plasmodium falciparum transporter linked to chloroquine ... · drug-resistant malaria in travellers...

Malaria 2010 The Good The Bad

And the Ugly?Kevin Kain MD

Director, Global Health Program, McLaughlin Centre for Molecular Medicine,

Professor of MedicineThe University of Toronto

Malaria Global M and M Snow et al. Nature. March 10, 2005

• 2.2 billion at risk = 1 in 3• Leading single agent cause of death of children • Typical village of 1000 60-70% will have

malaria/yr (25-33% of income of $300-400/yr)• 515 million clinical cases/yr (50% higher in Africa

and 200% higher outside Africa than WHO estimates)

• 25% of Pf outside Africa• Malaria robs African economies of $USD12B/yr

Malaria 2010 Attaran A. Nature 2004; 430:932

• “..RBM pledged to halve malaria deaths by 2010. Today RBM is at the halfway point and…deaths have actually increased”

• “RBM is not just a failure but a fatal betrayal by the United Nations”.

Malaria 2010 Attaran et al. Lancet 2006; 430:932

• “The World Bank, False Financial Accounts and Medical Malpractice in Malaria Programs”

• 100s of millions pledged for malaria never delivered

• “claimed success using false statistics”• “approved obsolete treatments” akin to

malpractice

Malaria 2010“There is today more attention and financing for malaria than

in the past 4 decades...yet no real change”.

R. Feachem et al. JAMA 2007;297:2281

EID May 2009

Geosentinel: Malaria in Travellers Leder et al CID 2004;39:1104 Elliot et al. JTM 2004;11:213

WTO visits Risk/10M RR• Caribbean 1.8 4• North Africa 3.2 7• South America 3.9 8• SE Asia 5.4 12• Central America 17.8 38• South Asia 25.3 54• Oceania 36 77• Sub-Saharan Africa 97.5 208

Geosentinel: Malaria in Travellers Leder et al CID 2004;39:1104 Elliot et al. JTM 2004;11:213

• N=1140 malaria cases in travellers• 60% PF = 90% SSA (33 SM = 3 deaths)• 24% PV = 30% acquired in SSA!• 5% of cases with trips <1 week! (34 d)• 97% developed symptoms after travel• Illness onset <4 wks = 80% Pf, 40% Pv• RISK: VFRs (only 15% pre-travel advice)• RISK: Missionary group: 73% had Pre

travel advice!!!!

VFRs: high risk travelers Leder et al. CID 2006

• Geosentinel database, n=2241• Compared to tourist travellers• VFRs sig. more likely to present with:• Malaria OR 5.0 (4.4-5.8)• Typhoid OR 4.3 (2.5-7.4)• Tb OR 77 (28-209)• STDs OR 10.2 (6-17)

VFRs sig. less pretravel advice (19% versus 59%)

HIV and malaria Kublin et al. Lancet 2005;365:233

• Prospective cohort Malawi • n=367 HIV-1+ adults• 148 had +Pf in follow up • Overall HIV-1 RNA doubled with Pf (96,000 to

169,000 copies/mL) (0.25 log increase)• If Pf >2000/uL and CD4>300 0.82 log• Returned to ~baseline by 8-9 wks• Malaria-induced increases in HIV viral load may

increase transmission (1 log=doubles transmission) and disease progression

HIV increases risk of severe malaria in non-immunes

Cohen et al. Clin Infect Dis. Dec 2005;41:1631• Prospective cohort RSA • n=336 with 10% with severe malaria• Risk factors for severe malaria

HIV +, CD4 >200, higher parasitemia• HIV+ non-immunes 4.2x more likely to

develop severe malaria than HIV-HIV-1+ non-immunes at increased risk of

severe malaria

HIV and malaria Abu-Raddad et al. Science Dec 8 2006;1603

• Mathematical Modeling • applied to Kisumu, Kenya • Malaria HIV inc. by 8%• HIV malaria inc. by 13%• In a population of 200,000

– Inc. of 8500 AIDS cases– Inc. of 1,000,000 malaria cases

Keen J et al. PLoS Med 2007

• Need PCR to detect Congenital malaria (>20%)

Risk for congenital malaria (cord blood +)

• HIV+ OR 5.4 (2-15)

• Placental monocytes OR 48 (5-505)

US Malaria fatalities Newman et al. AIM 2004;141:547

• >30,000 travellers/yr acquire malaria• 185 deaths 93% Pf• Largest risk group to die = VFRs• CFR 1.3% Pf (0- 4.4%)

.06% Pv• 18% diagnosed at autopsy• 1 in 100 with malaria die• 86% of deaths Preventable

Who dies from malaria? Tan KR et al. ASTMH 2009

VFRs=33%, Missionaries=27%, tourists=13%USA (n=34 deaths 2002-2008) TotalNo or wrong chemo. 100%Missed by MD 62%Lab misdiagnosis/delays 44%Inappropriate treatment 41%Diagnosis at autopsy 27%

Real time PCR for the detection of drug-resistant malaria in travellers

Farcas and Kain JCM 2004 and 2007 Farcas and Kain CID 2006

• Prospective “blinded” evaluation of real time detection of malaria and genetic markers of drug-resistance

• N = 260 febrile returned travellers• Assay time = 25 minutes• Sensitivity: 100% vs nested PCR• Specificity: 100% vs nested PCR

Return of CQ-sensitive malaria in Africa?

Kublin J et al JID 2003 & NEJM 2006

• 1993 Malawi replaced CQ with SP• Hypothesis: withdrawal of CQ

CQ sensitivity• pfcrt K76T 1993 85%

2000 15%• In vivo: CQ cleared 100% of 63

infections• In vitro: No resistance

Long lasting insecticidal nets (LLIN) Lindblade KA et al. TMIH Nov 2005;10:1141

• Randomized evaluation of 6 nets, western Kenya• Survival analysis comparing time to net failure

conventional vs LLINs (Bioassay <50% mortality)• N = 314 net to 177 households x 2 years• Controlled for # of washes• Of 2 “LLINs” (Olyset, Permanet) and 2 candidate

LLINs:InsectorTM had significantly higher failure rate ONLY PermanetTM performed significantly better than conventional nets (should be used in control programs)

Declining malaria in Africa Cessay S et al. Lancet Nov 2008;372:1545

O’Meara W et al. Lancet Nov 2008;372:1555 ProMED Dec 22, 2008; Jan 29 2009

• Retrospective analysis in Gambia and Kenya• 5 sites Gambia, one in Kenya • Gambia: smear+ cases dec. by 50-85%• hospitalizations by 27-74% and deaths by

90%• Kenya: 80% dec. in malaria admissions • NB: cerebral malaria cases increased! • NB: Travellers from Europe (64 cases and 3

deaths) USA (7 cases, 2 in ICU) from Gambia

• N = 894 RCT RTSS (with new adjuvant ASO1E) vs Rabies vaccine• ITT PE against clinical malaria 49% (95% CI 26-65%) • Well tolerated

Choices for chloroquine- resistant regions: 2010

ATQ/Proguanildoxycyclinemefloquine

(primaquine)

Feb 2010 CME at Sea: Malaria Prevention Slide 28 of 73

Lariam®: Label revisions 2008

• New precautions• New warnings• Medication guide for travelers• http://www.accessdata.fda.gov/scripts/cder/drugsatf

da/index.cfm?fuseaction=Search.Label_ApprovalHi story

• Google “Drugs@FDA”

Feb 2010 CME at Sea: Malaria Prevention Slide 29 of 73

New MFQ Warnings / Precautions

• Adverse Reactions / Post marketing– Pneumonitis, possible allergic– “ In a small number of patients, dizziness

and loss of balance have been reported to continue for months after mefloquine has been stopped”

• Medication Guide updated

Feb 2010 CME at Sea: Malaria Prevention Slide 30 of 73

Post market Safety Review: Pneumonitis

• 13 cases of pneumonitis or eosinophilic pneumonia with prophylactic (N = 6) and therapeutic (use (N= 5) of MFQ

• Onset of fever, chills, HA, myalgias, SOB, dyspnea, non-productive cough, abnl CXR, elevated WBC

• All hospitalized, 5 rec’d steroids, 1 patient died• FDA Drug Safety Newsletter: volume 1, (No. 4)

Summer 2008– http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/

ucm096049.htm

MFQ Misconceptions Chen L et al. JAMA 2008;297:2251

Jacquerioz Fet al. Cochrane Database Syst Rev 2009

• Meta-analysis of 8 RCTs n=4240 participants• Underpowered to detect differences in safety

and efficacy• Withdrawal and overall incidence of AEs

not higher with MFQ than comparator drugs

• Low-quality evidence that ATQ/Pro and doxy better tolerated WRT neuropsych and GI

• Women at greater risk of neuropsych AEs

Mefloquine for whom? No one?

Still consider MFQ for:• Previous users without AE and C/I• Long term high risk travel, esp. tight

budget• Pregnant women who cannot defer travel• Children: wkly dose registered for >5kg• Document: you advised client of risks!

Doxycycline… The Good• Broad spectrum

activity: rickettsia, lepto, bacteria mycoplasma, chlamydia

• No resistance reported

• Generics are inexpensive

• No dose change with renal failure

• No interactions with food

Doxycycline… the Bad• Drug interactions• Tooth enamel

discoloration??– No use in children

< 8 yo, nursing moms & pregnancy

• Daily dosing– Don’t miss a dose!

• GI upset• Pill esophagitis &

esophageal ulceration

• Photosensitivity• Vaginal yeast

infxn• Not causal, 28

days after return

Doxy: Drug Interactions• Decrease doxy serum levels

– Antacids containing cations (Ca, Al, Mg) bind doxy

– Oral iron, bismuth, laxatives (contain Mg)– Barbs, phenytoin, carbamazepine induce hepatic

microsomal activity– Do not take within 3 hours of doxy

• Increase doxy serum levels– Warfarin

• OCPs - no proven or accepted interactions

What we don’t know about doxy

• How photosensitive is doxycycline?• Is there an increase in vaginal yeast

infections in women using doxy as compared to other chemoprophylaxis drugs?

• Does doxycycline discolor teeth when used as chemoprophylaxis?

• Is the monohydrate salt better tolerated than the hyclate salt?

Doxycyline and Pregnancy Hellgren et al. J Trav Med 2010;7:1195

• Spon. miscarriage rate 15-20%• Cong. malformation rate ~5-6% (2-3%

apparent at birth)• “Crude” data rate of malformation same

with/without malaria chemoprophylaxis• Tetracyclines in preg stain primary teeth

(not permanent) >4 months• Doxy no tooth staining documented (only

C/I >4 months)• Swedes added doxy to drug choices for

early pregnancy (at least as safe as MFQ)

Atovaquone/Proguanil P. vivax Soto J et al. AJTMH 2006;75:430

• Randomized DBPC trial, Colombia• N = 180 males (24 unevaluable)• Randomized to AP versus placebo

Malaria cases 28 d cureAP (n=97) 1 Pv 96% (69-100%) Placebo (n=46) 11 Pv

2 Pf• ITT analysis PE = 87%• 1 failure low drug levels

ATQ/Pro DRESS syndrome: (also Stephen Johnson Syndrome)

drug eruption, eosinophilia and systemic symptoms

ATQ/Pro Resistance Just how common is it?

• AP~30 million tabs sold (>1.5 M travellers)• Prophylaxis failures with molecular

confirmation None documented

• Treatment failures with AP with genetic confirmation

~15 published cases of AP resistance plus several probable cases

Boggild A et al AJTMH 2007

ATQ/Pro Treatment failures Boggild et al. AJTMH 2007

Age/travel Pro Para Failed Cyt b45 WAF No 1.5% d28 Y268N28 WAF ? ? d28 Y268S 45 WAF ? 1.0% d21 Y268S 4 WAF CP 0.5% d28 Y268S 24 EAF No 3.0% d30 Y268S 3.5 WAF No 1.5% d30 Y268S 25 WAF P 1.5% d28 Y268S28 WAF CP 1.5% d28 Y268S32 WAF pyr ? d17/d15 Y268S38 CAF C 0.1% d16 ???

ATQ/Pro: What’s new? Boggild A et al. AJTMH 2007

Patel S et al. AJTMH 2007

Uses: Rx Pf (cure >95%) Rx MDR Pf (cure >95%) NOT for Pv Rx aloneProphylaxis Pf (>90%) and Pv (>80%)

Dose: Can use AP to Rx and prevent malaria in children down to 5 kgs

Atovaquone + proguanilEfficacy: PF non-immunes ~98%

PV non-immunes 84 (45-95%)Tolerance: good in all ages (2-85 yrs)

RCT better than MFQ, CQ/Pro, better or equal to doxy, rare skin AEs, SJSCaution: CI - CrCl < 30 ml/min

Convenience: daily Causal: yesCost: expensive

Boggild A et al AJTMH 2007

ATQ has causal activity Shapiro T et al. AJTMH 1999;60:831

• RDBPC volunteer challenge study (n=16)• ATQ (750 mg) or placebo D1-D8• ATQ (250 mg) on D1 ONLY• infected mosquito challenge D2• 4/4 placebo +Pf smear/PCR/culture• 0/12 AP +Pf by smear/PCR

-2 -1 +10 +2 +3 +4 weeks

42 doses of doxy, 100 mg daily

14 days of travel

-3 +5 +6

10 doses of mefloquine, 250 mg weekly

21 doses of primaquine, 30 mg daily

21 doses of ATQ/Pro, 1 tab daily

3 doses of ATQ/Pro, Pre-exposure ?

3 weekly doses of ATQ/Pro?

Theoretical, not proven!

Malaria: Risk Strategies Schlagenhauf P et al. Clin Micro Rev 2008;21:466

• 20 cases/103/yr local pop’n~1 death/105 travellers/2 wk trip

• 100 cases/103/yr local pop’n~8 death/105 travellers/2 wk trip~ close to annual death rate MVA

= 1 death/11,500 inhabitants/yr• Authors no routine chemopro. for

risks <10 cases/103/yr local pop’n(SBET = ATQ/Pro or Co-art)

Pregnancy and kids: HIGH risk of CRPF

• Don’t go (defer travel if possible)• extreme attention to PPM • seek MD attention ASAP if fever• chemosuppression

MFQ (after 1st trimester)CQ/Pro (safe but efficacy)ATQ/Pro (ATQ: class C; Pro: class B)(CQ+Azi IPTp. NOT FDA-approved)

CQ/PRO (MFQ) < 5 kgMFQ, ATQ/Pro > 5 kg

Chemosuppression - 2010 Summary

• ATQ/Pro, doxy, MFQ (PQ):“best choice for your client” HIGH RISK

• ~ 0.2-6% A/E D/C • MFQ & pregnancy high risk• MFQ & kids high risk > 5 kg

ATQ/Pro: short term, high risk

All travelers to malarious areas MUST:

• Understand malaria is a serious disease

• Know how to prevent it (PPM and drugs)

• Seek medical attention urgently if they develop fever

Fever From The Tropics Ryan, Wilson, Kain KC. NEJM 2002;347:505

1. malaria2. malaria3. malaria

Traveller Immigranthepatitis TBtyphoid TBdengue/Rickettsia TB

MALARIA:take home points Ryan, Wilson, Kain KC. NEJM 2002;347:505

Malaria deaths are preventable• Fever from the tropics - malaria

UPO (until proven otherwise)• Malaria EMERGENCY

STAT smears• Rx all Pf malaria drug resistant

Pregnancy Treatment of MDR malaria

• RCT artemether-lumefantrine x3d (n=125)• vs Artesunate x7d (n=128)• Open label Pregnant women 2/3rd trimester• ITT Cure rate (day 42):

AL: 82% (75-89)AS: 89.2% (82-96)No difference in birth outcomes

McGready R et al. PLoS Med Dec 2008;5:e253

Mosquito receptors for human sweat

Hallem et al. Nature 2004;427:212• From the Anopheles genome identified a

female specific odorant receptor (AgOr1)• Expressed it in a fruit fly neuron• Measured neuron response to single odors

4-methylphenol in human sweat• AgOr1 only expressed in female olfactory

tissue and is decreased with a blood meal• Activate or block receptor to trap or repel

Gin and Tonic? Effectiveness Meyer CG et al, TMIH 2004;9:1239

• Q; How much do I have to drink to prevent P. falciparum malaria?

• A; 20 G & Ts at 50:50 mix (my normal intake)(100 mLs each)

• Provides 58.3 mg/L provides ~peak [0.62 mg/L] Q, approaches the lower limit of therapeutic efficacy for Pf

Long Term Travellers Checkley A et al. Trends Para 2007;23:462

• Inform: fever urgent Dx & treatment• Identify: access to qualified medical

triage/care before ill• Discuss alternatives to continuous

prophylaxis e.g. seasonal• PPM ITNs 50%+ protection• Discuss SBET and follow up (different from

that used as prophylaxis) • Discuss risk of fake drugs (bring your own

from home)• RDTs consider for some (needs training!)

• Thai –Cambodian border

• ACT = mefloquine + ART

• Initial efficacy (1993) = 99%

• Current efficacy with DOT = 79%

• inc. pfmdr1 copy number and delayed parasite clearance times

• NW Thailand vs Cambodia (n=40/site)

• RCT Art 2MK x 7 d vs ART+MFQ

Cambodia Thailand

PCT 84 h 48h (P<.001)

Rx failure 30% 10%

• Rx failure did not correlate with MIC or copy #/mutations in Pfmdr or Pfserca (ATPase 6)

Monkey malaria in Humans Singh B et al. Lancet 2004;363:1017

Cox-Singh. CID 2008; 46:165. Ng EID May 2008• N = 208 malaria cases in Borneo• ~1/2 thought to be P. malariae• BUT: neg for PM DNA and ++ symptoms • 24 hr replication high parasitemia and severe

and fatal outcomes• 58% of 208 cases subsequently shown to be P.

knowlesi• A natural parasite of long-tailed macaques• Now Singapore, Malaysia, Philippines, Thailand • NB: 1st human Pk infection found in a US traveller

returned from Malaysia in 1965

Monkey malaria in Humans Singh B et al. Lancet 2004;363:1017

Cox-Singh. CID 2008; 46:165. Ng EID May 2008

Diagnosis: PCRRapid tests mixed “Pf+Pv” or

negTreatment of P. knowlesi• CQ alone (no PQ)• Quinine IV if severe

Bonobo apes “new“ Plasmodium falciparum and 1 related to P. malariae

source of Pf in humans (not P. reichenowi )Chimps 2 new Plasmodium sp. related to P. falciparum and

1 new one related to P. vivaxImplications: new human zoonotic malaria infections in humans

malaria eradication efforts

Severe P. vivax Malaria Tjitra et al. PLoS Medicine 2008;5:e128

Genton et al. PLoS Medicine 2008;5:e127

• 390M cases of P. vivax/yr (50% of malaria)

• Severe malaria at 2 sites in Oceania• Similar rates:

Pf (12-30%) CFR 2.2%Pv (9-30%) CFR 1.6%

• Pv: 20% of SM in Papuarespiratory distress 60%neuro 25%

Severe P. vivax Malaria Anstey et al. Trends in Para 2009;25:220

• Is this just a Papua problem? • What is the mechanism?

Pathobiology Pv Pf • Biomass - ++• Inflam response ++ +• Cytoadherence +/- +++• Rosetting +/- +• RBC fragility ++ (32) + (8)• EC activation + +++

Severe P. vivax Malaria Anstey et al. Trends in Para 2009;25:220

Pathogenesis• SMA CRPV inc. recrudescence

PRPV inc. relapses• ARDS [lung]& cap. perm. ALI• Coma ?• PM maternal anemia LBW• CRPV vs PRPV? • Re-Rx ACT+PQ or MFQ+PQ

New ACTs decreasing malaria cases increasing CM?

Drug resistance major threatSevere malaria host driven new RxMalaria deaths preventable

early Dx and RxFever emergency

malaria “UPO”stat Dx and urgent Rx

Take Home Points