ASSURING EFFECTIVE ANTIMALARIAL TREATMENT:

A PLAN FOR MOVING FORWARD

ASSURING EFFECTIVE ANTIMALARIAL TREATMENT:

A PLAN FOR MOVING FORWARD

CAROL HOPKINS SIBLEYATELIER PALUDISME

MADAGASGARMARCH 19, 2007

CAROL HOPKINS SIBLEYATELIER PALUDISME

MADAGASGARMARCH 19, 2007

MALARIA MORTALITY IN AFRICA HAS INCREASED

MALARIA MORTALITY IN AFRICA HAS INCREASED

WHAT ARE THE PRACTICAL CONSEQUENCES?WHAT ARE THE PRACTICAL CONSEQUENCES?

ESTIMATED ALL- CAUSE CHILD MORTALITYSNOW, TRAPE AND MARSH, 2001

ESTIMATED ALL- CAUSE CHILD MORTALITYSNOW, TRAPE AND MARSH, 2001

ESTIMATED MALARIA MORTALITYESTIMATED MALARIA MORTALITY

WHY THE OPPOSITE TRENDS ?WHY THE OPPOSITE TRENDS ?

MALARIA

ALL CAUSE

RESISTANCE TO THREECOMMON

INEXPENSIVE WELL TOLERATED

DRUGS HAS EVOLVED

RESISTANCE TO THREECOMMON

INEXPENSIVE WELL TOLERATED

DRUGS HAS EVOLVED

• CHLOROQUINE

• SULFADOXINE-PYRIMETHAMINE

• MEFLOQUINE

• CHLOROQUINE

• SULFADOXINE-PYRIMETHAMINE

• MEFLOQUINE

WHO/RBMREPORT

PASCAL RINGWALD

2004

WHO/RBMREPORT

PASCAL RINGWALD

2004

WHO SUMMARYWHO SUMMARY

2005 MAP OF RESISTANCE 3 CURRENT DRUGS

2005 MAP OF RESISTANCE 3 CURRENT DRUGS

HOW DO WE DEFINE DRUG RESISTANCEHOW DO WE DEFINE DRUG RESISTANCE

• IN VIVODOES A PROPERLY TREATED PATIENT RECOVER?

• IN VITROHOW SENSITIVE IS A PARASITE ISOLATE

TO DRUG ?• MOLECULAR

ARE MUTATIONS ASSOCIATED WITH RESISTANCE COMMON IN THE REGION?

• PHARMACOKINETICSDID THE PATIENT HAVE A CORRECT LEVEL OF

DRUG IN THE BLOOD?

• IN VIVODOES A PROPERLY TREATED PATIENT RECOVER?

• IN VITROHOW SENSITIVE IS A PARASITE ISOLATE

TO DRUG ?• MOLECULAR

ARE MUTATIONS ASSOCIATED WITH RESISTANCE COMMON IN THE REGION?

• PHARMACOKINETICSDID THE PATIENT HAVE A CORRECT LEVEL OF

DRUG IN THE BLOOD?

PATIENT RESPONSE TO TREATMENT FOLLOW UP 28 DAYS ++

SYMPTOMS AND PARASITES GONEALL 28 DAYS

SYMPTOMS REAPPEAR WITHIN 3 DAYSWITHIN 28 DAYS

PARASITES ONLY REAPPEARWITHIN 28 DAYS

PATIENT RESPONSE TO TREATMENT FOLLOW UP 28 DAYS ++

SYMPTOMS AND PARASITES GONEALL 28 DAYS

SYMPTOMS REAPPEAR WITHIN 3 DAYSWITHIN 28 DAYS

PARASITES ONLY REAPPEARWITHIN 28 DAYS

HOW DO WE MONITOR DRUG EFFICACY?

HOW DO WE MONITOR DRUG EFFICACY?

ETF

LPF

LTF

ACPR

WHAT FACTORS INFLUENCE THE CLINICAL RESPONSE?

WHAT FACTORS INFLUENCE THE CLINICAL RESPONSE?

• PRIOR EXPOSURE• PRIOR EXPOSURE

• POSSIBILITY OF REINFECTION• POSSIBILITY OF REINFECTION

• NUTRITIONAL STATUS• NUTRITIONAL STATUS

• OTHER INFECTIONS• OTHER INFECTIONS

• OTHER DRUG USE• OTHER DRUG USE

HOW IS THIS INFORMATION USED?HOW IS THIS INFORMATION USED?

WHO GUIDELINES- 2006

>15% CLINICAL/PARASTIOLOGICAL FAILURES-

CHANGE TO NEW DRUG

WHO GUIDELINES- 2006

>15% CLINICAL/PARASTIOLOGICAL FAILURES-

CHANGE TO NEW DRUG

WHAT HAVE WE LEARNED ABOUT THE EVOLUTION OF DRUG RESISTANCE?

WHAT HAVE WE LEARNED ABOUT THE EVOLUTION OF DRUG RESISTANCE?

• TWO IMPORTANT PHASES OF RESISTANCE• SELECTION OF RESISTANCE• PROPAGATION OF RESISTANCE

• TWO IMPORTANT PHASES OF RESISTANCE• SELECTION OF RESISTANCE• PROPAGATION OF RESISTANCE

FOCI OF CLINICAL RESISTANCE ARISE RELATIVELY RARELY TO CQ AND SP

BUT RESISTANCE STRAINS CAN RAPIDLY PREDOMINATE

BUT RESISTANCE STRAINS CAN RAPIDLY PREDOMINATE

1978

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1978

1981

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1982

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1978

1983

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1984

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1985

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1986

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1987

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1988

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

1989

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

FIRST REPORTS OF CHLOROQUINE RESISTANCE IN AFRICA

ADAPTED FROM CHARMOT ET AL, 1991

ADAPTED FROM CHARMOT ET AL, 1991

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

HUMAN MIGRATION

IS KEY TO

RESISTANCE SPREAD

DATA SUMMARIES ARE BY COUNTRYDATA SUMMARIES ARE BY COUNTRY

BUT …. RESISTANCE IS NOT UNIFORM WITHIN COUNTRIES

BUT …. RESISTANCE IS NOT UNIFORM WITHIN COUNTRIES

TREATMENT FAILURE = RESISTANCE?TREATMENT FAILURE = RESISTANCE?

DOSE OF DRUG ADEQUATE?DOSE OF DRUG ADEQUATE?

YESYESNONO

MARKERS OF DRUG

RESISTANCE?

MARKERS OF DRUG

RESISTANCE?

HIGHER THANSTANDARD?

HIGHER THANSTANDARD?

GENETIC ANALYSIS

OF PARASITE

GENETIC ANALYSIS

OF PARASITE

IN VITRO RESPONSE

OF PARASITES TO DRUGS

IN VITRO RESPONSE

OF PARASITES TO DRUGS

MAY NOT BE

RESISTANCE

MAY NOT BE

RESISTANCE

RESISTANCE?RESISTANCE?

INFECTED BLOOD + PBS

CF11 column

RESUSPEND IN MEDIUM AND SERUM

INCUBATE 37 O C 24-36 H

MEASURE GROWTH

DRUG CONCENTRATION

ABCDEFGHPA

TIEN

T IS

OLA

TE

CALCULATEDRUG RESPONSE

MEASUREMENT OF PARASITE DRUG SENSITIVITY IN VITRO

MEASUREMENT OF PARASITE DRUG SENSITIVITY IN VITRO

AVOIDS MAJORHOST FACTORS:

IMMUNITYNUTRITION

0102030405060708090

100110120

0 1E -9 1E -8 1E -7 1E -6 1E -5 [PYRIMETHAMINE

REL

ATIV

E G

RO

WTH

Y5D3S108S108NS108N + N51IF.S. 7 E4F.S. C1

IC50 3.4 x 10-8 IC50 4 x 10-7 IC50 9 x 10-7

DRUG RESPONSE OF FIELD SAMPLES SCREENED BY GROWTH IN VITRO

DRUG RESPONSE OF FIELD SAMPLES SCREENED BY GROWTH IN VITRO

MOLECULAR MARKERS OF DRUG RESISTANCEMOLECULAR MARKERS OF DRUG RESISTANCE

CQ Pfcrt SNPsPfmdr1 SNPs

SP Pfdhfr SNPsPfdhps SNPs

MEF Pfmdr1 COPY NUMBER

CQ Pfcrt SNPsPfmdr1 SNPs

SP Pfdhfr SNPsPfdhps SNPs

MEF Pfmdr1 COPY NUMBER

ONE GENE IS NECESSARY FOR CQ-RIn P. falciparum

ONE GENE IS NECESSARY FOR CQ-RIn P. falciparum

But probably is not sufficient! But probably is not sufficient!

PYRS Asn Cys Ser Ile

51 59 Pf DHFR 108 164

Asn Cys ASN Ile

ILE Cys ASN Ile

ILE ARG ASN Ile

DHFR MUTATIONS THAT CONFER PYRIMETHAMINE RESISTANCE IN FIELD ISOLATES

DHFR MUTATIONS THAT CONFER PYRIMETHAMINE RESISTANCE IN FIELD ISOLATES

ILE ARG ASN LEU

PYRR

Mugittu et al 2004

MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE

MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE

DHFRAND DHPS

ALLELESTANZANIA2002-2004

DHFRAND DHPS

ALLELESTANZANIA2002-2004

TRIPLE MUTANT dhfrDOUBLE MUTANT dhps

TRIPLE MUTANT dhfrDOUBLE MUTANT dhps

Pfmdr1 COPY NUMBER IS MARKER OF MEFLOQUINER

Pfmdr1 COPY NUMBER IS MARKER OF MEFLOQUINER

MQR

MQS

1.0

1.1

2.0

2.3

Wongsrichanalai C., 2005

MOLECULAR MARKERS OR

IN VITRO ANALYSIS GOOD SURROGATES

TO PREDICT CLINICAL TREATMENT FAILURE?

MOLECULAR MARKERS OR

IN VITRO ANALYSIS GOOD SURROGATES

TO PREDICT CLINICAL TREATMENT FAILURE?

KEY QUESTION:KEY QUESTION:

STUDIES IN PATIENTS AREEXPENSIVE

ANDTIME CONSUMING

STUDIES IN PATIENTS AREEXPENSIVE

ANDTIME CONSUMING

Mugittu et al 2004

MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE

MOLECULAR MARKERS CAN ASSESS PARASITE DRUG RESISTANCE

DHFRAND DHPS

ALLELESTANZANIA2002-2004

DHFRAND DHPS

ALLELESTANZANIA2002-2004

TRIPLE MUTANT dhfrDOUBLE MUTANT dhps

CLINICAL FAILURE

MOLECULAR MARKERS OF SP RESISTANCECORRLEATE WITH CLINICAL FAILURE

MOLECULAR MARKERS OF SP RESISTANCECORRLEATE WITH CLINICAL FAILURE

0 0.1 0.2 0.3 0.4PREVALENCE OF "TRIPLE/DOUBLE"

0

0.2

0.4

0.6

0.8

1.0C

LIN

ICAL

FA

ILU

RE

Observed-14Observed-28Observed-42Fit-14Fit-28Fit-42

0.5 0.6

PREV

ALE

NC

EO

F R

ESIS

TAN

T P[

AR

ASI

TES

(%)

10%

50%

100%

90%

90-93 93-95 95-97 97-99 00-02UNTIL LATE 80s

PM/SD INTRODUCED KILIFI, KENYA

10%

20%

30%

50%

HOW CAN WE FIT THIS TOGETHER?HOW CAN WE FIT THIS TOGETHER?

TR

IPL

E M

UT

AN

TS

DH

FR

PM R

ESIS

TANCE

in vi

tro

50%

30%

20%

10%

60%

70%

XX

X

% T

RIPL

E M

UTAN

TS

PM/SD RESISTANCEin vi

vo

DATA FROMALEXIS NZILA

EDWARD MBERU KAMAUCAROL SIBLEY

EARLY WARNINGS OF CLINICAL FAILURE

WHAT HAVE WE LEARNED?WHAT HAVE WE LEARNED?• RESISTANCE ARISES RARELY, BUT

SPREADS RELATIVELY QUICKLY

• CLINICAL TREATMENT FAILURE IS THE LAST STEP IN A LONG SERIES OF CHANGES

• EARLY WARNING OF RESISTANCE• SLOWER TIME TO CLEAR PARASITES

• IN VITRO INCREASES IN IC50 VALUE

• INCREASING PREVALENCE OF “RESISTANT” ALLELES

• RESISTANCE ARISES RARELY, BUT SPREADS RELATIVELY QUICKLY

• CLINICAL TREATMENT FAILURE IS THE LAST STEP IN A LONG SERIES OF CHANGES

• EARLY WARNING OF RESISTANCE• SLOWER TIME TO CLEAR PARASITES

• IN VITRO INCREASES IN IC50 VALUE

• INCREASING PREVALENCE OF “RESISTANT” ALLELES

WHAT DATA ARE MISSING?WHAT DATA ARE MISSING?• SURVEILLANCE SPOTTY• REPORTS LONG AFTER FACT• SURVEILLANCE SPOTTY• REPORTS LONG AFTER FACT

BUT THIS IS IMPROVING RAPIDLY

1986

Charmot et al 1991

4-5 years6-7 years8 years

VERY LONGLAG

BETWEENSEEING

RESISTANCEAND

CHANGINGDRUG

POLICY

VERY LONGLAG

BETWEENSEEING

RESISTANCEAND

CHANGINGDRUG

POLICY

NEED FAR BETTER COORDINATION AMONG GROUPS INVOLVED IN RESISTANCE DETERMINATIONNEED FAR BETTER COORDINATION AMONG GROUPS INVOLVED IN RESISTANCE DETERMINATION

WE HAVE ALWAYS PLAYED CATCH UPWE HAVE ALWAYS PLAYED CATCH UP

FROM WHITE, 1999

AS DRUGS FAIL, WE CHRONICLE THE FAILURES

WE NEED COORDINATED, OPEN ACCESSDATABASE FROM ALL ENDEMIC AREASWE NEED COORDINATED, OPEN ACCESSDATABASE FROM ALL ENDEMIC AREAS

NEEDS TO CONNECT WITH ROUTINE SURVEILLANCE

• CONSOLIDATE RECENT DATA ON “OLD”DRUGS

• CREATE AND MAINTAIN AN OPEN ACCESS DATABASE OF RESISTANCE DATA WORLDWIDE

• CONSOLIDATE RECENT DATA ON “OLD”DRUGS

• CREATE AND MAINTAIN AN OPEN ACCESS DATABASE OF RESISTANCE DATA WORLDWIDE

• WHERE DID RESISTANCE ARISE?

• OVER WHAT ROUTES DID SPREAD OCCUR?

• HOW DO SURROGATE MARKERS RELATE TO CLINICAL OUTCOMES?

• WHERE DID RESISTANCE ARISE?

• OVER WHAT ROUTES DID SPREAD OCCUR?

• HOW DO SURROGATE MARKERS RELATE TO CLINICAL OUTCOMES?

WHAT MUST WE DO NOW?WHAT MUST WE DO NOW?

THINGS USED TO BE SIMPLE…THINGS USED TO BE SIMPLE…

CHLOROQUINESULFADOXINE/PYRIMETHAMINE

QUININEMEFLOQUINE

MEFLOQUINE/ARTESUNATE

CHLOROQUINESULFADOXINE/PYRIMETHAMINE

QUININEMEFLOQUINE

MEFLOQUINE/ARTESUNATE

2006

RESISTANCE TO OLD DRUGS…. CHANGE TO COMBINATION THERAPY

RESISTANCE TO OLD DRUGS…. CHANGE TO COMBINATION THERAPY

2003

Countries which need ACT policy

Countries which adopted ACT

2006 ACT ADOPTIONS2006 ACT ADOPTIONS

MANY ACTs ARE IN USE OR IN TRIALMANY ACTs ARE IN USE OR IN TRIAL• ARTESUNATE-MEFLOQUINE

• ARTEMETHER-LUMEFANTRINE

• ARTESUNATE-AMODIAQUINE

• DIHYDROARTEMISININ-PIPERAQUINE

• CHLORPROGUANIL-DAPSONE-ARTESUNATE

• ARTESUNATE- SULFADOXINE-PYRIMETHAMINE

• ARTESUNATE-MEFLOQUINE

• ARTEMETHER-LUMEFANTRINE

• ARTESUNATE-AMODIAQUINE

• DIHYDROARTEMISININ-PIPERAQUINE

• CHLORPROGUANIL-DAPSONE-ARTESUNATE

• ARTESUNATE- SULFADOXINE-PYRIMETHAMINE

AND…..• CHLOROQUINE- SULFADOXINE-PYRIMETHAMINE

• AMODIAQUINE - SULFADOXINE-PYRIMETHAMINE

AND…..• CHLOROQUINE- SULFADOXINE-PYRIMETHAMINE

• AMODIAQUINE - SULFADOXINE-PYRIMETHAMINE

ACTs CURRENTLY EFFECTIVE, BUT……..

ACTs CURRENTLY EFFECTIVE, BUT……..

HOW CAN WE SUSTAIN MAXIMUM

USEFUL THERAPEUTIC LIFE OF ACTs?

HOW CAN WE SUSTAIN MAXIMUM

USEFUL THERAPEUTIC LIFE OF ACTs?

HOW CAN WE STAY AHEAD OF THE

EVOLUTIONARY CURVE?

HOW CAN WE STAY AHEAD OF THE

EVOLUTIONARY CURVE?

NETWORK MUST BE PROSPECTIVENETWORK MUST BE PROSPECTIVE

• CURRENT TOOLS ARE ADEQUATE

• MANY WELL PLACED SENTINAL SITES

• REAL TIME REPORTING MORE COMMON

• NEW INITIATIVES WITH COMPLEMENTARY OBJECTIVES

• CURRENT TOOLS ARE ADEQUATE

• MANY WELL PLACED SENTINAL SITES

• REAL TIME REPORTING MORE COMMON

• NEW INITIATIVES WITH COMPLEMENTARY OBJECTIVES

• GLOBAL FUND REQUIREMENTS• ACT CONSORTIUM• IPTp• IPTi

• GLOBAL FUND REQUIREMENTS• ACT CONSORTIUM• IPTp• IPTi

CLINICAL DRUG

EFFICACY

PHARMACO-LOGICAL

ASSESSMENTIN VITRODRUG

ASSESSMENT

MOLECULARMARKERS

OF RESISTANCE

WORLD ANTIMALARIAL RESISTANCE NETWORK WORLD ANTIMALARIAL RESISTANCE NETWORK

CLINICAL DRUG

EFFICACY

CLINICAL DRUG

EFFICACY

PHARMACO-LOGICAL

ASSESSMENT

PHARMACOLOGICAL ASSESSMENT OF DRUGS

PHARMACOLOGICAL ASSESSMENT OF DRUGS

WAS THE DRUG LEVEL ADEQUATE?

WAS THE DRUG LEVEL ADEQUATE?

WHY DID THE PATIENT FAIL TREATMENT?

WHY DID THE PATIENT FAIL TREATMENT?

CLINICAL FAILURE WITH ADEQUATE DRUG

CLINICAL FAILURE WITH ADEQUATE DRUG

PRESUMPTIVE RESISTANT PARASITES

PRESUMPTIVE RESISTANT PARASITES

IN VITRO ANALYSISIN VITRO ANALYSIS

PATIENT ISOLATES WITH INCREASEDDRUG RESISTANCE IN VITRO

PATIENT ISOLATES WITH INCREASEDDRUG RESISTANCE IN VITRO

CANDIDATES FOR INTENSIVE GENETIC ANALYSIS

CANDIDATES FOR INTENSIVE GENETIC ANALYSIS

IDENTIFICATION OF LOCI ASSOCIATED WITH RESISTANCE TO EACH

PARTNER IN ACT

IDENTIFICATION OF LOCI ASSOCIATED WITH RESISTANCE TO EACH

PARTNER IN ACT

HOW TO MOVE TO EVIDENCE BASED DRUG USE

HOW TO MOVE TO EVIDENCE BASED DRUG USE

Don deSavigny and Fred BinkaDon deSavigny and Fred Binka

WE’RE HERE

WE NEED TO MOVE TO HERE

DRUG RESISTANCE IN VIVODRUG RESISTANCE IN VIVO