDACIOUS GOAL Any goal short of eradicating malaria is accepting malaria; it s making peace with malaria; it s rich countries saying: We don t need to eradicate malaria around the world as long as we ve eliminated malaria in our own countries. That's just unacceptable. Melinda Gates, 2007 Bill & Melinda Gates Foundation 13

14 MALARIA ELIMINATION AND ERADICATION Hopes The past 15 years: Half way there with current tools, current strategies The next 15 years to End Malaria with Current tools, new strategies Challenges Barriers Bill & Melinda Gates Foundation 14

15 ACCELERATE TO ZERO We can accelerate the trajectory to malaria eradication by concurrently achieving three goals: 1) Identifying the human reservoir of infection in asymptomatic persons + 2) Eliminating the human reservoir + 3) combined with geographically and temporally targeted transmission prevention and strengthened surveillance and response Complete Detection: Detect the human parasite reservoir Complete Cure: Eliminate the human parasite reservoir Complete Prevention: Effective transmission prevention Eradication Mobilize for Action Bill & Melinda Gates Foundation 15

16 ACCELERATE TO ZERO We can accelerate the trajectory to malaria eradication by concurrently achieving three goals: 1) Identifying the human reservoir of infection in asymptomatic persons + 2) Eliminating the human reservoir + 3) combined with geographically and temporally targeted transmission prevention and strengthened surveillance and response Complete Detection: Detect the human parasite reservoir Complete Cure: Eliminate the human parasite reservoir Complete Prevention: Effective transmission prevention Eradication Mobilize for Action Bill & Melinda Gates Foundation 16

17 MALARIA ERADICATION IS THE ELIMINATION OF PLASMODIUM PARASITES FROM THE HUMAN POPULATION Malaria Eradication as defined in 1963 by WHO: Malaria eradication is to extirpate the roots of the infection the parasites from a given population so that the mosquitoes will find none to transmit. Emilio Pampana, A Textbook of Malaria Eradication. Oxford University Press Bill & Melinda Gates Foundation 17

18 COMPLETE DETECTION OF THE HUMAN PARASITE RESERVOIR WHY PARASITES IN PEOPLE ARE IMPORTANT Mosquitoes Humans Lifespan < 30 days > 70 years Duration of parasitemia < 5 days Up to 15 years Travel distance 1 km flight range Circle the globe Parasite biomass < 0.1% > 99.9% Bill & Melinda Gates Foundation 18

19 INTRODUCTION OF MALARIA RDTS Malaria Diagnostics Technology and Market Landscape. 2 nd edition. UNITAID July 2014 Bill & Melinda Gates Foundation 19

20 SCALE UP OF MALARIA RDTS Malaria Diagnostics Technology and Market Landscape. 2 nd edition. UNITAID July 2014 Bill & Melinda Gates Foundation 20

21 T3: TEST, TREAT, AND TRACK Universal coverage. Every suspected malaria case is tested with a quality diagnostic. Every confirmed case is treated with a quality assured ACT. Every treated case is tracked through timely and accurate surveillance systems. Information to guide policy and operational decisions Bill & Melinda Gates Foundation 21

22 TARGETING THE RESERVOIR OF PARASITES IN ASYMPTOMATIC PEOPLE MAY BE NECESSARY Symptomatic persons seeking care are the tip of the iceberg Higher parasitemias Microscopy and RDT (+) Asymptomatic persons who do not seek care are the majority of people in malaria endemic areas. Infected Lower Parasitemias Below the limit of detection of microscopy or current RDTs Not Infected True Negative Bill & Melinda Gates Foundation 22

23 CHALLENGES: RELATIVE CONTRIBUTION OF SUBMICROSCOPIC AND MICROSCOPIC PARASITEMIA TO TRANSMISSION IS UNKNOWN Low transmission setting Parasites/ul HRP2 levels symptomatic asymptomatic LOD of best RDT today > 100 p/ul asymptomatic > 800pg/ml > 10 p/ul 10% > 80pg/ml Assumption: HRP2 test with sensitivity of 8pg/ml > 1 p/ul 20% > 8pg/ml would detect 100% of infectious reservoir Transmission level (infectiousness)? 50% Bill & Melinda Gates Foundation 46

24 The Future Message. Complete Cure of the asymptomatic father and mother to save the life of the child? Bill & Melinda Gates Foundation 24

25 ACCELERATE TO ZERO We can accelerate the trajectory to malaria eradication by concurrently achieving three goals: 1) Identifying the human reservoir of infection in asymptomatic persons + 2) Eliminating the human reservoir + 3) combined with geographically and temporally targeted transmission prevention and strengthened surveillance and response Complete Detection: Detect the human parasite reservoir Complete Cure: Eliminate the human parasite reservoir Complete Prevention: Effective transmission prevention Eradication Mobilize for Action Bill & Melinda Gates Foundation 25

26 CLINICAL (INCOMPLETE) CURE VERSUS PARASITOLOGICAL (COMPLETE) CURE CLINICAL CURE Resolution of symptoms and prevention of severe disease and death. Clinical cure with an ACT only targets asexual stage parasites. Mature sexual stage 5 P. falciparum gametocytes in peripheral blood are not affected by ACTs. COMPLETE CURE Resolution of symptoms and prevention of severe disease and death plus complete parasitological cure. Clinical cure with an ACT for asexual stage parasites + single dose primaquine for sexual stage 5 P. falciparum gametocytes Bill & Melinda Gates Foundation 26

27 MIND THE GAP: STAGE 5 P. FALCIPARUM GAMETOCYTES 4AQ = 4 aminoquinolines such as chloroquine only effective on stage 1 and 2 Pf gametocytes Artemisinins = Artesunate, Dihydroartemisinin effective on stage 1-4 Pf gametocytes 8AQ = 8 aminoquinolines. Primaquine and tafenoquine are effective on stage 5 gametocytes Bill & Melinda Gates Foundation 27

28 Malaria Parasite Lifecycle Bill & Melinda Gates Foundation 28

29 Malaria Parasite Lifecycle Bill & Melinda Gates Foundation 29

30 SERCAP SINGLE EXPOSURE RADICAL CURE AND PROPHYLAXIS Product Characteristics: Single fixed dose combination tablet Radical cure of Pf and Pv malaria species infecting humans Affordable Long duration/ post-treatment prophylaxis Transmission blocking All lifecycle stages High barrier to resistance DAY 1 DAY 2 DAY 3 Bill & Melinda Gates Foundation 30

31 MALARIA ELIMINATION AND ERADICATION Hopes Current tools, current strategies Current tools, new strategies Challenges Barriers Bill & Melinda Gates Foundation 31

32 CHALLENGES Resistance: Emerging and spreading resistance to drugs and insecticides. Residual Transmission as defined as transmission remaining after LLINs and IRS. Heterogeneity increasing in settings where malaria prevalence has been reduced. Bill & Melinda Gates Foundation 32

33 CHALLENGES: EMERGING RESISTANCE Artemisinin Resistance in the Greater Mekong Subregion Pyrethroid resistance in Sub Saharan Africa Bill & Melinda Gates Foundation 33

34 EMERGING RESISTANCE: OUR WITS VERSUS THEIR GENES Malaria interventions should be chosen, tested, and implemented to minimize a detrimental evolutionary response (resistance). Natural selection of resistance genes is favored by genetic diversity, extended time and large population size. A selective pressure will reliably select out variants that survive in the new environment Bill & Melinda Gates Foundation 34

35 EMERGING RESISTANCE Lots of parasites Treat sick people Multiple times Treat during transmission season Greatest genetic diversity Greatest population, 1% parasitemia = parasites Bad Drugs Poor compliance Multiple doses No DOT Under dose kids and pregnant women Poor GI absorption Not enough drug Bill & Melinda Gates Foundation 35

36 COUNTERING EMERGING RESISTANCE Treat well people Treat during dry season Genetic diversity bottleneck Population size bottleneck, parasites Few parasites Enough drug Good Drugs SERCaP Directly observed Rx Properly dose kids and pregnant women Improved GI absorption Bill & Melinda Gates Foundation 36

37 DRY SEASON INTERVENTION Target the numerical, genetic, and species bottlenecks Reduced larval habitat = fixed few and findable Reduced or zero adult mosquitoes Anopheline species shifts Decreased number of people infected Fewer parasites in each infected person Healthier people (increased Hgb) Better road access Bill & Melinda Gates Foundation 37

38 MALARIA MOSQUITO POPULATIONS RESISTANT TO ALL CLASSES OF INSECTICIDE NOW REPORTED Deltamethrin LT 50 of 4 hours for Tissalé strain versus < 2 min for sensitive Kisumu strain. Link to commercial use of insecticides for agriculture? Constant et al, EID, 2012 Bill & Melinda Gates Foundation 38

39 Bill & Melinda Gates Foundation 39

40 RETROSPECTIVE ANALYSIS OF CHANGE IN INSECTICIDE USE MAY PROVIDE BEST EVIDENCE FOR IMPACT OF RESISTANCE Kigozi et al, PLOS One, 2012 Bill & Melinda Gates Foundation 40

41 WHAT CAN WE DO NOW? COMBINATION OF IRS AND LLINS Courtesy Hilary Ranson Little consensus of the value of combining LLINs and IRS likely to be very context specific. and insufficient knowledge of patterns of cross resistance Bill & Melinda Gates Foundation 41

42 WHAT CAN WE DO NOW? ROTATION OF IRS Courtesy Hilary Ranson Can rotations of IRS restore insecticide susceptibility? Very little known about fitness costs or cross resistance profiles Bill & Melinda Gates Foundation 42

43 WHAT CAN WE DO NOW? NEXT GENERATION LLINS Guidelines on how to evaluate these new products under development Agreement on standard methodologies to measure the intensity of resistance and define threshold of operationally significant resistance Clinical trials measuring their effectiveness in areas of pyrethroid resistance Courtesy Hilary Ranson Bill & Melinda Gates Foundation 43

44 WHAT CAN WE DO NOW? EFFECTIVE STEWARDSHIP Courtesy Hilary Ranson We ban monotherapy in drugs, why not insecticides? Bill & Melinda Gates Foundation 44

45 EMERGING RESISTANCE: OUR WITS VERSUS THEIR GENES Single-axis pressure (i.e. universal distribution of chloroquine or LLINs with a single insecticide) is the worst type of selective pressure from an evolutionary perspective. When using interventions that could drive resistance, hitting the parasite population as hard and fast as possible to achieve local elimination is a key to preventing the emergence of resistance. Bill & Melinda Gates Foundation 45

46 ACCELERATE TO ZERO We can accelerate the trajectory to malaria eradication by concurrently achieving three goals: 1) Identifying the human reservoir of infection in asymptomatic persons + 2) Eliminating the human reservoir + 3) combined with geographically and temporally targeted transmission prevention and strengthened surveillance and response Complete Detection: Detect the human parasite reservoir Complete Cure: Eliminate the human parasite reservoir Complete Prevention: Effective transmission prevention Eradication Mobilize for Action Bill & Melinda Gates Foundation 46

47 Transmission is an event When? Where? Bill & Melinda Gates Foundation 47

48 THE ENTOMOLOGICAL LABYRINTH: VECTOR SPECIES AND BEHAVIOR HETEROGENEITY: An. dirus MYANMAR An. minimus An. maculatus Anthropophily Outdoor 33% An. dirus Cow 6% Outdoor 33% Outdoor 45% Cow 6% Indoor 61% An. minimus Cow 17% Endophily Outdoor 45% Cow 17% Indoor 38% An. maculatus Outdoor 46% Cow 29% Outdoor 46% Cow 29% Indoor 25% DIRUS MINIMUS Indoor LC Outdoor LC CDC light trap Indoor 61% Indoor 38% Indoor 25%. dirus Cow 6% An. minimus An. maculatus An. minimus Outdoor 45% Cow 17% Cow 29% Outdoor An. 46% minimus An. maculatus MACULATUS Indoor 61% Zoophily Indoor 38% Indoor 25% An. maculatus Exophily Courtesy Franois Nosten Bill & Melinda Gates Foundation 48

49 RESIDUAL TRANSMISSION MIND THE GAP Durnez & Cossemans: Residual Transmission of Malaria Bill & Melinda Gates Foundation 49

50 CHALLENGES: THE RESIDUAL TRANSMISSION GAP Times and places where LLINs and IRS will not prevent transmission. Early evening and early morning Outside the house + human behaviors Species shifts An. arabiensis becomes a significant vector when An. Gambiae and An. funestus decline Behavior Shifts within species complexes Mosquito biting at an earlier hour Biting place Resting place Bill & Melinda Gates Foundation 50

51 PREVENT TRANSMISSION Develop and deploy interventions to prevent transmission by breaking the transmission cycle Vector Control Prevent Transmission Vaccines Drugs Bill & Melinda Gates Foundation 51

52 IVCC PUBLIC HEALTH INSECTICIDE PIPELINE AI Screen AI Screen AI Screen Secondary Screen Secondary Screen Optimisation Secondary Screen Optimisation Early dev Optimisation Early dev Development and regulatory Early dev Development and regulatory Registration Development and regulatory Registration Registration New Active Ingredients Screen in Negotiation Backup to portfolio Secondary Screen Optimisation Early dev Repurposing Chlorfenapyr Repurposing Product Devt. Product Devt. WHOPES Phase II & III WHOPES Phase II & III Repurposed Agricultural AIs Bill & Melinda Gates Foundation 52

53 NEW PARADIGMS Duo-nets: 2 plus active ingredients Spatial Repellents Attractive toxic sugar baits Genetically modified mosquitoes (HEGs) Biological control Novel personal protection Anopheline extinction with entomopathogenic fungi Achee NL et al. Spatial repellents: from discovery and development to evidence-based validation. Malar J May 14;11:164. Bill & Melinda Gates Foundation 53

54 Eave Tubes Bill & Melinda Gates Foundation 54

55 CHALLENGES: HETEROGENEITY FROM UNIVERSAL COVERAGE TO EFFECTIVE COVERAGE GFATM Proposal called for Universal Coverage with LLINs in all at risk areas However, risk was poorly defined and vector control was not efficiently targeted to places where it would have impact. In addition, An. albimanus, the main vector in Haiti, is an outdoor biter and rester making LLINs a suboptimal tool for prevention Recent CDC case control study that found no difference in bed net use between cases and controls (L. Slutsker pers. Comm.) Bill & Melinda Gates Foundation 55

56 THINK GLOBAL, ACT LOCAL: HOW TO DEFINE TO OPTIMAL INTERVENTION MIX AT THE RIGHT SCALE Everything about malaria is so molded and altered by local conditions that it becomes a thousand different diseases and epidemiological puzzles. Like chess, it is played with a few pieces, but is capable of an infinite variety of situations. Lewis Hackett 1937 Bill & Melinda Gates Foundation 56

57 MALARIA EXISTS IN A COMPLEX AND HETEROGENEOUS SYSTEM Ecology Epidemiology Biology Geographic micro heterogeneity Vector heterogeneity Human immune response heterogeneity Economic and structural factors Political factors Socio-cultural factors Bill & Melinda Gates Foundation 57

58 GLOBAL IMPACT WILL REQUIRE TAILORED LOCAL PROBLEM SOLVING Before DDT, malariologists were trained as problem solvers, after DDT malariologists were trained as solution implementers. José Antonio Nájera Bill & Melinda Gates Foundation 58

59 ACCELERATE TO ZERO We can accelerate the trajectory to malaria eradication by concurrently achieving three goals: 1) Identifying the human reservoir of infection in asymptomatic persons + 2) Eliminating the human reservoir + 3) combined with geographically and temporally targeted transmission prevention and strengthened surveillance and response Complete Detection: Detect the human parasite reservoir Complete Cure: Eliminate the human parasite reservoir Complete Prevention: Effective transmission prevention Eradication Mobilize for Action Bill & Melinda Gates Foundation 59

60 CONCURRENT DEPLOYMENT OF DRUGS AND PREVENT TRANSMISSION INTERVENTIONS Quinine plus insecticide most certainly lowered the sick rate much faster than quinine alone, an observation which has been repeated over and over and over again. Park Ross 1936 Bill & Melinda Gates Foundation 60

61 THE RISE AND FALL OF MALARIA IN A WEST AFRICAN RURAL COMMUNITY, DIELMO, SENEGAL, FROM 1990 TO 2012: A 22 YEAR LONGITUDINAL STUDY. Lancet Infect Dis Jun;14(6): Entomological inoculation rate ranged from infected bites per person per year in 1990 to in 2000, and 7 6 in Parasite prevalence in children declined from 87% in 1990 to 0 3 % in In adults, it declined from 58% to 0 3%. The greatest changes were associated with the replacement of chloroquine with ACTs and the introduction of LLINs. Current tools and strategies (control) are very effective. Rapid decline of clinical immunity allows rapid detection and treatment of novel infections and thus has a key role in sustaining effectiveness of combining artemisininbased combination therapy and ITNs despite increasing pyrethroid resistance in An. gambiae. Bill & Melinda Gates Foundation 61

62 Lancet Infect Dis Jun;14(6): Bill & Melinda Gates Foundation 62

63 FUTURE P. FALCIPARUM ERADICATION PARADIGM Not infected Asymptomatic Infected Asymptomatic LLINs IRS + New tools Target Population ACT + PQ Transmission reservoir eradicated Complete Prevention (Vector +/- Vaccine) Infected Symptomatic Three types of people RDT + ACT + PQ Kills gametocytes Goal: Prevent death and severe disease & interrupt transmission in malaria endemic areas Interventions Outcomes: Uninfected Bill & Melinda Gates Foundation 63

64 MALARIA ELIMINATION AND ERADICATION Hopes Current tools, current strategies Current tools, new strategies Challenges Barriers Bill & Melinda Gates Foundation 64

65 POLITICAL AND PEOPLE BARRIERS All geographies Lack of coordination Lack of commitment High Burden geographies Bad and ineffective governance Low burden geographies Out of site, out of mind Remote & hard to reach Bill & Melinda Gates Foundation 65

66 FINANCIAL BARRIERS Projected costs to maintain control measures are immense: An estimated US$ 5.1 billion is needed every year between 2011 and 2020 to achieve universal access to malaria interventions. World Malaria Report 2012 Bill & Melinda Gates Foundation 66

67 LET S FINISH THE JOB Eradication is Saving lives now, Saving lives forever Eradication is biologically possible and the only sustainable goal Eradication will require new concepts, new tools, and new strategies. The next decade will be a period of intense experimentation and learning, leading to a rapidly evolving policy environment for new tools and technologies. An end of one-size-fits-all approach. Bill & Melinda Gates Foundation 67

68 TRENDS FOR TRAVEL MEDICINE Decreasing prevalence in many areas When will this translate into changing practice? No chemoprophylaxis recommended Alternate strategies such as SBET Increasing malaria free zones in endemic countries Increasing use of chemoprophylaxis in endemic countries Individual travelers Elimination efforts Bill & Melinda Gates Foundation 68

69 SEASONAL MALARIA CHEMOPREVENTION Bill & Mlinda Gates Foundation 69

70 Bill & Melinda Gates Foundation 70

71 DAVID SHLIM S ISTM PRESIDENTIAL MISSION STATEMENT The ideal form of travel medicine would be the kind that makes it unnecessary Bill & Melinda Gates Foundation 71

72 Our vision A world free of malaria Bill & Melinda Gates Foundation 72